Kidney disease can be discovered incidentally during a routine medical evaluation or with evidence of kidney dysfunction, such as hypertension, edema, nausea, or hematuria. The initial approach in both situations should be to assess the cause and severity of renal abnormalities. In all cases this evaluation includes (1) an estimation of disease duration, (2) a careful urinalysis, and (3) an assessment of the glomerular filtration rate (GFR). The history and physical examinations, though equally important, are variable among renal syndromes—thus, specific symptoms and signs are discussed under each disease entity.
Kidney disease may be acute or chronic. Acute kidney injury is worsening of kidney function over hours to days, resulting in the retention of nitrogenous wastes (such as urea nitrogen) and creatinine in the blood. Retention of these substances is called azotemia. Chronic kidney disease (CKD) results from an abnormal loss of kidney function over months to years. Differentiating between the two is important for diagnosis, treatment, and outcome. Oliguria is unusual in CKD. Anemia (from low kidney erythropoietin production) is rare in the initial period of acute kidney disease. Small kidneys are most consistent with CKD, whereas normal to large-size kidneys can be seen with both chronic and acute disease.
A urinalysis can provide information similar to a kidney biopsy in a way that is cost-effective and noninvasive. The urine is collected in midstream or, if that is not feasible, by bladder catheterization. The urine should be examined within 1 hour after collection to avoid destruction of formed elements. Urinalysis includes a dipstick examination followed by microscopic assessment if the dipstick has positive findings. The dipstick examination measures urinary pH, protein, hemoglobin, glucose, ketones, bilirubin, nitrites, and leukocyte esterase. Urinary specific gravity is often reported. Microscopy provides examination of formed elements—crystals, cells, casts, and infecting organisms.
Various findings on the urinalysis are indicative of certain patterns of kidney disease. A bland (normal) urinary sediment is common, especially in CKD and acute disorders that are not intrinsic to the kidney, such as limited effective blood flow to the kidney or obstruction of the urinary outflow tract. Casts are composed of Tamm-Horsfall urinary mucoprotein in the shape of the nephron segment where they were formed. Heavy proteinuria and lipiduria are consistent with the nephrotic syndrome. The presence of hematuria with dysmorphic red blood cells, red blood cell casts, and proteinuria is indicative of glomerulonephritis. Dysmorphic red blood cells are misshapen during abnormal passage from the capillary through the glomerular basement membrane (GBM) into the urinary space of Bowman capsule. Pigmented granular casts and renal tubular epithelial cells alone or in casts suggest acute tubular necrosis. White blood cells, including neutrophils and eosinophils, white blood cell casts (Table 22–1), red blood cells, and small amounts of protein can be found in interstitial nephritis and pyelonephritis; Wright and Hansel stains can detect eosinophiluria. Pyuria alone can indicate a urinary tract infection. Hematuria and proteinuria are discussed more thoroughly below.
Table 22–1. Significance of specific urinary casts.
Proteinuria is defined as excessive protein excretion in the urine, generally > 150–160 mg/24 h in adults. Significant proteinuria is a sign of an underlying kidney abnormality, usually glomerular in origin when > 1–2 g/d. Less than 1 g/d can be due to multiple causes along the nephron segment, as listed below. Proteinuria can be accompanied by other clinical abnormalities—elevated blood urea nitrogen (BUN) and serum creatinine levels, abnormal urinary sediment, or evidence of systemic illness (eg, fever, rash, vasculitis).
There are several reasons for development of proteinuria: (1) Functional proteinuria is a benign process stemming from stressors such as acute illness, exercise, and “orthostatic proteinuria.” The latter condition, generally found in people under age 30 years, usually results in urinary protein excretion of < 1 g/d. The orthostatic nature of the proteinuria is confirmed by measuring an 8-hour overnight supine urinary protein excretion, which should be < 50 mg. (2) Overload proteinuria can result from overproduction of circulating, filterable plasma proteins (monoclonal gammopathies), such as Bence Jones proteins associated with multiple myeloma. Urinary protein electrophoresis will exhibit a discrete protein peak. Other examples of overload proteinuria include myoglobinuria in rhabdomyolysis and hemoglobinuria in hemolysis. (3) Glomerular proteinuria results from effacement of epithelial cell foot processes and altered glomerular permeability with an increased filtration fraction of normal plasma proteins, as in diabetic nephropathy. Glomerular diseases exhibit some degree of proteinuria. The urinary protein electrophoresis will have a pattern exhibiting a large albumin spike indicative of increased permeability of albumin across a damaged GBM. (4) Tubular proteinuria occurs as a result of faulty reabsorption of normally filtered proteins in the proximal tubule, such as beta-2-microglobulin and immunoglobulin light chains. Causes include acute tubular necrosis, toxic injury (lead, aminoglycosides), drug-induced interstitial nephritis, and hereditary metabolic disorders (Wilson disease and Fanconi syndrome).
Evaluation of proteinuria by urinary dipstick primarily detects albumin, while overlooking positively charged light chains of immunoglobulins. These proteins can be detected by the addition of sulfosalicylic acid to the urine specimen. Precipitation without dipstick detection of albumin indicates the presence of paraproteins.
The next step is an estimation of daily urinary protein excretion. The simplest method is to collect a random urine sample. The ratio of urinary protein concentration to urinary creatinine concentration ([Uprotein]/[Ucreatinine]) correlates with 24-hour urine protein collection (< 0.2 is normal and corresponds to excretion of < 200 mg/24 h). The benefit of a urine protein-to-creatinine ratio is the ease of collection and the lack of error from overcollection or undercollection of urine. In a 24-hour urine collection, a finding of > 150–160 mg is abnormal, and > 3.5 g is consistent with nephrotic-range proteinuria. If a patient has proteinuria with or without loss of kidney function, kidney biopsy may be indicated, particularly if the kidney disease is acute in onset. The clinical sequelae of proteinuria are discussed in the section Nephrotic Spectrum Glomerular Diseases below.
Hematuria is significant if there are more than three red cells per high-power field on at least two occasions. It is usually detected incidentally by the urine dipstick examination or clinically following an episode of macroscopic hematuria. The diagnosis must be confirmed via microscopic examination, as false-positive dipstick tests can be caused by myoglobin, oxidizing agents, beets and rhubarb, hydrochloric acid, and bacteria. Transient hematuria is common, but in patients younger than 40 years, it is less often of clinical significance due to lower concern for malignancy.
Hematuria may be due to renal or extrarenal causes. Extrarenal causes are addressed in Chapters 23 and 39; most worrisome are urologic malignancies. Renal causes account for approximately 10% of cases and are best considered anatomically as glomerular or nonglomerular. The most common extraglomerular sources include cysts, calculi, interstitial nephritis, and renal neoplasia. Glomerular causes include immunoglobulin A (IgA) nephropathy, thin GBM disease, membranoproliferative glomerulonephritis (MPGN), other hereditary glomerular diseases (eg, Alport syndrome), and systemic nephritic syndromes. Currently, the United States Health Preventive Services Task Force does not recommend screening for hematuria. See Chapter 23 for evaluation of hematuria.
The GFR provides a useful index of kidney function at the level of the glomerulus. Patients with kidney disease can have a decreased GFR from any process that causes loss of nephron (and thus glomerular) mass. However, they can also have a normal or increased GFR, either from hyperfiltration at the glomerulus or disease at a different segment of the nephron, interstitium, or vascular supply. The GFR measures the amount of plasma ultrafiltered across the glomerular capillaries and correlates with the ability of the kidneys to filter fluids and various substances. Daily GFR in normal individuals is variable, with a range of 150–250 L/24 h or 100–120 mL/min/1.73 m2 of body surface area. GFR can be measured indirectly by determining the renal clearance of plasma substances that are not bound to plasma proteins, are freely filterable across the glomerulus, and are neither secreted nor reabsorbed along the renal tubules. The formula used to determine the renal clearance of a substance is
where C is the clearance, U and P are the urine and plasma concentrations of the substance (mg/dL), and is the urine flow rate (mL/min). In clinical practice, the clearance rate of endogenous creatinine, the creatinine clearance, is one way of estimating GFR. Creatinine is a product of muscle metabolism produced at a relatively constant rate and cleared by renal excretion. It is freely filterable by the glomerulus and not reabsorbed by the renal tubules. With stable kidney function, creatinine production and excretion are equal; thus, plasma creatinine concentrations remain constant. However, it is not a perfect indicator of GFR for the following reasons: (1) A small amount is normally eliminated by tubular secretion, and the fraction secreted progressively increases as GFR declines (overestimating GFR); (2) with severe kidney failure, gut microorganisms degrade creatinine; (3) an individual’s meat intake and muscle mass affect baseline plasma creatinine levels; (4) commonly used drugs such as aspirin, cimetidine, probenecid, and trimethoprim reduce tubular secretion of creatinine, increasing the plasma creatinine concentration and falsely indicating kidney dysfunction; and (5) the accuracy of the measurement necessitates a stable plasma creatinine concentration over a 24-hour period, so that during the development of and recovery from acute kidney injury, when the serum creatinine is changing, the creatinine clearance is unhelpful. Of note, the creatinine clearance is the traditional estimation equation used for consideration of drug dosing in patients with kidney disease.
One way to measure creatinine clearance is to collect a timed urine sample and determine the plasma creatinine level midway through the collection. An incomplete or prolonged urine collection is a common source of error. A method of estimating the completeness of the collection is to calculate a 24-hour creatinine excretion; the amount should be constant:
The creatinine clearance (Ccr) is approximately 100 mL/min/1.73 m2 in healthy young women and 120 mL/min/1.73 m2 in healthy young men. The creatinine clearance declines by an average of 0.8 mL/min/yr after age 40 years as part of the aging process, but this is variable, with 35% of subjects in one study having no decline in kidney function over 10 years.
The four-variable estimated GFR is a complex equation, including serum creatinine, age, weight, and race, that is often reported alongside serum creatinine measurements and more accurate than creatinine clearance. This was derived from data collected for the Modification of Diet and Renal Disease (MDRD) study and has been validated in several other populations. Several web-based calculators will calculate the estimated GFR; one location is www.nephron.com.
Other useful, well-validated estimators of GFR include the CKD-EPI formula. This is more accurate and precise than the MDRD equation at higher levels of true GFR, possibly decreasing false-positive results. This formula may perform better in elderly populations; however, this estimation equation did not include large numbers of nonwhite patients.
Cystatin C is another endogenous marker of GFR, filtered freely at the glomerulus and produced at a relatively constant rate, irrespective of muscle mass. It is reabsorbed and partially metabolized in the renal tubular epithelial cells. Adding the measurement of cystatin C to serum creatinine improves the accuracy of the estimated GFR. A large published meta-analysis showed that cystatin C alone or in combination with serum creatinine is a stronger predictor of important clinical events, such as end-stage renal disease (ESRD) or death, than serum creatinine alone. Although not yet used extensively in clinical practice, use of cystatin C holds promise for improving classification of kidney disease and predicting outcomes among at-risk individuals.
Creatinine clearance (Ccr) can also be estimated using the Cockcroft and Gault formula, which incorporates age, sex, and weight to estimate creatinine clearance from plasma creatinine levels without any urinary measurements:
For women, the creatinine clearance is multiplied by 0.85 because muscle mass is less. This formula overestimates GFR in patients who are obese or edematous and is most accurate when normalized for body surface area of 1.73 m2. Dosing of many medications is still based on values of creatinine clearance from the Cockcroft-Gault equation.
BUN is another index used in assessing kidney function. It is synthesized mainly in the liver and is the end product of protein catabolism. Urea is freely filtered by the glomerulus, and about 30–70% is reabsorbed in the renal tubules. Unlike creatinine clearance, which overestimates GFR, urea clearance underestimates GFR. Urea reabsorption may be decreased in volume replete patients, whereas volume depletion causes increased urea reabsorption, in conjunction with increased sodium reabsorption, from the kidney, increasing BUN. A normal BUN:creatinine ratio is 10:1, although this can vary between individuals. With volume depletion, the ratio can increase to 20:1 or higher. Other causes of increased BUN include increased catabolism (gastrointestinal [GI] bleeding, cell lysis, and corticosteroid usage), increased dietary protein, and decreased renal perfusion (heart failure, renal artery stenosis) (Table 22–2). Reduced BUN is seen in liver disease and in the syndrome of inappropriate antidiuretic hormone (SIADH) secretion.
Table 22–2. Conditions affecting BUN independently of GFR.
As patients approach ESRD, a more accurate measure of GFR than creatinine clearance is the average of the creatinine and urea clearances. The creatinine clearance overestimates GFR, as mentioned above, while the urea clearance underestimates GFR. Therefore, an average of the two more accurately approximates the true GFR.
Indications for percutaneous needle biopsy include (1) unexplained acute kidney injury or CKD; (2) acute nephritic syndromes; (3) unexplained proteinuria and hematuria; (4) previously identified and treated lesions to plan future therapy; (5) systemic diseases associated with kidney dysfunction, such as systemic lupus erythematosus (SLE), Goodpasture syndrome, and granulomatosis with polyangiitis (formerly Wegener granulomatosis), to confirm the extent of renal involvement and to guide management; (6) suspected transplant rejection, to differentiate it from other causes of acute kidney injury; and (7) to guide treatment. If a patient is unwilling to accept therapy based on biopsy findings, the risk of biopsy may outweigh its benefit. Relative contraindications include a solitary or ectopic kidney (exception: transplant allografts), horseshoe kidney, ESRD, congenital anomalies, and multiple cysts. Absolute contraindications include an uncorrected bleeding disorder, severe uncontrolled hypertension, renal infection, renal neoplasm, hydronephrosis, or an uncooperative patient.
Prior to biopsy, patients should not use medications that prolong clotting times and should have well-controlled blood pressure. Blood work should include a hemoglobin, platelet count, prothrombin time, and partial thromboplastin time. After biopsy, hematuria occurs in nearly all patients. Less than 10% will have macroscopic hematuria. Patients should remain supine for 4–6 hours postbiopsy. A patient with a 6-hour postbiopsy hematocrit > 3% lower than baseline should be closely monitored.
Percutaneous kidney biopsies are generally safe. Approximately 1% of patients will experience significant bleeding requiring blood transfusions. More than half of patients will have at least a small hematoma. Risk of major bleeding persists up to 72 hours after the biopsy. Any type of anticoagulation therapy should be held for 5–7 days postbiopsy if possible. The risks of nephrectomy and mortality are about 0.06–0.08%. When a percutaneous needle biopsy is technically not feasible and kidney tissue is deemed clinically essential, a closed biopsy via interventional radiologic techniques or open biopsy under general anesthesia can be done.
Inker LA et al; CKD-EPI Investigators. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012 Jul 5;367(1):20–9. Erratum in: N Engl J Med. 2012 Nov 22;367(21):2060. [PMID: 22762315]
Maripuri S et al. Outpatient versus inpatient observation after percutaneous native kidney biopsy: a cost minimization study. Am J Nephrol. 2011;34(1):64–70. [PMID: 21677428]
Shlipak MG et al; CKD Prognosis Consortium. Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med. 2013 Sep 5;369(10):932–43. [PMID: 24004120]
Vivante A et al. Hematuria and risk for end-stage kidney disease. Curr Opin Nephrol Hypertens. 2013 May;22(3):325–30. [PMID: 23449218]
ESSENTIALS OF DIAGNOSIS
Sudden increase in BUN or serum creatinine.
Oliguria can be associated.
Symptoms and signs depend on cause.
Acute kidney injury is defined as a sudden decrease in kidney function, resulting in an inability to maintain acid-base, fluid and electrolyte balance and to excrete nitrogenous wastes. A clinically applicable definition of acute kidney injury has been developed. The RIFLE criteria describe three progressive levels of acute kidney injury (risk, injury, and failure) based on the elevation in serum creatinine or decline in urinary output with two outcome measures (loss and ESRD). Risk, injury, and failure are defined, respectively, as a 1.5-fold increase in serum creatinine, a twofold or threefold increase in serum creatinine, or a decline in urinary output to 0.5 mL/kg/h over 6, 12, or 24 hours. These definitions were created by an international consensus panel and correlate with prognosis. The AKIN criteria are also predictive of outcomes, and closely follow the RIFLE criteria, with the addition of a change in serum creatinine of ≥ 0.3 mg/day qualifying as a risk for injury. In the absence of functioning kidneys, serum creatinine concentration will typically increase by 1–1.5 mg/dL daily, although with certain conditions, such as rhabdomyolysis, serum creatinine can increase more rapidly. On average, 5% of hospital admissions and 30% of intensive care unit (ICU) admissions carry a diagnosis of acute kidney injury, and it will develop in 25% of hospitalized patients. Patients with acute kidney injury of any type are at higher risk for all-cause mortality according to prospective cohorts, whether or not there is substantial renal recovery. The rates of acute kidney injury in the hospital setting have increased steadily since the 1980s and are continuing to rise.
The uremic milieu of acute kidney injury can cause nonspecific symptoms. When present, symptoms are often due to uremia or its underlying cause. Uremia can cause nausea, vomiting, malaise, and altered sensorium. Hypertension can occur, and fluid homeostasis is often altered. Hypovolemia can cause states of low blood flow to the kidneys, sometimes termed “prerenal” states, whereas hypervolemia can result from intrinsic or “postrenal” disease. Pericardial effusions can occur with uremia, and a pericardial friction rub can be present. Effusions may result in cardiac tamponade. Arrhythmias occur, especially with hyperkalemia. The lung examination may show rales in the presence of hypervolemia. Acute kidney failure can cause nonspecific diffuse abdominal pain and ileus as well as platelet dysfunction; thus, bleeding and clotting disorders are more common in these patients. The neurologic examination reveals encephalopathic changes with asterixis and confusion; seizures may ensue.
Elevated BUN and serum creatinine levels are present, though these elevations do not distinguish acute kidney disease from CKD. Hyperkalemia can occur from impaired renal potassium excretion. With hyperkalemia, the ECG can reveal peaked T waves, PR prolongation, and QRS widening. A long QT segment can occur with hypocalcemia. Anion gap and non-gap metabolic acidosis (due to decreased organic and nonorganic acid clearance) is often noted. Hyperphosphatemia occurs when phosphorus cannot be secreted by damaged tubules either with or without increased cell catabolism. Anemia can occur as a result of decreased erythropoietin production over weeks, and associated platelet dysfunction is typical.
Acute kidney injury can be divided into three categories: prerenal causes (kidney hypoperfusion leading to lower GFR), intrinsic kidney disease, and postrenal causes (obstructive uropathy). Identifying the cause is the first step toward treating the patient (Table 22–3).
Table 22–3. Classification and differential diagnosis of acute kidney injury.
Prerenal causes are the most common etiology of acute kidney insults and injury, accounting for 40–80% of cases, depending on the population studied. Prerenal azotemia is due to renal hypoperfusion, which is an appropriate physiologic change. If reversed quickly with restoration of renal blood flow, renal parenchymal damage often does not occur. If hypoperfusion persists, ischemia can result, causing intrinsic kidney injury.
Decreased renal perfusion can occur in several ways, such as a decrease in intravascular volume, a change in vascular resistance, or low cardiac output. Causes of volume depletion include hemorrhage, GI losses, dehydration, excessive diuresis, extravascular space sequestration, pancreatitis, burns, trauma, and peritonitis.
Changes in vascular resistance can occur systemically with sepsis, anaphylaxis, anesthesia, and afterload-reducing drugs. Blockers of the renin-angiotensin-aldosterone system, such as angiotensin-converting enzyme (ACE) inhibitors, limit efferent renal arteriolar constriction out of proportion to the afferent arteriolar constriction; thus, GFR will decrease with these medications. Nonsteroidal anti-inflammatory drugs (NSAIDs) minimize afferent arteriolar vasodilation by inhibiting prostaglandin-mediated signals. Thus, in cirrhosis and heart failure, when prostaglandins are recruited to increase renal blood flow, NSAIDs will have particularly deleterious effects. Epinephrine, norepinephrine, high-dose dopamine, anesthetic agents, and cyclosporine also can cause renal vasoconstriction. Renal artery stenosis causes increased resistance and decreased renal perfusion.
Low cardiac output is a state of low effective renal arterial blood flow. This occurs in states of cardiogenic shock, heart failure, pulmonary embolism, and pericardial tamponade. Arrhythmias and valvular disorders can also reduce cardiac output. In the ICU setting, positive pressure ventilation will decrease venous return, also decreasing cardiac output.
When GFR falls acutely, it is important to determine whether acute kidney injury is due to prerenal or intrinsic renal causes. The history and physical examination are important, and urinalysis can be helpful. The BUN:creatinine ratio will typically exceed 20:1 due to increased urea reabsorption. In an oliguric patient, another useful index is the fractional excretion of sodium (FENa). With decreased GFR, the kidney will reabsorb salt and water avidly if there is no intrinsic tubular dysfunction. Thus, patients with prerenal causes should have a low fractional excretion percent of sodium (< 1%). Oliguric patients with intrinsic kidney dysfunction typically have a high fractional excretion of sodium (> 1–2%). The FENa is calculated as follows: FENa = clearance of Na+/GFR = clearance of Na+/Ccr:
Renal sodium handling is more accurately assessed by the FENa in oliguric states than in nonoliguric states because the FENa could be relatively low in nonoliguric acute tubular necrosis if sodium intake and excretion are relatively low. (Oliguria is defined as urinary output < 400–500 mL/d, or < 20 mL/h.) The equation was created and validated to assess the difference between oliguric acute tubular necrosis and pre-renal states. Diuretics can cause increased sodium excretion. Thus, if the FENa is high within 12–24 hours after diuretic administration, the cause of acute kidney injury may not be accurately predicted. Acute kidney injury due to glomerulonephritis can have a low FENa because sodium reabsorption and tubular function may not be compromised.
Treatment of prerenal insults depends entirely on the causes, but maintenance of euvolemia, attention to serum electrolytes, and avoidance of nephrotoxic drugs are benchmarks of therapy. This involves careful assessment of volume status, cardiac function, diet, and drug usage.
Postrenal causes are the least common reason for acute kidney injury, accounting for approximately 5–10% of cases, but important to detect because of their reversibility. Postrenal azotemia occurs when urinary flow from both kidneys, or a single functioning kidney, is obstructed. Occasionally, postrenal uropathies can occur when a single kidney is obstructed if the contralateral kidney cannot adjust for the loss in function, (eg, in a patient with advanced CKD). Obstruction leads to elevated intraluminal pressure, causing kidney parenchymal damage, with marked effects on renal blood flow and tubular function, and a decrease in GFR.
Postrenal causes include urethral obstruction, bladder dysfunction or obstruction, and obstruction of both ureters or renal pelvises. In men, benign prostatic hyperplasia is the most common cause. Patients taking anticholinergic drugs are particularly at risk. Obstruction can also be caused by bladder, prostate, and cervical cancers; retroperitoneal fibrosis; and neurogenic bladder. Less common causes are blood clots, bilateral ureteral stones, urethral stones or strictures, and bilateral papillary necrosis.
Patients may be anuric or polyuric and may complain of lower abdominal pain. Polyuria can occur in the setting of partial obstructions with resultant tubular dysfunction and an inability to appropriately reabsorb salt and water loads. Obstruction can be constant or intermittent and partial or complete. On examination, the patient may have an enlarged prostate, distended bladder, or mass detected on pelvic examination.
Laboratory examination may initially reveal high urine osmolality, low urine sodium, high BUN:creatinine ratio, and low FENa (as tubular function may not be compromised initially). These indices are similar to a prerenal picture because extensive intrinsic renal damage has not occurred. After several days, the urine sodium increases as the kidneys fail and are unable to concentrate the urine—thus, isosthenuria is present. The urine sediment is generally benign.
Patients with acute kidney injury and suspected postrenal insults should undergo bladder catheterization and ultrasonography to assess for hydroureter and hydronephrosis. After reversal of the underlying process, these patients often undergo a postobstructive saliuresis and diuresis, and care should be taken to avoid volume depletion. Rarely, obstruction is not diagnosed by ultrasonography. For example, patients with retroperitoneal fibrosis from tumor or radiation may not show dilation of the urinary tract. If suspicion does exist, a CT scan or MRI can establish the diagnosis. Prompt treatment of obstruction within days by catheters, stents, or other surgical procedures can result in partial or complete reversal of the acute process.
Intrinsic renal disorders account for up to 50% of all cases of acute kidney injury. Intrinsic dysfunction is considered after prerenal and postrenal causes have been excluded. The sites of injury are the tubules, interstitium, vasculature, and glomeruli.
• If a patient has signs of acute kidney injury that have not reversed over 1–2 weeks, but no signs of acute uremia, the patient can usually be referred to a nephrologist rather than admitted.
• If a patient has signs of persistent urinary tract obstruction, the patient should be referred to a urologist.
The patient should be admitted if there is sudden loss of kidney function resulting in abnormalities that cannot be handled expeditiously in an outpatient setting (eg, hyperkalemia, volume overload, uremia) or other requirements for acute intervention, such as emergent urologic intervention or dialysis.
Kinsey GR et al. Pathogenesis of acute kidney injury: foundation for clinical practice. Am J Kidney Dis. 2011 Aug;58(2):291–301. [PMID: 21530035]
Palevsky PM et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis. 2013 May;61(5):649–72. [PMID: 23499048]
ESSENTIALS OF DIAGNOSIS
Acute kidney injury.
Ischemic or toxic insult.
Urine sediment with pigmented granular casts and renal tubular epithelial cells is pathognomonic but not essential.
Acute kidney injury due to tubular damage is termed “acute tubular necrosis” and accounts for approximately 85% of intrinsic acute kidney injury. The two major causes of acute tubular necrosis are ischemia and nephrotoxin exposure. Ischemic acute kidney injury is characterized not only by inadequate GFR but also by renal blood flow inadequate to maintain parenchymal cellular perfusion. Renal tubular damage with low effective arterial blood flow to the kidney, often termed a “prerenal” state, can result in tubular necrosis and apoptosis. This occurs in the setting of prolonged hypotension or hypoxemia, such as volume depletion, shock, and sepsis. Major surgical procedures can involve prolonged periods of hypoperfusion, which are exacerbated by vasodilating anesthetic agents. Aside from the serum creatinine, other urinary and serum biomarkers, including neutrophil gelatinase-associated lipocalin and cystatin C, are being investigated to diagnose and treat acute kidney injury earlier in its course, with the potential for better outcomes. Studies investigating the utility of a careful examination of the urinary sediment show promise as a diagnostic and prognostic tool for acute tubular necrosis.
Exogenous nephrotoxins more commonly cause damage than endogenous nephrotoxins.
Aminoglycosides cause some degree of acute tubular necrosis in up to 25% of hospitalized patients receiving therapeutic levels of the drugs. Nonoliguric kidney injury typically starts to occur after 5–10 days of exposure. Predisposing factors include underlying kidney damage, volume depletion, and advanced age. Aminoglycosides can remain in renal tissues for up to a month, so kidney function may not recover for some time after stopping the medication. Monitoring of peak and trough levels is important, but trough levels are more helpful in predicting renal toxicity. Gentamicin is as nephrotoxic as tobramycin; streptomycin is the least nephrotoxic of the aminoglycosides, likely due to the number of cationic amino side chains present on each molecule.
Amphotericin B is typically nephrotoxic after a dose of 2–3 g. This causes a type I renal tubular acidosis with severe vasoconstriction and distal tubular damage, which can lead to hypokalemia and nephrogenic diabetes insipidus. Vancomycin, intravenous acyclovir, and several cephalosporins have been known to cause acute tubular necrosis.
Radiographic contrast media may be directly nephrotoxic. Contrast nephropathy is the third leading cause of new-onset acute kidney injury in hospitalized patients. It probably results from the synergistic combination of direct renal tubular epithelial cell toxicity and renal medullary ischemia. Predisposing factors include advanced age, preexisting kidney disease (serum creatinine > 2 mg/dL), volume depletion, diabetic nephropathy, heart failure, multiple myeloma, repeated doses of contrast, and recent exposure to other nephrotoxic agents, including NSAIDs and ACE inhibitors. The combination of preexisting diabetes mellitus and kidney dysfunction poses the greatest risk (15–50%) for contrast nephropathy. Lower volumes of contrast with lower osmolality are recommended in high-risk patients. Toxicity usually occurs within 24–48 hours after the radiocontrast study. Nonionic contrast media may be less toxic, but this has not been well proven. Prevention should be the goal when using these agents. The mainstay of therapy is a liter of intravenous 0.9% saline over 10–12 hours both before and after the contrast administration—cautiously in patients with preexisting cardiac dysfunction. Intravenous volume repletion is superior to oral solutions in small studies. Neither mannitol nor furosemide offers benefit over 0.9% (normal) saline administration. In fact, furosemide may lead to increased rates of renal dysfunction in this setting. It is unclear whether N-acetylcysteine can prevent kidney injury. In some small studies, N-acetylcysteine given before and after contrast decreases the incidence of dye-induced nephrotoxicity. However, a large prospective randomized controlled trial showed no benefit of N-acetylcysteine in over 2300 patients, some of whom had CKD, randomized to either 1200 mg orally twice versus placebo before and after angiographic procedures. Acetylcysteine is a thiol-containing antioxidant with little toxicity whose mechanism of action is unclear. With little harm and possible benefit, administering acetylcysteine 600 mg orally every 12 hours twice, before and after a dye load, for patients with preexisting risk factors at risk for acute kidney injury, is a reasonable strategy. Intravenous N-acetylcysteine, 1200 mg prior to an emergent procedure, has shown benefit compared with placebo and may be a good option if a patient needs contrast dye urgently. The primary endpoint was a 25% increase in serum creatinine within 48–96 hours after the procedure. Some investigators have shown a benefit using sodium bicarbonate (154 mEq/L, intravenously at 3 mL/kg/h for 1 hour before the procedure, then 1 mL/kg/h for 6 hours after the procedure) over a more conventional regimen of normal saline as the isotonic volume expander. However, others have shown sodium bicarbonate was not superior to sodium chloride when using similar administration regimens. Other nephrotoxic agents should be avoided during the day before and after dye administration. The largest randomized trial to date will investigate intravenous normal saline versus bicarbonate and N-acetylcysteine versus placebo to prevent contrast-induced nephropathy in a 2×2 design, with a result predicted for 2017.
Cyclosporine toxicity is usually dose dependent. It causes distal tubular dysfunction (a type 4 renal tubular acidosis) from severe vasoconstriction. Regular blood level monitoring is important to prevent both acute and chronic nephrotoxicity. With patients who are taking cyclosporine to prevent kidney allograft rejection, kidney biopsy is often necessary to distinguish transplant rejection from cyclosporine toxicity. Renal function usually improves after reducing the dose or stopping the drug.
Other exogenous nephrotoxins include antineoplastics, such as cisplatin and organic solvents, and heavy metals such as mercury, cadmium, and arsenic.
Endogenous nephrotoxins include heme-containing products, uric acid, and paraproteins. Myoglobinuria as a consequence of rhabdomyolysis leads to acute tubular necrosis. Necrotic muscle releases large amounts of myoglobin, which is freely filtered across the glomerulus. The myoglobin is reabsorbed by the renal tubules, and direct damage can occur. Distal tubular obstruction from pigmented casts and intrarenal vasoconstriction can also cause damage. This type of kidney injury occurs in the setting of crush injury, or muscle necrosis from prolonged unconsciousness, seizures, cocaine, and alcohol abuse. Dehydration and acidosis predispose to the development of myoglobinuric acute kidney injury. Patients may complain of muscular pain and often have signs of muscle injury. Rhabdomyolysis of clinical importance commonly occurs with a serum creatine kinase (CK) > 20,000–50,000 international units/L. One study showed that 58% of patients with acute kidney injury from rhabdomyolysis had CK levels > 16,000 international units/L. Only 11% of patients without kidney injury had CK values < 16,000 international units/L. The globin moiety of myoglobin will cause the urine dipstick to read falsely positive for hemoglobin: the urine appears dark brown, but no red cells are present. With lysis of muscle cells, patients also become hyperkalemic, hyperphosphatemic, and hyperuricemic. Hypocalcemia may ensue due to phosphorus and calcium precipitation. The mainstay of treatment is volume repletion. Adjunctive treatments with mannitol and alkalinization of the urine have not been proved to change outcomes in human trials. As the patient recovers, calcium can move back from tissues to plasma, so early exogenous calcium administration for hypocalcemia is not recommended unless the patient is symptomatic or the level becomes exceedingly low in an unconscious patient. Such repletion could result in hypercalcemia later in the course of the illness.
Hemoglobin can cause a similar form of acute tubular necrosis. Massive intravascular hemolysis is seen in transfusion reactions and in certain hemolytic anemias. Reversal of the underlying disorder and hydration are the mainstays of treatment.
Hyperuricemia can occur in the setting of rapid cell turnover and lysis. Chemotherapy for germ cell neoplasms and leukemia and lymphoma are the primary causes. Spontaneous tumor lysis syndrome is a less common cause. Acute kidney injury occurs with intratubular deposition of uric acid crystals; serum uric acid levels are often > 15–20 mg/dL and urine uric acid levels > 600 mg/24 h. A urine uric acid to urine creatinine ratio > 1.0 indicates risk of acute kidney injury. Allopurinol or rasburicase can be used prophylactically, and rasburicase with or without dialysis is often used for treatment in diagnosed cases.
Bence Jones protein seen in conjunction with multiple myeloma can cause direct tubular toxicity and tubular obstruction. Other renal complications from multiple myeloma include hypercalcemia and renal tubular dysfunction, including proximal renal tubular acidosis (see Multiple Myeloma, below).
See Acute Kidney Injury.
Hyperkalemia and hyperphosphatemia are commonly encountered. BUN:creatinine ratio is usually < 20:1 because tubular function is not intact, per the mechanisms described in the general section on acute kidney injury (Table 22–3). Urinalysis may show evidence of acute tubular damage. The urine sediment may be brown. Urinary output can be either oliguric or nonoliguric, with oliguria portending a worse prognosis. Urine sodium concentration is typically elevated, but the FENa is more indicative of tubular function, as discussed above. On microscopic examination, an active sediment may show pigmented granular casts or “muddy brown” casts. Renal tubular epithelial cells and epithelial cell casts can be present (see Table 22–1).
Treatment is aimed at hastening recovery and avoiding complications. Preventive measures should be taken to avoid volume overload and hyperkalemia. Loop diuretics have been used in large doses (eg, furosemide in doses ranging from 20 mg to 160 mg orally or intravenously twice daily, or as a continuous infusion) to affect adequate diuresis. However, a prospective randomized controlled trial has shown no difference between the administration of large doses of diuretics versus placebo on either recovery from acute kidney injury or death. Widespread use of diuretics in critically ill patients with acute kidney injury should only be encouraged in states of volume overload when appropriate. Disabling side effects of supranormal dosing include hearing loss and cerebellar dysfunction. This is mainly due to peak furosemide levels; this risk can be minimized by the use of a furosemide drip. A starting dose of 0.1–0.3 mg/kg/h is appropriate, increasing to a maximum of 0.5–1 mg/kg/h. A bolus of 1–1.5 mg/kg should be administered at the beginning of each dose escalation. Intravenous thiazide diuretics can be used to augment urinary output; chlorothiazide, 250–500 mg intravenously every 8–12 hours, is a reasonable choice. Another good choice to augment diuresis is metolazone at doses of 2.5–5 mg given orally once to twice daily, 30 minutes prior to loop diuretics. It is less expensive than intravenous chlorothiazide and has reasonable bioavailability. Short-term effects of loop diuretics include activation of the renin–angiotensin system. A 2012 prospective randomized trial showed the lack of benefit on mortality from plasma ultrafiltration over the use of intravenous diuretics in patients with decompensated heart failure. This intervention can be considered in ICU patients with acute kidney injury in need of volume removal who are nonresponsive to diuretics with the caveat that the intervention has not ultimately improved population-based survival. Nutritional support should maintain adequate intake while preventing excessive catabolism. Dietary protein restriction of 0.6 g/kg/d helps prevent metabolic acidosis. Hypocalcemia and hyperphosphatemia can be improved with diet and phosphate-binding agents taken with meals three times daily; examples include aluminum hydroxide (500 mg orally) over the short term, and calcium carbonate (500–1500 mg orally), calcium acetate (667 mg, two or three tablets), sevelamer carbonate (800–1600 mg orally), and lanthanum carbonate (1000 mg orally) over longer periods. Hypocalcemia should not be treated in patients with rhabdomyolysis unless they are symptomatic. Hypermagnesemia can occur because of reduced magnesium excretion by the renal tubules, so magnesium-containing antacids and laxatives should be avoided in these patients. Dosages of all medications must be adjusted according to the estimated degree of renal impairment for drugs eliminated by the kidney.
Indications for dialysis in acute kidney injury from acute tubular necrosis or other intrinsic disorders include life-threatening electrolyte disturbances (such as hyperkalemia), volume overload unresponsive to diuresis, worsening acidosis, and uremic complications (eg, encephalopathy, pericarditis, and seizures). In gravely ill patients, less severe but worsening abnormalities may also be indications for dialytic support. Two prospective randomized control trials, each with more than 1100 patients, showed that an intensive dialysis dose was not superior to a more conventional dose.
The clinical course of acute tubular necrosis is often divided into three phases: initial injury, maintenance, and recovery. The maintenance phase is expressed as either oliguric (urinary output < 500 mL/d) or nonoliguric. Nonoliguric acute tubular necrosis has a better outcome. Conversion from oliguric to nonoliguric states with the use of diuretics has not been shown to change the prognosis. While dopamine has sometimes been used for this purpose, numerous studies have shown that its use in this setting has not been beneficial. Average duration of the maintenance phase is 1–3 weeks but may be several months. Cellular repair and removal of tubular debris occur during this period. The recovery phase can be heralded by diuresis. GFR begins to rise; BUN and serum creatinine fall.
The mortality rate associated with acute kidney injury is 20–50% in hospitalized settings, and up to 70% for those in the ICU requiring dialysis with additional comorbid illnesses. Increased mortality is associated with advanced age, severe underlying disease, and multisystem organ failure. Leading causes of death are infections, fluid and electrolyte disturbances, and worsening of underlying disease. Mortality rates have started to improve slightly according to two retrospective cohort studies conducted within the last 10 years.
• Studies have shown that nephrology referral improves outcome in acute kidney injury.
• For fluid, electrolyte, and acid-base abnormalities that are recalcitrant to interventions.
A patient with symptoms or signs of acute kidney injury that require immediate intervention, such as administration of intravenous fluids, dialytic therapy, or that requires a team approach that cannot be coordinated as an outpatient.
ESSENTIALS OF DIAGNOSIS
Transient maculopapular rash.
Acute or chronic kidney injury.
Pyuria (including eosinophiluria), white blood cell casts, and hematuria.
Acute interstitial nephritis accounts for 10–15% of cases of intrinsic renal failure. An interstitial inflammatory response with edema and possible tubular cell damage is the typical pathologic finding.
Although drugs account for over 70% of cases, acute interstitial nephritis also occurs in infectious diseases, immunologic disorders, or as an idiopathic condition. The most common drugs are penicillins and cephalosporins, sulfonamides and sulfonamide-containing diuretics, NSAIDs, rifampin, phenytoin, and allopurinol. Proton pump inhibitors can also cause acute interstitial nephritis. Infectious causes include streptococcal infections, leptospirosis, cytomegalovirus, histoplasmosis, and Rocky Mountain spotted fever. Immunologic entities are more commonly associated with glomerulonephritis, but SLE, Sjögren syndrome, sarcoidosis, and cryoglobulinemia can cause interstitial nephritis.
Clinical features can include fever (> 80%), rash (25–50%), arthralgias, and peripheral blood eosinophilia (80%). The classic triad of fever, rash, and arthralgias is present in only 10–15% of cases. The urine often contains white cells (95%), red cells, and white cell casts. Proteinuria can be a feature, particularly in NSAID-induced interstitial nephritis, but is usually modest (< 2 g/24 h). Eosinophiluria is neither very sensitive nor specific but can be detected by Wright or Hansel stain.
Acute interstitial nephritis often carries a good prognosis. Recovery occurs over weeks to months. Urgent dialytic therapy may be necessary in up to one-third of all referred patients before resolution but patients rarely progress to ESRD. Those with prolonged courses of oliguric failure and advanced age have a worse prognosis. Treatment consists of supportive measures and removal of the inciting agent. If kidney injury persists after these steps, a short course of corticosteroids can be given, although the data to support use of corticosteroids are not substantial. Short-term, high-dose methylprednisolone (0.5–1 g/d intravenously for 1–4 days) or prednisone (60 mg/d orally for 1–2 weeks) followed by a prednisone taper can be used in these more severe cases of drug-induced interstitial nephritis.
ESSENTIALS OF DIAGNOSIS
Hematuria, dysmorphic red cells, red cell casts, and mild proteinuria.
Dependent edema and hypertension.
Acute kidney injury.
Acute glomerulonephritis is a relatively uncommon cause of acute kidney injury, accounting for about 5% of cases. Pathologically, inflammatory glomerular lesions are seen. These include mesangioproliferative, focal and diffuse proliferative, and crescentic lesions. The larger the percentage of glomeruli involved and the more severe the lesion, the more likely it is that the patient will have a poor clinical outcome.
Categorization of acute glomerulonephritis can be done by serologic analysis. Markers include anti-GBM antibodies, antineutrophil cytoplasmic antibodies (ANCAs), and other immune markers of disease.
Immune complex deposition usually occurs when moderate antigen excess over antibody production occurs. Complexes formed with marked antigen excess tend to remain in the circulation. Antibody excess with large antigen–antibody aggregates usually results in phagocytosis and clearance of the precipitates by the mononuclear phagocytic system in the liver and spleen. Causes include IgA nephropathy (Berger disease), peri-infectious or post-infectious glomerulonephritis, endocarditis, lupus nephritis, cryoglobulinemic glomerulonephritis (often associated with hepatitis C virus [HCV]), and MPGN.
Anti-GBM–associated acute glomerulonephritis is either confined to the kidney or associated with pulmonary hemorrhage. The latter is termed “Goodpasture syndrome.” Injury is related to autoantibodies aimed against type IV collagen in the GBM rather than to immune complex deposition.
Pauci-immune acute glomerulonephritis is a form of small-vessel vasculitis associated with ANCAs, causing primary and secondary kidney diseases that do not have direct immune complex deposition or antibody binding. Tissue injury is believed to be due to cell-mediated immune processes. An example is granulomatosis with polyangiitis, a systemic necrotizing vasculitis of small arteries and veins associated with intravascular and extravascular granuloma formation. In addition to glomerulonephritis, these patients can have upper airway, pulmonary, and skin manifestations of disease. Cytoplasmic ANCA (c-ANCA) is the common pattern. Microscopic polyangiitis is another pauci-immune vasculitis causing acute glomerulonephritis. Perinuclear staining (p-ANCA) is the common pattern in this scenario. ANCA-associated and anti-GBM-associated acute glomerulonephritis can evolve to crescentic glomerulonephritis and often have poor outcomes unless treatment is started early. Both are described more fully below.
Other vascular causes of acute glomerulonephritis include hypertensive emergencies and the thrombotic microangiopathies such as hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura (see Chapter 14).
Patients with acute glomerulonephritis are often hypertensive and edematous, and have an abnormal urinary sediment. The edema is found first in body parts with low tissue tension, such as the periorbital and scrotal regions.
Serum creatinine can rise over days to months, depending on the rapidity of the underlying process. The BUN:creatinine ratio is not a reliable marker of kidney function and is more reflective of the underlying volume status of the patient. Dipstick and microscopic evaluation will reveal evidence of hematuria, moderate proteinuria (usually < 3 g/d), and cellular elements such as red cells, red cell casts, and white cells. Red cell casts are specific for glomerulonephritis, and a detailed search is warranted. Either spot urinary protein-creatinine ratios or 24-hour urine collections can quantify protein excretion; the latter can quantify creatinine clearance when renal function is stable. However, in cases of rapidly changing serum creatinine values, the urinary creatinine clearance is an unreliable marker of GFR. The FENa is usually low unless the renal tubulo-interstitial space is affected, and renal dysfunction is marked (see Table 22–3).
Further tests include complement levels (C3, C4, CH50) that are low in immune complex glomerulonephritis aside from IgA nephropathy and normal in pauci immune and anti-GBM related glomerulonephritis. Other tests include ASO titers, anti-GBM antibody levels, ANCAs, antinuclear antibody titers, cryoglobulins, hepatitis serologies, blood cultures, renal ultrasound, and occasionally kidney biopsy.
Depending on the nature and severity of disease, treatment can consist of high-dose corticosteroids and cytotoxic agents such as cyclophosphamide. Plasma exchange can be used in Goodpasture disease and pauci-immune glomerulonephritis as a temporizing measure until chemotherapy can take effect. Treatment and prognosis for specific diseases are discussed more fully below.
Ad-hoc working group of ERBP; Fliser D et al. A European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines on acute kidney injury: part 1: definitions, conservative management and contrast-induced nephropathy. Nephrol Dial Transplant. 2012 Dec;27(12):4263–72. [PMID: 23045432]
Hoste EA et al. Epidemiology of acute kidney injury. Contrib Nephrol. 2010;165:1–8. [PMID: 20427949]
Lafrance JP et al. Acute kidney injury associates with increased long-term mortality. J Am Soc Nephrol. 2010 Feb;21(2):345–52. [PMID: 20019168]
Perazella MA et al. Diagnostic value of urine microscopy for differential diagnosis of acute kidney injury in hospitalized patients. Clin J Am Soc Nephrol. 2008 Nov;3(6):1615–9. [PMID: 18784207]
ESSENTIALS OF DIAGNOSIS
Cardiac dysfunction: signs or symptoms of heart failure, ischemic injury or arrhythmias.
Kidney disease: acute or chronic, depending on type of cardiorenal syndrome.
Cardiorenal syndrome is a pathophysiologic disorder of the heart and kidneys wherein the acute or chronic deterioration of one organ results in the acute or chronic deterioration of the other. This syndrome has been classified into five types.
Type 1 consists of acute kidney injury stemming from acute cardiac disease. Type 2 is CKD due to chronic cardiac disease. Type 3 is acute cardiac disease as a result of acute kidney injury. Type 4 is chronic cardiac decompensation from CKD. Type 5 consists of heart and kidney dysfunction due to other acute or chronic systemic disorders (such as sepsis). Identifying and defining this common syndrome may assist in the future with treatments to improve its morbidity and mortality.
Bart BA et al; Heart Failure Clinical Research Network. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012 Dec 13;367(24):2296–304. [PMID: 23131078]
ESSENTIALS OF DIAGNOSIS
Decline in the GFR over months to years
Persistent proteinuria or abnormal renal morphology may be present.
Hypertension in most cases.
Symptoms and signs of uremia when nearing end-stage disease.
Bilateral small or echogenic kidneys on ultrasound in advanced disease.
CKD affects more than 20 million Americans, or one in nine adults. Most are unaware of the condition because they remain asymptomatic until the disease is near end-stage. The National Kidney Foundation’s staging system helps clinicians formulate practice plans (Table 22–4). Over 70% of cases of late-stage CKD (stage 5 CKD and ESRD) in the United States are due to diabetes mellitus or hypertension/vascular disease. Glomerulonephritis, cystic diseases, chronic tubulointerstitial diseases, and other urologic diseases account for the remainder (Table 22–5). Genetic polymorphisms of theAPOL-1 gene have been shown to be associated with an increased risk of the development of CKD in African Americans.
Table 22–4. Stages of chronic kidney disease: A clinical action plan.1,2
Table 22–5. Major causes of chronic kidney disease.
CKD usually leads to a progressive decline in kidney function even if the inciting cause can be identified and treated or removed. Destruction of nephrons leads to compensatory hypertrophy and supranormal GFR of the remaining nephrons in order to maintain overall homeostasis. As a result, the serum creatinine may remain relatively normal even in the face of significant loss of renal mass and is, therefore, a relatively insensitive marker for renal damage and scarring. In addition, compensatory hyperfiltration leads to overwork injury in the remaining nephrons, which in turn causes progressive glomerular sclerosis and interstitial fibrosis. Angiotensin receptor blockers (ARBs) and ACE inhibitors can help reduce hyperfiltration injury and are particularly helpful in slowing the progression of proteinuric CKD. Fortunately, an individual’s decreased renal mass as a result of kidney donation is unlikely to result in CKD later in life.
CKD is an independent risk factor for cardiovascular disease (CVD); proteinuric CKD confers an even higher risk of cardiovascular mortality. Most patients with stage 3 CKD die of underlying CVD prior to progression to ESRD.
In the early stages, CKD is asymptomatic. Symptoms develop slowly with the progressive decline in GFR, are nonspecific, and do not manifest until kidney disease is far advanced (GFR < 5–10 mL/min/1.73 m2). At this point, the build-up of metabolic waste products, or uremic toxins, can result in the uremic syndrome (Table 22–6). General symptoms of uremia may include fatigue and weakness; anorexia, nausea, vomiting, and a metallic taste in the mouth are also common. Patients or family members may report irritability, memory impairment, insomnia, restless legs, paresthesias, and twitching. Generalized pruritus without rash may occur. Decreased libido and menstrual irregularities are common. Pericarditis, a rare complication of CKD, may present with pleuritic chest pain. Drug toxicity can develop as renal clearance worsens; in particular, since insulin is renally cleared, hypoglycemia may develop and can be life-threatening in patients with diabetes.
Table 22–6. Symptoms and signs of uremia.
The most common physical finding in CKD is hypertension. It is often present in early stages of CKD and tends to worsen with CKD progression as sodium excretion is impaired. In later stages of CKD, this sodium retention may lead to typical physical signs of volume overload. Uremic signs are seen with a profound decrease in GFR (< 5–10 mL/min/1.73 m2) and may include a generally sallow and ill appearance, halitosis (uremic fetor), and the uremic encepholophathic signs of decreased mental status, asterixis, myoclonus, and possibly seizures if very advanced.
Symptoms and signs of uremia warrant immediate hospital admission and nephrology consultation for initiation of dialysis. The uremic syndrome improves or resolves with dialytic therapy.
In any patient with kidney disease, it is important to identify and correct all possibly reversible insults or exacerbating factors (Table 22–7). Urinary tract infections, obstruction, extracellular fluid volume depletion, hypotension, nephrotoxins (such as NSAIDs or aminoglycosides), severe or emergent hypertension, and heart failure should be excluded.
Table 22–7. Reversible causes of kidney injury.
CKD is usually defined by an abnormal GFR persisting for at least 3 months. Persistent proteinuria or abnormalities on renal imaging (eg, polycystic kidneys) are also diagnostic of CKD, even when estimated GFR is normal. It is helpful to plot the inverse of serum creatinine (1/SCr) versus time or estimated GFR (if reported by the laboratory) versus time. If three or more prior measurements are available, the time to ESRD can be estimated (Figure 22–1). If the slope of the line acutely declines, new and potentially reversible renal insults should be excluded as outlined above. Anemia, hyperphosphatemia, hypocalcemia, hyperkalemia, and metabolic acidosis can occur with both acute kidney disease and CKD. The urinary sediment can show broad waxy casts as a result of dilated, hypertrophic nephrons. Proteinuria may be present. If so, it should be quantified as described above. Quantification of urinary protein is important for several reasons. First, it helps narrow the differential diagnosis of the etiology of the CKD (Table 22–5); for example, glomerular diseases tend to present with protein excretion of > 1 g/d. Second, the presence of proteinuria is associated with more rapid progression of CKD and cardiovascular mortality.
Figure 22–1. Decline in kidney function (expressed as the reciprocal of serum creatinine as shown here, or as estimated glomerular filtration rate [eGFR]) plotted against time to end-stage renal disease (ESRD). The solid line indicates the linear decline in kidney function over time. The dotted line indicates the approximate time to ESRD.
The finding of small, echogenic kidneys bilaterally (< 9–10 cm) by ultrasonography supports a diagnosis of CKD, although normal or even large kidneys can be seen with adult polycystic kidney disease, diabetic nephropathy, HIV-associated nephropathy, multiple myeloma, amyloidosis, and obstructive uropathy.
The complications of CKD tend to occur at relatively predictable stages of disease as noted in Figure 22–2.
Figure 22–2. Complications of chronic kidney disease (CKD) by stage and glomerular filtration rate (GFR). Complications arising from CKD tend to occur at the stages depicted, although there is considerable variability noted in clinical practice. HTN, hypertension; PTH, parathyroid hormone. (Adapted, with permission, from William Bennett, MD.)
Patients with CKD experience greater morbidity and mortality from CVD in comparison to the general population. Death from cardiovascular causes accounts for 45% of all deaths of patients receiving dialysis. Between 80% and 90% of patients with CKD die, primarily of CVD, before reaching the need for dialysis. The precise biologic mechanisms for this enhanced mortality are unclear but may have to do with the uremic milieu including abnormal phosphorus and calcium homeostasis, increased burden of oxidative stress, increased vascular reactivity, increased left ventricular hypertrophy, and underlying coexistent comorbidities such as hypertension and diabetes mellitus.
1. Hypertension—Hypertension is the most common complication of CKD; it tends to be progressive and salt-sensitive. Hyperreninemic states and exogenous erythropoietin administration can also exacerbate hypertension.
As with other patient populations, control of hypertension should focus on both nonpharmacologic therapy (eg, diet, exercise, weight loss, treatment of obstructive sleep apnea) and pharmacologic therapy. CKD results in disturbed sodium homeostasis such that the ability of the kidney to adjust to variations in sodium and water intake becomes limited as GFR declines. A low salt diet (2 g/d) is often essential to control blood pressure and help avoid overt volume overload. Diuretics are nearly always needed to help control hypertension (see Table 11–5); thiazides work well in early CKD, but in those with a GFR < 30 mL/min/1.73 m2, loop diuretics are more effective. Beware, however, that volume contraction as a result of very low sodium intake (especially with intercurrent illness) or over-diuresis in the presence of impaired sodium homeostasis can result in acute kidney injury. Initial drug therapy for proteinuric patients should include ACE inhibitors or ARBs (see Table 11–7). When an ACE inhibitor or an ARB is initiated or uptitrated, patients must have serum creatinine and potassium checked within 7–14 days. Hyperkalemia or a rise in serum creatinine > 30% from baseline mandates reduction or cessation of the drug. Results of the NEPHRON-D study suggest that an ACE inhibitor and ARBs should not be used in combination. Second-line antihypertensive agents include calcium channel blockers and beta-blockers. Hypertension in CKD can be difficult to control and additional agents from other classes are often needed. Current guidelines suggest a blood pressure goal of <140/90 mm Hg for patients with CKD; a goal of 125/75 mm Hg may be beneficial for patients with proteinuria. Treatment of blood pressure significantly below these goals is not supported by current data and may be dangerous in some populations, such as the elderly. Randomized controlled trials to assess optimal BP control in CKD are ongoing.
2. Coronary artery disease—Patients with CKD are at higher risk for death from CVD than the general population. Traditional modifiable risk factors for CVD, such as hypertension, tobacco use, and hyperlipidemia, should be aggressively treated in patients with CKD. Uremic vascular calcification involving disordered phosphorus homeostasis and other mediators may also be a cardiovascular risk factor in these patients.
3. Heart failure—The complications of CKD result in increased cardiac workload via hypertensive disease, volume overload, and anemia. Patients with CKD may also have accelerated rates of atherosclerosis and vascular calcification resulting in vessel stiffness. All of these factors contribute to left ventricular hypertrophy and diastolic dysfunction, which are present in most patients starting dialysis. Over time, systolic dysfunction may also develop. Diuretic therapy, in addition to prudent fluid and salt restriction, is usually necessary. Thiazides may be adequate therapy for most patients through CKD stage 3, but loop diuretics are usually needed when the GFR is < 30 mL/min/1.73 m2; higher doses may be needed as renal function declines. Digoxin is excreted by the kidney, and its toxicity is exacerbated in the presence of electrolyte disturbances which are common in CKD. The proven efficacy of ACE inhibitors in heart failure holds true for patients with CKD. Despite the risks of hyperkalemia and worsening renal function, ACE inhibitors and ARBs can be used for patients with advanced CKD with close blood pressure and blood chemistry monitoring.
4. Pericarditis—Pericarditis may develop in uremic patients but is rare; typical findings include pleuritic chest pain and a friction rub. Development of a significant effusion may result in pulsus paradoxus, an enlarged cardiac silhouette on chest radiograph, and low QRS voltage and electrical alternans on ECG. The effusion is generally hemorrhagic, and anticoagulants should be avoided if this diagnosis is suspected. Cardiac tamponade can occur; therefore, uremic pericarditis is a mandatory indication for hospitalization and initiation of hemodialysis.
The metabolic bone disease of CKD refers to the complex disturbances of calcium and phosphorus metabolism, parathyroid hormone (PTH), active vitamin D, and possibly fibroblast growth factor-23 (FGF-23) homeostasis (see Chapter 21 and Figure 22–3). A typical pattern seen as early as CKD stage 3 is hyperphosphatemia, hypocalcemia, hypovitaminosis D, and secondary hyperparathyroidism as a result of the first three abnormalities. These abnormalities can cause vascular calcification, which may be partly responsible for the accelerated CVD and excess mortality seen in the CKD population. Epidemiologic studies in humans show an association between elevated phosphorus levels and increased risk of cardiovascular mortality in early CKD through ESRD. As yet, there are no intervention trials suggesting the best course of treatment in these patients; control of mineral and PTH levels per current guidelines is discussed below.
Figure 22–3. Mineral abnormalities of chronic kidney disease (CKD). Decline in glomerular filtration rate (GFR) and loss of renal mass lead directly to increased serum phosphorus and hypovitaminosis D. Both of these abnormalities result in hypocalcemia and hyperparathyroidism. Many CKD patients also have nutritional 25(OH) vitamin D deficiency. PTH, parathyroid hormone.
Bone disease, or renal osteodystrophy, in advanced CKD is common and there are several types of lesions. Renal osteodystrophy can only be diagnosed by bone biopsy, which is rarely done. The most common bone disease, osteitis fibrosa cystica, is a result of secondary hyperparathyroidism and the osteoclast-stimulating effects of PTH. This is a high-turnover disease with bone resorption and subperiosteal lesions; it can result in bone pain and proximal muscle weakness. Adynamic bone disease, or low-bone turnover, is becoming more common; it may result iatrogenically from suppression of PTH or via spontaneously low PTH production. Osteomalacia is characterized by lack of bone mineralization. In the past, osteomalacia was associated with aluminum toxicity—either as a result of chronic ingestion of prescribed aluminum-containing phosphorus binders or from high levels of aluminum in impure dialysate water. Currently, osteomalacia is more likely to result from hypovitaminosis D; there is also theoretical risk of osteomalacia associated with use of bisphosphonates in advanced CKD.
All of the above entities increase the risk of fractures. Aluminum exposure should be avoided. In addition, treatment may involve correction of calcium, phosphorus, and 25-OH vitamin D levels toward normal values, and mitigation of hyperparathyroidism. Understanding the interplay between these abnormalities can help target therapy (Figure 22–3). Declining GFR leads to phosphorus retention. This results in hypocalcemia as phosphorus complexes with calcium, deposits in soft tissues, and stimulates PTH. Loss of renal mass and low 25-OH vitamin D levels often seen in CKD patients result in low 1,25(OH) vitamin D production by the kidney. Because 1,25(OH) vitamin D is a suppressor of PTH production, hypovitaminosis D also leads to secondary hyperparathyroidism.
The first step in treatment of metabolic bone disease is control of hyperphosphatemia (defined as a serum phosphorus of ≤ 4.5 mg/dL in pre-ESRD CKD, or ≤ 5.5 mg/dL in ESRD patients). This involves dietary phosphorus restriction initially (see section on dietary management), followed by the administration of oral phosphorus binders if targets are not achieved (see below). Oral phosphorus binders, such as calcium carbonate (650 mg/tablet) or calcium acetate (667 mg/capsule), block absorption of dietary phosphorus in the gut and are given thrice daily with meals. These should be titrated to a serum phosphorus of < 4.6 mg/dL in stage 3–4 CKD and < 4.6–5.5 mg/dL in ESRD. Maximal recommended elemental calcium doses are 1500 mg/d (eg, nine tablets of calcium acetate); doses should be decreased if serum calcium rises above 10 mg/dL. Phosphorus-binding agents that do not contain calcium are sevelamer and lanthanum. Sevelamer, 800–3200 mg, and lanthanum carbonate, 500–1000 mg, are given at the beginning of meals and may be combined with calcium-containing binders. Aluminum hydroxide is a highly effective phosphorus binder but can cause osteomalacia and neurologic complications when used long-term. It can be used in the acute setting for serum phosphorus > 7 mg/dL or for short periods (eg, 3 weeks) in CKD patients.
Once serum phosphorus levels are controlled, active vitamin D (1,25[OH] vitamin D, or calcitriol) or active vitamin D analogs are recommended to treat secondary hyperparathyroidism in stage 3–5 CKD. Serum 25-OH vitamin D levels should be measured and brought to normal (see Chapter 26) prior to considering administration of active vitamin D. Active vitamin D (calcitriol) increases serum calcium and phosphorus levels; both need to be monitored closely during calcitriol therapy, and its dose should be decreased if hypercalcemia or hyperphosphatemia occurs. Typical calcitriol dosing is 0.25 or 0.5 mcg orally daily or every other day. Cinacalcet targets the calcium-sensing receptors of the parathyroid gland and suppresses PTH production. Cinacalcet, 30–90 mg orally once a day, can be used if elevated serum phosphorus or calcium levels prohibit the use of vitamin D analogs; cinacalcet can cause hypocalcemia. Optimal PTH levels in CKD are not known, but because skeletal resistance to PTH develops with uremia, relatively high levels are targeted in advanced CKD to avoid adynamic bone disease. Expert guidelines generally suggest goal PTH levels near or just above the upper limit of normal for moderate CKD, and at least twofold and up to ninefold the upper limit of normal for ESRD.
1. Anemia—The anemia of CKD is primarily due to decreased erythropoietin production, which often becomes clinically significant during stage 3 CKD. Many patients are iron deficient as well due to impaired GI iron absorption.
Erythropoiesis-stimulating agents (eg, recombinant erythropoietin [epoetin] and darbepoetin) are FDA-approved in CKD for a goal hemoglobin (Hgb) of 10–11 g/dL if no other treatable causes for anemia are present. There is likely no benefit of starting erythropoiesis-stimulating agents before Hgb values are < 9 g/dL. The starting dose of epoetin is 50 units/kg (3000–4000 units/dose) once or twice a week, and darbepoetin is started at 0.45 mcg/kg and can be administered every 2–4 weeks. These agents can be given intravenously (eg, to the hemodialysis patient) or subcutaneously (eg, to the predialysis or dialysis patient); subcutaneous dosing of erythropoietin is roughly 30% more effective than intravenous dosing. Erythropoiesis-stimulating agents should be titrated to a Hgb of 10–11 g/dL for optimal safety; studies show that targeting a higher Hgb increases risk of stroke and possibly other cardiovascular events. When titrating doses, Hgb levels should rise no more than 1 g/dL every 3–4 weeks. Hypertension is a complication of treatment with erythropoiesis-stimulating agents in about 20% of patients. The dosage may require adjustment, or antihypertensive drugs may need to be given.
Iron stores must be adequate to ensure response to erythropoiesis-stimulating agents. Hepcidin, a molecule that blocks GI iron absorption and mobilization of iron from body stores, tends to be high in CKD. Therefore, traditional measures of iron stores are measured in CKD patients but are targeted to higher goals; in CKD, a serum ferritin < 100–200 ng/mL or iron saturation < 20% is suggestive of iron deficiency. Iron stores should be repleted with oral or parenteral iron prior to the initiation of an erythropoietic agent. Iron therapy should probably be withheld if the serum ferritin is > 500–800 ng/mL, even if the iron saturation is < 20%. Oral therapy with ferrous sulfate, gluconate, or fumarate, 325 mg once to three times daily, is the initial therapy in pre-ESRD CKD. For those that do not respond due to poor GI absorption or lack of tolerance, intravenous iron may be necessary.
The preliminary investigation of anemia in any CKD patient should also include assessment of thyroid function tests, and serum vitamin B12 testing prior to initiating therapy with a erythropoiesis-stimulating agent.
2. Coagulopathy—The coagulopathy of advanced stage CKD is mainly caused by platelet dysfunction; a prolonged bleeding time may result. Clinically, patients can have petechiae, purpura, and an increased tendency for bleeding during surgery.
Treatment is required only in patients who are symptomatic. Raising the Hgb to 9–10 g/dL in anemic patients can reduce risk of bleeding via improved clot formation. Desmopressin (25 mcg intravenously every 8–12 hours for two doses) is a short-lived but effective treatment for platelet dysfunction and it is often used in preparation for surgery. Conjugated estrogens, 2.5–5 mg orally for 5–7 days, may have an effect for several weeks but are seldom used. Dialysis improves the bleeding time. Cryoprecipitate (10–15 bags) is rarely used and lasts < 24 hours.
Potassium balance generally remains intact in CKD until stages 4–5. However, hyperkalemia may occur at earlier stages when certain conditions are present, such as type 4 renal tubular acidosis (seen in patients with diabetes mellitus), high potassium diets, or medications that decrease renal potassium secretion (amiloride, triamterene, spironolactone, eplerenone, NSAIDs, ACE inhibitors, ARBs) or block cellular potassium uptake (beta-blockers). Other causes include acidemic states, and any type of cellular destruction causing release of intracellular contents, such as hemolysis and rhabdomyolysis.
Treatment of acute hyperkalemia is discussed in Chapter 21 (see Table 21–6). Cardiac monitoring is indicated for any ECG changes seen with hyperkalemia or a serum potassium level > 6.0–6.5 mEq/L. Chronic hyperkalemia is best treated with dietary potassium restriction (2 g/d) and minimization or elimination of any medications that may impair renal potassium excretion, as noted above. Loop diuretics may also be administered for their kaliuretic effect as long as the patient is not volume-depleted.
Damaged kidneys are unable to excrete the 1 mEq/kg/d of acid generated by metabolism of dietary animal proteins in the typical Western diet. The resultant metabolic acidosis is primarily due to loss of renal mass; distal tubular defects may contribute to or worsen the acidosis. Excess hydrogen ions are buffered by the large bone stores of calcium carbonate and calcium phosphate. This results in leaching of calcium and phosphorus from the bone and contributes to the metabolic bone disease described above and to growth retardation in children with CKD. Chronic acidosis can also result in muscle protein catabolism. The serum bicarbonate level should be maintained at > 21 mEq/L. The most commonly used therapy is oral sodium bicarbonate in doses of 0.5–1.0 mEq/kg/d divided twice daily and titrated as needed. Citrate salts increase the absorption of dietary aluminum and should be avoided in CKD.
Uremic encephalopathy, resulting from the aggregation of uremic toxins, does not occur until GFR falls below 5–10 mL/min/1.73 m2. Symptoms begin with difficulty in concentrating and can progress to lethargy, confusion, seizure, and coma. Physical findings may include altered mental status, weakness, and asterixis. These findings improve with dialysis.
Other neurologic complications, which can manifest with advanced CKD include peripheral neuropathies (stocking-glove or isolated mononeuropathies), erectile dysfunction, autonomic dysfunction, and restless leg syndrome. These may not improve with dialysis therapy.
There is risk of hypoglycemia in treated diabetic patients with advanced CKD due to decreased renal elimination of insulin. Doses of oral hypoglycemics and insulin may need reduction. Metformin is associated with risk of lactic acidosis when the GFR is < 50 mL/min/1.73 m2 and should be discontinued at this point.
Decreased libido and erectile dysfunction are common in advanced CKD. Men have decreased testosterone levels; women are often anovulatory. Women with serum creatinine < 1.4 mg/dL are not at increased risk for poor outcomes in pregnancy; however, those with serum creatinine > 1.4 mg/dL may experience faster progression of CKD with pregnancy. Fetal survival is not compromised, however, unless CKD is advanced. Despite a high degree of infertility in patients with ESRD, pregnancy can occur in this setting; however, fetal mortality approaches 50%, and babies who survive are often premature. In female patients with ESRD, renal transplantation with a well-functioning allograft affords the best chances for a successful pregnancy.
Treatment of the underlying cause of CKD is vital. Control of diabetes should be aggressive in early CKD; risk of hypoglycemia increases in advanced CKD, and glycemic targets may need to be relaxed to avoid this dangerous complication. Blood pressure control is vital to slow progression of all forms of CKD; agents that block the renin-angiotensin-aldosterone system are particularly important in proteinuric disease (see section on hypertension regarding blood pressure goals). Several small studies suggest a possible benefit of oral alkali therapy in slowing CKD progression when acidemia is present; there is also theoretic value in lowering uric acid levels in those with concomitant hyperuricemia, but clinical data are lacking. Obese patients should be encouraged to lose weight. Management of traditional cardiovascular risk factors should also be emphasized.
Patients with CKD should be evaluated by a renal nutritionist. Specific recommendations should be made concerning protein, salt, water, potassium, and phosphorus intake to help manage CKD progression and complications.
1. Protein restriction—Protein restriction to 0.6–0.8 g/kg/d may retard CKD progression and is likely not harmful in the otherwise well-nourished patient; it is not advisable in those with cachexia or low serum albumin in the absence of the nephrotic syndrome.
2. Salt and water restriction—In advanced CKD, the kidney is unable to adapt to large changes in sodium intake. Intake > 3–4 g/d can lead to hypertension and volume overload, whereas intake of < 1 g/d can lead to volume depletion and hypotension. A goal of 2 g/d of sodium is reasonable for most patients. Daily fluid restriction to 2 L may be needed if volume overload is present.
3. Potassium restriction—Restriction is needed once the GFR has fallen below 10–20 mL/min/1.73 m2, or earlier if the patient is hyperkalemic. Patients should receive detailed lists describing potassium content of foods and should limit their intake to < 50–60 mEq/d (2 g).
4. Phosphorus restriction—The phosphorus level should be kept in the “normal” range (< 4.5 mg/dL) predialysis, and between 3.5 and 5.5 mg/dL in ESRD, with a dietary restriction of 800–1000 mg/d. Foods rich in phosphorus such as cola beverages, eggs, dairy products, nuts, beans, and meat should be limited, although care must be taken to avoid protein malnutrition. Highly processed foods are often preserved with highly bioavailable phosphorus and should be avoided. Below a GFR of 20–30 mL/min/1.73 m2, dietary restriction is rarely sufficient to reach target levels, and phosphorus binders are usually required (see above).
Many drugs are excreted by the kidney; dosages should be adjusted for GFR. Insulin doses may need to be adjusted as noted above. Magnesium-containing medications, such as laxatives or antacids, should be avoided as should phosphorus-containing medicines, particularly cathartics. Morphine metabolites are active and can accrue in advanced CKD; this problem is not encountered with other opioid agents. Drugs with potential nephrotoxicity (NSAIDs, intravenous contrast, as well as others noted in the Acute Kidney Injury section) should be avoided.
When GFR declines to 5–10 mL/min/1.73 m2 (with or without overt uremic symptoms), renal replacement therapy (hemodialysis, peritoneal dialysis, or kidney transplantation) is required to sustain life. Patient education is important in understanding which mode of therapy is most suitable, as is timely preparation for treatment; therefore, referral to a nephrologist should take place in late stage 3 CKD, or when the GFR is declining rapidly. Such referral has been shown to improve mortality. Preparation for ESRD treatment requires a team approach with the involvement of dieticians, social workers, primary care clinicians, and nephrologists. For very elderly patients, or those with multiple debilitating or life-limiting comorbidities, dialysis therapy may not meaningfully prolong life, and the option of palliative care should be discussed with the patient and family. Conversely, for patients who are otherwise relatively healthy, evaluation for possible kidney transplantation should be considered prior to initiation of dialysis.
1. Dialysis—Dialysis initiation should be considered when GFR is 10 mL/min/1.73 m2. Studies suggest that the well-selected patient without overt uremic symptoms may wait to initiate dialysis until GFR is closer to 7 mL/min/1.73 m2. Other indications for dialysis, which may occur when GFR is 10–15 mL/min/1.73 m2 include (1) uremic symptoms, (2) fluid overload unresponsive to diuresis, and (3) refractory hyperkalemia.
A. HEMODIALYSIS—Vascular access for hemodialysis can be accomplished by an arteriovenous fistula (the preferred method) or prosthetic graft; creation of dialysis access should be considered well before dialysis initiation. An indwelling catheter is used when there is no useable vascular access. Because catheters confer a high risk of bloodstream infection, they should be considered a temporary measure. Native fistulas typically last longer than prosthetic grafts but require a longer time after surgical construction for maturation (6–8 weeks for a fistula versus 2 weeks for a graft). Infection, thrombosis, and aneurysm formation are complications seen more often in grafts than fistulas. Staphylococcus species are the most common cause of soft-tissue infections and bacteremia.
Treatment at a hemodialysis center occurs three times a week. Sessions last 3–5 hours depending on patient size and type of dialysis access. Other hemodialysis schedules can be considered depending on available resources and patient preferences. Home hemodialysis is often performed more frequently (3–6 days per week for shorter sessions) and requires a trained helper. Results of trials comparing quotidian modalities (nocturnal and frequent home hemodialysis) to conventional in-center dialysis have not thus far shown significant mortality differences, but there may be improvements in blood pressure control, mineral metabolism, and quality of life.
B. PERITONEAL DIALYSIS—With peritoneal dialysis, the peritoneal membrane is the “dialyzer.” Dialysate is instilled into the peritoneal cavity through an indwelling catheter; water and solutes move across the capillary bed that lies between the visceral and parietal layers of the membrane into the dialysate during a “dwell.” After equilibration, the dialysate is drained, and fresh dialysate is instilled—this is an “exchange.”
There are different kinds of peritoneal dialysis: continuous ambulatory peritoneal dialysis (CAPD), in which the patient exchanges the dialysate four to six times a day manually; continuous cyclic peritoneal dialysis (CCPD), which utilizes a cycler machine to automatically perform exchanges at night.
Peritoneal dialysis permits significant patient autonomy. Its continuous nature minimizes the symptomatic volume and electrolyte shifts observed in hemodialysis patients, and poorly dialyzable compounds (such as phosphates) are better cleared, which permits less dietary restriction. However, peritoneal dialysate removes large amounts of albumin, and nutritional status must be closely watched.
The most common complication of peritoneal dialysis is peritonitis. Peritonitis may present with nausea and vomiting, abdominal pain, diarrhea or constipation, and fever. The dialysate is usually cloudy; and a diagnostic peritoneal fluid cell count is > 100 white blood cells/mcL of which over 50% are polymorphonuclear neutrophils. Staphylococcus aureus is the most common infecting organism, but streptococci and gram-negative species are also common.
2. Kidney transplantation—Up to 50% of all patients with ESRD are otherwise healthy enough to be suitable for transplantation, although standard criteria for recipient selection are lacking between transplant centers. Older age is becoming less of a barrier, as long as reasonable life expectancy is anticipated. Two-thirds of kidney allografts come from deceased donors, with the remainder from living related or unrelated donors. About 99,000 patients are on the waiting list for a deceased donor transplant in the United States; the average wait is 2–6 years, depending on geographic location and recipient blood type.
The 1- and 5-year kidney graft survival rates are approximately 97% and 85%, respectively, for living donor transplants and 91% and 71%, respectively, for deceased donor transplants.
Immunosuppressive regimens to prevent allograft rejection generally include a combination of a corticosteroid, an antimetabolite (azathioprine or mycophenolate mofetil), and a calcineurin inhibitor (tacrolimus or cyclosporine) or mTor inhibitor (sirolimus). Maintenance doses must balance the risk of allograft rejection as well as the adverse effects of immunosuppressives, including the development of certain cancers, infections, new onset diabetes, and chronic allograft dysfunction (calcineurin inhibitor). Additionally, calcineurin inhibitors have a narrow therapeutic window, and their hepatic metabolism is affected by many drugs (especially azoles and calcium channel blockers). Any changes in the transplant recipient’s medical regimen should, therefore, occur only after consultation with a trained pharmacist or transplant nephrologist. Transplant recipients are at higher risk for CVD than the general population.
3. Medical management of ESRD—As noted above, some patients are not candidates for transplantation and may not benefit from dialysis. Studies suggest that very elderly persons who do not die soon after dialysis initiation rapidly lose functional status in the first year of treatment. The decision to initiate dialysis in patients with limited life expectancy should be weighed against possible deleterious changes in quality of life. For patients with ESRD who elect not to undergo dialysis, death occurs within days to months. In general, uremia develops and patients lose consciousness prior to death. Arrhythmias can occur as a result of electrolyte imbalance. Volume overload and dyspnea can be managed by volume restriction and opioids as described in Chapter 5. Involvement of a palliative care team is essential.
Compared with kidney transplant recipients and age-matched controls, mortality is higher for patients undergoing dialysis. There is likely little difference in survival for well-matched peritoneal versus hemodialysis patients.
Survival rates on dialysis depend on the underlying disease process. Five-year Kaplan-Meier survival rates vary from 36% for patients with diabetes to 53% for patients with glomerulonephritis. Overall 5-year survival is currently estimated at 39%. Patients undergoing dialysis have an average life-expectancy of 3–5 years, but survival for as long as 25 years may be achieved depending on comorbidities. The most common cause of death is cardiac disease (> 50%). Other causes include infection, cerebrovascular disease, and malignancy. Diabetes, advanced age, a low serum albumin, lower socioeconomic status, and inadequate dialysis are all significant predictors of mortality; high fibroblast growth factor (FGF)-23 levels have emerged as a novel marker for mortality in ESRD.
• A patient with stage 3–5 CKD should be referred to a nephrologist for management in conjunction with the primary care provider.
• A patient with other forms of CKD such as those with significant proteinuria (> 1 g/d) or polycystic kidney disease should be referred to a nephrologist at earlier stages.
• Admission should be considered for patients with decompensation of problems related to CKD, such as worsening of acid-base status, electrolyte abnormalities, and volume status that cannot be appropriately treated in the outpatient setting.
• Admission is appropriate when a patient needs to start dialysis and is not stable for outpatient initiation.
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Gansevoort RT et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013 Jul 27;382(9889):339–52. [PMID: 23727170]
James PA et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507–20. [PMID: 24352797]
Kovesdy CP et al. Blood pressure and mortality in U.S. veterans with chronic kidney disease: a cohort study. Ann Intern Med. 2013 Aug 20;159(4):233–42. [PMID: 24026256]
Levey AS et al. Chronic kidney disease. Lancet. 2012 Jan 14;379(9811):165–80. [PMID: 21840587]
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Qaseem A et al. Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2013 Dec 17;159(12):835–47. [PMID: 24145991]
Thiruchelvam PT et al. Renal transplantation. BMJ. 2011 Nov 14;343:d7300. [PMID: 22084316]
Turner JM et al. Treatment of chronic kidney disease. Kidney Int. 2012 Feb;81(4):351–62. [PMID: 22166846]
ESSENTIALS OF DIAGNOSIS
Produced by atherosclerotic occlusive disease (80–90% of patients) or fibromuscular dysplasia (10–15%).
Acute kidney injury in patients starting ACE inhibitor therapy.
Atherosclerotic ischemic renal disease accounts for nearly all cases of renal artery stenosis. Fibromuscular dysplasia is a rare cause of renal artery stenosis. Approximately 5% of Americans with hypertension suffer from renal artery stenosis. It occurs most commonly in those over 45 years of age with a history of atherosclerotic disease. Other risk factors include CKD, diabetes mellitus, tobacco use, and hypertension.
Patients with atherosclerotic ischemic renal disease may have refractory hypertension, new-onset hypertension (in an older patient), pulmonary edema with poorly controlled blood pressure, and acute kidney injury upon starting an ACE inhibitor. In addition to hypertension, physical examination may reveal an audible abdominal bruit on the affected side. Fibromuscular dysplasia primarily affects young women. Unexplained hypertension in a woman younger than 40 years is reason to screen for this disorder.
Laboratory values can show elevated BUN and serum creatinine levels in the setting of significant renal ischemia.
Abdominal ultrasound can reveal asymmetric kidney size when one renal artery is affected out of proportion to the other or small hyperechoic kidneys if both are affected.
Three prevailing methods used for screening are Doppler ultrasonography, CT angiography, and magnetic resonance angiography (MRA). Doppler ultrasonography is highly sensitive and specific (> 90% with an experienced ultrasonographer) and relatively inexpensive. However, this method is extremely operator and patient dependent. Measurements of blood flow must be made at the aorta and along each third of the renal artery in order to assess the disease. This test is a poor choice for patients who are obese, unable to lie supine, or have interfering bowel gas patterns.
CT angiography consists of intravenous digital subtraction angiography with arteriography and is a noninvasive procedure. The procedure uses a spiral (helical) CT scan with intravenous contrast injection. The sensitivities from various studies range from 77% to 98%, with less varying specificities in a range of 90–94%.
MRA is an excellent but expensive way to screen for renal artery stenosis, particularly in those with atherosclerotic disease. Sensitivity is 77–100%, although one study with particular flaws showed a sensitivity of only 62%. Specificity ranges from 71% to 96%. Turbulent blood flow can cause false-positive results. The imaging agent for MRA (gadolinium) has been associated with nephrogenic systemic fibrosis, which occurs primarily in patients with a GFR of < 15 mL/min/1.73 m2, and rarely in patients with a GFR of 15–30 mL/min/1.73 m2. It has also been seen in those with acute kidney injury and kidney transplants.
Renal angiography is the gold standard for diagnosis. CO2 subtraction angiography can be used in place of dye when the risk of dye nephropathy exists—eg, in diabetic patients with kidney injury. Lesions are most commonly found in the proximal third or ostial region of the renal artery. The risk of atheroembolic phenomena after angiography ranges from 5% to 10%. Fibromuscular dysplasia has a characteristic “beads-on-a-string” appearance on angiography.
Treatment of atherosclerotic ischemic renal disease is controversial. Options include medical management, angioplasty with or without stenting, and surgical bypass. Two large randomized trials have shown that vascular intervention is no better than optimal medical management in typical patients with renal artery stenosis. Angioplasty might reduce the number of antihypertensive medications but does not significantly change the progression of kidney dysfunction in comparison to patients medically managed. Stenting produces significantly better angioplastic results. However, blood pressure and serum creatinines are similar at 6 months of observation compared with both angioplasty and stents. Angioplasty is equally as effective as, and safer than, surgical revision.
Treatment of fibromuscular dysplasia with percutaneous transluminal angioplasty is often curative, which is in stark contrast to treatment for atherosclerotic causes.
Boateng FK et al. Renal artery stenosis: prevalence of, risk factors for, and management of in-stent stenosis. Am J Kidney Dis. 2013 Jan;61(1):147–60. [PMID: 23122491]
Cooper CJ et al; CORAL Investigators. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014 Jan 2;370(1):13–22. [PMID: 24245566]
Textor SC et al. Renovascular hypertension and ischemic nephropathy. Am J Hypertens. 2010 Nov;23(11):1159–69. [PMID: 20864945]
Abnormalities of glomerular function can be caused by damage to the major components of the glomerulus: the epithelium (podocytes), basement membrane, capillary endothelium, or mesangium. The damage may be caused by overwork injury, such as in CKD; by an inflammatory process, such as SLE; by a podocyte protein mutation, such as in hereditary focal and segmental glomerulosclerosis; or a deposition disease, such as diabetes or amyloidosis. A specific histologic pattern of glomerular injury results from this damage and can be seen on kidney biopsy.
Clinically, a glomerular disease can be classified as being in one of two spectra—either in the nephritic spectrum or the nephrotic spectrum (Figure 22–4). In the “least severe” end of the nephritic spectrum, the findings of glomerular hematuria (ie, dysmorphic red blood cells with some degree of proteinuria) are characteristic. The nephritic syndrome, comprising glomerular hematuria, subnephrotic proteinuria (<3 g/d), edema, and elevated creatinine, falls in the mid-portion of the spectrum. The rapidly progressive glomerulonephridities (RPGNs) are at the “most severe” and clinically urgent end of the nephritic spectrum.
Figure 22–4. Glomerular diseases present within one of the clinical spectra shown, the exact presentation is determined by the severity of the underlying disease and the pattern of injury. Nephritic diseases are characterized by the presence of an active urine sediment with glomerular hematuria and often with proteinuria. Nephrotic spectrum diseases are proteinuric with bland urine sediments (no cells or cellular casts). All glomerular diseases may progress to a chronic, scarred state. (Adapted, with permission, from Megan Troxell, MD, PhD.)
The nephrotic spectrum comprises diseases that present with primarily proteinuria of at least 0.5–1 g/d and a bland urine sediment (no cells or cellular casts). The more severe end of the nephrotic spectrum comprises the nephrotic syndrome, which is characterized by the constellation of nephrotic-range proteinuria of > 3 g/d, hypoalbuminuria, edema, and hyperlipidemia. Differentiating between a clinical presentation within the nephritic spectrum versus the nephrotic spectrum is important because it helps narrow the differential diagnosis of the underlying glomerular disease (Tables 22–8 and 22–9).
Table 22–8. Classification and findings in glomerulonephritis: Nephritic spectrum presentations.
Table 22–9. Classification and findings in glomerulonephritis: Nephrotic spectrum presentations.
Glomerular diseases can also be classified according to whether they cause only renal abnormalities (primary renal disease) or whether the renal abnormalities result from a systemic disease (secondary renal disease).
Further evaluation prior to kidney biopsy may include serologic testing for systemic diseases that can result in glomerular damage (Figure 22–5).
Cattran D. KDIGO clinical practice guideline for glomerulonephritis. Chapter 2: general principles in the management of glomerular disease. 2012 Dec;(Suppl 2):156–62.http://www.kdigo.org/clinical_practice_guidelines/GN.php
Haas M et al. Histologic classification of glomerular diseases: clinicopathologic correlations, limitations exposed by validation studies, and suggestions for modification. Kidney Int. 2013 Oct 2. [Epub ahead of print] [PMID: 24088958]
Hogan J et al. Diagnostic tests and treatment options in glomerular disease: 2014 update. Am J Kidney Dis. 2013 Nov 14. [Epub ahead of print] [PMID: 242390510]
ESSENTIALS OF DIAGNOSIS
Glomerular hematuria (dysmorphic red blood cells), modest proteinuria (usually 0.3–3 g/d).
Red blood cell casts may be present if glomerular bleeding is heavy.
Nephritic syndrome in more severe/inflammatory cases:
–Glomerular hematuria and proteinuria.
–Rising creatinine over days to months.
Rapidly progressive glomerulonephritis in most severe cases:
-Glomerular hematuria and proteinuria.
-Hypertension and edema uncommon.
-Rising creatinine over days to months.
Glomerulonephritis is a term given to those diseases that present in the nephritic spectrum and usually signifies an inflammatory process causing renal dysfunction. It can be acute, developing over days to weeks, with or without resolution, or may be more chronic and indolent with progressive scarring. As noted above, diseases that cause a nephritic spectrum presentation may present with glomerular hematuria with some proteinuria, with nephritic syndrome, or with RPGN (Figure 22–4). The presentation depends on the severity of the underlying inflammation and the pattern of injury caused by the disease process.
If the nephritic syndrome is present, edema is first seen in regions of low tissue pressure such as the periorbital and scrotal areas. Hypertension in the nephritic syndrome is due to sodium retention resulting from acute decrease in GFR. Heavy glomerular bleeding from inflammation may result in gross hematuria (smoky or cola-colored urine).
1. Serologic testing—Serologic tests, including complement levels, antinuclear antibodies, cryoglobulins, hepatitis serologies, ANCAs, anti-GBM antibodies, and antistreptolysin O (ASO) titers (Figure 22–5), are done based on the history and physical examination to narrow the differential diagnosis of the nephritic spectrum disorder.
Figure 22–5. Serologic analysis of patients with glomerulonephritis. MPGN, membranoproliferative glomerulonephritis. (Modified, with permission, from Greenberg A et al. Primer on Kidney Diseases. Academic Press, 1994 and Jennette JC, Falk RJ. Diagnosis and management of glomerulonephritis and vasculitis presenting as acute renal failure. Med Clin North Am. 1990;74(4):893–908. © Elsevier.)
2. Urinalysis—The urine dipstick is positive for protein and blood. Urinary microscopy reveals red blood cells that are misshapen or dysmorphic from traversing a damaged glomerular filtration barrier. Red blood cell casts are seen with heavy glomerular bleeding and tubular stasis. When quantified, proteinuria is usually subnephrotic (< 3 g/d).
3. Biopsy—Kidney biopsy should be considered if there are no contraindications (eg, bleeding disorders, thrombocytopenia, uncontrolled hypertension). Important morphologic information is gleaned from light, electron, and immunofluorescent microscopy.
General measures for all include treatment of hypertension and of fluid overload if present. Antiproteinuric therapy with an ACE inhibitor or ARB should be considered for those without acute kidney injury. For those with profound acute kidney injury, dialysis may be needed. The inflammatory glomerular injury may require immunosuppressant agents (see specific diseases discussed below).
Any patient in whom a glomerulonephritis is suspected should be referred to a nephrologist.
Any suspicion of acute nephritic syndrome or RPGN warrants consideration of immediate hospitalization.
ESSENTIALS OF DIAGNOSIS
Symptoms 1–3 weeks after infection (often pharyngitis or impetigo).
Postinfectious glomerulonephritis is most often due to infection with nephritogenic group A beta-hemolytic streptococci. It can occur sporadically or in clusters and during epidemics. It commonly appears after pharyngitis or impetigo with onset 1–3 weeks after infection (average 7–10 days).
Other infections have been associated with postinfectious glomerulonephritis including bacteremic states (especially with S aureus), bacterial pneumonias, deep-seated abscesses, gram-negative infections, infective endocarditis, and shunt infections. Viral, fungal, and parasitic causes of postinfectious glomerulonephritis pattern of glomerular injury include hepatitis B or C, HIV, cytomegalovirus infection, infectious mononucleosis, coccidioidomycosis, malaria, mycobacteria, syphilis, and toxoplasmosis.
Disease presentation can vary widely across the nephritic spectrum from asymptomatic glomerular hematuria (especially in epidemic cases) to nephritic syndrome with hypertension, oliguria, edema, and perhaps gross glomerular hematuria (smokey-colored urine).
Serum complement levels are low; in postinfectious glomerulonephritis due to group A streptococcal infection, anti-streptolysin O (ASO) titers can be high unless the immune response has been blunted with previous antibiotic treatment. Glomerular hematuria and subnephrotic proteinuria are present; severe cases may demonstrate elevated serum creatinine and urinary red blood cell casts. Kidney biopsy shows a diffuse proliferative pattern of injury on light microscopy. Immunofluorescence demonstrates granular deposition of IgG and C3 in the mesangium and along the capillary basement membrane. Electron microscopy shows large, dense subepithelial deposits or “humps.”
The underlying infection should be identified and treated appropriately; otherwise, treatment for postinfectious glomerulonephritis is supportive. Antihypertensives, salt restriction, and diuretics should be used if needed. Corticosteroids have not been shown to improve outcome. Prognosis depends on the severity of the glomerular injury and age of the patient. Children are more likely to fully recover; adults are more prone to the development of severe disease (RPGN with crescent formation) and CKD.
Cattran D et al. KDIGO clinical practice guideline for glomerulonephritis. Chapter 9: infection-related glomerulonephritis. Kidney Int. 2012 Dec;(Suppl 2):200–8.http://www.kdigo.org/clinical_practice_guidelines/GN.php
Nasr SH et al. Bacterial infection-related glomerulonephritis in adults. Kidney Int. 2013 May;83(5):792–803. [PMID: 23302723]
ESSENTIALS OF DIAGNOSIS
Proteinuria: minimal to nephrotic range.
Glomerular hematuria: microscopic is common; macroscopic (gross) after infection.
Positive IgA staining on kidney biopsy.
IgA nephropathy (Berger disease) is a primary renal disease of IgA deposition in the glomerular mesangium. The inciting cause is unknown but is likely due to deficient O-linked glycosylation of IgA subclass 1 molecules. IgA nephropathy can be a primary (renal-limited) disease, or it can be secondary to hepatic cirrhosis, celiac disease, and infections such as HIV and cytomegalovirus. Susceptibility to IgA nephropathy seems to be inheritable.
IgA nephropathy is the most common primary glomerular disease worldwide, particularly in Asia. It is most commonly seen in children and young adults, with males affected two to three times more commonly than females.
An episode of gross hematuria is the most common presenting symptom. Frequently, this is associated with a mucosal viral infection such as an upper respiratory infection. The urine becomes red or smokey-colored 1–2 days after illness onset—a so-called “synpharyngitic” presentation in contradistinction to the latent period seen in postinfectious glomerulonephritis. IgA nephropathy can present anywhere along the nephritic spectrum from asymptomatic microscopic hematuria to RPGN. Rarely, nephrotic syndrome can be present as well.
There are no serologic tests that aid in this diagnosis; serum IgA subclass 1 testing may be a possibility in the future. Serum complements are normal. The typical pattern of injury seen on kidney biopsy is a focal glomerulonephritis with mesangial proliferation; immunofluorescence demonstrates diffuse mesangial IgA and C3 deposits.
The disease course of primary IgA nephrology varies widely among patients; treatment approach needs to be tailored to risk for progression. Patients with low risk for progression (no hypertension, normal GFR, minimal proteinuria) can be monitored annually. Patients at higher risk (proteinuria > 1.0 g/d, decreased GFR, or hypertension or any combination of these three conditions) should be treated with an ACE inhibitor or ARB. Therapy should be titrated to reduce proteinuria to < 1 g/d and to control blood pressure in the range of 125/75 mm Hg to 130/80 mm Hg. Corticosteroids may be beneficial in patients with GFR > 50 mL/min/1.73 m2 and persistent proteinuria > 1 g/d despite a 3- to 6-month trial of an ACE inhibitor or ARB. One such regimen (methylprednisolone, 1 g/d intravenously for 3 days during months 1, 3, and 5, plus prednisone in a dosage of 0.5 mg/kg orally every other day for 6 months) showed a 2% doubling of creatinine after 6 years in the treatment group versus a 21% doubling of creatinine in the control group. For the rare patient with IgA neuropathy and a rapidly progressive clinical course with crescent formation on biopsy, cyclophosphamide and corticosteroid therapy should be considered (see section on ANCA-associated vasculitis below). Kidney transplantation is an excellent option for patients with ESRD, but recurrent disease has been documented in 30% of patients 5–10 years post-transplant. Fortunately, recurrent disease rarely leads to failure of the allograft.
Approximately one-third of patients experience spontaneous clinical remission. Progression to ESRD occurs in 20–40% of patients. The remaining patients have chronic microscopic hematuria and a stable serum creatinine. The most unfavorable prognostic indicator is proteinuria > 1 g/d; other unfavorable prognostic indicators include hypertension, tubulointerstitial fibrosis, glomerulosclerosis, or glomerular crescents on biopsy, and abnormal GFR on presentation.
Beck L et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013 Sep;62(3):421–24. [PMID: 23871408]
Wyatt RJ et al. IgA nephropathy. N Engl J Med. 2013 Jun 20;368(25):2402–14. [PMID: 23782179]
Henoch-Schönlein purpura is a systemic small-vessel leukocytoclastic vasculitis associated with IgA subclass 1 deposition in vessel walls. It is most common in children and is often associated with an inciting infection, such as group A streptococcus or other exposure. There is a male predominance. It classically presents with palpable purpura in the lower extremities and buttock area; arthralgias; and abdominal symptoms, such as nausea, colic, and melena. A decrease in GFR is common with a nephritic presentation. The renal lesions can be identical to those found in IgA nephropathy, and the underlying pathophysiology appears to be similar. Most patients with microscopic hematuria and minimal proteinuria recover fully over several weeks. Progressive CKD and possibly ESRD are more likely to develop in those with the nephrotic syndrome and the presence of both nephritic and nephrotic syndrome poses the worst renal prognosis. Histologic classification of the lesions in children may also provide prognostic information. To date, although several treatment regimens of various immunosuppressive agents have been clinically tested, none have been definitively proven to alter the course of severe Henoch-Schönlein purpura nephritis. Rituximab treatment and plasma exchange have been successful for severe disease according to several case reports, but clinical trials are lacking. Rapidly progressive disease with crescent formation on biopsy may be treated as in ANCA-associated vasculitis (see section below).
Further details about Henoch-Schönlein purpura are provided in Chapter 20.
Beck L et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013 Sep;62(3):424–25. [PMID: 23871408]
Pauci-immune necrotizing glomerulonephritis is caused by the following systemic ANCA-associated small-vessel vasculitides: granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), microscopic polyangiitis, and Churg-Strauss disease (see Chapter 20). ANCA-associated glomerulonephritis can also present as a primary renal lesion without systemic involvement; this is termed “idiopathic crescentic glomerulonephritis.” The pathogenesis of these entities appears to involve cytokine-primed neutrophils presenting cytoplasmic antigens on their surfaces (proteinase 3 and myeloperoxidase). Circulating ANCAs then bind to these antigens and activate a neutrophil respiratory burst with consequent vascular damage. Putative environmental exposures that may encite the initial response include S aureus and silica. Immunofluorescence of kidney biopsy specimens do not reveal any evidence of immunoglobulin or complement deposition, hence the term “pauci-immune.” Renal involvement classically presents as an RPGN, but more indolent presentations can be seen as well.
Symptoms of a systemic inflammatory disease, including fever, malaise, and weight loss may be present and usually precede initial presentation by several months. In addition to hematuria and proteinuria from glomerular inflammation, some patients exhibit purpura from dermal capillary involvement and mononeuritis multiplex from nerve arteriolar involvement. Ninety percent of patients with granulomatosis with polyangiitis have upper (especially sinus) or lower respiratory tract symptoms with nodular lesions that can cavitate and bleed. Hemoptysis is a concerning sign and usually warrants hospitalization and aggressive immunosuppression.
Serologically, ANCA subtype analysis is done to determine whether antiproteinase-3 antibodies (PR3-ANCA) or antimyeloperoxidase antibodies (MPO-ANCA) are present. Most patients with granulomatosis with polyangiitis are PR3 positive; the remainder are MPO positive or, more rarely, do not demonstrate ANCA serologically. Microscopic angiitis is generally associated with MPO ANCA. Renal biopsy demonstrates necrotizing lesions and crescents on light microscopy; immunofluorescence is negative for immune complex deposition.
Treatment should be instituted early if aggressive disease is present. Induction therapy of high-dose corticosteroids (methylprednisolone, 1–2 g/d intravenously for 3 days, followed by prednisone, 1 mg/kg orally for 1 month, with a slow taper over the next 6 months) and cytotoxic agents (cyclophosphamide, 0.5–1 g/m2 intravenously per month or 1.5–2 mg/kg orally for 3–6 months) is followed by long-term azathioprine or mycophenolate mofetil. Rituximab has been shown to be noninferior to cyclophosphamide for induction. Plasma exchange has been shown to be beneficial in conjunction with induction therapy; however, a 2011 meta-analysis calls into question the strength of this benefit. Patients receiving cyclophosphamide should receive prophylaxis for Pneumocystis jirovecii, such as trimethoprim-sulfamethoxazole double-strength orally 3 days per week.
Without treatment, prognosis is extremely poor. However, with aggressive treatment, complete remission can be achieved in about 75% of patients. Prognosis depends on the extent of renal involvement before treatment is started and may be worse in those with PR3-associated disease. ANCA titers may be monitored to follow treatment efficacy; rising titers may herald relapse.
Beck L et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013 Sep;62(3):429–33. [PMID: 23871408]
Kallenberg CG et al. Pathogenesis of ANCA-associated vasculitis: new possibilities for intervention. Am J Kidney Dis. 2013 Dec;62(6):1176–87. [PMID: 23810690]
Sinico RA et al. Renal involvement in anti-neutrophil cytoplasmic autoantibody associated vasculitis. Autoimmun Rev. 2013 Feb;12(4):477–82. [PMID: 22921791]
Tesar V et al. ANCA-associated renal vasculitis—an update. Contrib Nephrol. 2013;181:216–28. [PMID: 23689583]
Goodpasture syndrome is defined by the clinical constellation of glomerulonephritis and pulmonary hemorrhage; injury to both is mediated by antibodies to epitopes in the GBM (Figure 22–5). Up to one-third of patients with anti-GBM glomerulonephritis have no evidence of concomitant lung injury (anti-GBM disease). Anti-GBM–associated glomerulonephritis accounts for 10–20% of patients with acute RPGN. The incidence peaks in the second and third decades of life during which time males are predominantly affected and lung involvement is more common, and again in the sixth and seventh decades with less gender predominance. Lung involvement has been associated with pulmonary infection, tobacco use, and hydrocarbon solvent exposure; HLA-DR2 and -B7 antigens may predispose as well.
The onset of disease may be preceded by an upper respiratory tract infection; hemoptysis, dyspnea, and possible respiratory failure may ensue. Other findings are consistent with an RPGN, although some cases may present with much milder forms of the nephritic spectrum of disease (eg, glomerular hematuria and proteinuria with minimal renal dysfunction).
Chest radiographs may demonstrate pulmonary infiltrates if pulmonary hemorrhage is present. Serum complement levels are normal. Circulating anti-GBM antibodies are present in over 90% of patients. A small percentage of patients also have elevated ANCA titers; these patients should be treated with plasma exchange as for anti-GBM disease. Kidney biopsy typically shows crescent formation on light microscopy, with linear IgG staining along the GBM on immunofluorescence.
Treatment is a combination of plasma exchange therapy to remove circulating antibodies, and administration of immunosuppressive drugs to prevent formation of new antibodies and control the inflammatory response. Corticosteroids are typically given initially in pulse doses of methylprednisolone, 1–2 g/d for 3 days, then prednisone orally 1 mg/kg/d. Cyclophosphamide is administered intravenously at a dose of 0.5–1 g/m2 per month or orally at a dosage of 2–3 mg/kg/d. Daily plasma exchange is performed for up to 2 weeks. Patients with oliguria and a serum creatinine > 6–7 mg/dL, or who require dialysis upon presentation have a poor prognosis. Anti-GBM antibody titers should decrease as the clinical course improves.
Beck L et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013 Sep;62(3):433–34. [PMID: 23871408]
Dammacco F et al. Goodpasture’s disease: a report of ten cases and a review of the literature. Autoimmun Rev. 2013 Sep;12(11):1101–8. [PMID: 23806563]
Essential (mixed) cryoglobulinemia is a vasculitis associated with cold-precipitable immunoglobulins (cryoglobulins). The most common underlying etiology is HCV infection; in these cases, there is clonal expansion of B lymphocytes, which produce IgM rheumatoid factor. Rheumatoid factor, HCV antigen and polyclonal anti-HCV IgG form complexes that deposit in vessels and incite inflammation. Other overt or occult infections (eg, viral, bacterial, and fungal) as well as some connective tissue diseases can also be causative.
Patients exhibit purpuric and necrotizing skin lesions in dependent areas, arthralgias, fever, and hepatosplenomegaly. Serum complement levels are depressed. Rheumatoid factor is often elevated when cryoglobulins are present. Kidney biopsy may show several different patterns of injury; there may be crescent formation, glomerular capillary thrombi, or MPGN (see below). Treatment consists of aggressively targeting the causative infection. Pulse corticosteroids, plasma exchange, rituximab and cytotoxic agents have been used when risk of exacerbating the underlying infection is resolved, or when no infection is present. See also section on Hepatitis C Virus–Associated Renal Disease.
De Vita S et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum. 2012 Mar;64(3):843–53. [PMID: 22147661]
Terrier B et al. Cryoglobulinemia vasculitis: an update. Curr Opin Rheumatol. 2013 Jan;25(1):10–8. [PMID: 23196322]
MPGN is a relatively rare pattern of glomerular injury that can be caused by a wide range of known etiologies or can be idiopathic. Clinically, it can present anywhere along the nephritic spectrum from asymptomatic glomerular hematuria to acute nephritic syndrome with bouts of gross hematuria, to RPGN; nephrotic syndrome can also be seen. Traditionally, MPGN has been classified into several histologic subtypes; this classification is now in evolution. Type I is relatively more common and can be idiopathic (especially in children and young adults) or secondary to chronic infection (most commonly HCV), a paraproteinemia, or an underlying autoimmune disease such as lupus. The pathogenesis is likely a chronic antigenemia leading to classical complement pathway activation with immune complex deposition; however, it is now recognized that some cases may result from alternative complement pathway dysregulation. Type II MPGN is caused by several inherited or acquired abnormalities in the alternative complement pathway. Both types result in low circulating C3 complement; immune complex type I also has low C4. Light microscopy of both types shows varying degrees of mesangial hypercellularity, endocapillary proliferation and capillary wall remodeling resulting in double contours of the GBM (“tram track” appearance). Immunofluorescence and electron microscopy provide distinguishing information. Type II MPGN reveals C3 deposition without immunoglobulin staining on immunofluorescence, and electron microscopy demonstrates thick ribbon-like electron dense deposits along the GBM; thus, type II disease is also known as “dense deposit disease.” Conversely, type I MPGN has scattered subendothelial and subepithelial deposits on electron microscopy. When there is immunoglobulin and C3 staining on immunofluorescence in type I MPGN, it is also called immune complex MPGN (more common type); when a type I case demonstrates only C3 staining on immunofluorescence, it is now termed C3 glomerulonephritis (C3 GN). Together, dense deposit disease (type II) and C3 GN are now termed “C3 glomerulopathies”; both result from inherited or acquired alternative complement dysregulation/activation.
Treatment of type I immune complex MPGN should be directed at the underlying cause, if such is found. Treatment of idiopathic immune complex disease is controversial and controlled trial data are lacking. For those with nephrotic syndrome and declining GFR, a combination of oral cyclophosphamide or mycophenolate mofetil plus corticosteroids could be considered; patients with RPGN and crescents on biopsy may be treated the same as those with ANCA-associated disease provided secondary causes have been ruled out. Despite therapy, most will progress to ESRD. Treatment for the C3 glomerulopathies is in evolution as novel therapies to target the dysregulated alternative complement cascade are being explored. Less favorable prognostic findings include type II/dense deposit disease, early decline in GFR, hypertension, and persistent nephrotic syndrome. All types of MPGN recur with high frequency after renal transplantation; however, type II recurs more commonly. Plasma exchange has been used with mixed results to treat posttransplant recurrence of MPGN.
Appel GB. Membranoproliferative glomerulonephritis—mechanisms and treatment. Contrib Nephrol. 2013;181:163–74. [PMID: 23689578]
Beck L et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013 Sep;62(3):417–19. [PMID: 23871408]
Bomback AS et al. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat Rev Nephrol. 2012 Nov;8(11):634–42. [PMID: 23026947]
Renal disease can occur in the setting of HCV infection. The three patterns of renal injury associated with HCV are secondary MPGN (type I disease), cryoglobulinemic glomerulonephritis, and membranous nephropathy—the former is the most common lesion seen. The clinical presentation is dictated by the underlying pattern of injury. Many patients have elevated serum transaminases and an elevated rheumatoid factor. Hypocomplementemia is very common, with C4 typically more reduced than C3; complement levels and rheumatoid factor tend to be normal if there is a membranous pattern of injury.
In patients with HCV–associated MPGN not receiving treatment for liver disease, the main indications for therapy are poor renal function, nephrotic syndrome, new or worsening hypertension, tubulointerstitial disease on biopsy, and progressive disease. IFN-alpha may result in suppression of viremia and improvement in hepatic function. Renal function rarely improves unless viral suppression occurs, and renal function often worsens when therapy is stopped. Ribavirin is relatively contraindicated in kidney disease because of the dose-related hemolysis that occurs with impaired GFR. Despite this, some case series have shown benefit with combined IFN-alpha and ribavirin in closely monitored settings. Early case reports suggest that addition of the newer protease inhibitors may be safe and effective for treating HCV-related renal disease. Rituximab may be considered in addition to antiviral therapy, though controlled trials are lacking.
Fabrizi F et al. Hepatitis C virus infection, mixed cryoglobulinemia, and kidney disease. Am J Kidney Dis. 2013 Apr;61(4):623–37. [PMID: 23102733]
Tang SC et al. Hepatitis C virus-associated glomerulonephritis. Contrib Nephrol. 2013;181:194–206. [PMID: 23689581]
Renal involvement in SLE is very common, with estimates ranging from 35% to 90%—the higher estimates encompassing subclinical disease. Rates of lupus nephritis are highest in non-whites. The pathogenesis may be dysregulated cellular apoptosis resulting in autoantibodies against nucleosomes; antibody/nucleosome complexes then bind to components of the glomerulus to form immune complex glomerular disease.
The term “lupus nephritis” encompasses many possible patterns of renal injury—most cases present within the nephritic spectrum (class I–IV). Nonglomerular syndromes include tubulointerstitial nephritis and vasculitis. All patients with SLE should have routine urinalyses to monitor for the appearance of hematuria or proteinuria. If urinary abnormalities are detected, kidney biopsy is often performed. The 2003 International Society of Nephrology and Renal Pathology Society (ISN/RPS) classification of renal glomerular lesions is class I, minimal mesangial nephritis; class II, mesangial proliferative nephritis; class III, focal (< 50% of glomeruli affected with capillary involvement) proliferative nephritis; class IV, diffuse (> 50% of glomeruli affected with capillary involvement) proliferative nephritis; class V, membranous nephropathy; and class VI, advanced sclerosis without residual disease activity. Classes III and IV, the most severe forms of lupus nephritis, are further classified as active or chronic, and global or segmental, which confers additional prognostic value.
Individuals with class I and class II lesions generally require no treatment; corticosteroids or calcineurin inhibitors should be considered for those with class II lesions with nephrotic-range proteinuria. Transformation of these types to a more active lesion may occur and is usually accompanied by an increase in lupus serologic activity (eg, rising titers of anti-double-stranded DNA antibodies and falling C3 and C4 levels) and increasing proteinuria or falling GFR. Repeat biopsy in such patients is recommended. Some experts recommend hydroxychloroquine treatment in all patients with lupus nephritis, regardless of histological class. Patients with extensive class III lesions and all class IV lesions should receive aggressive immunosuppressive therapy. The features signifying the poorest prognosis in patients with class III or IV lesions include elevated serum creatinine, lower complement levels, male sex, presence of antiphospholipid antibodies, nephrotic-range proteinuria, black race (possibly in association with APOL1 risk alleles), and poor response to therapy. Immunosuppressive therapy for class V lupus nephritis is indicated if superimposed proliferative lesions exist. Class VI lesions should not be treated.
Treatment of class III or IV lupus nephritis consists of induction therapy, followed by maintenance treatment. All induction therapy includes corticosteroids (eg, methylprednisolone 1 g intravenously daily for 3 days followed by prednisone, 1 mg/kg orally daily with subsequent taper over 6–12 months) in combination with either cyclophosphamide or mycophenolate mofetil. Data suggest that blacks and Hispanics respond more favorably to mycophenolate mofetil rather than cyclophosphamide; in addition, mycophenolate mofetil has a more favorable side-effect profile than cyclophosphamide and should be favored when preservation of fertility is a consideration. Mycophenolate mofetil induction is typically given at 2–3 g/d, then tapered to 1–2 g/d for maintenance. Cyclophosphamide induction regimens vary but usually involve monthly intravenous pulse doses (500–1000 mg/m2) for 6 months. Induction is followed by daily oral mycophenolate mofetil or azathioprine maintenance therapy; mycophenolate mofetil may be superior to azathioprine maintenance and causes few adverse effects. Maintenance with calcineurin inhibitors may also be considered, but the relapse rate is high upon discontinuation of these agents. With standard therapy, remission rates with induction vary from 80% for partial remission to 50–60% for full remission; it may take more than 6 months to see these effects. Relapse is common and rates of disease flare are higher in those who do not experience complete remission; similarly, progression to ESRD is more common in those who relapse more frequently, or in whom no remission has been achieved. Studies to assess safety and efficacy of newer biologic immunomodulatory drugs for lupus nephritis are ongoing.
The normalization of various laboratory tests (double-stranded DNA antibodies, serum C3, C4, CH50 levels) can be useful in monitoring treatment. Urinary protein levels and sediment activity are also helpful markers. Patients with SLE who undergo dialysis have a favorable prospect for long-term survival; interestingly, systemic lupus symptoms may become quiescent with the development of ESRD. Patients with SLE undergoing kidney transplants can have recurrent renal disease, although rates are relatively low.
Beck L et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013 Sep;62(3):425–29. [PMID: 23871408]
Bose B et al. Ten common mistakes in the management of lupus nephritis. Am J Kidney Dis. 2013 Dec 11. [Epub ahead of print] [PMID: 24332767]
Hogan J et al. Update on the treatment of lupus nephritis. Curr Opin Nephrol Hypertens. 2013 Mar;22(2):224–30. [PMID: 23328501]
Lech M et al. The pathogenesis of lupus nephritis. J Am Soc Nephrol. 2013 Sep;24(9):1357–66. [PMID: 23929771]
ESSENTIALS OF DIAGNOSIS
Bland urine sediment (few if any cells or cellular casts).
Nephrotic syndrome consists of the following:
Urine protein excretion > 3 g per 24 hours.
Hypoalbuminemia (albumin < 3 g/dL).
Oval fat bodies may be seen in the urine.
In American adults, the most common cause of nephrotic spectrum glomerular disease is diabetes mellitus. Other causes of this presentation include minimal change disease, focal segmental glomerulosclerosis (FSGS), membranous nephropathy, and amyloidosis. Any of these entities can present on the less severe end of the spectrum with a bland urinalysis and proteinuria, or with the most severe presentation of the nephrotic syndrome. Serum creatinine may or may not be abnormal at the time of presentation, depending on the severity, acuity and chronicity of the disease.
Patients with subnephrotic range proteinuria do not manifest symptoms of the renal disease. In those with the nephrotic syndrome, peripheral edema is present and is most likely due to sodium retention and, at albumin levels < 2 g/dL (20 g/L), arterial underfilling from low plasma oncotic pressure. Edema may present in dependent regions, such as the lower extremities, or it may become generalized and include periorbital edema. Dyspnea due to pulmonary edema, pleural effusions, and diaphragmatic compromise with ascites can occur.
1. Urinalysis—Proteinuria occurs as a result of effacement of podocytes (foot processes) and an alteration of the negative charge of the GBM. The urinary dipstick is a good screening test for proteinuria; however, it only detects albumin. The addition of sulfosalicylic acid to the urine causes total protein to precipitate, allowing for the possible discovery of paraproteins (and albumin). A spot urine protein to urine creatinine ratio gives a reasonable approximation of grams of protein excreted per day; a 24-hour urine sample for protein excretion is rarely needed.
Microscopically, the urinary sediment has relatively few cellular elements or casts. However, if marked hyperlipidemia is present, urinary oval fat bodies may be seen. They appear as “grape clusters” under light microscopy and “Maltese crosses” under polarized light.
2. Blood chemistries—The nephrotic syndrome results in hypoalbuminemia (< 3 g/dL [30 g/L]) and hypoproteinemia (< 6 g/dL [60 g/L]). Hyperlipidemia occurs in over 50% of patients with early nephrotic syndrome, and becomes more frequent and worsens in degree as the severity of the nephrotic syndrome increases. A fall in oncotic pressure triggers increased hepatic production of lipids (cholesterol and apolipoprotein B). There is also decreased clearance of very low-density lipoproteins, causing hypertriglyceridemia. Patients may also have an elevated erythrocyte sedimentation rate as a result of alterations in some plasma components such as increased levels of fibrinogen. Patients may become deficient in vitamin D, zinc, and copper from loss of binding proteins in the urine.
Laboratory testing to determine the underlying cause may include complement levels, serum and urine protein electrophoresis, antinuclear antibodies, and serologic tests for viral hepatitides.
3. Kidney biopsy—Kidney biopsy is often performed in adults with new-onset idiopathic nephrotic syndrome if a primary renal disease that may require immunosuppressive therapy is suspected. Chronically and significantly decreased GFR indicates irreversible kidney disease mitigating the usefulness of kidney biopsy. In the setting of long-standing diabetes mellitus type 1 or 2, proteinuric renal disease is rarely biopsied unless atypical features (such as significant glomerular hematuria or cellular casts) are also present, or if there is other reason to suspect an additional renal lesion.
In those with subnephrotic proteinuria or mild nephrotic syndrome, dietary protein restriction may be helpful in slowing progression of renal disease (see CKD section). In those with very heavy proteinuria (> 10 g/d) protein malnutrition may occur and daily protein intake should replace daily urinary protein losses.
In both diabetic and nondiabetic patients, therapy that is aimed at reducing proteinuria may also reduce progression of renal disease. ACE inhibitors and ARBs lower urine protein excretion by reducing glomerular capillary pressure; they also have antifibrotic effects. These agents can be used in patients with reduced GFR as long as significant hyperkalemia (potassium > 5.2–5.5 mEq/L) does not occur and serum creatinine rises < 30%; patients should be monitored closely to avoid acute kidney injury and hyperkalemia. A recent prospective, randomized multicenter study to evaluate the combination of an ACE inhibitor and ARB versus ARB alone for slowing the progression of diabetic nephropathy was terminated early due to safety concerns in the dual therapy arm; such combination therapy cannot, therefore, be generally recommended.
Dietary salt restriction is essential for managing edema; most patients also require diuretic therapy. Both thiazide and loop diuretics are highly protein bound; therefore with hypoalbuminemia and decreased GFR, diuretic delivery to the kidney is reduced, and patients often require larger doses. A combination of loop and thiazide diuretics can potentiate the diuretic effect and may be needed for patients with refractory fluid retention.
Hypercholesterolemia and hypertriglyceridemia occur as noted above. Dietary modification and exercise should be advocated; however, effective lipid-lowering usually also requires pharmacologic treatment (see Chapter 28). Rhabdomyolysis, however, is more common in patients with CKD who take gemfibrozil in combination with statins; combining fenofibrate or niacin with a statin poses less risk.
Patients with serum albumin < 2 g/dL can become hypercoagulable. Nephrotic patients have urinary losses of antithrombin, protein C, and protein S and increased platelet activation. Patients are prone to renal vein thrombosis, pulmonary embolus, and other venous thromboemboli, particularly with membranous nephropathy. Anticoagulation therapy with warfarin is warranted for at least 3–6 months in patients with evidence of thrombosis in any location. Patients with renal vein thrombosis, pulmonary embolus, or recurrent thromboemboli require indefinite anticoagulation. After an initial clotting event, ongoing nephrotic syndrome poses a risk of thrombosis recurrence, and continued anticoagulation should be considered until resolution of the nephrotic syndrome.
Any patient noted to have nephrotic syndrome should be referred immediately to a nephrologist for consideration of volume and blood pressure management, assessment for kidney biopsy, and treatment of the underlying disease. Proteinuria of > 1 g/d without the nephrotic syndrome also merits nephrology referral, though with less urgency.
Patients with edema refractory to outpatient therapy or rapidly worsening kidney function that may require inpatient interventions should be admitted.
Cadnapaphornchai MA et al. The nephrotic syndrome: pathogenesis and treatment of edema formation and secondary complications. Pediatr Nephrol. 2013 Aug 30. [Epub ahead of print] [PMID: 23989393]
Gbadegesin RA et al. Genetic testing in nephrotic syndrome—challenges and opportunities. Nat Rev Nephrol. 2013 Mar;9(3):179–84. [PMID: 23321566]
Reiser J et al. Podocyte biology and pathogenesis of kidney disease. Annu Rev Med. 2013;64:357–66. [PMID: 23190150]
ESSENTIALS OF DIAGNOSIS
Kidney biopsy shows no changes on light microscopy.
Characteristic foot-process effacement on electron microscopy.
Minimal change disease is the most common cause of proteinuric renal disease in children, accounting for about 80% of cases. It often remits upon treatment with a course of corticosteroids. Indeed, children with nephrotic syndrome are often treated for minimal change disease empirically without a biopsy diagnosis. Biopsy should be considered for children with nephrotic syndrome who exhibit unusual features (such as signs of other systemic illness), who are steroid-resistant (see below), or who relapse frequently upon withdrawal of corticosteroid therapy. Minimal change disease is less common in adults, accounting for 20–25% of cases of primary nephrotic syndrome in those over age 40 years. This entity can be idiopathic but also occurs following viral upper respiratory infections (especially in children), in association with neoplasms such as Hodgkin disease, with drugs (lithium), and with hypersensitivity reactions (especially to NSAIDs and bee stings).
Patients often exhibit the manifestations of full-blown nephrotic syndrome. They are more susceptible to infection, have a tendency toward thromboembolic events, develop severe hyperlipidemia, and may experience protein malnutrition. Minimal change disease can rarely cause acute kidney injury due to tubular changes and interstitial edema.
There is no helpful serologic testing. Glomeruli show no changes on light microscopy or immunofluorescence. On electron microscopy, there is a characteristic effacement of podocyte foot processes. Mesangial cell proliferation may be seen in a subgroup of patients; this finding is associated with more hematuria and hypertension and poor response to standard corticosteroid treatment.
Treatment is with prednisone, 60 mg/m2/d orally; remission in steroid-responsive minimal change disease generally occurs within 4–8 weeks. Adults often require longer courses of therapy than children, requiring up to 16 weeks to achieve a response. Treatment should be continued for several weeks after complete remission of proteinuria, and dosing tapers should be individualized. A significant number of patients will relapse and require repeated corticosteroid treatment. Patients with frequent relapses or corticosteroid resistance may require cyclophosphamide or a calcineurin inhibitor to induce subsequent remissions. Rituximab may also be considered in adults but appears less promising in children. Progression to ESRD is rare. Complications most often arise from prolonged corticosteroid use.
Beck L et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013 Sep;62(3):405–10. [PMID: 23871408]
Hogan J et al. The treatment of minimal change disease in adults. J Am Soc Nephrol. 2013 Apr;24(5):702–11. [PMID: 23431071]
ESSENTIALS OF DIAGNOSIS
Varying degrees of proteinuria, may have nephrotic syndrome.
Associated with coagulopathy, eg, renal vein thrombosis, if nephrotic syndrome present.
“Spike and dome” pattern on kidney biopsy from subepithelial deposits.
Secondary causes notably include hepatitis B virus and carcinomas.
Membranous nephropathy is the most common cause of primary nephrotic syndrome in adults and often presents in the fifth and sixth decades. It is an immune-mediated disease characterized by immune complex deposition in the subepithelial portion of glomerular capillary walls. The antigen in the primary form of the disease appears to be a phospholipase A2 receptor (PLA2R) on the podocyte in 70–80% of patients. Secondary disease is associated with underlying carcinomas; infections, such as hepatitis B and C, endocarditis, and syphilis; autoimmune disease, such as SLE, mixed connective tissue disease, and thyroiditis; and certain drugs, such as NSAIDs and captopril. The course of disease is variable, with about 50% of patients progressing to ESRD over 3–10 years. Poorer outcome is associated with concomitant tubulointerstitial fibrosis, male sex, elevated serum creatinine, hypertension, and heavy proteinuria (> 10 g/d).
Patients with membranous nephropathy and nephrotic syndrome have a higher risk of hypercoagulable state than those with nephrosis from other etiologies; there is a particular predisposition to renal vein thrombosis in these patients.
Patients may be asymptomatic or may have edema or frothy urine. Venous thrombosis, such as an unprovoked deep venous thrombosis may be an initial sign. There may be symptoms or signs of an underlying infection or neoplasm (especially lung, stomach, breast, and colon cancers) in secondary membranous nephropathy.
See above for laboratory findings in the nephrotic syndrome. Evaluation for secondary causes including serologic testing for SLE, syphilis, viral hepatidites, and age- and risk-appropriate cancer screening should be performed. Serum evaluation for circulating PLA2R antibodies to assess for idiopathic membranous nephropathy may be available in the future. By light microscopy, capillary wall thickness is increased without inflammatory changes or cellular proliferation; when stained with silver methenamine, a “spike and dome” pattern results from to projections of excess GBM between the subepithelial deposits. Immunofluorescence shows IgG and C3 staining along capillary loops. Electron microscopy shows a discontinuous pattern of dense deposits along the subepithelial surface of the basement membrane.
Underlying causes must be excluded prior to consideration of treatment. Idiopathic/primary disease treatment depends on the risk of renal disease progression. Roughly 30% of patients present with subnephrotic proteinuria (< 3 g/d) and most have a good prognosis with conservative management, including antiproteinuric therapy with ACE inhibitor or ARB if blood pressure is > 125/75 mmHg. Spontaneous remission may develop even in those with heavy proteinuria (about 30% of cases). Thus, use of immunosuppressive agents should be limited to those at highest risk for progression and with salvageable renal function. Patients with nephrotic syndrome despite 6 months of conservative management and serum creatinine < 3.0 may elect therapy with corticosteroids and chlorambucil or cyclophosphamide for 6 months. Calcineurin inhibitors with or without corticosteroids may be considered as well. Uncontrolled trials with rituximab have shown benefit. Remission may take up to 6 months. Patients with primary membranous nephropathy are excellent candidates for transplant.
Beck L et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013 Sep;62(3):413–17. [PMID: 23871408]
Hofstra JM et al. Treatment of idiopathic membranous nephropathy. Nat Rev Nephrol. 2013 Aug;9(8):443–58. [PMID: 23820815]
Ma H et al. The role of complement in membranous nephropathy. Semin Nephrol. 2013 Nov;33(6):531–42. [PMID: 24161038]
This is a relatively common renal pattern of injury resulting from damage to podocytes. The list of possible causes of podocyte injury is long and diverse and includes primary renal disease due to (1) heritable abnormalities in any of several podocyte proteins, (2) polymorphisms in the APOL1 gene in those of African descent, or (3) increased levels of soluble urokinase receptors or increased expression of CD80 (B7-1) on podocytes. Secondary FSGS may result from overwork injury, obesity, hypertension, chronic urinary reflux, HIV infection, or analgesic or bisphosphonate exposure. Clinically, patients present with proteinuria; 80% of children and 50% of adults have overt nephrotic syndrome in primary FSGS. Decreased GFR is present in 25–50% at time of diagnosis. Patients with FSGS and nephrotic syndrome typically progress to ESRD in 6–8 years. There is no helpful serologic testing.
Diagnosis requires kidney biopsy. Light microscopy shows sclerosis of portions (or segments) of some, but not all glomeruli (thus, focal and not diffuse disease). IgM and C3 are seen in the sclerotic lesions on immunofluorescence, although it is presumed that these immune components are simply trapped in the sclerotic glomeruli and are not pathogenic. Electron microscopy shows fusion of epithelial foot processes as seen in minimal change disease.
Treatment for primary FSGS should include conservative measures, such as diuretics for edema, ACE inhibitors or ARBs to target proteinuria and hypertension, and statins or niacin for hyperlipidemia. Those with primary disease and nephrotic syndrome may benefit from high-dose oral prednisone (1 mg/kg/d) for 4–16 weeks followed by a slow taper; this may induce remission within 5–9 months in over half of patients. In those with steroid-resistance or intolerance, calcineurin inhibitors and mycophenolate mofetil can be considered. Patients with primary FSGS who progress to ESRD and undergo renal transplantation risk a relatively high relapse rate and graft loss; plasma exchange therapy, and possibly rituximab, just prior to transplant and with early signs of relapse appears to be beneficial.
Beck L et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013 Sep;62(3):410–13. [PMID: 23871408]
Bose B et al. Glomerular diseases: FSGS. Clin J Am Soc Nephrol. 2013 Aug 29. [Epub ahead of print] [PMID: 23990165]
Ponticelli C et al. Current and emerging treatments for idiopathic focal and segmental glomerulosclerosis in adults. Expert Rev Clin Immunol. 2013 Mar;9(3):251–61. [PMID: 23445199]
Amyloidosis is caused by extracellular deposition of an abnormally folded protein (amyloid). There are several different proteins that have the potential to form amyloid fibrils. The most common is AL amyloid, due to a plasma cell dyscrasia, in which the protein is a monoclonal Ig light chain; this is also known as primary amyloid disease. Secondary amyloid disease is a result of a chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, or chronic infection. In these cases, there is deposition of the acute phase reactant serum amyloid A protein, termed “AA amyloid disease.” Proteinuria, decreased GFR, and the nephrotic syndrome are presenting symptoms and signs; evidence of other organ involvement is not uncommon in these cases. Serum and urine protein electrophoresis should be done as a screening test; if a monoclonal spike is found, serum free light chains should be quantified. Amyloid-affected kidneys are often enlarged (> 10 cm). Pathologically, glomeruli are filled with amorphous deposits that show green birefringence with Congo red staining.
Treatment options are few. Remissions can occur in AA amyloidosis if the underlying disease is treated. AL amyloidosis progresses to ESRD in an average of 2–3 years. Five-year overall survival is < 20%, with death occurring from ESRD and heart disease. The use of alkylating agents and corticosteroids—eg, melphalan and prednisone—can reduce proteinuria and improve renal function in a small percentage of patients. New therapies, including the proteosome inhibitor bortezomib, may hold promise but data from controlled trials are lacking. Significant reduction in serum free light chain burden (> 90%) has been shown to correlate with improved renal outcomes. Melphalan and stem cell transplantation are associated with high toxicity (45% mortality) but induce remission in 80% of the remaining patients; however, few patients are eligible for this treatment. Renal transplant is an option in patients with AA amyloid.
Gertz MA. Immunoglobulin light chain amyloidosis: 2013 update on diagnosis, prognosis, and treatment. Am J Hematol. 2013 May;88(5):416–25. [PMID: 23605846]
Gillmore JD et al. Pathophysiology and treatment of systemic amyloidosis. Nat Rev Nephrol. 2013 Oct;9(10):574–86. [PMID: 23979488]
Venner CP et al. Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood. 2012 May 10;119(19):4387–90. [PMID: 22331187]
ESSENTIALS OF DIAGNOSIS
Prior evidence of diabetes mellitus, typically over 10 years.
Albuminuria usually precedes decline in GFR.
Other end-organ damage, such as retinopathy, is common.
Diabetic nephropathy is the most common cause of ESRD in the United States. Type 1 diabetes mellitus carries a 30–40% risk of nephropathy after 20 years, whereas type 2 has a 15–20% risk after 20 years. ESRD is much more likely to develop in persons with type 1 diabetes mellitus, in part due to fewer comorbidities and deaths before ESRD ensues. With the current epidemic of obesity and type 2 diabetes mellitus, rates of diabetic nephropathy are projected to continue to increase. Patients at higher risk include males, African Americans, Native Americans, and those with a positive family history. Mortality rates are higher for diabetics with kidney disease compared to those without CKD.
Diabetic nephropathy develops about 10 years after the onset of diabetes mellitus. It may be present at the time type 2 diabetes mellitus is diagnosed. The first stage of diabetic nephropathy is hyperfiltration with an increase in GFR, followed by the development of microalbuminuria (30–300 mg/d). With progression, albuminuria increases to > 300 mg/d and can be detected on a urine dipstick as overt proteinuria; the GFR subsequently declines over time. Yearly screening for microalbuminuria is recommended for all diabetic patients to detect disease at its earliest stage; however, diabetic nephropathy can, less commonly result in nonproteinuric CKD.
The most common lesion in diabetic nephropathy is diffuse glomerulosclerosis, but nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) is pathognomonic. The kidneys are usually enlarged as a result of cellular hypertrophy and proliferation. Kidney biopsy is not required in most patients, though, unless atypical findings are present, such as sudden onset of proteinuria, nephritic spectrum features (see above), massive proteinuria (>10 g/d), urinary cellular casts, or rapid decline in GFR.
Patients with diabetes are prone to other renal diseases. These include papillary necrosis, chronic interstitial nephritis, and type 4 (hyporeninemic hypoaldosteronemic) renal tubular acidosis. Patients are more susceptible to acute kidney injury from many insults, including intravenous contrast material and concomitant use of an ACE inhibitor or ARBs with NSAIDs.
With the onset of microalbuminuria, aggressive treatment is necessary. Strict glycemic control should be emphasized early in diabetic nephropathy, with recognition of risk of hypoglycemia as CKD becomes advanced (see CKD section). Treatment of hypertension to a goal of 130/80 mm Hg in most patients, and 125/75 mm Hg in overtly proteinuric patients also slows progression. ACE inhibitors and ARBs in those with microalbuminuria lower the rate of progression to overt proteinuria and slow progression to ESRD by reducing intraglomerular pressure and via antifibrotic effects. Even in patients with markedly diminished GFR, these agents may provide benefit; close monitoring for hyperkalemia or a decline in GFR more than 30% with the initiation or uptitration of this therapy is required. The NEPHRON-D trial, in which patients with diabetic nephropathy were randomized to combination ARB and ACE inhibitor therapy or ARB and placebo, was stopped early due to lack of efficacy and increased adverse events of hyperkalemia and acute kidney injury in the combination group. Treatment of other cardiovascular risk factors and obesity is crucial. Many with diabetes have multiple comorbid conditions; therefore, in patients undergoing dialysis who progress to ESRD, mortality over the first 5 years is high. Patients who are relatively healthy, however, benefit from renal transplantation.
Appel G. Detecting and controlling diabetic nephropathy: what do we know? Cleve Clin J Med. 2013 Apr;80(4):209–17. [PMID: 23547091]
Forbes JM et al. Mechanisms of diabetic complications. Physiol Rev. 2013 Jan;93(1):137–88. [PMID: 23303908]
Fried LF et al; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013 Nov 14;369(20):1892–903. [PMID: 24206457]
HIV-associated nephropathy usually presents as the nephrotic syndrome and declining GFR in patients with HIV infection. Most patients are of African descent, likely due to the now recognized association of APOL1 polymorphisms with increased risk for HIV-associated nephropathy. Often, patients have low CD4 counts and have AIDS, but HIV-associated nephropathy can also be the initial presentation of HIV disease. Patients with HIV are at risk for renal disease other than HIV-associated nephropathy (eg, toxicity from highly active antiretroviral therapy [HAART], vascular disease, and diabetes, or an immune complex–mediated glomerular disease); such diseases tend to be nonnephrotic.
Kidney biopsy shows a focal segmental glomerulosclerosis pattern of injury (described above) with glomerular collapse; severe tubulointerstitial damage may also be present.
HIV-associated nephropathy is becoming less common in the era of HIV screening and more effective antiretroviral therapy. Small, uncontrolled studies have shown that HAART slows progression of disease. ACE inhibitors or ARBs can be used to control blood pressure and slow disease progression. Corticosteroid treatment has been used with variable success at a dosage of 1 mg/kg/d, along with cyclosporine. Patients who progress to ESRD and are otherwise healthy are good candidates for renal transplantation.
Maggi P et al. Renal complications in HIV disease: between present and future. AIDS Rev. 2012 Jan–Mar;14(1):37–53. [PMID: 22297503]
Yahaya I et al. Interventions for HIV-associated nephropathy. Cochrane Database Syst Rev. 2013 Jan 31;1:CD007183. [PMID: 23440812]
Tubulointerstitial disease may be acute or chronic. Acute disease is most commonly associated with medications, infectious agents, and systemic rheumatologic disorders. Interstitial edema, infiltration with polymorphonuclear neutrophils, and tubular cell necrosis can be seen. (See Acute Kidney Injury, above, and Table 22–10.) Chronic disease is associated with insults from an acute factor or progressive insults without any obvious acute cause. Interstitial fibrosis and tubular atrophy are present, with a mononuclear cell predominance. The chronic disorders are described below.
Table 22–10. Causes of acute tubulointerstitial nephritis (abbreviated list).
ESSENTIALS OF DIAGNOSIS
Kidney size is small and contracted.
Decreased urinary concentrating ability.
Hyperchloremic metabolic acidosis.
The primary causes of chronic tubulointerstitial disease are discussed below. Other causes include multiple myeloma and gout, which are discussed in the section on multisystem disease with variable kidney involvement.
The most common cause of chronic tubulointerstitial disease is obstructive uropathy from prolonged obstruction of the urinary tract. The major causes are prostatic disease in men; ureteral calculus in a single functioning kidney; bilateral ureteral calculi; carcinoma of the cervix, colon, or bladder; and retroperitoneal tumors or fibrosis.
Reflux nephropathy from vesicoureteral reflux is primarily a disorder of childhood and occurs when urine passes retrograde from the bladder to the kidneys during voiding. It is the second most common cause of chronic tubulointerstitial disease. It occurs as a result of an incompetent vesicoureteral sphincter. Urine can extravasate into the interstitium; an inflammatory response develops, and fibrosis occurs. The inflammatory response is due to either bacteria or normal urinary components.
Analgesic nephropathy is most commonly seen in patients who ingest large quantities of analgesic combinations. The drugs of concern are phenacetin, paracetamol, aspirin, and NSAIDs, with acetaminophen a possible but less certain culprit. Ingestion of at least 1 g/d for 3 years of these analgesics is considered necessary for kidney dysfunction to develop. This disorder occurs most frequently in individuals who are using analgesics for chronic headaches, muscular pains, and arthritis. Most patients grossly underestimate their analgesic use.
Tubulointerstitial inflammation and papillary necrosis are seen on pathologic examination. Papillary tip and inner medullary concentrations of some analgesics are tenfold higher than in the renal cortex. Phenacetin—once a common cause of this disorder and now rarely available—is metabolized in the papillae by the prostaglandin hydroperoxidase pathway to reactive intermediates that bind covalently to interstitial cell macromolecules, causing necrosis. Aspirin and other NSAIDs can cause damage by their metabolism to active intermediates which can result in cell necrosis. These drugs also decrease medullary blood flow (via inhibition of prostaglandin synthesis) and decrease glutathione levels, which are necessary for detoxification.
Environmental exposure to heavy metals—such as lead, cadmium, mercury, and bismuth—is seen infrequently now in the United States but can cause tubulointerstitial disease. Individuals at risk for lead-induced tubulointerstitial disease are those with occupational exposure (eg, welders who work with lead-based paint) and drinkers of alcohol distilled in automobile radiators (“moonshine” whiskey users). Lead is filtered by the glomerulus and is transported across the proximal convoluted tubules, where it accumulates and causes cell damage. Fibrosed arterioles and cortical scarring also lead to damaged kidneys. The proximal tubular dysfunction from cadmium exposure can cause hypercalciuria and nephrolithiasis.
Polyuria is common because tubular damage leads to inability to concentrate the urine. Volume depletion can also occur as a result of a salt-wasting defect in some individuals.
Patients can become hyperkalemic both because the GFR is lower and the distal tubules become aldosterone resistant. A hyperchloremic renal tubular acidosis is characteristic from a component of type 4 or type 1 renal tubular acidosis. Less commonly, a proximal renal tubular acidosis is seen due to direct proximal tubular damage. The cause of the renal tubular acidosis is threefold: (1) reduced ammonia production, (2) inability to acidify the distal tubules, and (3) proximal tubular bicarbonate wasting. The urinalysis is nonspecific, as opposed to that seen in acute interstitial nephritis. Proteinuria is typically < 2 g/d (owing to inability of the proximal tubule to reabsorb freely filterable proteins); a few cells may be seen; and broad waxy casts are often present.
1. Obstructive uropathy—In partial obstruction, patients can exhibit polyuria (possibly due to vasopressin insensitivity and poor ability to concentrate the urine) or oliguria (due to decreased GFR). Azotemia and hypertension (due to increased renin-angiotensin production) are usually present. Abdominal, rectal, and genitourinary examinations are helpful. Urinalysis can show hematuria, pyuria, and bacteriuria but is often benign. Abdominal ultrasound may detect mass lesions, hydroureter, and hydronephrosis. CT scanning and MRI provide more detailed information.
2. Vesicoureteral reflux—Typically vesicoureteral reflux is diagnosed in young children with a history of recurrent urinary tract infections. This entity can be detected before birth via screening fetal ultrasonography. After birth, a voiding cystourethrogram can be done. Less commonly, this entity is not diagnosed until adolescence or young adulthood when hypertension and substantial proteinuria, unusual in most tubular diseases. At this point, renal ultrasound or IVP can show renal scarring and hydronephrosis. IVP is relatively contraindicated in patients with kidney dysfunction who are at higher risk for contrast nephropathy. On kidney biopsy, focal glomerulosclerosis can be seen in those with kidney damage. Although most damage occurs before age 5 years, progressive renal deterioration to ESRD continues as a result of the early insults.
3. Analgesics—Patients can exhibit hematuria, mild proteinuria, polyuria (from tubular damage), anemia (from GI bleeding or erythropoietin deficiency), and sterile pyuria. As a result of papillary necrosis, sloughed papillae can be found in the urine. An IVP may be helpful for detecting these—contrast will fill the area of the sloughed papillae, leaving a “ring shadow” sign at the papillary tip. However, IVP is rarely used in patients with significant kidney dysfunction, given the need for dye and associated acute kidney injury.
4. Heavy metals—Proximal tubular damage from lead exposure can cause decreased secretion of uric acid, resulting in hyperuricemia and saturnine gout. Patients commonly are hypertensive. Diagnosis is most reliably performed with a calcium disodium edetate (EDTA) chelation test. Urinary excretion of > 600 mg of lead in 24 hours following 1 g of EDTA indicates excessive lead exposure. The proximal tubular dysfunction from cadmium can cause hypercalciuria and nephrolithiasis.
Treatment depends first on identifying the disorder responsible for kidney dysfunction. The degree of interstitial fibrosis that has developed can help predict recovery of renal function. Once there is evidence for loss of parenchyma (small shrunken kidneys or interstitial fibrosis on biopsy), little can prevent the progression toward ESRD. Treatment is then directed at medical management. Tubular dysfunction may require potassium and phosphorus restriction and sodium, calcium, or bicarbonate supplements.
If hydronephrosis is present, relief of obstruction should be accomplished promptly. Prolonged obstruction leads to further tubular damage—particularly in the distal nephron—which may be irreversible despite relief of obstruction. Neither surgical correction of reflux nor medical therapy with antibiotics can prevent deterioration toward ESRD once renal scarring has occurred.
Patients in whom lead nephropathy is suspected should continue chelation therapy with EDTA if there is no evidence of irreversible renal damage (eg, renal scarring or small kidneys). Continued exposure should be avoided.
Treatment of analgesic nephropathy requires withdrawal of all analgesics. Stabilization or improvement of renal function may occur if significant interstitial fibrosis is not present. Ensuring volume repletion during exposure to analgesics may also have some beneficial effects.
• Patients with stage 3–5 CKD should be referred to a nephrologist when tubulointerstitial diseases are suspected. Other select cases of stage 1–2 CKD should also be referred.
• Patients with urologic abnormalities should be referred to a urologist.
Mattoo TK. Vesicoureteral reflux and reflux nephropathy. Adv Chronic Kidney Dis. 2011 Sep;18(5):348–54. [PMID: 21896376]
Wei L et al. Estimated GFR reporting is associated with decreased nonsteroidal anti-inflammatory drug prescribing and increased renal function. Kidney Int. 2013 Jul;84(1):174–8. [PMID: 23486517]
Renal cysts are epithelium-lined cavities filled with fluid or semisolid material. They develop primarily from renal tubular elements. One or more simple cysts are found in 50% of individuals over the age of 50 years. They are rarely symptomatic and have little clinical significance. In contrast, generalized cystic diseases are associated with cysts scattered throughout the cortex and medulla of both kidneys and can progress to ESRD (Table 22–11).
Table 22–11. Clinical features of renal cystic disease.
Simple cysts account for 65–70% of all renal masses. They are generally found at the outer cortex and contain fluid that is consistent with an ultrafiltrate of plasma. Most are found incidentally on ultrasonographic examination. Simple cysts are typically asymptomatic but can become infected.
The main concern with simple cysts is to differentiate them from malignancy, abscess, or polycystic kidney disease. Renal cystic disease can develop in dialysis patients. These cysts have a potential for progression to malignancy. Ultrasound and CT scanning are the recommended procedures for evaluating these masses. Simple cysts must meet three sonographic criteria to be considered benign: (1) echo free, (2) sharply demarcated mass with smooth walls, and (3) an enhanced back wall (indicating good transmission through the cyst). Complex cysts can have thick walls, calcifications, solid components, and mixed echogenicity. On CT scan, the simple cyst should have a smooth thin wall that is sharply demarcated. It should not enhance with contrast media. A renal cell carcinoma will enhance but typically is of lower density than the rest of the parenchyma. Arteriography can also be used to evaluate a mass preoperatively. A renal cell carcinoma is hypervascular in 80%, hypovascular in 15%, and avascular in 5% of cases.
If a cyst meets the criteria for being benign, periodic reevaluation is the standard of care. If the lesion is not consistent with a simple cyst, follow-up with a urologic consultant and possible surgical exploration is recommended.
Skolarikos A et al. Conservative and radiological management of simple cysts: a comprehensive review. BJU Int. 2012 Jul;110(2):170–8. [PMID: 22414207]
ESSENTIALS OF DIAGNOSIS
Multiple cysts in bilateral kidneys; total number depends on age.
Large, palpable kidneys on examination.
Combination of hypertension and abdominal mass suggestive of disease.
Family history is compelling but not necessary.
Chromosomal abnormalities present in some patients.
This disorder is among the most common hereditary diseases in the United States, affecting 500,000 individuals, or 1 in 800 live births. Fifty percent of patients will have ESRD by age 60 years. The disease has variable penetrance but accounts for 10% of dialysis patients in the United States. At least two genes account for this disorder: ADPKD1 on the short arm of chromosome 16 (85–90% of patients) andADPKD2 on chromosome 4 (10–15%). Patients with the PKD2 mutation have slower progression of disease and longer life expectancy than those with PKD1. Other sporadic cases without these mutations have also been recognized.
Abdominal or flank pain and microscopic or gross hematuria are present in most patients. A history of urinary tract infections and nephrolithiasis is common. A family history is positive in 75% of cases, and > 50% of patients have hypertension (see below) that may antedate the clinical manifestations of the disease. Patients have large kidneys that may be palpable on abdominal examination. The combination of hypertension and an abdominal mass should suggest the disease. Forty to 50 percent have concurrent hepatic cysts. Pancreatic and splenic cysts occur also. Hemoglobin and hematocrit tend to be maintained as a result of erythropoietin production by the cysts. The urinalysis may show hematuria and mild proteinuria. In patients with PKD1, ultrasonography confirms the diagnosis—two or more cysts in patients under age 30 years (sensitivity of 88.5%), two or more cysts in each kidney in patients age 30–59 years (sensitivity of 100%), and four or more cysts in each kidney in patients age 60 years or older are diagnostic for autosomal dominant polycystic kidney disease. If sonographic results are unclear, CT scan is recommended and highly sensitive.
Abdominal or flank pain is caused by infection, bleeding into cysts, and nephrolithiasis. Bed rest and analgesics are recommended. Cyst decompression can help with chronic pain.
Gross hematuria is most commonly due to rupture of a cyst into the renal pelvis, but it can also be caused by a kidney stone or urinary tract infection. Hematuria typically resolves within 7 days with bed rest and hydration. Recurrent bleeding should suggest the possibility of underlying renal cell carcinoma, particularly in men over age 50 years.
An infected renal cyst should be suspected in patients who have flank pain, fever, and leukocytosis. Blood cultures may be positive, and urinalysis may be normal because the cyst does not communicate directly with the urinary tract. CT scans can be helpful because an infected cyst may have an increased wall thickness. Bacterial cyst infections are difficult to treat. Antibiotics with cystic penetration should be used, eg, fluoroquinolones or trimethoprim-sulfamethoxazole and chloramphenicol. Treatment may require 2 weeks of parenteral therapy followed by long-term oral therapy.
Up to 20% of patients have kidney stones, primarily calcium oxalate. Hydration (2–3 L/d) is recommended.
Fifty percent of patients have hypertension at time of presentation, and it will develop in most patients during the course of the disease. Cyst-induced ischemia appears to cause activation of the renin–angiotensin system, and cyst decompression can lower blood pressure temporarily. Hypertension should be treated aggressively, as this may prolong the time to ESRD. (Diuretics should be used cautiously since the effect on renal cyst formation is unknown.)
About 10–15% of these patients have arterial aneurysms in the circle of Willis. Screening arteriography is not recommended unless the patient has a family history of aneurysms, is employed in a high risk profession (such as airline pilot), or is undergoing elective surgery with a high risk of developing moderate to severe hypertension.
Vascular problems include mitral valve prolapse in up to 25% of patients, aortic aneurysms, and aortic valve abnormalities. Colonic diverticula are more common in patients with polycystic kidneys.
Vasopressin receptor antagonists have been shown to slow down the rate of change in total kidney volume and to lower the rate of worsening kidney function. Other agents, octreotide and sirolimus, have shown a decreased rate of cyst growth but no decrease in the rate of decline in kidney function. Avoidance of caffeine may prevent cyst formation due to effects on G-coupled proteins. Treatment of hypertension and a low-protein diet may slow the progression of disease, although this is not well proven.
Schrier RW. Randomized intervention studies in human polycystic kidney and liver disease. J Am Soc Nephrol. 2010 Jun;21(6):891–3. [PMID: 20431043]
Steinman TI. Polycystic kidney disease: a 2011 update. Curr Opin Nephrol Hypertens. 2012 Mar;21(2):189–94. [PMID: 22274800]
Torres VE et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec 20;367(25):2407–18. [PMID: 23121377]
Watnick T et al. mTOR inhibitors in polycystic kidney disease. N Engl J Med. 2010 Aug 26;363(9):879–81. [PMID: 20581393]
This disease is a relatively common and benign disorder that is present at birth and not usually diagnosed until the fourth or fifth decade. It can be caused by autosomal dominant mutations in the MCKD1 orMCKD2 genes on chromosomes 1 and 16, respectively. Kidneys have a marked irregular enlargement of the medullary and interpapillary collecting ducts. This is associated with medullary cysts that are diffuse, giving a “Swiss cheese” appearance in these regions.
Medullary sponge kidney presents with gross or microscopic hematuria, recurrent urinary tract infections, or nephrolithiasis. Common abnormalities are a decreased urinary concentrating ability and nephrocalcinosis; less common is incomplete type I distal renal tubular acidosis. The diagnosis can be made by CT, which shows cystic dilatation of the distal collecting tubules, a striated appearance in this area, and calcifications in the renal collecting system.
There is no known therapy. Adequate fluid intake (2 L/d) helps prevent stone formation. If hypercalciuria is present, thiazide diuretics are recommended because they decrease calcium excretion. Alkali therapy is recommended if renal tubular acidosis is present.
Renal function is well maintained unless there are complications from recurrent urinary tract infections and nephrolithiasis.
This is a disorder previously believed to be rare but is now recognized as more common and as the cause of ESRD in younger individuals. It is associated with almost universal progression to ESRD. The childhood type—juvenile nephronophthisis—is an autosomal recessive disorder caused by mutations in the NPH1, NPH2, and NPH3 genes; the type appearing in adulthood—medullary cystic disease—is autosomal dominant. Both types are manifested by multiple small renal cysts at the corticomedullary junction and medulla. The cortex becomes fibrotic, and as the disease progresses, interstitial inflammation and glomerular sclerosis appear.
Patients with both forms exhibit polyuria, pallor, and lethargy. Hypertension occurs at the later stages of disease. The juvenile form causes growth retardation and ESRD before age 20 years. Patients require large amounts of salt and water as a result of renal salt wasting. Ultrasound and CT scan show small, scarred kidneys, and an open kidney biopsy may be necessary to recover tissue from the corticomedullary junction.
There is no current medical therapy that will prevent progression to renal failure. Adequate salt and water intake are essential to replenish renal losses.
Multiple myeloma is a malignancy of plasma cells (see Chapter 13). Renal involvement occurs in about 25% of all patients. “Myeloma kidney” is the presence of light chain immunoglobulins (Bence Jones protein) in the urine causing renal toxicity. Bence Jones protein causes direct renal tubular toxicity and results in tubular obstruction by precipitating in the tubules. The earliest tubular damage results in Fanconi syndrome (a type II proximal renal tubular acidosis). The proteinuria seen with multiple myeloma is primarily due to light chains that are not detected on urine dipstick, which mainly detects albumin. Hypercalcemia and hyperuricemia are frequently seen. Glomerular amyloidosis can develop in patients with multiple myeloma; in these patients, dipstick protein determinations are positive due to glomerular epithelial cell foot process effacement and albumin “spilling” into Bowman capsule with resultant albuminuria. Other conditions resulting in renal dysfunction include plasma cell infiltration of the renal parenchyma and a hyperviscosity syndrome compromising renal blood flow. Therapy for acute kidney injury attributed to multiple myeloma includes correction of hypercalcemia, volume repletion, and chemotherapy for the underlying malignancy. Plasmapheresis had been considered appropriate to decrease the burden of existing monoclonal proteins while awaiting chemotherapeutic regimens to take effect. However, in the largest randomized prospective trial to date, plasmapheresis did not provide any renal benefit to these patients. Pheresis therapy still remains controversial.
Bridoux F et al. Optimizing treatment strategies in myeloma cast nephropathy: rationale for a randomized prospective trial. Adv Chronic Kidney Dis. 2012 Sep;19(5):333–41. [PMID: 22920644]
Haynes R et al. Myeloma kidney: improving clinical outcomes? Adv Chronic Kidney Dis. 2012 Sep;19(5):342–51. [PMID: 22920645]
Renal dysfunction associated with sickle cell disease is most commonly due to sickling of red blood cells in the renal medulla because of low oxygen tension and hypertonicity. Congestion and stasis lead to hemorrhage, interstitial inflammation, and papillary infarcts. Clinically, hematuria is common. Damage to renal capillaries also leads to diminished concentrating ability. Isosthenuria (urine osmolality equal to that of serum) is routine, and patients can easily become dehydrated. Papillary necrosis occurs as well. These abnormalities are also encountered in patients with sickle cell trait. Sickle cell glomerulopathy is less common but will inexorably progress to ESRD. Its primary clinical manifestation is proteinuria. Optimal treatment requires adequate hydration and control of the sickle cell disease.
Maigne G et al. Glomerular lesions in patients with sickle cell disease. Medicine (Baltimore). 2010 Jan;89(1):18–27. [PMID: 20075701]
Nath KA et al. Vasculature and kidney complications in sickle cell disease. J Am Soc Nephrol. 2012 May;23(5):781–4. [PMID: 22440903]
The classic renal manifestation of tuberculosis is the presence of microscopic pyuria with a sterile urine culture—or “sterile pyuria.” More often, other bacteria are also present. Microscopic hematuria is often present with pyuria. Urine cultures are the gold standard for diagnosis. Three to six first morning midstream specimens should be performed to improve sensitivity. Papillary necrosis and cavitation of the renal parenchyma occur less frequently, as do ureteral strictures and calcifications. Adequate drug therapy can result in resolution of renal involvement.
Chapagain A et al. Presentation, diagnosis, and treatment outcome of tuberculous-mediated tubulointerstitial nephritis. Kidney Int. 2011 Mar;79(6):671–7. [PMID: 21160461]
Latus J et al. Tubulointerstitial nephritis in active tuberculosis—a single center experience. Clin Nephrol. 2012 Oct;78(4):297–302. [PMID: 22704252]
The kidney is the primary organ for excretion of uric acid. Patients with proximal tubular dysfunction have decreased excretion of uric acid and are more prone to gouty attacks. Depending on the pH and uric acid concentration, deposition can occur in the tubules, the interstitium, or the urinary tract. The more alkaline pH of the interstitium causes urate salt deposition, whereas the acidic environment of the tubules and urinary tract causes uric acid crystal deposition at high concentrations.
Three disorders are commonly seen: (1) uric acid nephrolithiasis, (2) acute uric acid nephropathy, and (3) chronic urate nephropathy. Kidney dysfunction with uric acid nephrolithiasis stems from obstructive physiology. Acute uric acid nephropathy presents similarly to acute tubulointerstitial nephritis with direct toxicity from uric acid crystals. Chronic urate nephropathy is caused by deposition of urate crystals in the alkaline medium of the interstitium; this can lead to fibrosis and atrophy. Epidemiologically, hyperuricemia and gout have been associated with worsening cardiovascular outcomes.
Treatment between gouty attacks involves avoidance of food and drugs causing hyperuricemia, aggressive hydration, and pharmacotherapy aimed at reducing serum uric acid levels (such as with allopurinol and febuxostat). These disorders are seen in both “overproducers” and “underexcretors” of uric acid. The latter situation may seem counterintuitive; however, these patients have hyperacidic urine, which explains the deposition of relatively insoluble uric acid crystals. For those with uric acid nephrolithiasis, fluid intake should exceed 3 L/d, and use of a urinary alkalinizing agent can be considered.
Goicoechea M et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010 Aug;5(8):1388–93. [PMID: 20538833]
Nephrogenic systemic fibrosis is a multisystem disorder seen only in patients with CKD (primarily with a GFR < 15 mL/min/1.73 m2, but rarely with a GFR of 15–29 mL/min/1.73 m2), acute kidney injury, and after kidney transplantation. Histopathologically, there is an increase in dermal spindle cells positive for CD34 and procollagen I. Collagen bundles with mucin and elastic fibers are also noted.
Nephrogenic systemic fibrosis was first recognized in hemodialysis patients in 1997 and has been strongly linked to use of contrast agents containing gadolinium. Incidence is projected to be 1–4% in the highest risk (ESRD) population that has received gadolinium, and lower in patients with less severe kidney dysfunction. The FDA has issued a warning regarding avoidance of exposure to this agent for patients with GFR < 30 mL/min/1.73 m2.
Nephrogenic systemic fibrosis affects several organ systems, including the skin, muscles, lungs, and cardiovascular system. The most common manifestation is a debilitating fibrosing skin disorder that can range from skin-colored to erythematous papules, which coalesce to brawny patches. The skin can be thick and woody in areas and is painful out-of-proportion to findings on examination.
Several case reports and series have described benefit for patients after treatment with corticosteroids, photopheresis, plasmapheresis, and sodium thiosulfate. The true effectiveness of these interventions is still unclear. Alternative or no imaging agents should be used for patients requiring MR with contrast at risk for nephrogenic systemic fibrosis.
Agarwal R et al. Gadolinium-based contrast agents and nephrogenic systemic fibrosis: a systematic review and meta-analysis. Nephrol Dial Transplant. 2009 Mar;24(3):856–63. [PMID: 18952698]
1Other diseases with variable involvement described elsewhere in this chapter include systemic lupus erythematosus, diabetes mellitus, and the vasculitides such as granulomatosis with polyangiitis and Goodpasture disease.