Brenner and Rector's The Kidney, 8th ed.

CHAPTER 22. Approach to the Patient with Kidney Disease

Ramesh Saxena   Robert D. Toto

  

 

Presentations in Kidney Disease, 705

  

 

Acute Kidney Injury, 705

  

 

History, 705

  

 

Physical Examination, 707

  

 

Urinalysis, 709

  

 

Blood Tests, 709

  

 

Urine Chemistry Evaluation, 710

  

 

Assessing Urine Output, 710

  

 

Imaging, 710

  

 

Chronic Kidney Disease, 711

  

 

Establishing Chronicity of Disease, 711

  

 

Risk Factors for Chronic Kidney Disease, 713

  

 

Prevalence of Chronic Kidney Disease, 713

  

 

Definition and Staging of Chronic Kidney Disease, 713

  

 

Evaluation of Chronic Kidney Disease, 713

Kidney disease manifests in many ways. A patient may be completely asymptomatic or may be desperately ill with a life-threatening emergency. Nephrologists must know how to recognize and deal with various presentations and be familiar with and adept at evaluating and managing them. In general, a careful and thorough history and physical examination coupled with routine laboratory testing and renal ultrasonography are sufficient to direct further evaluation in order to make an accurate diagnosis. At present, these techniques constitute the mainstay for diagnosis of most genetic renal diseases as well. In the future, however, genetic testing will provide more direct and accurate diagnosis of many renal diseases.

A greater appreciation for the prevalence of chronic kidney disease (CKD) in the population has led to improvements in identification and diagnosis of CKDs and slowing down their progression to end-stage renal disease (ESRD). This chapter is divided into two sections, presentations of patients with kidney disease and methods of evaluation of acute kidney injury (AKI) and CKD.

PRESENTATIONS IN KIDNEY DISEASE

Differentiating AKI and CKD is an important distinction ( Table 22-1 ). Kidney disease progresses toward the end stage in most patients with CKD (see Chapters 17 and 18 ). In contrast, most patients with AKI recover renal function, which returns to normal with no long-term sequelae. However, outcome in AKI depends on three factors: (1) early recognition, (2) establishment of cause, and (3) appropriate clinical management. [1] [2] [3] [4] [5] Evaluation is similar for AKI and CKD but must be performed much more rapidly in patients with AKI. Moreover, diagnostic tools may differ to some extent. For these reasons, the evaluation procedures for AKD and CKD overlap to some extent but are described separately in order of urgency.


TABLE 22-1   -- Differentiation of Acute from Chronic Kidney Disease

History

Long-standing history suggests chronic kidney disease

Renal osteodystrophy

Radiographic evidence of osteitis fibrosa cystica, osteomalacia

Renal size (length)

 Small kidneys (e.g., <9 cm)

Chronic kidney disease of any cause

 Normal or enlarged kidney disease (9–12 cm)

Acute kidney injury of any cause

Chronic kidney disease

Human immunodeficiency virus (HIV) nephropathy

Diabetic nephrophathy

Amyloidosis

 Enlarged kidneys (>12 cm)

Autosomal dominant polycystic kidney disease

Tuberous sclerosis

Obstructive nephropathy

 Renal biopsy

Histologic diagnosis

 

 

 

ACUTE KIDNEY INJURY

AKI is defined as a sudden decrease in kidney function. Early manifestations of AKI vary and depend in part on context and underlying cause.[6] For example, some patients with toxic nephropathies (e.g., induced by nonsteroidal anti-inflammatory drugs [NSAIDs]) may be completely asymptomatic, so that kidney failure is discovered through laboratory evaluation ( Table 22-2 ). In contrast, AKI due to acute hemolytic uremic syndrome (HUS) may manifest as oliguria, symptoms and signs of volume overload, life-threatening electrolyte abnormalities, and severe neurologic dysfunction.[1]


TABLE 22-2   -- Presentations of Renal Failure

Symptomatic presentation

  

 

General

  

 

Fatigue

  

 

Weakness

  

 

Cardiovascular

  

 

Hypertension

  

 

Pulmonary congestion

  

 

Cough

  

 

Dyspnea

  

 

Hemoptysis

  

 

Neurologic

  

 

Encephalopathy

  

 

Seizure

  

 

Peripheral neuropathy

  

 

Gastrointestinal

  

 

Anorexia

  

 

Nausea

  

 

Vomiting

  

 

Abdominal pain

  

 

Bleeding

  

 

Muscloskeletal

  

 

Muscle weakness

  

 

Periarticular or articular pain

  

 

Bone pain

  

 

Genitourinary

  

 

Hematuria

  

 

Dysuria

  

 

Cutaneous

  

 

Pruritus

  

 

Necrosis

  

 

Vasculitis

  

 

Bruising

Asymptomatic presentation

  

 

Hypertension

  

 

Proteinuria

  

 

Hematuria

  

 

Abnormal renal imaging findings

 

 

 

History

The nephrologist must perform a careful history to determine the cause of AKI. The history should initially focus on causes of kidney hypoperfusion and nephrotoxin exposure. Detailed history of recent events causing alterations in cardiovascular and volume status and use of drugs or toxins should be sought. Presenting complaints of patients suffering from volume depletion leading to kidney hypoperfusion include orthostatic dizziness, presyncope, and syncope. Common causes of volume depletion, such as vomiting, diarrhea, excessive sweating, burns, and renal salt wasting (e.g., diabetic ketoacidosis), must be investigated. In contrast, presenting complaints in patients with renal hypoperfusion due to primary (e.g., glomerulonephritis, HUS, atheroembolic renal disease) or secondary (e.g., congestive heart failure) renal sodium-retaining states include headaches (caused by hypertension), dyspnea, and peripheral edema due to extracellular fluid volume expansion. A history of recent trauma with or without blood loss or muscle trauma should raise the possibility of ischemia, myoglobin-induced tubular necrosis, or both. Fever, rash, and joint pains are associated with lupus nephritis, syste-mic necrotizing vasculitides, endocarditis, drug allergy, and infectious diseases (e.g., Hantavirus), all of which are causes of intrinsic kidney failure. [7] [8] [9] [10] A history of dyspnea or hemoptysis may be a sign of Goodpasture syndrome, Wegener granulomatosis, Churg-Strauss vasculitis, lupus nephritis, or pulmonary edema due to volume overload associated with an acute glomerulonephritis. [10] [11]

In the hospital setting, meticulous review of medical records in patients with AKI should include a careful search for ischemic and nephrotoxic insults.[12] Postoperative AKI often develops as a consequence of an ischemic or nephrotoxic event. [13] [14] Abdominal pain and flank pain are signs of AKI. Obstructive uropathies, acute inflammation of the kidney causing renal enlargement that stretches the renal capsule, can cause pain. Flank pain may also be observed in renal vein thrombosis. Upper quadrant pain may also a sign of acute renal infarction (e.g., renal artery emboli). Prominent neurologic signs are often observed in thrombotic thrombocytopenic purpura (TTP), HUS, toxic nephropathies, and some poisonings such as with aspirin. [15] [16] Constitutional and nonspecific symptoms, such as malaise, weakness, fatigue, anorexia, nausea, and vomiting, are common in patients with AKI but do not alone establish an etiologic diagnosis.

A history of nephrotoxin exposure is an extremely important component of the evaluation of a patient with AKI.[12] Both endogenous and exogenous toxins can give rise to renal failure ( Table 22-3 ). Myoglobin, hemoglobin, and light chains are nephrotoxic. Therefore, muscle damage, hemolysis, and myeloma should be considered in the patient with AKI. [17] [18] [19] [20] [21] The search should include a careful examination not only for known nephrotoxins such as NSAIDs, [22] [23] acetaminophen,[12] angiotensin-converting enzyme (ACE) inhibitors, [24] [25] antibiotics, [12] [20] [26] calcineurin inhibitors, [27] [28] [29] mannitol and intravenous immunoglobulin, [30] [31] high-dose vitamin K in transplant recipients,[32] interferon-α,[33] chemotherapeutic agents including cisplatin and others, [12] [34] radiocontrast agents, [35] [36] [37] diuretics[12] but also any agent that may be new to the patient's regimen. This search is important because drugs that uncommonly cause AKI may otherwise be overlooked (e.g., anticonvulsants, antidepressants).


TABLE 22-3   -- Some Substances Reported to Cause Acute Kidney Injury

Endogenous substances

  

 

Myoglobin

  

 

Uric acid

  

 

Calcium phosphorus

  

 

Light chains

  

 

Atheroemboli

Exogenous substances

  

 

Antibiotics

  

 

Aminoglycosides

  

 

Penicillins

  

 

Cephalosporins

  

 

Fluoroquinolones

  

 

Sulfa drugs

  

 

Pentamidine

  

 

Foscarnet

  

 

Cidofivir

  

 

Acyclovir

  

 

Angiotensin-converting enzyme inhibitors

  

 

Angiotensin II receptor 1 antagonists

  

 

Analgesics and nonsteroidal anti-inflammatory drugs

  

 

Acetaminophen

  

 

Aspirin

  

 

Nonselective cyclooxygenase inhibitors

  

 

Cyclooxygenase-2 inhibitors

  

 

Calcineurin inhibitors

  

 

Cyclosporine

  

 

Tacrolimus

  

 

Chemotherapeutic agents

  

 

Cisplatin

  

 

Mitomycin C

  

 

Methotrexate

  

 

Cystosine arabinoside

  

 

Interleukin-2

  

 

Reverse transcriptase inhibitors

  

 

Indinavir

  

 

Stavudine

  

 

Mannitol

  

 

Immunomodulatory agents

  

 

Interferon-α

  

 

Therapeutic immunoglobulins

  

 

Radiocontrast agents

  

 

Heavy metals and poisons

  

 

Mercury

  

 

Arsenic

  

 

Cadmium

  

 

Lead

  

 

Ethylene glycol

  

 

Antidepressants and anticonvulsants

  

 

Celexa

  

 

Phenytoin

  

 

Carbamazepine

 

 

 

In addition, over-the-counter drugs, including acetaminophen, herbal and health care products, [38] [39] antibiotics, antihypertensives, and poisons, should be considered in all patients in whom the cause of AKI is not readily apparent. For example, occult ingestion of ethylene glycol can lead to AKI from nephrocalcinosis.[40] In this situation, patients survive the initial metabolic acidosis and present 1 to 2 weeks after the ingestion. Cancers, including solid tumors and lymphoma, may cause intrinsic renal failure as a result of hypercalcemia or tumor infiltration.[41]

Endogenous nephrotoxins include abnormal proteins, myoglobin, hemoglobin, uric acid, and calcium-phosphorus complexes. Tumor lysis, usually occurring in patients with bulky abdominal lymphomas, can be caused by acute uric acid nephropathy or deposition of calcium and phosphorus, leading to severe, even anuric AKI.[42] AKI may be the presenting finding in patients with nontraumatic rhabdomyolysis, from cocaine use, infections or tonic-clonic seizures. Hemoglobinuric renal failure may be the initial presentation in a severe episode of acute intravascular hemolysis. [18] [19] Occupational exposure to heavy metals can cause acute tubular necrosis (ATN). This disorder can be observed in welders and miners after exposure to mercury, lead, cadmium, or other metals. [12] [43] In addition, infections can cause renal failure either by direct renal damage or by immune-mediated mechanisms. [10] [44] [45] A history of acquired immunodeficiency syndrome (AIDS) may be a clue to the cause of AKI due to underlying disease or to nephrotoxic drugs such as reverse transcriptase inhibitors, antibiotics, or chemotherapeutic agents.[46]

A history of the color and volume of the patient's urine as well as the pattern of urination can be useful in some settings. For example, abrupt anuria suggests urinary obstruction, severe acute glomerulonephritis, or vascular obstruction due to renal artery emboli or atherosclerotic occlusion of the aortorenal bifurcation. [16] [47] [48] Also, patients with anti-glomerular basement membrane (anti-GBM)–mediated crescentic glomerulonephritis may present with anuria and require dialysis.[48] History of gradually diminishing urine output may indicate urethral stricture or, in an older man, bladder outlet obstruction due to prostate enlargement. Gross hematuria in the setting of ARF suggests acute glomerulonephritis or ureteral obstruction by tumor, blood clots, or renal papillae. [49] [50]

Physical Examination

The physical examination can provide many clues to the underlying cause of and potential therapy for AKI. Careful examination of organ systems as described in this section may help direct the nephrologist to the correct diagnosis.

Skin

Petechiae, purpura, and ecchymoses are clues to inflammatory and vascular causes of kidney failure, including infectious diseases, TTP, and disseminated intravascular coagulation (DIC). Cutaneous infarcts may result from embolic phenomena, and cutaneous vasculitis manifesting as palpable purpura occurs in patients with septic shock, atheroembolic disease, systemic vasculitis, and infective endocarditis and should be looked for ( Fig. 22-1 ).[51] Diffuse erythematous maculopapular rash may be observed in cases of drug-induced (e.g., sulfa drug) allergic interstitial nephritis or in systemic collagen vascular disease such as systemic lupus erythematosus. Reduced skin turgor is a common finding in prerenal ARF caused by volume depletion, although this sign is less reliable in the elderly.

001014

000519

FIGURE 22-1  A, Pretibial purpura in a patient with glomerulonephritis due to systemic necrotizing vasculitis. B, Digital infarction of the fifth digit, typical of systemic atheroembolism syndrome.

000519

 

Eye

Search for uveitis (interstitial nephritis and necrotizing vasculitis), ocular muscle paralysis (ethylene glycol poisoning and necrotizing vasculitis), signs of severe hypertension, atheroembolic lesions (Hollenhorst crystals), Roth spots (endocarditis), and cytoid bodies (cotton-wool exudates are seen in acute lupus nephritis). Ophthalmoplegia may be present in patients with systemic necrotizing vasculitis. Conjunctivitis can be a result of vasculitis or drug toxicity or a manifestation of ESRD (“red eyes of renal failure”), the latter due to conjunctival calcium deposition.

Cardiovascular and Volume Status

Meticulous and accurate assessment of the cardiovascular and volume status is the most important aspect in the diagnosis and initial management of AKI. Pulse rate and blood pressure (BP) should be measured in the supine and standing (or seated with legs dangling) positions whenever possible in patients with suspected volume depletion. Close inspection of jugular venous pulse level as well as heart and lungs and detection of peripheral edema are essential. Evidence for volume depletion, including orthostatic hypotension, dry mucous membranes, and decreased skin turgor, as well as signs of sepsis, congestive heart failure, and cardiac tamponade should be sought in patients with low BP or overt hypotension. However, it is often difficult to assess the volume status from physical findings alone in older patients as well as in patients with heart failure, severe liver disease, obesity, and severe edematous states. In some cases, it may be necessary to place a central venous catheter (e.g., pulmonary artery catheter) to measure right heart pressures, cardiac output, and systemic vascular resistance.

In a hypotensive, oliguric patient, volume status can vary greatly. Despite similar decreases in effective arterial blood volume, hypotension and oliguria may be present in patients with severe congestive heart failure (extracellular volume expansion) and those with severe volume depletion. Measurement of BP, urine output, and urine sodium concentration does not distinguish these two conditions, yet the management of congestive heart failure is quite different from that of volume depletion. Patients with heart failure may need vasodilators, inotropic agents, and diuretics, whereas those with volume depletion need infusions of large volumes of fluid such as saline, blood products, or both (Tables 22-4 and 22-5 [4] [5]).


TABLE 22-4   -- Evaluation of Cardiovascular and Volume Status

Volume Depletion

Volume Overload

Hypotension (± orthostatic)

Hypertension

Decreased skin turgor

Edema, ascites, pleural effusions

Dry mucous membranes

S3 gallop

Normal or decreased jugular venous pulse

Elevated jugular venous pulse

Absence of sweat

 

Clear lungs, no volume overload on chest radiograph

Rales, volume overload on chest radiograph

 

 

 


TABLE 22-5   -- Impact of Physical Examination on the Management of Two Prerenal Patients with Different Volume Status

Parameter

Patient 1 (Volume Depletion)

Patient 2 (Cardiogenic Shock)

Blood pressure (mm Hg)

90/60

90/60

Urine output (mL/hr)

20

20

Urine sodium (mEg/L)

<20

<20

Physical findings

Decreased turgor, no sweat

S3 gallop, rales, peripheral edema

Pulmonary capillary wedge pressure (cm H2O)

2

30

Right atrial pressure (cm H2O)

2

15

Cardiac index (L/min/1.73 m2)

2.1

1.5

Systemic vascular resistance (dynes/cm-5)

2590

2933

Management

Intravenous saline, ± inotrope

Inotrope, vasodilator, diuretic

 

 

 

In severe hypertension, AKI may be due to malignant nephrosclerosis (e.g., essential hypertension, scleroderma), glomerulonephritis, or atheroembolic disease. [48] [49] [51] [52] [53] Cardiac murmurs are associated with endocarditis or atrial myxoma, which can cause AKI owing to fulminant glomerulonephritis. A pericardial friction rub in a patient with new renal failure may be a sign of impending cardiac tamponade and is an indication for emergency dialysis. In this situation, progressive hypotension is dramatic but can be temporarily stabilized by a rapid intravenous bolus infusion of fluids.

Abdomen

Abdominal examination may reveal a palpable bladder (urinary obstruction). Also, tenderness in the upper quadrants can be associated with ureteral obstruction or renal infarction. Ascites may be observed in fulminant hepatic failure, severe nephrotic syndrome, and Budd-Chiari syndrome, all of which are associated with AKI. Abdominal bruit evokes the diagnosis of severe atherosclerotic disease, which can engender renal failure from renal artery stenosis, thrombosis of the aortorenal bifurcation, or atheroembolic renal disease. Flank mass can be a sign of renal obstruction from tumor or retroperitoneal fibrosis.[54] In addition, a tense, distended abdomen in a patient who has just undergone surgery raises the possibility of abdominal compartment syndrome. [55] [56]

Extremities

Examination of the extremities for signs of edema, evidence of tissue ischemia, muscle tenderness (e.g., rhabdomyolysis causing myoglobinuric renal failure), and arthritis (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, infections) may provide clues to the diagnosis of renal failure. Nail signs of hypoalbuminemia (paired bands of pallor in the nailbed [Muerhcke lines]) may be a clue to underlying nephrotic syndrome, which may predispose the patient to ATN.

Neuropsychiatric Features

Neuropsychiatric abnormalities are common in AKI. They range from signs of uremic encephalopathy (confusion, somnolence, stupor, coma, seizures) to focal neurologic abnormalities in specific diseases such as the vasculitides, systemic lupus erythematosus, and infection. As previously mentioned, cranial nerve palsies can be seen in patients with ethylene glycol poisoning and vasculitides, including Wegener granulomatosis and polyarteritis nodosa. Altered and changing mental status is common in thrombotic microangiopathies and systemic atheroembolism.

Urinalysis (see also Chapters 23 and 24 )

The urinalysis is essential in the evaluation of AKI and should be performed by the nephrologist.[57] Abnormal urinary sediment strongly suggests an intrarenal cause for kidney failure. Gross color changes in the urine may be seen with various intrinsic renal diseases. For example, the urine of a patient with ATN frequently appears “dirty” brown and opaque on gross examination owing to the presence of tubular casts.[1] Reddish-brown urine or “Coca-Cola” urine is a characteristic of some patients with acute glomerulonephritis and of those with pigment-associated tubular necroses, including myoglobinuria and hemoglobinuria. Bilious urine in patients with combined liver and renal disease appears yellow-brown owing to bile pigments.

Qualitative assessments for proteinuria and heme pigment are helpful in identifying glomerulonephritis, interstitial nephritis, and toxic and infectious causes of tubular necrosis. Microscopic examination of urine sediment after centrifugation is extremely helpful for differentiating prerenal from intrarenal causes of kidney failure ( Fig. 22-2 ). As shown in Table 22-6 , the urine sediment in ATN typically has granular “muddy brown” casts and renal tubular cells. Interstitial nephritis is often accompanied by pyuria, microhematuria, eosinophiluria, and fine granular and white blood cell casts. Glomerulonephritis is heralded by hematuria with dysmorphic red blood cells (RBCs) and RBC casts. In addition, granular casts, fat globules, and oval fat bodies may be seen in glomerulopathies associated with heavy proteinuria. Uric acid crystals suggest ATN associated with acute uric acid nephropathy from tumor lysis syndrome. Calcium oxalate crystals may be present in ethylene glycol poisoning with AKI due to nephrocalcinosis, and acetaminophen crystals may be observed in acute acetaminophen poisoning.

000021

000519

FIGURE 22-2  Urine sediment in a patient with acute renal failure, illustrating fine (A) and coarse (B) granular casts typical of acute tubular necrosis.

000519

 


TABLE 22-6   -- Urine Tests in the Differential Diagnosis of Acute Kidney Injury

Diagnosis

Urinalysis

Urine-to-Plasma Osmolality

Una (mEq/L)

Fractional Excretion of Na

Prerenal

Normal

>1.0

<20

<1.0

Acute tubular necrosis

Granular casts, epithelial cells

≤1.0

>20

>1.0

Interstitial nephritis

RBCs, WBCs, ± eosinophils, granular casts

≤1.0

>20

>1.0

Glomerulonephritis

RBCs, RBC casts, marked proteinuria

>1.0

<20

<1.0

Vascular disorders

Normal or RBCs, proteinuria

>1.0

<20

<1.0

Postrenal

Normal or RBCs, casts, pyuria

<1.0

>20

>1.0

 

RBC, red blood cell; Una, urine sodium concentration; WBC, white blood cell.

 

 


Blood Tests (see also Chapter 24 )

Increases in blood urea nitrogen (BUN) and serum creatinine (Cr) levels are hallmarks of kidney failure. The rate of rise in BUN and Cr levels varies considerably from patient to patient. The normal BUN/Cr ratio of 10 : 1 is usually maintained in cases of intrinsic AKI (see Table 22-6 ). The ratio is usually elevated (>20 : 1) in prerenal conditions and in some patients with obstructive uropathy. Also, in patients with significant upper gastrointestinal bleeding, the BUN/Cr ratio may increase further as digested blood proteins are absorbed and metabolized by the liver. In contrast, the BUN/Cr ratio may be reduced in liver failure, malnutrition, and rhabdomyolysis. In these conditions, low BUN/Cr ratio occurs as a result of a relative decrease in urea production, an increase in Cr production, or both.

Hypofiltration and abnormal tubular function lead to hyperkalemia, hypocalcemia, and hyperphosphatemia. Serum potassium concentration is frequently elevated in patients with AKI as a result of hypofiltration, decreased tubular secretion, and in some cases, excessive cellular release (e.g., rhabdomyolysis). Hypokalemia may be observed with severe volume depletion (e.g., from vomiting, diarrhea, diuretics). Hypocalcemia and hyperphosphatemia result from hypofiltration and complexation as well as hypovitaminosis D. Hypercalcemia is observed in patients with myeloma and other cancers, milk-alkali syndrome, hypervitaminosis D, and other hypercalcemic states that cause volume depletion.[58]

Anemia is almost invariably seen in AKI. Clues to the cause of ARF can be obtained from examination of the peripheral blood smear. For example, the presence of schistocytes suggests TTP, HUS, malignant hypertension, and DIC. Spherocytes are common in the immunohemolytic anemia of lupus nephritis. Ghost cells or cells containing malarial parasites substantiate the diagnosis of hemoglobin-induced AKI.

Hyperuricemia is also common in AKI and is not diagnostic of tumor lysis syndrome.[42] When the diagnosis of tumor lysis syndrome is entertained, urinalysis and urine chemistry evaluation are essential.

Urine Chemistry Evaluation (see also Chapters 23 and 24 )

Urine electrolyte measurement in a patient with ARF is performed to test functional integrity of the renal tubules. The single most informative test is the fractional excretion of sodium (FENa), defined as

000725

In prerenal azotemia, the FENa is usually less than 1.0%, and in ATN, it is usually greater than 1.0%. Exceptions to this general rule occur in some patients with ATN due to severe burns, radiocontrast nephropathy, or underlying liver disease. FENa may be less than 1.0% in these conditions owing to the combination of severe renal vasoconstriction, low tubular flow rate, and focal or patchy tubular injury. FENa is typically less than 1.0% in patients with acute glomerulonephritis, because tubular function remains intact with increased, rather than decreased, proximal tubular sodium reabsorption. Also, FENa is most accurate for differentiating prerenal from intrarenal ARF when determined in a patient with hypotension and oliguria. Because of these limitations, FENa alone should not be used in assessing the cause of AKI.

Urine-to-plasma osmolality ratio (U/P Osm) is another useful test of tubular function in the setting of AKI. With intact tubular function, the urinary osmolality exceeds plasma osmolality three- to fourfold, whereas when tubules are damaged and concentrating capacity is impaired, urine is isosthenuric to plasma. Therefore, a U/P Osm value of 1 or less is consistent with ATN, and a value greater than 1 is consistent with a prerenal cause. lf the urine is scant in amount and sample volume is low, routine urinalysis is the best diagnostic test. Diagnosis of acute uric acid nephropathy can be substantiated by the urine uric acid-to-urine creatinine ratio. A value greater than 1 suggests this diagnosis.[1] Urine uric acid-to-urine creatinine ratio can be used to help differentiate acute uric acid nephropathy from other causes in patients with malignancy. A ratio of urine uric acid-to-creatinine greater than 1 suggests acute uric acid nephropathy, and a ratio less than 1, other causes.

Assessing Urine Output

Whereas knowledge of the urine output is not particularly helpful in diagnosing the cause of AKI, it is very important for directing management and for predicting outcome. Anuria is defined as urine output less than 100 mL/day. Oliguric renal failure is defined as a 24-hour urine output between 100 and 400 mL/day. Nonoliguric renal failure is defined as urine output greater than 400 mL/day. In patients with suprapubic discomfort and an obviously distended bladder or in patients with a history of declining urine output or documented oliguria, a bladder catheter should be temporarily placed to relieve or rule out bladder outlet obstruction. Patients with oliguric renal failure are easier to manage and have a lower overall mortality rate than those with oliguria or anuria (see discussions on management and survival in accompanying sections). Also, measurement of subsequent daily urine output is important for management of patients.

Fluid Challenge

In patients with suspected prerenal cause of renal failure from significant intravascular volume depletion, an intravenous infusion of normal saline (or colloid such as albumin, dextran, or blood products) may be helpful. In this circumstance, a fluid challenge should improve renal blood flow with correction of renal failure and increased urine output. This maneuver usually consists of an infusion of 1 to 2 L of normal saline administered over 1 to 4 hours. The actual rate prescribed depends on repeated bedside evaluation and clinical judgment. Failure of this maneuver to improve the vital signs and urine output can help point to intrarenal or postrenal causes of renal failure. Caution must be exercised during fluid challenge because of the potential for producing pulmonary edema in patients with congestive heart failure or intrarenal failure, which are unlikely to improve with volume expansion. Therefore, the rate of fluid challenge should be adjusted and the patient should be carefully and repeatedly examined to reduce the risk of precipitating pulmonary edema.

Imaging (see also Chapter 27 )

Renal Ultrasonography and Doppler Flow Scanning

Ultrasonography should be performed whenever urinary tract obstruction is considered in the differential diagnosis of AKI. The test is readily available, noninvasive, accurate, reliable, and very reproducible.[59] In some cases, such as ureteral encasement by tumor or fibrosis, ureteral and renal pelvis dilatation may not be detected by ultrasonography. Increased echogenicity of renal parenchyma is a common and nonspecific indicator of intrinsic renal disease. In some cases of ATN, renal parenchymal echogenicity may be normal.

Renal blood flow is reduced in most cases of AKI regardless of the etiology. Doppler flow scanning can detect low renal blood flow and abnormal flow associated with renal artery stenosis. Absence of renal blood flow on Doppler scanning suggests complete thrombosis of the renal circulation.[59]

Nuclear Scan

Radionuclide imaging with 99mTc-labeled diethylene-triaminepenta-acetic acid (99mTc-DTPA) or I[131]-labeled iodohippurate (I[131]-Hippuran) or Mag3 scans can be used to assess renal blood flow and tubular function in AKI. However, the utility of this evaluation is similar to that of Doppler flow scanning. Unfortunately, marked delay in tubular excretion of nuclide occurs in both prerenal and intrarenal diseases; thus, this technique is of little value in the evaluation of most patients with AKI. However, it is helpful if it reveals a complete absence of blood flow.

Computed Tomography and Magnetic Resonance Imaging

Computed tomography (CT) or magnetic resonance imaging (MRI) may be useful in detecting parenchymal renal disease and obstructive uropathy. These modalities are of limited value and in most cases do not provide more information with regard to renal blood flow than does Doppler flow scanning. However, an increase in T2-weighted signal on an MRI may be seen in some cases of acute tubulointerstitial nephritis ( Fig. 22-3 ). Magnetic resonance venography is helpful in the evaluation of renal vein thrombosis.

001018

000519

FIGURE 22-3  T2-weighted magnetic resonance image of a patient with biopsy-proven acute tubulointerstitial nephritis. Note increased signal diffusely throughout the cortex of both kidneys.

000519

 

Lately, an increasing number of reports have suggested an association between exposure to gadolinium-containing contrast agents during MRI studies and nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (NFD/NSF), a progressive debilitating in patients with CKD and ESRD.[60] In light of these reports, the Food and Drug Administration has issued a public health advisory regarding the use of agents in CKD patients and has recommended the physicians to carefully weigh risks and benefits of using gadolinium in patients with moderate CKD (GFR < 60 ml/min/1.73 m2) to ESRD. It also recommends considering prompt dialysis to eliminate the contrast agent although there are no published data to suggest utility of dialysis to prevent NSF.

Renal Angiography

A renal angiogram is helpful in patients with AKI due to vascular disorders, including renal artery stenosis with AKI from ACE inhibition, renal artery emboli, and aortic atherosclerosis with acute aortorenal occlusion, as well as in cases of systemic necrotizing vasculitides such as polyarteritis nodosa and Takayasu arteritis. Takayasu arteritis can affect the distal aorta and manifest as advanced renal failure.

Renal Biopsy

When clinical, biochemical, and noninvasive imaging studies are insufficient for diagnosis and management of AKI, a renal biopsy should be considered. Some studies show that biopsy in the setting of AKI often has unexpected findings. [52] [61] [62] [63] Renal biopsy is considered the “gold standard” for diagnostic accuracy in AKI, but in clinical practice, it is not often performed. An exception is biopsy of a renal transplant, which is performed relatively commonly in patients with AKI because of the need to exclude transplant rejection as the cause.

Patients presenting with the clinical syndrome of rapidly progressive glomerulonephritis should undergo percutaneous renal biopsy as soon as possible unless there is an overt contraindication. This condition is considered a medical emergency because effective kidney-preserving therapy may be indicated and, if so, should be instituted as soon as possible.[63] For example, in a febrile patient with endocarditis who is receiving broad-spectrum antibiotics, a biopsy may be necessary to distinguish between glomerulonephritis and acute tubulointerstitial nephritis. These conditions require different therapeutic interventions.

CHRONIC KIDNEY DISEASE

Patients with CKD most often present with nonspecific complaints or are asymptomatic and are referred to a nephrologist because of abnormal blood or urine findings.[64] As with AKD, it is important to establish the cause of CKD. Once this has been accomplished, further evaluation may be important in order to maximize the potential to preserve or restore glomerular filtration rate (GFR). Evaluation methods for CKD are similar to those for AKI; however, specific evaluations based on cause and chronicity are essential in patients with CKD. In particular, evaluation of cardiovascular risk factors is critical because of the high rate of cardiovascular complications in CKD. [65] [66] [67] [68]This section focuses on CKD in the pre-ESRD period.

Establishing Chronicity of Disease

History and measurement of renal size are helpful in establishing chronicity of kidney disease.[59] It is important to note that no specific blood or urine test unequivocally differentiates AKD from CKD. For example, a common misconception is that very high blood levels of urea nitrogen or very low levels of blood hemoglobin signify CKD. Similarly, other biochemical markers such as parathyroid hormone level or phosphate concentration should not be used to establish chronicity of kidney disease. Cr concentration in the fingernail can establish Chronicity, but the determination is not widely available in practice.[69]

History

In symptomatic patients with CKD, symptoms have often been present for months or years.[70] Urinary symptoms suggesting CKD include difficulty with urination, history of urinary tract infections, passage of kidney stones, dribbling, dysuria, and especially, nocturia. The last, a common symptom in CKD, is usually found when sought during history taking. Other long-standing symptoms associated with kidney disease are often present in patients with nocturia. However, the history does not always distinguish AKD from CKD. Reasons for the lack of specificity include poor patient recall and patient adaptation to slow development of uremia and lack of recognition of subtle symptoms or changes in behavior. Thus, patients with CKD may appear to present with very recent onset of symptoms that belies chronicity. Furthermore, compensatory mechanisms in the kidney and extrarenal adaptation to the uremic milieu account for the fact that many patients with CKD are asymptomatic, even in later stages of the disease ( Table 22-7 ).[70] This is unfortunate because late nephrology referral and evaluation of patients with CKD are associated with greater morbidity and mortality.[71] For this reason, referral of patients in early stages of CKD (1 to 3; see later) has been suggested.[72]


TABLE 22-7   -- Risk Factors for Chronic Kidney Disease

  

 

Established risk factors[*]

  

 

Age

  

 

Gender (male predilection)

  

 

Race (African American, Hispanic, Native American)

  

 

High blood pressure

  

 

Diabetes mellitus

  

 

Obesity

  

 

Metabolic syndrome

  

 

Proteinuria

  

 

Family history of kidney disease

  

 

Smoking

  

 

Atherosclerosis

  

 

Exposure to nephrotoxins such as analgesics, aristolochic acid, heavy metals

  

 

Dyslipidemia

  

 

Reduced nephron number at birth

  

 

Recurrent urinary tract infection

  

 

Emerging risk factors[*]

  

 

Oxidative stress

  

 

Elevated plasma homocysteine level

  

 

Anemia

  

 

Prothrombotic factors (e.g., plasminogen inhibitor activator-1)

 

*

See also Chapter 18 .

 

A common early sign of uremic encephalopathy is sleep disturbance. Typically, patients have difficulty falling asleep, awaken during the night, and again have difficulty falling asleep, with subsequent early morning awakening accompanied by daytime sleeping. Subsequent loss of short-term memory, difficulty concentrating, and episodes of confusion occur. Because patients are often unaware of these abnormalities, the history should be supplemented by interviewing a family member whenever possible.

A history of recent infection, chronic rash, or long-standing arthritis may indicate a primary renal or systemic disease that is chronic in nature. A history of human immunodeficiency virus (HIV) infection should be sought in patients with proteinuria and CKD of unknown cause. Routine inquiry into the following risk factors should be conducted: hypertension, diabetes mellitus, congestive heart failure, chronic liver disease, known or suspected hepatitis B or C infection, and rheumatologic diseases. A previous history of urologic disorders or procedures may provide clues to the detection and diagnosis of obstructive and reflux nephropathies and congenital anomalies of the urinary tract. For example, long-standing history of dysuria, nocturia, stranguria, recurrent bladder or kidney infection, trauma, and urinary frequency may indicate vesicoureteral reflux.[73] A history of abnormal findings on a urinalysis conducted as part of an entrance examination for education, military service, or other purposes may provide clues to diagnosis of CKD. A history of back pain or bone pain, particularly in an older patient with CKD, should raise the possibility of malignancy, especially multiple myeloma.

A history of nephrotoxin exposure is essential. Nephrotoxins take many forms, including prescription medication, over-the-counter drugs, and environmental substances. Recent or long-standing history of ingestion of combination analgesic agents (phenacetin, acetaminophen, aspirin) is important in establishing the diagnosis of analgesic nephropathy.[74] Environmental exposure to lead, arsenic, mercury, or silicon or ingestion of certain herbal remedies (e.g., slimming regimens containing aristolochic acid) can lead to the diagnosis of CKD. [43] [75] [76] [77] [78] [79] Exposure to cancer chemotherapeutic agents, herbal remedies, over-the-counter drugs (such as pamidronate for chronic hypercalcemia or osteoporosis), lithium in patients with bipolar disorders, and cyclosporine in recipients of solid organ transplants can cause CKD. [12] [80] [81] A history of recurrent urinary tract infection with flank pain, fever, polyuria, and nocturia suggests chronic pyelonephritis.

A family pedigree should be constructed during the ascertainment of a family history in search for inherited diseases. Family history of common diseases, including diabetes and hypertension, should be explored as common causes (diabetes, hypertensive nephrosclerosis) of CKD aggregate in families. [82] [83] [84] [85] African Americans have a higher incidence of CKD than whites, but the reasons for this discrepancy are incompletely understood. [86] [87]Although genetic predisposition seems possible, it has yet to be proved. Family history of anemia and sickle cell disease is important, particularly in African American patients.[88] For approximately 50% of patients with CKD attributed to hypertension or diabetes, at least one family member has the disorder. [83] [89] A pedigree comprising parents, grandparents, great-grandparents, siblings, and offspring is important for identifying autosomal dominant (e.g., autosomal dominant polycystic kidney disease), sex-linked (e.g., Fabry disease), Alport's syndrome, and autosomal recessive (e.g., medullary cystic disease) diseases. These diseases require radiologic evaluation and, often, renal biopsy to establish the diagnosis.[90] Detailed family history improves the diagnosis of genetic diseases and aids in future diagnostic and therapeutic interventions in CKD that will be based on genetic tests.

Physical Examination

BP should be measured in all patients undergoing evaluation for kidney disease. Standard technique for accurate measurement should be used (see later).

The skin should be examined for excoriations due to uremic pruritus, which are often seen on the back, torso, and lower extremities. Vitiligo and periungual fibromas may be seen in tuberous sclerosis. Neurofibromas may be a clue to renal disease caused by underlying renal artery stenosis in patients with neurofibromatosis. Hyperpigmented macules in the pretibial skin are often observed in patients with cryoglobulinemic disease, and livedo reticularis may be observed in those with atherosclerotic ischemic nephropathy. A general sallow appearance of the skin is also a common finding in patients with stage 5 CKD.

Funduscopic examination may demonstrate vascular findings, such as microaneurysms and proliferative retinopathy characteristic of diabetic retinopathy. Arteriolar narrowing, arteriovenous nicking, hemorrhage, and exudates consistent with hypertension are also common. Less common findings that are more difficult to demonstrate on routine examination are anterior lenticonus and retinal flecks characteristic of Alport syndrome. Angioid streaks may be present in those with Fabry disease. Ocular palsy may be present in patients with vasculitides (e.g., Wegener granulomatosis), and diffuse conjunctivitis is a sign of calcium-phosphorus deposition in CKD with secondary hyperparathyroidism.

High-tone sensorineural hearing loss is overt in about 50% of patients with Alport syndrome. Nasal and oropharyngeal ulcers may be present in those with active lupus nephritis. The presence of perforated nasal septum should raise the suspicion for Wegener granulomatosis in patients with hypertensive proteinuric renal disease. Examination for carotid bruit as a manifestation of underlying atherosclerosis may also provide a clue to the presence of renovascular hypertension and ischemic nephropathy as a cause of CKD.

Assessment of the cardiovascular and volume status is essential, because abnormal findings require early and rapid intervention before completion of the evaluation for CKD. For example, volume depletion in a patient with advanced CKD may be a “reversible” cause of ESRD. Cardiopulmonary examination for signs of volume overload is essential not only for diagnosis but also for subsequent evaluation and management of CKD. For example, many patients have underlying heart diseases such as left ventricular hypertrophy and heart failure. Cardiac murmurs may be present in patients with endocarditis or atrial myxoma associated with glomerulonephritis.

Abdominal examination should include a search for palpable kidneys, as observed in polycystic kidney disease and tuberous sclerosis. A flank mass can be found in patients with retroperitoneal fibrosis, lymphoma, or other tumors that can obstruct the ureters. A palpable bladder or enlarged prostate gland suggests chronic urinary outlet obstruction.

Musculoskeletal examination, including examination for edema, should be performed. Synovial thickening in small joints of the hands may be seen in systemic lupus erythematosus and rheumatoid arthritis, both of which may be associated with CKD. Clubbing may be a clue to bacterial endocarditis or chronic suppurative conditions (e.g., lung abscess) that may lead to development of secondary amyloidosis involving the kidney. Neurologic signs in patients with CKD include peripheral sensorimotor neuropathy and central nervous system manifestations. Generalized muscle weakness and diminished deep tendon reflexes are common.

Urinalysis

Urinalysis is not particularly useful for differentiating AKD from CKD. Similar findings, such as pyuria, hematuria, and proteinuria, indicating interstitial nephritis can be seen in AKI or CKD. Presence of oval fat bodies in the urine, signifying high-grade proteinuria, implies a glomerular disease, as does the presence of dysmorphic RBCs. [91] [92] Calcium oxalate crystals may be seen in the urine of patients with hereditary or secondary forms of oxalosis causing kidney disease. The presence of calcium phosphate and sodium urate crystals may signify previous stone disease as a cause of CKD. Triple phosphate crystals may suggest recurrent urinary tract infection and staghorn calculi causing CKD. As described later, proteinuria is an important finding in any patient with CKD.

Renal Osteodystrophy

Radiographic evidence for renal osteodystrophy is present in CKD but not in ARF. Elevated plasma parathyroid hormone concentration can be present in both AKI and CKD but is not sufficient evidence for the diagnosis of osteodystrophy. Radiographs of the shoulders, ribs, hands, and pelvis illustrating signs of osteitis fibrosa cystica strongly suggest CKD; this finding is rarely if ever observed in ARF. A possible exception may be a patient with parathyroid cancer in whom severe primary hyperparathyroidism may induce hypercalcemic AKI.

Renal Mensuration

The most sensitive and specific test for establishing the chronicity of kidney disease is measurement of renal size. Renal ultrasonography remains the technique of choice to screen for renal size abnormalities.[59] The details of this procedure are discussed in Chapter 27 . The finding of small kidneys (i.e., small relative to body size) on renal ultrasonography (or other method, such as a plain film of the abdomen, CT and MRI scans) is a reliable indicator of CKD. However, it is important to note that kidney size varies from individual to individual and between evaluation methods (e.g., CT versus ultrasonography). In contrast to the finding of small kidneys as a sign of CKD, the finding of normal size or large kidneys is a sensitive but not specific sign of AKD. That is, patients with AKI have normal or enlarged kidneys; however, normal or enlarged kidneys are observed in many forms of CKD including HIV nephropathy, diabetic nephropathy, and autosomal dominant polycystic kidney disease (see Table 22-1 ). Enlarged multicystic kidneys are a highly characteristic feature of polycystic kidney disease, and ultrasonography is the screening procedure of choice for this disease (see Chapter 27 ).[59]

Renal Biopsy

Renal biopsy is the most definitive method of differentiating AKI from CKD.[62] A biopsy is used to establish diagnosis, determine treatment regimen, collect prognostic information, and track the clinical course of CKD, especially in glomerulonephritis. Histologic findings of chronicity include glomerulosclerosis, tubular atrophy, and interstitial fibrosis. The latter finding is the best indicator of chronicity and prognosticator of long-term outcome. Renal biopsy is a low-risk procedure in stable patients with CKD, including the elderly.[59]

Risk Factors for Chronic Kidney Disease (see also Chapter 18 )

It is now recognized that a number of factors increase the risk for development of CKD (see Table 22-7 ). [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] Among the strongest factors associated with increased risk for CKD are diabetes mellitus and hypertension.[106] Currently, nearly 50% of new cases of ESRD occur in diabetic patients, and 27% in hypertensive patients. Additional clinical factors associated with increased risk for CKD are autoimmune disease, chronic systemic infection, urinary tract infection, obstruction of the urinary tract, cancer, family history, reduced renal mass, low birth weight, drug exposure, and recovery after AKI (see later). Older age and ethnicity are also important.[106] It is well known that certain ethnic minorities have a markedly higher risk for CKD, including African Americans, Mexican Americans, Native Americans, Asians, and Pacific Islanders. [83] [106] [107] [108] [109] Cigarette smoking, metabolic syndrome, and obesity as well as dyslipidemia have been linked with development of CKD. [110] [111] [112]

Prevalence of Chronic Kidney Disease (see also Chapter 17 )

It is estimated that approximately 20 million Americans have CKD. [106] [113] Both the prevalence and the incidence of CKD are increasing.[106] The most common causes of CKD leading to ESRD are diabetes mellitus, hypertension, glomerulonephritis, and cystic kidney disease, which together account for 90% of all new cases of CKD. In the United States, estimates of prevalence of CKD vary from 10 to 20 million, depending on the definition. Confusion in terminology as well as methods for defining CKD and its severity have hampered our ability to identify patients and, therefore, how to approach the problem of CKD. The Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines for CKD evaluation, classification, and stratification published by the National Kidney Foundation provide a framework designed to address the growing burden of CKD in the United States.[70]The guidelines emphasize the need for prevention, early diagnosis, and treatment of CKD.

Definition and Staging of Chronic Kidney Disease (see also Chapter 17 )

CKD is defined as kidney damage with or without decreased GFR, manifested as either pathologic abnormalities or markers of kidney damage, including abnormalities in composition of blood or urine, abnormality renal imaging findings, and a GFR less than 60 mL/min 1.73 m2. This broad definition includes patients with or without symptoms of kidney disease ( Fig. 22-4 ).[70]

000691

000519

FIGURE 22-4  Clinical signs and symptoms in chronic kidney disease according to stage. With advancing stage, both symptoms and signs tend to worsen. HTN, hypertension.

000519

 

Staging of CKD is based on estimate of GFR ( Table 22-8 ).[70] Observational studies, administrative databases, and clinical trials indicate that patients with CKD are at increased risk for both progression to ESRD and cardiovascular morbidity and mortality. [114] [115] This situation is accounted for in part by the fact that many risk factors are common to both progression of kidney disease and cardiovascular complications, such as diabetes, hypertension, and dyslipidemia. However, even after adjustment for common risk factors, the incidence of myocardial infarction and cerebrovascular events is higher in patients with CKD, suggesting that CKD is a risk factor for cardiovascular disease.[116] Therefore, management of risk factors is paramount in this patient population.


TABLE 22-8   -- Staging of Chronic Kidney Disease

Stage

Description

Estimated GFR[*]

Evaluation Plan

 

At increased risk

>90 (with CKD risk factors)

Screening CKD risk reduction

1

Kidney damage with normal or increased GFR

≥90

Diagnose and treat cause, slow progression, evaluate risk of cardiovascular disease

2

Kidney damage with mild decrease in GFR

60–89

Estimate progression

3

Moderate decrease in GFR

30–59

Evaluate and treat complications

4

Severe decrease in GFR

15–29

Prepare for renal replacement therapy

5

Kidney failure

<15

Initiate renal replacement therapy

 

*

GFR = 186 · Scr-1.154 · Age-0.203 [· 0.742 for female and/or · 1.210 for African American] CKD, chronic kidney disease; GFR; glomerular filtration rate; Scr, serum creatinine level.

 

Evaluation of Chronic Kidney Disease

Estimation of Glomerular Filtration Rate (see also Chapter 23 )

GFR is generally considered the best overall estimate of renal function and therefore should be used to evaluate onset and progression of kidney disease. In addition, estimating GFR is useful for determining dosage regimens for therapeutic agents whose excretion is primarily renal. This later consideration is very important not only in general medicine but also in geriatrics and oncology, specialties in which serum Cr concentration alone gives a poor estimate of renal function. Moreover, it is known that, as GFR declines, the number of complications and comorbidities associated with CKD increases.

Estimation of GFR can be accomplished by formal measurement of inulin or iothalamate or other clearance markers. These methods are most accurate but are also cumbersome, inconvenient, and expensive. Estimating GFR on the basis of a patient's age, gender, ethnicity, and serum Cr concentration is a practical method that is gaining widespread acceptance. [116] [117] This estimate is derived from regression models based on demographic, anthropometric, and biochemical data in participants in clinical trials who underwent repeated direct measurement of GFR by iothalamate clearance. Similar methods using Cr clearance as an estimate of GFR are based on regression models developed from 24-hour urine samples (detailed analysis of these methods is presented in Chapter 23 ). The most widely used estimate of GFR is based on data obtained in the Modification of Diet in Renal Disease (MDRD) Study, a large-scale clinical trial, sponsored by the National Institutes of Health, of diet and BP control in patients with established CKD.[118] The equation for estimating GFR based on these variables and the staging of CKD on basis of GFR, as recommended by the National Kidney Foundation, are outlined in Table 22-8 .

An important aspect of this method of estimating GFR is the determination of serum Cr concentration for a single estimate of GFR as well as repeated measures over time. First, it should be remembered that measurement error could result in spurious overestimation or underestimation of GFR. In addition, laboratory methods for measuring serum Cr concentration vary, and the variations can result in substantial differences in estimated GFR (see equation in Table 22-8 ). For this reason, it is appropriate to measure serum Cr value in new patients in the nephrologist's own laboratory and to repeat the measurements in the same laboratory with the same method over time.

Second, dietary intake can have an important effect on serum Cr concentration. It is known that meals containing cooked meat can transiently but significantly raise serum Cr concentration. Calculation of GFR from a serum Cr value obtained after a patient has eaten a meal containing a large amount of Cr, which would yield a falsely high Cr value for that patient, would lead to a spurious underestimation of the patient's GFR. Therefore, it is important to measure serum Cr concentration in a fasting blood specimen to increase the likelihood of an accurate estimate. Also, steady-state serum Cr concentration may change as a result of a long-term change in dietary protein intake. [117] [119] Thus, high animal protein intake increases, and low animal protein intake decreases, the steady-state serum Cr. Estimating GFR at two time points in a patient who markedly alters his or her dietary animal protein intake in the interim may confound the interpretation of GFR estimation and lead to an erroneous conclusion regarding changes in the patient's renal function. Finally, it should be remembered that estimating GFR from serum Cr values is subject to inaccuracy and imprecision beyond changes in serum Cr concentration, errors in Cr measurement, and nonstandardization of methods for Cr measurement.[120]

Recently, cystatin C has been proposed as novel marker for kidney function. Cystatin C is an endogenous small-molecular-weight protein present in normal human plasma. Its production rate is relatively constant and independent of muscle mass, and it is excreted from the body by the kidney through filtration, not secretion. In these respects, it is a superior marker of filtration function than serum Cr. Moreover, in elderly individuals enrolled in the Cardiovascular Health Study, cystatin C appeared to be a better predictor of clinical outcomes than serum Cr.[121]

Hypertension (see also Chapter 42 )

Ninety percent of patients with CKD experience hypertension (BP >130/80 mm Hg) during the course of the disease. Uncontrolled hypertension accelerates the rate of progression regardless of the cause of renal failure. Clinical trials and epidemiologic studies indicate that hypertension is a major risk factor for progressive kidney disease. Evaluation of subjects screened in a multiple risk factor intervention trial who were monitored over a 16-year period showed that (1) higher BP was a strong and independent risk factor for the development of ESRD and (2) the relative risk for ESRD increased with rising systolic BP independent of diastolic BP. In patients with type 2 diabetes mellitus, there is almost a linear relationship between increase in mean arterial BP and yearly decrease in GFR. Analysis of National Health and Nutrition Evaluation Survey (NHANES) III data suggests that adequate BP control is achieved in only 11% of patients with hypercreatininemia (serum Cr > 1.5 mg/dL).[122] More recent analysis of NHANES IV indicates that only 37% of hypertensive patients with CKD have BP controlled to a level of less than 130/80 mm Hg.[123] Risk factors for uncontrolled hypertension included age older than 65, black race, and presence of albuminuria. In general, older people with hypertension are unaware of their BP elevation, and the majority of those who are aware have poor control rates. CKD prevalence is higher in older age groups, in which systolic hypertension is very common. Currently, the median age of patients with CKD entering treatment programs in the United States is 64.8 years.[106]

Documentation of BP is essential in the assessment of CKD because this parameter is strongly associated with kidney disease progression and cardiovascular mortality. BP should be measured often with standardized techniques promulgated by the American Heart Association and National Heart Lung and Blood Institute. The goal BP for patients with CKD is 120 to 139 mm Hg systolic and 70 to 85 mm Hg diastolic, depending on the disease type. For example, goal BP for diabetic patients with hypertension is less than 130 mm Hg systolic and less than 80 mm Hg diastolic[124]; for patients with hypertensive nephrosclerosis, the goal BP is 130 to 140 mm Hg systolic and 80 to 89 mm Hg diastolic.[125]

Figure 22-5A illustrates the mean rate of decline in GFR plotted as a function of mean controlled systolic BP in nine clinical trials of both diabetic and nondiabetic patients with CKD.The dotted line labeled “Normal” indicates the normal rate of decline in GFR of about 0.75 mL/min/yr observed with aging alone in normal men older than 45 years. As can be seen in the graph, lower systolic BP values are associated with slower rate of decline in GFR. Figure 22-5B illustrates the hypothetical effect of lowering systolic BP from a range of 150 to 160 mm Hg to a range of 120 to 130 mm Hg on the decline in GFR in an individual patient. Although this figure is only an estimate, it serves as a reminder to the treating nephrologist and as an educational tool for patients about the importance and potential benefit of BP control in renal outcome.

000849

000519

FIGURE 22-5  A, Relationship between blood pressure and decline in glomerular filtration rate (GFR) in chronic kidney disease, based on data from clinical trials (see text for details). Results from nine clinical trials, five in patients with diabetic nephropathy and four in patients with nondiabetic nephropathy, indicate that mean rate of decline in GFR is directly associated with level of mean systolic blood pressure (SBP) during the trial. Note that even at normal systolic blood pressure, the rate of decline in GFR in patients with nephropathy is more than twice that associated with aging in normal individuals (dotted horizontal line). B, Effect of an intervention that lowers blood pressure on the rate of decline in GFR and the time of onset of end-stage renal disease (ESRD) in a theoretical patient with chronic kidney disease and hypertension.

000519

 

Detection and Estimation of Proteinuria (see also Chapter 23 )

Evaluation of all patients with CKD should include testing for proteinuria. Strategies aimed at reducing proteinuria have been shown to slow the rate of decline in GFR in CKD due to hypertension, diabetes, and the glomerulonephritides.[125] Detection and quantification of microalbuminuria in patients with CKD and a negative urine protein dipstick test result should be performed on an initial visit. For the patient in whom a urine protein dipstick test result is positive, quantification of proteinuria should be performed as described later. For individuals referred for proteinuria with a negative urine protein dipstick test result but positive sulfosalicylic acid test result or a 24-hour urine sample demonstrating protein, a test for urine light chains should be performed. As discussed in Chapter 18 , unrelenting proteinuria has been shown to greatly increase risk for progression of CKD in diabetic and nondiabetic nephropathies including the glomerulonephritides, hypertensive nephrosclerosis, and autosomal dominant polycystic kidney disease.

Proteinuria has been extensively studied as a marker for progression of renal disease. Clinical trials have shown that patients with impaired renal function and high-grade proteinuria (>1 g/day) progress at a faster rate than those with low-grade proteinuria (≥1 g/day). [99] [104] For example, in both diabetic and nondiabetic patients with proteinuric renal disease, acceleration of renal disease progression correlates with the level of baseline proteinuria. Even in patients with controlled essential hypertension and no evidence of renal disease, the onset of proteinuria may be a marker of future decline of renal function. Also, the MDRD Study demonstrated that baseline proteinuria was an independent risk factor for progression of renal disease in nondiabetic patients and that the extent of proteinuria reduction might be a measure of the effectiveness of BP control.[126] Normal individuals excrete less than 150 mg/day of protein. Loss of protein (albumin) in the urine becomes apparent on reagent test strip tests when the urine contains 300 mg/L or more, or 300 mg or more albumin/g Cr ( Table 22-9 ).


TABLE 22-9   -- Microalbuminuria and Macroalbuminuria

 

Microalbuminuria

Macroalbuminuria

Definition (mg albumin/mg creatinine)

>30–299

≥300

Routine dipstick test result

Negative

Positive

Renal significance

At risk for nephropathy

Marker of rapid progression

Effect on cardiovascular risk

Increased

Increased

 

 

 

The recommended method of screening for abnormal albuminuria is to first measure albumin by urine dipstick test. If the result is negative, it is preferable to obtain a freshly voided morning urine sample (“spot” or “random”) and send it to the laboratory for measurement of albumin and Cr and calculation of the albumin-to-Cr ratio. Collection of a 24-hour urine sample to screen for albuminuria is not recommended; instead, a random specimen should be collected for determination of urine albumin– or protein-to-urine creatinine ratio.[101] Under normal circumstances, urinary albumin, measured as the ratio of albumin to Cr, in a random urine sample is less than 30 mg/g Cr.

Microalbuminuria, defined as an albumin excretion in the range between 30 and 300 mg/g Cr, is not detected by the routine dipstick method (which, by the way, detects only albumin, not other proteins such as light chains). Macroalbuminuria is defined as an albumin excretion rate of more than 300 mg/g Cr. Both are markers for risk for progression of nephropathy in patients with type 1 and type 2 diabetes and for increased risk of cardiovascular death.[94] [127] More-over, more than 300 mg/g of protein is associated with higher risk of progression of kidney disease in hypertensive nephrosclerosis.

A simple algorithm for screening and evaluation of proteinuria is illustrated in Figure 22-6 . Monitoring proteinuria or albuminuria in CKD can be accomplished without 24-hour urine collection, but instead by repeated determinations of the urine albumin-to-Cr or urine protein-to-Cr. As with screening samples, these determinations should be performed on freshly voided morning urine samples.

000168

000519

FIGURE 22-6  Algorithm for evaluation of proteinuria in chronic kidney disease. ACEi, angiotensin-converting enzyme inhibitors; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; ARB, angiotensin type 1 receptor blocker; GBM, glomerular basement membrane; HBSAg, hepatitis surface B antigen; Hep C Ab, hepatitis C antibody; Scr, serum creatinine level; SPEP, serum protein electrophoresis; U/A, urinalysis; UPEP, urine protein electrophoresis.

000519

 

Obesity

Two recent observational studies indicate that obesity may be an independent risk factor for development of CKD. [128] [129] These studies raise the possibility that factors other than hypertension and diabetes obesity may play a role in development of kidney disease.

Cardiovascular Disease in Chronic Kidney Disease (see also Chapter 48 )

CKD is an independent risk factor for cardiovascular disease and all-cause mortality.[115] Observational studies indicate that rates of both stroke and myocardial infarction are higher in patients with CKD before development of ESRD. For example, Go and co-workers[130] reported on the risk of all-cause mortality and cardiovascular hospitalizations among 1.2 million participants in the Northern California Kaiser-Permanente health care system. They found a graded increase in mortality and cardiovascular hospitalizations as estimated GFR declined. This association was independent of traditional cardiovascular risk factors. In prospective clinical trials, an increased serum Cr value at baseline raised risk for stroke, myocardial infarction, and all-cause cardiovascular mortality.[131] These data suggest that CKD, independent of common risk factors such as age, BP, diabetes, and proteinuria, may be an independent coronary heart disease risk factor.

CKD markedly increases the risk of cardiovascular death from cardiac events and stroke. [106] [116] The mortality risk in patients with CVD is 10- to 30-fold higher than that in normal, age-matched populations. Median survival after an acute myocardial infarction in patients undergoing dialysis is less than 18 months, even in the thrombolytic era. Hypertensive patients with hypercreatininemia are at higher risk of myocardial infarction and stroke,[2] and diabetic patients with proteinuria are at greater risk for fatal myocardial infarction and stroke.[12] Prevalence of left ventricular hypertrophy and congestive heart failure is strikingly elevated in patients with CKD stages 2 through 5,[132]including those undergoing dialysis. Morbidity and mortality for congestive heart failure and coronary heart disease are also excessive in CKD.

Figure 22-7 illustrates that CVD and CKD may be manifestations of a similar disease process. Cardiovascular and renal disease have the following types of markers in common: clinical, [133] [134] pathophysiologic (e.g., increased angiotensin II activity, up-regulation of inflammatory and fibrosis producing cytokines),[135] histopathologic, biochemical,[135] acute and chronic inflammation,[135] and subclinical signs of atherosclerosis (e.g., increased common carotid artery intima-media thickness). [136] [137] Furthermore, the constellation of cardiovascular disease risk factors found in the obesity metabolic syndrome have been linked to higher risk for development of both cardiovascular disease and CKD.[138]

001087

000519

FIGURE 22-7  Competing outcomes in patients with chronic kidney disease (CKD). Cardiovascular disease and CKD may be manifestations of a similar disease process. Patients with CKD are at high risk for both fatal cardiovascular (CV) and noncardiovascular (non-CV) events as well as progression to end-stage renal disease (ESRD). Risk factors for these competing outcomes may be identical. CHF, congestive heart failure; LVH, left ventricular hypertrophy.

000519

 

Assessing Comorbidity

Most patients with CKD have comorbidities, the number rising with increasing stage of CKD.[70] Extrarenal diseases play a key role in the progression of CKD as well as associated morbidity and mortality.[139]

Diabetes Mellitus

Diabetes accounts for nearly 50% of all new cases of ESRD in the United States and an increasing percentage of cases of ESRD around the world. Recognition of diabetes as a comorbidity is essential in evaluation of CKD.

Assessment of blood glucose control by measurement of hemoglobin A1c should be conducted in patients with diabetes mellitus, because hyperglycemia is associated with progression to nephropathy. Elevated plasma glucose raises the risk of progression to diabetic kidney disease in both type 1 and type 2 diabetes. [126] [140] Undiagnosed and untreated, diabetic kidney disease progresses rapidly. It is critical to evaluate glycemic control and BP in diabetic patients, because optimal management of these risk factors can slow progression of kidney disease.

Cardiovascular morbidity is common in patients with CKD and the major cause of death. [124] [141] Evaluation of cardiac status and function should include a careful history for coronary artery disease and congestive heart failure. This is particularly important in older patients with CKD, who are more than 100-fold more likely to die before development of ESRD than are age-matched normal persons.[141] In addition, diabetes is associated with many comorbidities that complicate the course of CKD, including high rates of heart failure and peripheral vascular disease complications.

Homocysteine

Studies in CKD and non-CKD populations indicate that hyperhomocysteinemia is a risk factor for cardiovascular death.[142] Plasma homocysteine concentration rises with decreasing renal function in CKD.[143] The mechanism of hyperhomocysteinemia in CKD is incompletely understood; however, abnormal enzyme activity, substrate limitation, and abnormal renal excretion have all been cited as possible causes.[144] Hyperhomocysteinemia is associated with progression of CKD in diabetic and nondiabetic patients but is not an independent risk factor.[145]

Current guidelines do not recommend measurement of homocysteine level, because whether long-term lowering of homocysteine reduces the risk of either cardiovascular disease or progression of CKD is not known.[145]Administration of folic acid, 5 mg/day, in patients with CKD can lower plasma homocysteine levels.[146] It remains to be determined whether this therapy decreases cardiovascular complications or affects progression of kidney disease in patients with CKD. Recently, intervention studies using homocysteine in the general population have not demonstrated a reduction in cardiovascular events. [147] [148] [149] However, the health risk of folic acid in doses of up to 5 mg/day is rather low, and the agent is inexpensive. Until clinical trials determine whether folic acid or other treatment of hyperhomocysteinemia is beneficial in patients with CKD, clinical judgment should be used in determining whether to prescribe folic acid for this purpose.

Dyslipidemia

Fasting serum total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levelsshould be measured in patients with CKD. Clinical evidence indicates that dyslipidemia may contribute to the onset and progression of CKD as well as of cardiovascular disease in patients with CKD.[150] Both hypertriglyceridemia and hypercholesterolemia have been associated with declining kidney function. [93] [151] Dyslipidemia is believed to play a role in both the development of cardiovascular disease and the progression of renal disease in patients with pre-ESRD or kidney transplants regardless of the underlying cause (e.g., diabetes, hypertension).[93] The most common dyslipidemia observed in patients with CKD is atherogenic dyslipidemia—a combination of hypertriglyceridemia, low levels of high-density lipoprotein (HDL) cholesterol, and high levels of small, dense LDL particles.[152] In addition, isolated hypercholesterolemia and combined hypercholesterolemia and hypertriglyceridemia are common in patients with CKD and nephrotic syndrome. [153] [154] Increased levels of lipoprotein (a) are also common in CKD.[155]Cardiovascular morbidity and mortality are increased in patients with hypercreatininemia (serum Cr level > 1.4 mg/dL), and most patients with CKD have multiple risk factors, including hypertension, proteinuria, metabolic syndrome, increased lipoprotein (a), hyperhomocysteinemia, anemia, and elevated calcium phosphorous product. Consequently, it is reasonable to expect that treatment of dyslipidemia in this population is at least as important as in populations without renal disorders.[156] Two recently completed double-blind randomized placebo-controlled clinical trials in hemodialysis patients and post-transplant patients failed to demonstrate a benefit of statin intervention for major cardiovascular morbidity and mortality. [157] [158] There are no long-term cardiovascular outcome trials in predialysis populations that have demonstrated a benefit of any lipid-lowering treatment with statins or other lipid-lowering drugs.

Current evidence supports use of the Adult Treatment Program (ATP) III guidelines for coronary heart disease in the management of dyslipidemia in patients with CKD.[152] The ATP III guidelines focus on LDL cholesterol as the primary target but also recognize the importance of atherogenic dyslipidemia as a risk factor. As noted previously, this pattern of lipid levels is the most common dyslipidemia observed in patients with CKD, including those with type 2 diabetes.

Coronary risk equivalent is defined by the National Cholesterol Education Program (NCEP) as the level of risk equivalent to that of a patient with clinical coronary heart disease. CKD is emerging as a coronary heart disease risk equivalent,[115] although it has not yet been recognized as such by the NCEP. Several lines of evidence point to CKD as a coronary risk equivalent, including clinical trials showing high prevalence of diabetes mellitus (recognized as a coronary risk equivalent) in CKD epidemiologic studies [106] [115] [141] [151] [159] and a high prevalence of traditional and nontraditional risk factors for coronary artery disease (see Table 22-2 ). Finally, the prevalence and magnitude of major risk factors for coronary disease increase as renal failure progresses (e.g., hypertension, insulin resistance, hyperhomocysteinemia).[133]

Secondary Hyperparathyroidism and Vascular Calcification

Derangements in calcium and phosphorus metabolism that develop during the course of CKD are caused by multiple mechanisms, including alterations in dietary intake, development of secondary hyperparathyroidism and hypovita-minosis D, and alterations in calcium-sensing receptor and bone-associated proteins.[160] Serum calcium, phosphorus, parathyroid hormone, and 1,25-dihydroxyvitamin D3 levels should be measured in patients with CKD. Although the serum calcium level drops, the serum phosphorus level rises, leading to an abnormal increase in the calcium-phosphorus product, [Ca] × [Pi]. [161] [162] The normal product is about 40 mg2/dL2. Experimentally, even small increases in [Ca] × [Pi] may increase calcification of soft tissue, including vascular tissues. Furthermore, mobilization of calcium and phosphorus from bone as a consequence of elevated parathyroid hormone may worsen the increase in [Ca] × [Pi].[162] Also, patients with stages 3 through 5 CKD not on dialysis have an eightfold higher risk for increased coronary artery calcification as detected by electron-beam CT than those without CKD. This increase was largely due to the high calcium burden in coronary arteries of diabetics with CKD. [163] [164] [165] [166] [167] [168] [169] Hyperphosphatemia activates bone-associated proteins that increase smooth muscle cell proliferation and vascular calcification, including osteo-calcin, bone morphogenetic protein 2a (BMP 2a), alkaline phosphatase, and osteonectin, but down-regulates p21, a cyclin-dependent kinase complex that inhibits proliferation.[162] The net effect is the development of renal osteodystrophy and vascular calcification. The latter consequence is ominous: It contributes to an acceleration in the rate of atherosclerosis and cardiovascular events in CKD. Increased [C] × [Pi] is associated with greater mortality in patients undergoing hemodialysis as well as with a higher increased coronary artery calcification score in such patients. [137] [164] [165] [166] [167] [168] [169] For this reason, levels of calcium, phosphorus, and calcium-phosphorus product should be evaluated and monitored in all patients with CKD, and early treatment to reduce an elevated [Ca] × [Pi] should be considered.[170] In addition, the majority of patients with CKD stage 3 (or higher) have vitamin D deficiency (low plasma 25(OH) vitamin D3 level) in association with secondary hyperparthyroidism. Therefore, measurement of plasma 25(OH) vitamin is recommended by the National Kidney Foundation.[170] In this situation, repletion of 25(OH) vitamin D3, the precursor of 1.25 (OH)2 vitamin D3 is recommended to correct vitamin D deficiency and secondary hyperparathyroidism. Outcomes trials in hemodialysis patient populations examining the role of hyperparathyroidism are limited. The Dialysis Cardiovascular Outcomes Revisited (DCOR) trial enrolled more than 2000 patients randomized either to the non-calcium-containing phosphate binder sevelamer HCl or to calcium-containing phosphate binders and followed them for 3 years.[171] The results indicate no overall benefit of sevelamer versus calcium-containing binder. However, in subgroup analysis, older (>65 yr) study participants randomized to sevelamer had fewer cardiovascular events.

Malnutrition

Malnutrition is common in patients with stages 4 and 5 CKD and is associated with reduced survival. [70] [172] [173] Patients with stages 4 and 5 CKD have reduced energy intake, abnormal levels and metabolism of plasma amino acids, and dysregulation in carbohydrate and lipid metabolism (see later). Clinical evidence indicates that estimation of dietary protein intake is an important component of evaluation of CKD. Malnutrition is identified clinically from a dietary history of decreased energy and nutrient intake along with weight loss, physical signs of muscle wasting, and declining serum albumin, transthyretin, and transferrin levels. Anthropometric analysis indicates that patients with stages 4 and 5 disease have abnormal decreases in midarm muscle circumference and increased scapular, brachial, and thigh skin fold thicknesses. Abnormal amino acid, carbohydrate, and lipid metabolism is also present in patients with stages 4 and 5 CKD.

Markers of Inflammation and Oxidative Stress

Currently, routine clinical determinations of markers of inflammation and oxidative stress are not recommended. Intensive research is ongoing in an effort to elucidate the role of these factors in onset, progression, and complications of CKD. [174] [175] [176] There is little doubt that inflammation plays an important role in the development and progression of most CKDs. The kidney itself at end stage is characterized histologically in virtually all cases by hallmarks of chronic inflammation, including infiltration by white blood cells and fibrosis. Markers of inflammation, including C-reactive protein, interleukins 1 and 6, and tumor necrosis factor, are elevated in plasma of patients with CKD. These markers correlate with signs and symptoms of malnutrition and may play a pathogenetic role in development and persistence of malnutrition. Currently, these markers are used for experimental purposes but may become useful clinically in the future for monitoring nutrition as CKD progresses.

Metabolic Acidosis

Measurement of serum bicarbonate concentration as part of routine electrolyte analysis is essential in patients with CKD. When doubt exists as to the cause of low plasma bicarbonate value in a patient with CKD, arterial blood pH and Pco2 should be measured to confirm the presence of metabolic acidosis, concomitant primary respiratory alkalosis, or both.

Treatment of metabolic acidosis to raise bicarbonate concentration above 22 mEq/L can reduce the risk of organ dysfunction caused by the effects of metabolic acidosis on brain, heart, bone, muscles, and liver. Metabolic acidosis develops in CKD as a result of failure of the kidney's normal acid excretion ability. The consequences of chronic metabolic acidosis due to renal failure include loss of calcium from bone, hypercalciuria, fatigue, dyspnea, weakness, and protein catabolism.[177] Metabolic acidosis activates ubiquitin-sensitive proteasome pathways and branched-chain amino acid dehydrogenate in skeletal muscle cells, leading to greater protein breakdown and decreasing hepatic albumin synthesis. [178] [179] The precise pH level at which these events occur in humans is not known; however, general practice is to keep serum bicarbonate from declining below 22 mEq/L, and a normal value is desirable.

Anemia

Hemoglobin, serum iron, total iron-binding capacity, ferritin, and RBC indices and reticulocyte count must be measured as screening tests for anemia in all patients with CKD. Additional tests for other causes of anemia, such as vitamin B12, folic acid, hemoglobin electrophoresis, and tests for hemolysis should be performed on the basis of the history, physical findings, and results of the initial screen for anemia. Anemia is a major risk factor for morbidity and mortality in CKD, and practice guidelines for its management have been published. Current guidelines define anemia as a blood hemoglobin concentration less than 11 g/dL in premenopausal women and less than 12 g/dL in men and postmenopausal women.[180] This definition has led to a higher prevalence of anemia diagnosis in women, because in normal premenopausal women, blood hemoglobin level is lower than that in men.[181]

Anemia develops in more than 90% of patients with CKD as kidney disease progresses, and is multifactorial. [70] [182] The major factor in development of anemia is decreased blood level of erythropoietin due to reductions in renal synthesis and secretion of erythropoietin.[183] However, uremia contributes to this process in several ways, including direct inhibition of erythropoietin's effects on erythroprogenitor cells, anorexia leading to reduced intake of hemoglobin substrates (protein, vitamins, iron), decreased RBC life span, and reduced iron absorption. Low blood hemoglobin level due to reduced renal production of erythropoetin may begin in CKD as early as stage 2. [184] [185]Reduced oxygen-carrying capacity consequent to anemia in CKD results in organ hypoxia, which in turn aggravates uremic symptoms such as fatigue, deteriorating cognitive ability, dyspnea on exertion, and reduced physical ability.

Anemia also plays an important role in the development of congestive heart failure and left ventricular hypertrophy, the latter being observed in up to 40% of patients with stage 4 CKD and 80% of patients with stage 5 disease. [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] [197] Left ventricular hypertrophy is associated with subsequent development of ischemic heart disease and congestive heart failure as well as sudden cardiac death. [198] [199] Both hypertension and anemia are independent risk factors for left ventricular growth in CKD, and the increased risks attributed to hypertension and anemia are similar.

Anemia may also be a risk factor for progression of CKD. Several small studies indicate that treatment of anemia may slow the progression of CKD, and mild anemia (hemoglobin < 13.8 g/dL) is associated with a higher risk of ESRD in patients with type 2 diabetes and nephropathy.[200] In a recent study involving 88 patients, early treatment of anemia with erythropoietin decreased the incidence of ESRD after 3 years follow up. A higher hemoglobin was achieved and maintained during the study. Clinical trials to test whether treatment or prevention of anemia slows progression of CKD are in progress. Finally, anemia is an independent risk factor for all-cause mortality in patients with stage 5 CKD. Thus, for each 1 g/dL decrease in blood hemoglobin level below normal, mortality rate rises 18%.

Currently, practice guidelines recommend treatment of anemia attributed to erythropoietin deficiency with erythropoietin and iron (when indicated) to achieve a hemoglobin level of 12 g/dL for both men and women regardless of stage of CKD.[180] Therefore, patients with hemoglobin levels less than 11 g/dL are candidates for treatment. This issue is discussed in detail in Chapter 55 .

References

1. Esson ML, Schrier RW: Diagnosis and treatment of acute tubular necrosis.  Ann Intern Med  2002; 137:744-752.

2. Paganini EP, Kanagasundaram NS, Larive B, Greene T: Prescription of adequate renal replacement in critically ill patients.  Blood Purif  2001; 19:238-244.

3. Chertow GM, Levy EM, Hammermeister KE, et al: Independent association between acute renal failure and mortality following cardiac surgery.  Am J Med  1998; 104:343-348.

4. Mehta RL, Pascual MT, Gruta CG, et al: Refining predictive models in critically ill patients with acute renal failure.  J Am Soc Nephrol  2002; 13:1350-1357.

5. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ: Acute renal failure in intensive care units: Causes, outcome, and prognostic factors of hospital mortality. A prospective, multicenter study. French Study Group on Acute Renal Failure.  Crit Care Med  1996; 24:192-198.

6. Thadhani R, Pascual M, Bonventre JV: Medical progress: Acute renal failure.  N Engl J Med  1996; 334:1448-1460.

7. O'Hare A, Olson JL, Connolly MK, et al: Renal insufficiency with monoclonal gammopathy and urticarial vasculitis.  Am J Kidney Dis  2002; 39:203-207.

8. Fechner FP, Faquin WC, Pilch BZ: Wegener's granulomatosis of the orbit: A clinicopathological study of 15 patients.  Laryngoscope  2002; 112:1945-1950.

9. Austin HA: Clinical evaluation and monitoring of lupus kidney disease.  Lupus  1998; 7:618-621.

10. Toto RD: Acute tubulointerstitial nephritis.  Am J Med Sci  1990; 299:392-410.

11. Saxena R, Arvatsson B, Bygren P, Wieslander J: Circulating autoantibodies as serological markers in the differential dagnosis of pulmonary-renal syndrome.  J Int Med  1995; 238:143-152.

12. Bennett WM: Drug nephrotoxicity: An overview.  Ren Fail  1997; 19:221-224.

13. Hladunewich M, Rosenthal MH: Pathophysiology and management of renal insufficiency in the perioperative and critically ill patient.  Anesthesiol Clin North Am  2000; 18:773-789.

14. Ouriel K, Geary K, Green RM, et al: Factors determining survival after ruptured aortic aneurysm: The hospital, the surgeon, and the patient.  J Vasc Surg  1990; 11:493-496.

15. Hasegawa Y, Nagasawa T: [Thrombotic thrombocytopenic purpura].  Ryoikibetsu Shokogun Shirizu  2000;152-154.

16. Remuzzi G, Ruggenenti P: The hemolytic uremic syndrome.  Kidney Int  1995; 48:2-19.

17. Segasothy M, Swaminathan M, Kong NC: Acute renal failure in falciparum malaria.  Med J Malaysia  1994; 49:412-415.

18. Valbonesi M, De Luigi MC, Lercari G, et al: Acute intravascular hemolysis in two patients transfused with dry-platelet units obtained from the same ABO incompatible donor.  Int J Artif Organs  2000; 23:642-646.

19. Moore KP, Holt SG, Patel RP, et al: A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure.  J Biol Chem  1998; 273:31731-31737.

20. De Vriese AS, Robbrecht DL, Vanholder RC, et al: Rifampicin-associated acute renal failure: Pathophysiologic, immunologic, and clinical features.  Am J Kidney Dis  1998; 31:108-115.

21. Bruneel F, Gachot B, Wolff M, et al: Resurgence of blackwater fever in long-term European expatriates in Africa: Report of 21 cases and review.  Clin Infect Dis  2001; 32:1133-1140.

22. Toto RD, Anderson SA, Brown-Cartwright D, et al: Effects of acute and chronic dosing of NSAIDs in patients with renal insufficiency.  Kidney Int  1986; 30:760-768.

23. Sturmer T, Elseviers MM, De Broe ME: Nonsteroidal anti-inflammatory drugs and the kidney.  Curr Opin Nephrol Hypertens  2001; 10:161-163.

24. Toto RD, Mitchell H, Milam C, Pettinger WA: Reversible renal insufficiency due to converting enzyme inhibitors in hypertensive nephrosclerosis.  Ann Intern Med  1991; 115:513-519.

25. Bridoux F, Hazzan M, Pallot JL, et al: Acute renal failure after the use of angiotensin-converting-enzyme inhibitors in patients without renal artery stenosis.  Nephrol Dial Transplant  1992; 7:100-104.

26. Schwarz A, Krause PH, Kunzendorf U, et al: The outcome of acute interstitial nephritis: Risk factors for the transition from acute to chronic interstitial nephritis.  Clin Nephrol  2000; 54:179-190.

27. Mazzali M, Dias EP, Ribeiro-Alves MA, et al: Nonrecurrent hemolytic uremic syndrome (HUS de novo) as cause of acute renal failure after renal transplant.  Ren Fail  1997; 19:271-277.

28. Suehiro A: [Thrombotic thrombocytopenic purpura: pathophysiology and treatment].  Rinsho Ketsueki  2000; 41:463-467.

29. Parving HH, Tarnow L, Nielsen FS, et al: Cyclosporine nephrotoxicity in type 1 diabetic patients: A 7-year follow-up study.  Diabetes Care  1999; 22:478-483.

30. Ahsan N: Intravenous immunoglobulin induced-nephropathy: A complication of IVIG therapy.  J Nephrol  1998; 11:157-161.

31. Cayco AV, Perazella MA, Hayslett JP: Renal insufficiency after intravenous immune globulin therapy: A report of two cases and an analysis of the literature.  J Am Soc Nephrol  1997; 8:1788-1794.

32. Chung YC, Huang MT, Chang CN, et al: Prolonged nonoliguric acute renal failure associated with high-dose vitamin K administration in a renal transplant recipient.  Transplant Proc  1994; 26:2129-2131.

33. Dimitrov Y, Heibel F, Marcellin L, et al: Acute renal failure and nephrotic syndrome with alpha interferon therapy.  Nephrol Dial Transplant  1997; 12:200-203.

34. Daugaard G: Cisplatin nephrotoxicity: Experimental and clinical studies.  Danish Med Bull  1990; 37:1-12.

35. Asif A, Garces G, Preston RA, Roth D: Current trials of interventions to prevent radiocontrast-induced nephropathy.  Am J Therapeutics  2005; 12:127-132.

36. Morcos SJ: Prevention of contrast media-induced nephrotoxicity after angiographic procedures.  J Vasc Interv Radiol  2005; 16:13-23.

37. Barrett BJ, Parfey PS: Preventing nephropathy induced by contrast medium.  N Engl J Med  2006; 354:379-386.

38. Combest W, Newton M, Combest A, Kosier JH: Effects of herbal supplements on the kidney.  Urol Nurs  2005; 26:381-386.

39. Steenkamp V, Stewart MJ: Nephrotoxicity associated with exposure to plant toxins, with particular reference to Africa.  Ther Drug Monit  2005; 27:270-277.

40. Aakervik O, Svendsen J, Jacobsen D: [Severe ethylene glycol poisoning treated with fomepizole (4-methylpyrazole)].  Tidsskr Nor Laegeforen  2002; 122:2444-2446.

41. van Gelder T, Michiels JJ, Mulder AH, et al: Renal insufficiency due to bilateral primary renal lymphoma.  Nephron  1992; 60:108-110.

42. Arrambide K, Toto RD: Tumor lysis syndrome.  Semin Nephrol  1993; 13:273-280.

43. Bhowmik D, Mathur R, Bhargava Y, et al: Chronic interstitial nephritis following parenteral copper sulfate poisoning.  Ren Fail  2001; 23:731-735.

44. Stokes MB, Chawla H, Brody RI, et al: Immune complex glomerulonephritis in patients coinfected with human immunodeficiency virus and hepatitis C virus.  Am J Kidney Dis  1997; 29:514-525.

45. Zikos D, Grewal KS, Craig K, et al: Nephrotic syndrome and acute renal failure associated with hepatitis A virus infection.  Am J Gastroenterol  1995; 90:295-298.

46. Rao TK: Acute renal failure syndromes in human immunodeficiency virus infection.  Semin Nephrol  1998; 18:378-395.

47. Ismail-Allouch M, Burke G, Nery J, et al: Rapidly progressive focal segmental glomerulosclerosis occurring in a living related kidney transplant donor: Case report and review of 21 cases of kidney transplants for primary FSGS.  Transplant Proc  1993; 25:2176-2177.

48. Bolton WK: Rapidly progressive glomerulonephritis.  Semin Nephrol  1996; 16:517-526.

49. Packham DK, Hewitson TD, Yan HD, et al: Acute renal failure in IgA nephropathy.  Clin Nephrol  1994; 42:349-353.

50. Piqueras AI, White RH, Raafat F, et al: Renal biopsy diagnosis in children presenting with haematuria.  Pediatr Nephrol  1998; 12:386-391.

51. Frock J, Bierman M, Hammeke M, Reyes A: Atheroembolic renal disease: Experience with 22 patients.  Nebr Med J  1994; 79:317-321.

52. Preston RA, Stemmer CL, Materson BJ, et al: Renal biopsy in patients 65 years of age or older: An analysis of the results of 334 biopsies.  J Am Geriatr Soc  1990; 38:669-674.

53. Lefebvre C, Lambert M, Pirson Y: [Pulmonary-renal syndrome: Diagnostic and therapeutic strategy.].  Acta Clin Belg  1995; 50:94-102.

54. Monev S: Idiopathic retroperitoneal fibrosis: Prompt diagnosis preserves organ function.  Cleve Clin J Med  2002; 69:160-166.

55. Surge M: Abdominal compartment syndrome.  Curr Opin Crit Care  2005; 11:333-338.

56. Malbrain MLNG, Chiumello D, Pelosi P, et al: Incidence and prognosis of intraabdominal hypertension in a mixed population of critically ill patients: A multiple-center epidemiological study.  Crit Care Med  2005; 33:315-322.

57. Hall PM: The clinical usefulness of urinalysis.  Cleve Clin J Med  1994; 61:177-178.

58. Duthie JS, Solanki HP, Krishnamurthy M, Chertow BS: Milk-alkali syndrome with metastatic calcification.  Am J Med  1995; 99:102-103.

59. O'Neill WC: Sonographic evaluation of renal failure. Review.  Am J Kidney Dis  2000; 35:1021-1038.

60. Cheung S, Abramova L, Saath G, et al: Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents—St. Louis, Missouri, 2002-2006.  MMWR  2007; 56:137-141.

61. Haas M, Spargo BH, Wit EJ, Meehan SM: Etiologies and outcome of acute renal insufficiency in older adults: A renal biopsy study of 259 cases.  Am J Kidney Dis  2000; 35:433-447.

62. Korbet SM: Percutaneous renal biopsy.  Semin Nephrol  2002; 22:254-267.

63. Solez K, Racusen LC: Role of the renal biopsy in acute renal failure.  Contrib Nephrol  2001;68-75.

64. Rahman M, Smith MC: Chronic renal insufficiency: A diagnostic and therapeutic approach.  Arch Intern Med  1998; 158:1743-1752.

65. Go AS, Chertow GM, Fan D, et al: Chronic kidney disease and risks of death, cardiovascular events and hospitalization.  N Engl J Med  2004; 351:1296-1305.

66. Anavekar NS, McMurray JJV, Velasquez EJ, et al: Relationship between renal dysfunction and cardiovascular outcomes after myocardial infarction.  N Engl J Med  2004; 351:1285-1295.

67. Vanholder R, Massy Z, Argiles A, et al: Chronic kidney disease as cause of cardiovascular morbidity and mortality.  Nephrol Dial Transplant  2005; 20:1048-1056.

68. Tomakova MP, Skali H, Kenchaiah S, et al: Chronic kidney disease, cardiovascular risk, and response to angiotensin-convertng enzyme inhibitionafter myocardial infarction: The Survival And Ventricular Enlargement (SAVE) study.  Circulation  2004; 110:3667-3673.

69. Shand BI, Bailey MA, Bailey RR: Fingernail creatinine as a determinant of the duration of renal failure.  Clin Nephrol  1997; 47:135-136.

70. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative.  Am J Kidney Dis 2002  2002; 39:S1-S246.

71. Sack AG: Impact of timing of nephrology referral and pre-ESRD care on mortality risk among new ESRD patients in the United States.  Am J Kidney Dis  2003; 41:310-318.

72. Kinchen KS, Sadler J, Fink N, et al: The timing of specialist evaluation in chronic kidney disease and mortality.  Ann Intern Med  2002; 137:479-486.

73. Kamil ES: Recent advances in the understanding and management of primary vesicoureteral reflux and reflux nephropathy.  Curr Opin Nephrol Hypertens  2000; 9:139-142.

74. Fored CM, Ejerblad E, Lindblad P, et al: Acetaminophen, aspirin, and chronic renal failure.  N Engl J Med  2001; 345:1801-1808.

75. Lin JL, Tan DT, Hsu KH, Yu CC: Environmental lead exposure and progressive renal insufficiency.  Arch Intern Med  2001; 161:264-271.

76. Calvert GM, Steenland K, Palu S: End-stage renal disease among silica-exposed gold miners: A new method for assessing incidence among epidemiologic cohorts.  JAMA  1997; 277:1219-1223.

77. Hogan SL, Satterly KK, Dooley MA, et al: Silica exposure in anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and lupus nephritis.  J Am Soc Nephrol  2001; 12:134-142.

78. Steenland K, Sanderson W, Calvert GM: Kidney disease and arthritis in a cohort study of workers exposed to silica.  Epidemiology  2001; 12:405-412.

79. Cronin AJ, Maidment G, Cook T, et al: Aristolochic acid as a causative factor in a case of Chinese herbal nephropathy.  Nephrol Dial Transplant  2002; 17:524-525.

80. Markowitz GS, Appel GB, Fine PL, et al: Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate.  J Am Soc Nephrol  2001; 12:1164-1172.

81. Bennett WM, Burdmann EA, Andoh TF, et al: Nephrotoxicity of immunosuppressive drugs.  Nephrol Dial Transplant  1994; 9(suppl 4):141-145.

82. Freedman BB, Wilson CH, Spray BJ, et al: Familial clustering of end-stage renal disease in blacks with lupus nephritis.  Am J Kidney Dis  1997; 29:729-732.

83. Freedman BI, Soucie JM, McClellan WM: Family history of end-stage renal disease among incident dialysis patients.  J Am Soc Nephrol  1997; 8:1942-1945.

84. Freedman BI, Bowden DW, Rich SS, Appel RG: Genetic initiation of hypertensive and diabetic nephropathy.  Am J Hypertens  1998; 11:251-257.

85. Byrne C, Nedelman J, Luke RG: Race, socioeconomic status, and the development of end-stage renal disease.  Am J Kidney Dis  1994; 23:16-22.

86. Longenecker JC, Coresh J, Klag MJ, et al: Validation of comorbid conditions on the end-stage renal disease medical evidence report: The CHOICE study. Choices for Healthy Outcomes in Caring for ESRD.  J Am Soc Nephrol  2000; 11:520-529.

87. Tarver-Carr ME, Powe NR, Eberhardt MS, et al: Excess risk of chronic kidney disease among African-American versus white subjects in the United States: A population-based study of potential explanatory factors.  J Am Soc Nephrol  2002; 13:2363-2370.

88. Falk RJ, Jennette JC: Sickle cell nephropathy.  Adv Nephrol Necker Hosp  1994; 23:133-147.

89. Hsu SI, McClellan W, Ramirez SPB: Family history of renal disease is a predictor of proteinuria in a large multi-racial Southeast Asian population. Abstract.  J Am Soc Nephrol  2001; 12:210A.

90. Torres VE, Harris PC: Mechanism of disease: Autosomal dominant and recessive polycystic kidney diseases.  Nature Clin Prac Nephrol  2006; 2:40-55.

91. Hyodo T, Kumano K, Sakai T: Differential diagnosis between glomerular and nonglomerular hematuria by automated urinary flow cytometer: Kitasato University Kidney Center criteria.  Nephron  1999; 82:312-323.

92. Singhal R, Mittal BV: Haematuria: Glomerular or non-glomerular?.  Indian J Pathol Microbiol  1996; 39:281-286.

93. Attman PO, Alaupovic P, Samuelsson O: Lipoprotein abnormalities as a risk factor for progressive nondiabetic renal disease.  Kidney Int  1999; 56:S14-S17.

94. Bigazzi R, Bianchi S, Baldari D, Campese VM: Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension.  J Hypertens  1998; 16:1325-1333.

95. Cappelli P, Di Liberato L, Albertazzi A: Role of dyslipidemia in the progression of chronic renal disease.  Ren Fail  1998; 20:391-397.

96. Foley RN, Parfrey PS, Sarnak MJ: Epidemiology of cardiovascular disease in chronic renal disease.  J Am Soc Nephrol  1998; 9:S16-S23.

97. Goldfarb-Rumyantzev AS, Pappas L: Prediction of renal insufficiency in Pima Indians with nephropathy of type 2 diabetes mellitus.  Am J Kidney Dis  2002; 40:252-264.

98. Hovind P, Tarnow L, Rossing P, et al: Progression of diabetic nephropathy: Role of plasma homocysteine and plasminogen activator inhibitor-1.  Am J Kidney Dis  2001; 38:1376-1380.

99. Isreb MA, Daoud TM, Chatha MP, Leehey DJ: Risk factors for progression of renal disease in patients with type 2 diabetes.  J Am Soc Nephrol  2002; 13:685A-686A.

100. Keane WF, Eknoyan G: Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): A position paper of the National Kidney Foundation.  Am J Kidney Dis  1999; 33:1004-1010.

101. Klag MJ, Whelton PK, Randall BL, et al: End-stage renal disease in African-American and white men: 16-year MRFIT findings.  JAMA  1997; 277:1293-1298.

102. Krop JS, Coresh J, Chambless LE, et al: A community-based study of explanatory factors for the excess risk for early renal function decline in blacks vs whites with diabetes: The Atherosclerosis Risk in Communities study.  Arch Intern Med  1999; 159:1777-1783.

103. Locatelli F, Alberti D, Graziani G, et al: Factors affecting chronic renal failure progression: Results from a multicentre trial. The Northern Italian Cooperative Study Group.  Miner Electrolyte Metab  1992; 18:295-302.

104. Peterson JC, Adler S, Burkart JM, et al: Blood-pressure control, proteinuria, and the progression of renal-disease—The Modification of Diet in Renal Disease study.  Ann Intern Med  1995; 123:754-762.

105. Stehouwer CD, Gall MA, Twisk JW, et al: Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: Progressive, interrelated, and independently associated with risk of death.  Diabetes  2002; 51:1157-1165.

106. U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States,  Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005.

107. Coresh J, Jaar B: Further trends in the etiology of end-stage renal disease in African-Americans.  Curr Opin Nephrol Hypertens  1997; 6:243-249.

108. Haywood LJ: Hypertension in minority populations: Access to care.  Am J Med  1990; 88:17S-20S.

109. Pugh JA, Medina RA, Cornell JC, Basu S: NIDDM is the major cause of diabetic end-stage renal disease: More evidence from a tri-ethnic community.  Diabetes  1995; 44:1375-1380.

110. Chuahirun T, Wesson DE: Cigarette smoking and increased urine albumin excretion are interrelated predictors of nephropathy progression in type 2 diabetes.  Am J Kidney Dis  2003; 41:13-21.

111. Chen J, Muntner P, Hamm L, et al: The metabolic syndrome and chronic kidney disease in US adults.  Ann Intern Med  2004; 140:167-174.

112. Hsu C-Y, McCulloch CE, Iribarren C, et al: Body mass index and risk for end-stage renal disease.  Ann Intern Med  2006; 144:21-28.

113. Coresh J, Astor BC, Greene T, et al: Prevalence of chronic kidney disease and decreased kidney function in the adult US population. Third National Health and Nutrition Examination Survey.  Am J Kidney Dis  2003; 41:1-12.

114. Jones CA, Francis ME, Eberhardt MS, et al: Microalbuminuria in the US population: Third National Health and Nutrition Examination Survey.  Am J Kidney Dis  2002; 39:445-459.

115. Mann JFE, Gerstein HC, Pogue J, et al: Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: The HOPE Randomized Trial.  Ann Intern Med  2001; 134:629-636.

116. Muntner P, Coresh J, Klag MJ, et al: History of myocardial infarction and stroke among incident end-stage renal disease cases and population-based controls: An analysis of shared risk factors.  Am J Kidney Dis  2002; 40:323-330.

117. Levey AS: Measurement of renal function in chronic renal disease.  Kidney Int  1990; 38:167-184.

118. Levey AS, Bosch JP, Lewis JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group.  Ann Intern Med  1999; 130:461-470.

119. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine.  Nephron  1979; 16:31-41.

120. Toto RD, Kirk KA, Coresh J, et al: Evaluation of serum creatinine for estimating glomerular filtration rate in African Americans with hypertensive nephrosclerosis: Results from the African-American Study of Kidney Disease and Hypertension (AASK) Pilot Study.  J Am Soc Nephrol  1997; 8:279-287.

121. Shlipak MG, Sarnak MJ, Katz R, et al: Cystatin C and the risk of death and cardiovascular events among elderly persons.  N Engl J Med  2005; 351:2049-2060.

122. Coresh J, Wei GL, McQuillan G, et al: Prevalence of high blood pressure and elevated serum creatinine level in the United States: Findings from the Third National Health and Nutrition Examination Survey (1988-1994).  Arch Intern Med  2001; 161:1207-1216.

123. Perlata CA, Hicks LS, Chertaw GM, et al: Control of hypertension in adults with chronic kidney disease in the United States.  Hypertension  2005; 45:1119-1124.

124. Bakris GL, Williams M, Dworkin L, et al: Preserving renal function in adults with hypertension and diabetes: A consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group.  Am J Kidney Dis  2000; 36:646-661.

125. Wright Jr JT, Bakris G, Greene T, et al: Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial.  JAMA  2002; 288:2421-2431.

126. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.  Lancet  1998; 352:837-853.

127. Adler AI, Stevens RJ, Manley SE, et al: Development and progression of nephropathy in type 2 diabetes. The United Kingdom Prospective Diabetes Study (UKPDS 64).  Kidney Int  2003; 63:225-232.

128. Chen J, Munter P, Hamm L, et al: The metabolic syndrome and chronic kidney disease in US adults.  Ann Intern Med  2004; 140:167-174.

129. Hsu C-Y, McCulloch CE, Iribarren C, et al: Body mass index and risk for end-stage renal disease.  Ann Intern Med  2006; 144:21-28.

130. Go AS, Chertow GM, Fan D, et al: Chronic kidney disease and risks of death, cardiovascular events and hospitalization.  N Engl J Med  2004; 351:1296-1305.

131. Shulman NB, Ford CE, Hall WD, et al: Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the Hypertension Detection and Follow-up program. The Hypertension Detection and Follow-up Group.  Hypertension  1989; 13(suppl 5):I80-I93.

132. Middleton RJ, Parfrey PS, Foley RN: Left ventricular hypertrophy in the renal patient.  J Am Soc Nephrol  2001; 12:1079-1084.

133. Shlipak MG, Fried LF, Crump C, et al: Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency.  Circulation  2003; 107:87-92.

134. Stenvinkel P, Heimburger O, Paultre F, et al: Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure.  Kidney Int  1999; 55:1899-1911.

135. Festa A, D'Agostino R, Howard G, et al: Chronic subclinical inflammation as part of the insulin resistance syndrome. The Insulin Resistance Atherosclerosis Study (IRAS).  Circulation  2000; 102:42-47.

136. Panichi V, Migliori M, De Pietro S, et al: C-reactive protein as a marker of chronic inflammation in uremic patients.  Blood Purif  2000; 18:183-190.

137. Goodman WG, Goldin J, Kuizon BD, et al: Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.  N Engl J Med  2000; 342:1478-1483.

138. Hayden JM, Reaven PD: Cardiovascular disease in diabetes mellitus type 2: A potential role for novel cardiovascular risk factors.  Curr Opin Lipidol  2000; 11:519-528.

139. Miskulin DC, Meyer KB, Martin AA, et al: Comorbidity and its change predict survival in incident dialysis patients.  Am J Kidney Dis  2003; 41:149-161.

140. The Diabetes Control and Complications Trial Research Group : The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.  N Engl J Med  1993; 329:977-986.

141. Sarnak MJ, Levey AS: Epidemiology, diagnosis, and management of cardiac disease in chronic renal disease.  J Thromb Thrombolysis  2000; 10:169-180.

142. Brattstrom L, Wilcken DE: Homocysteine and cardiovascular disease: Cause or effect?.  Am J Clin Nutr  2000; 72:315-323.

143. Parsons DS, Reaveley DA, Pavitt DV, Brown EA: Relationship of renal function to homocysteine and lipoprotein(a) levels: The frequency of the combination of both risk factors in chronic renal impairment.  Am J Kidney Dis  2002; 40:916-923.

144. Friedman AN, Bostom AG, Levey AS, et al: Plasma total homocysteine levels among patients undergoing nocturnal versus standard hemodialysis.  J Am Soc Nephrol  2002; 13:265-268.

145. Beto JA, Bansal VK: Interventions for other risk factors: Tobacco use, physical inactivity, menopause, and homocysteine.  Am J Kidney Dis  1998; 32:S172-S183.

146. Bostom AG, Shemin D, Gohh RY, et al: Treatment of mild hyper homocysteinemia in renal transplant recipients versus hemodialysis patients.  Transplantation  2000; 69:2128-2131.

147. The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators : Homocysteine lowering with folic acid and B vitamins in vascular disease.  N Engl J Med  2006; 354:1567-1577.

148. Bonaa KH, Njolstad I, Ueland PM, et al: Homocysteine lowering and cardiovascular events after acute nyocardial infarction.  N Engl J Med  2006; 354:1578-1588.

149. Wrone EM, Hornberger JM, Zehnder JL, et al: Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease.  J Am Soc Nephrol  2004; 15:420-426.

150. Longenecker JC, Klag MJ, Marcovina SM, et al: Small apolipoprotein(a) size predicts mortality in end-stage renal disease: The CHOICE study.  Circulation  2002; 106:2812-2818.

151. Muntner P, Coresh J, Smith JC, et al: Plasma lipids and risk of developing renal dysfunction: The Atherosclerosis Risk in Communities Study.  Kidney Int  2000; 58:293-301.

152. Toto RD, Vega G, Grundy SM: Cholesterol management in patients with chronic kidney disease.   In: Brayd H, Wilcox C, ed. Therapy in Nephrology and Hypertension,  Philadelphia and New York: Lippincott Williams & Wilkins; 2003:631-639.

153. Toto RD, Grundy SM, Vega GL: Pravastatin treatment of very low density, intermediate density, and low density lipoproteins in hypercholesterolemia and combined hyperlipedemia secondary to the nephrotic syndrome.  Am J Nephrol  2000; 70:12-17.

154. Vega GL, Toto RD, Grundy S: Metabolism of low-density lipoproteins in nephrotic dyslipidemia: Comparison of hypercholesterolemia alone and combined hyperlipidemia.  Kidney Int  1995; 47:579-586.

155. Kronenberg F, Kuen E, Ritz E, et al: Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure.  J Am Soc Nephrol  2000; 11:105-115.

156. Gundy SM: United States Cholesterol Guidelines 2001: Expanded scope of intensive low-density lipoprotein-lowering therapy.  Am J Cardiol  2001; 88:23J-27J.

157. Wanner C, Krane V, Marz W, et al: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.  N Engl J Med  2005; 353:238-248.

158. Holdaas H, Fellstrom B, Jardine AG, et al: Effect of fluvastatin on cardiac outcomes in renal transplant recipients: A multicenter, randomized, placebo-controlled trial.  Lancet  2003; 361:2024-2031.

159. Lewis EJ, Hunsicker LG, Clarke WR, et al: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.  N Engl J Med  2001; 345:851-860.

160. Ho LT, Sprague SM: Renal osteodystrophy in chronic renal failure.  Semin Nephrol  2002; 22:488-493.

161. Chertow GM, Burke SK, Dillon MA, Slatopolsky E: Long-term effects of sevelamer hydrochloride on the calcium × phosphate product and lipid profile of haemodialysis patients.  Nephrol Dial Transplant  1999; 14:2907-2914.

162. Cozzolino M, Dusso A, Slatopolsky E: Role of calcium-phosphorus product and bone-associated proteins in vascular calcification in renal failure.  J Am Soc Nephrol  2001; 12:2511-2516.

163. Kramer H, Toto R, Peshock R, et al: Association between chronic kidney disease and coronary artery calcification. The Dallas Heart study.  J Am Soc Nephrol  2005; 16:507-513.

164. Sigrist M, Bungay P, Taal MW, McIntyre CW: Vascular calcification and cardio-vascular function in chronic kidney disease.  Nephrol Dial Transplant  2006; 21:707-714.

165. Block GA, Port FK: Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: Recommendations for a change in management.  Am J Kidney Dis  2000; 35:1226-1237.

166. Goodman WG, Goldin J, Kuizon BD, et al: Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.  N Engl J Med  2000; 342:1478-1483.

167. Chertow GM, Burke SK, Raggi P: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.  Kidney Int  2002; 62:245-252.

168. Raggi P, Boulay A, Chasan-Taber S, et al: Cardiac calcification in adult hemodialysis patients: A link between end-stage renal disease and cardiovascular disease?.  J Am Coll Cardiol  2002; 39:695-701.

169. Hsu CY, Cummings SR, McCulloch CE, Chertow GM: Bone mineral density is not diminished by mild to moderate chronic renal insufficiency.  Kidney Int  2002; 61:1814-1820.

170. National Kidney Foundation Kidney Disease Outcomes Quality Initiative: Clinical practice guidelines for bone metabolism and disease in chronic kidney disease.  Am J Kidney Dis  2003; 42(suppl 3):S1-S201.

171. Suki WN, Zabaneh R, Congiano J, et al: The DCOR trial—A prospective randomized trial assessing the impact on outcomes of sevelamer in dialysis patients.  J Am Soc Nephrol  2005; 16:281A.

172. Lawson JA, Lazarus R, Kelly JJ: Prevalence and prognostic significance of malnutrition in chronic renal insufficiency.  J Renal Nutr  2001; 11:16-22.

173. Chertow GM, Johansen KL, Lew N, et al: Vintage, nutritional status, and survival in hemodialysis patients.  Kidney Int  2000; 57:1176-1181.

174. Festa A, D'Agostino R, Howard G, et al: Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study.  Kidney Int  2000; 58:1703-1710.

175. Fernandez-Real JM, Ricart W: Insulin resistance and inflammation in an evolutionary perspective: The contribution of cytokine genotype/phenotype to thriftiness.  Diabetologia  1999; 42:1367-1374.

176. Panichi V, Migliori M, De Pietro S, et al: C-reactive protein as a marker of chronic inflammation in uremic patients.  Blood Purif  2000; 18:183-190.

177. DuBose TDJ: Hyperkalemic hyperchloremic metabolic acidosis: Pathophysiologic insights.  Kidney Int  1997; 51:591-602.

178. Mitch WE, Price SR: Mechanisms activated by kidney disease and the loss of muscle mass.  Am J Kidney Dis  2001; 38:1337-1342.

179. Mitch WE: Insights into the abnormalities of chronic renal disease attributed to malnutrition.  J Am Soc Nephrol  2002; 13(suppl 1):S22-S27.

180. IV: NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2000. [Erratum appears in Am J Kidney Dis 38:442, 2001.].  Am J Kidney Dis  2001; 37:S182-S238.

181. Hsu CY, McCulloch CE, Curhan GC: Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: Results from the Third National Health and Nutrition Examination Survey.  J Am Soc Nephrol  2002; 13:504-510.

182. Astor BC, Muntner P, Levin A, et al: Association of kidney function with anemia: The Third National Health and Nutrition Examination Survey (1988-1994).  Arch Intern Med  2002; 162:1401-1408.

183. Richardson D: Clinical factors influencing sensitivity and response to epoetin.  Nephrol Dial Transplant  2002; 17(suppl 1):53-59.

184. Kazmi WH, Kausz AT, Khan S, et al: Anemia: An early complication of chronic renal insufficiency.  Am J Kidney Dis  2001; 38:803-812.

185. Obrador G, Ruthazer R, Arora P, et al: Prevalence of and factors associated with suboptimal care before initiation of dialysis in the United States.  J Am Soc Nephrol  1999; 10:1793-1800.

186. Besarab A, Levin A: Defining a renal anemia management period.  Am J Kidney Dis  2000; 36:S13-S23.

187. Foley RN, Parfrey PS, Morgan J, et al: Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy.  Kidney Int  2000; 58:1325-1335.

188. Gotch FA, Levin NW, Port FK, et al: Clinical outcome relative to the dose of dialysis is not what you think: The fallacy of the mean. Editorial.  Am J Kidney Dis  1997; 30:1-15.

189. Levin A: Anemia and left ventricular hypertrophy in chronic kidney disease populations: A review of the current state of knowledge.  Kidney Int Suppl  2002;35-38.

190. Levin A: The role of anaemia in the genesis of cardiac abnormalities in patients with chronic kidney disease.  Nephrol Dial Transplant  2002; 17:207-210.

191. Levin A, Thompson CR, Ethier J, et al: Left ventricular mass index increase in early renal disease: Impact of decline in hemoglobin.  Am J Kidney Dis  1999; 34:125-134.

192. Levin A: Anaemia in the patient with renal insufficiency: Documenting the impact and reviewing treatment strategies.  Nephrol Dial Transplant  1999; 14:292-295.

193. Levin A, Djurdjev O, Barrett B, et al: Cardiovascular disease in patients with chronic kidney disease: Getting to the heart of the matter.  Am J Kidney Dis  2001; 38:1398-1407.

194. Foley RN: Should hemoglobin be normalized in uremic patients?.  Clin Nephrol  2002; 58(suppl 1):S58-S61.

195. Foley RN, Parfrey PS, Harnett JD, et al: The impact of anemia on cardiomyopathy, morbidity and mortality in end-stage renal disease.  Am J Kidney Dis  1996; 28:53-61.

196. Foley RN, Parfrey PS, Morgan J, et al: Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy.  Kidney Int  2000; 58:1325-1335.

197. Hegarty J, Foley RN: Anaemia, renal insufficiency and cardiovascular outcome.  Nephrol Dial Transplant  2001; 16(suppl 1):102-104.

198. Levin A, Singer J, Thompson CR, et al: Prevalent left ventricular hypertrophy in the predialysis population: Identifying opportunities for intervention.  Am J Kidney Dis  1996; 27:347-354.

199. Eknoyan G: The importance of early treatment of the anaemia of chronic kidney disease.  Nephrol Dial Transplant  2001; 16(suppl 5):45-49.

200. Mohanram A, Zhang J, Shahinfar S, et al: Anemia and end-stage renal disease in patients with type 2 diabetes and nephropathy.  Kidney Int  2004; 66:1131-1138.