A 38-year-old man presents to an outpatient clinic with several nonspecific complaints. The patient relates that for the past 3 to 4 months, he has become easily fatigued and has been unable to concentrate at work. He has also developed poor appetite and pain in his thighs, knees, and legs. He has been generally healthy in the past but has not seen a physician in 6 years. Eight years ago, when he visited an emergency center for the treatment of a laceration on his arm, he was informed that his blood pressure was elevated. The patient is currently afebrile; his blood pressure is 160/94 mm Hg; pulse is 84 beats/min and regular. He has several areas of skin ecchymosis over his knees and thighs. His white blood cell (WBC) count is 6500, hemoglobin 9 g/dL, hematocrit 35%, blood urea nitrogen 80 mg/dL, serum creatinine 8.5 mg/dL, and serum potassium 5.0 mEq/L.
What is the most likely diagnosis?
How will you assess the severity and stage of his disease?
What are the treatment options for this patient?
ANSWERS TO THE CASE 55: Renal Failure/Renal Transplantation
Summary: A 38-year-old man presents with new onset renal failure and uremia. The cause of the renal failure is unknown but is suspected to be contributed by poor control of hypertension.
• Diagnosis: Probable chronic renal failure (CRF) with uremia.
• Severity and stage of disease: The severity and stage of CRF can be estimated based on urinary creatinine clearance.
• Treatment: Dialysis and renal transplant are treatment options in the patient with end-stage disease.
1. Be able to describe and recognize the stages of CRF and complications associated with this condition.
2. Learn the principles of hemodialysis and options for dialysis access.
3. Learn the outcome and management principles for patients undergoing renal transplant.
The initial evaluation and management in this patient consists of determining the cause of his renal failure and identifying potentially treatable causes. Because the patient has described symptoms for the past 3 to 4 months and has no recent physiologic insults or medication usage that would predispose him to acute renal insults, this process most likely represents CRF. Renal ultrasonography is useful to assess renal size and number, identify urinary obstruction, renal vascular obstruction, and tumor infiltration. The assessment of creatinine clearance allows for estimation of glomerular filtration rate (GFR), which would help stage his renal disease. Evaluation and treatment of complications associated with CRF are important, including dietary changes and pharmacological therapy to address metabolic complications such as hyperkalemia and hyperphosphatemia. Cardiovascular complications are common in this population and account for approximately 50% of the annual mortality in CRF patients. Echocardiography is helpful to assess for left ventricular hypertrophy (LVH), which is a strong predictor for future adverse cardiac events. In addition, echocardiography may help identify uremic pericarditis and pericardial effusion. If the evaluations verify (end-stage disease) GFR of less than 15 mL/min/1.73 m2, hemodialysis should be initiated to improve the patient’s quality of life and minimize acute metabolic complications. Ultimately, for a patient with irreversible renal failure, chronic dialysis and renal transplant are the two long-term options.
APPROACH TO: Chronic Renal Failure
CHRONIC RENAL FAILURE (CRF): Classified by the National Kidney Foundation Clinical Practice Guidelines as kidney damage of greater than 3 months’ duration and/or GRF less than 60 mL/min/1.73 m2.
CHRONIC RENAL DISEASE STAGES:
Stage 1: kidney damage with normal or increased GFR (GFR >90)
Stage 2: kidney damage with mild decrease in GFR (GFR 60-89)
Stage 3: moderate decrease in GFR (GFR 30-59)
Stage 4: severe decrease in GFR (GFR 15-29 predialysis stage)
Stage 5: kidney failure (GFR <15, usually indication for chronic dialysis)
Management for patients with GFR greater than 15 mL/min generally consists of dietary and fluid management, pharmacologic management, and close monitoring of complications. Dietary potassium restriction is important for patients with GRF approaching 20 in avoiding hyperkalemia. The initiation of strategies to prevent secondary hyperparathyroidism is important and should include the control of hyperphosphatemia with dietary phosphate restriction, phosphate binder administration at meal time, administration of synthetic 1,25 dihydroxy vitamin D, and subtotal parathyroidectomy for patients with uncontrolled tertiary hyperparathyroidism.
Because anemia is one of the leading causes of LVH and produces significant morbidity and mortality, anemia should be managed early and relatively aggressively with the administration of recombinant human erythropoietin. Hypertension in the setting of CRF is extremely common and contributes to LVH; therefore, intense therapy using a variety of antihypertensive medications is indicated.
Uremia produces an immunodeficiency state that is not reversible with hemodialysis. The mechanisms causing immunodeficiency in these patients remain undetermined at this time; however, because of this condition, CRF patients are at increased risk of developing bacterial, viral, mycobacterial infections, and anergic states. Close monitoring for infections and aggressive treatment of infections are critical in this patient population.
There are a number of neurologic complications that occur with CRF, and these include uremic encephalopathy, uremic peripheral neuropathy that is a mixed motor and sensory distal neuropathy, and uremic autonomic neuropathy producing postural hypotension and hypotension during dialysis; some of these neurologic conditions improve with dialysis.
Hemodialysis Dialysis Access
Hemodialysis access became the standard for the treatment of renal failure in the 1960s. Essentially, the dialysis machine or dialyzer has two spaces separated by a semipermeable membrane, where blood passes through one side of the membrane and dialysate passes on the other side of the membrane. Through diffusion, excess water and solutes pass from the blood to the dialysate, resulting in the elimination of the excess water and waste. Hemodialysis requires the placement of dialysis access that includes specialized large-bore venous catheters through which blood can be drawn off at a high rate (350-400 mL/min) through one lumen and returned through a separate lumen. Hemodialysis catheters are classified as temporary access (days) or intermediate-term access (weeks to months); intermediate-term catheters contain a cuff barrier and subcutaneous tunneled portion, which are barriers against contamination by skin flora and are associated with lower catheter-related infections and complications than the temporary dialysis catheters.
For critically ill patients, cannulation of the femoral vein for the initiation of dialysis is rapid and safe; however, femoral catheters are associated with increased infections when left in for more than a few days. For most patients, the internal jugular veins are the ideal sites for either temporary or intermediate-catheter insertion. Subclavian vein catheter placement should be avoided because of the potential for thrombosis and stenosis, which would affect venous return and compromise the success of future upper extremity arterial-venous fistulas from that side. Dialysis catheter–related bacteremia and sepsis are major causes of morbidity and mortality in this patient population. In addition, dialysis catheter malfunction are common causes of morbidity and mortality, as thrombosis, formation of fibrin sheath, and malposition can all cause inadequate blood flow for hemodialysis.
Long-Term Hemodialysis Access: Arteriovenous fistulas (AVF) constructed by directly connecting native arteries to superficial extremity veins are the first choice for long-term access in all patients. Commonly constructed AVF include the radial artery to cephalic vein fistula (Brescia-Cimino fistula), brachial artery-cephalic vein fistula in the upper arm, and brachial-basilic fistula in the upper arm. The major limitations to AVF creation are inadequate size and quality of the veins. Because injuries to the vein can occur with blood draws and IV insertions, it is extremely important to preserve the upper extremity veins in any patient in whom long-term dialysis is anticipated. Most AVF require approximately 6 weeks to mature before they can be accessed for dialysis; therefore, it is common to place an intermediate-term dialysis catheter for dialysis in the interim period. For individuals without adequate veins and requiring long-term hemodialysis, a variety of arterial venous grafts can be placed. Expanded polytetrafluoroethylene is the most common material employed for AV grafts. AV grafts are less desirable than AVF because of increased complications associated with this type of access, and complications associated with AV grafts include infection and pseudointimal hyperplasia on the venous end of the graft-vein connection leading to graft thrombosis.
In peritoneal dialysis (PD), the peritoneal surface and the peritoneal microvasculature are the site of exchange of fluids and solute between the patient and the dialysate. In properly selected patients, this form of dialysis allows the patients to ambulate and carry on some of the activities of daily living during dialysis. Peritoneal infections and peritoneal dialysis catheter–related complications are potential limitations associated with this process. Because the dialysis in most cases occurs at home, the ideal patients for PD need to be functional and capable of performing the dialysis process and troubleshoot when minor problems arise.
Renal transplantation has been demonstrated to offer CRF patients better quality of life and is projected to improve overall survival by 10 years when compared to chronic dialysis. The three most common causes of CRF treated by renal transplant are diabetes mellitus (27%), hypertension (20%), and glomerular diseases (21%). Currently, patients on the renal transplant waitlist in the United States outnumber kidney-transplanted patients by a ratio of approximately 4:1; consequently, the median time on the waitlist prior to receiving transplant has been approximately 39 months. The patient who is an ideal candidate for renal transplant is a young individual without a systemic disease process that will damage the transplanted kidney and does not have coexisting conditions that will lead to significant morbidity and mortality. In the United States, patients are considered for renal transplant when their GFR falls below 20 mL/min. Preoperatively, all patients undergo psychiatric evaluation to identify possible conditions that would contribute to poor compliance with immunosuppressive therapy and follow-up, assessment for possible malignant conditions, and evaluation to rule out urinary obstructive process and reflux as a cause of CRF. In addition, all patients undergo evaluation for ABO and human leukocyte antigen (HLA) typing. All candidates also are evaluated for possible infections that include human immunodeficiency virus (HIV), hepatitis B and C, cytomegalovirus (CMV), and syphilis. In patients with prior history of cancer, the individual must be at least 2 years without evidence of disease prior to being considered for transplant. Age alone is no longer a contraindication to organ transplant, as up to 20% of patients on the waitlist are older than 65 years.
Living Donor versus Cadaveric Transplantation
Living donor transplantation currently accounts for 40% of the kidneys transplanted in the United States. Because of overall better medical conditions of the donors and short cold ischemia time, living donor transplanted kidneys tend to have better early and late graft functions in comparison to cadaveric grafts. With the introduction of laparoscopic donor nephrectomy, the morbidity associated with kidney harvest has been further reduced. Recent reported living donor transplantation results have shown graft survival rates of 95%, 80%, and 56% at 1, 5, and 10 years, respectively.
Traditionally, cadaveric organs are retrieved from brain-dead donors between the ages of 3 and 60 years and without systemic degenerative diseases such as hypertension and diabetes, and history of a stroke. However, given the current shortage of cadaveric organs and the aging recipient population, kidneys from expanded criteria donors (ECDs) are now utilized. A donor is considered an ECD if he/she is older than 60 years or between 50 and 60 years of age who died of a stroke, with history of hypertension, diabetes, or elevated serum creatinine. The 1- and 5-year graft survival rates reported for non-ECD kidneys are 90% and 70%, respectively, and for ECD kidneys the 1- and 5-year graft survival rates reported are 81% and 53%, respectively.
Posttransplantation Immune Suppression and Acute Graft Rejection
Immunosuppressive agents are administered to all patients following renal transplant, except for those patients receiving organs from identical twin donors.
Corticosteroid interferes with the immune process at multiple sites and has been one of the traditional agents used in maintenance therapy and for acute rejection. Because of the significant side effects associated with steroid use and the availability of newer agents, many centers now have immune suppression protocols that include steroid withdrawal after weeks to months. Cyclosporin leads to the inhibition of calcineurin activity and inhibition in IL-2 production. The introduction of cyclosporine in the 1980s represented a major breakthrough in immune suppression. Major side effects associated with cyclosporine include nephrotoxicity, gingival hyperplasia, hypertension, and hyperkalemia. Tacrolimus is also a calcineurin inhibitor causing inhibition in IL-2, IL-3, IL-4, and gamma-interferon production. Tacrolimus is considered a significantly more potent immune suppressive agent than cyclosporine; however, its application is associated with increased side effects that include nephrotoxicity, hypertension, hyperkalemia, hypomagnesemia, CNS symptoms (headaches, tremors, and seizures), and insulin resistance. Sirolimus (rapamycin) is a T-cell inhibitor that acts through a pathway that is different from the calcineurin pathway. Even though sirolimus is less nephrotoxic than cyclosporine and tacrolimus, its application is associated with thrombocytopenia, hyperlipidemia, and poor wound healing. Mycophenolate mofetil (MMF) and azathioprine (Imuran) are inhibitors of B- and T-cell proliferation. MMF is often combined with cyclosporine for the prevention of rejection. Azathioprine is an older agent that is substituted for MMF when intolerance develops. Antilymphocyte antibodies such as OKT3 (a monoclonal murine antibody against the CD3 receptor complex on T cells) are effective as part of an induction regimen or for the treatment of steroid-resistant acute rejections. Large doses and prolonged antilymphocyte therapy can produce severe side effects, including serious viral infections, thrombocytopenia, and leukopenia.
Acute graft rejection occurs in 10% to 20% of patients during the first few weeks to months after transplant. Classically, this is manifested as fever, malaise, hypertension, oliguria, increase in serum creatinine, and tenderness and swelling over the transplanted kidney. When clinically suspected or confirmed by biopsy, patients with acute graft rejection are generally treated initially with high-dose corticosteroids, and in steroid-resistant rejection cases, antilymphocytic antibodies are often given.
Infections Following Transplant
Thirty to sixty percent of patients develop some form of infection during the first year following transplant, and infections during this period of time contribute to 50% of the mortality during the early posttransplant period. Bacterial infections are the most common infections during the first month following transplant, and during the subsequent time period, opportunistic infections including CMV, Pneumocystis jiroveci (formerly P carinii), aspergillosis, toxoplasmosis, cryptococcosis, nocardiosis, and blastomycosis become more common causes of infections. Prophylactic antimicrobial therapy with trimethoprim–sulfamethoxazole for the first 6 months after transplant has been found to be effective in reducing the risk of P jiroveci infections.
Malignancies Following Transplant
Suppression of the immune system posttransplant has been shown to increase the risk of malignancy by 3 to 14 times greater in comparison to the general population. The greatest risks in this population appear to be the development of viral-associated neoplasms, including squamous cell carcinoma (human papilloma virus [HPV]), cervical cancer (HPV), Kaposi sarcoma (Epstein-Barr virus [EBV]), non-Hodgkin lymphoma (EBV), and hepatocellular carcinoma (hepatitis B and C). Lymphomas or posttransplant lymphoproliferative disorders are the most common posttransplant malignancies, and the occurrence is related to the intensity and duration of the anti–T-cell therapy. Fortunately, reduction in immunosuppression often may lead to the regression of posttransplant lymphoproliferative disorders.
Chronic allograft nephropathy refers to chronic fibrotic changes and accelerated loss of renal functions that occurs in the transplanted kidneys. This process generally develops years after allograft transplant and presents as progressive increase in serum creatinine, proteinuria, and microscopic hematuria. Confirmation of this diagnosis is by biopsy. Currently, there is no effective treatment of this condition, which is the major cause of late graft failure. In general, immunosuppressive treatment is gradually tapered in these individuals to limit the nephrotoxicity associated with calcineurin inhibitors.
55.1 Which of the following is the most likely cause of fever in a patient at 8 months following a successful cadaveric renal transplant?
A. Methicillin-resistant Staphylococcus urinary tract infection
B. CMV infection
C. Chronic allograft nephropathy
D. Cyclosporin-associated fevers
E. Graft versus host disease
55.2 A 24-year-old man underwent a cadaveric renal transplant 4 weeks previously. He comes into the emergency department with complaints of feeling warm. He is noted to have a fever to 39°C (102.2°F), increasing serum creatinine, and tenderness over his right costovertebral area, the area over his transplanted kidney. Which of the following treatment strategies is most appropriate?
A. Initiation of broad-spectrum antibiotics directed toward urinary tract infection organisms
B. Reexploration to treat localized infection associated with the transplanted kidney
C. Beginning of empiric therapy for CMV
D. Renal biopsy and pulse steroid therapy
E. Ultrasound and color-flow Doppler evaluation of the transplanted kidney
55.3 A patient with CRF is currently undergoing hemodialysis. He asks his physician about the possibility of receiving a kidney transplant. The physician informs the patient that he is not a candidate for transplant. Which of the following is the most likely reason for unsuitability of transplant if present in this individual?
A. Age 66 years
B. Colon cancer treated 4 years ago and in remission
C. GFR of 28 mL/min
D. Urinary obstruction and reflux
E. HIV nephropathy
55.1 B. Fever in the posttransplant patient can be due to a number of possible processes, including infections and acute rejection. Bacterial infection involving the urinary tract is high on the list of possible infections within the first 4 weeks after transplant. At 8 months after transplant, infections are most likely from opportunistic organisms. Cyclosporin is associated with many side effects, but fever is not one of them. Graft versus host disease is observed most commonly in patients following allogeneic bone marrow transplant, when the graft develops rejection of the host antigens.
55.2 D. Fever, increasing serum creatinine, and graft tenderness are signs of acute rejection. For all patients with this presentation, infections need to be considered and ruled out. Renal graft biopsy is helpful when histological features of acute rejection are seen; however, because of sampling error, clinically suspicious rejection episodes are treated empirically, when other causes are not identified. Ultrasound evaluation of blood flow to the transplanted kidney is important to rule out vascular compromise to the graft when graft dysfunction occurs following implantation.
55.3 D. A condition such as urinary obstruction that will likely damage the transplanted kidney is a criterion that usually disqualifies a patient for transplant. Age above 65 is no longer a contraindication for renal transplant. The GFR threshold for transplant is usually 20 mL/min or less. HIV infection is no longer an absolute contraindication for renal transplantation, provided that the patient is receiving HAART (highly active antiretroviral therapy) and has CD4 greater than 200.
Infections and dialysis access complications are the two major causes of mortality in the chronic dialysis population.
It is important to take steps to anticipate the potential need for hemodialysis and avoid damages to central and peripheral veins in all patients with CRF.
Currently, US patients on the waitlist outnumber kidney-transplanted patients by a ratio of 4:1.
The median time on the waitlist for recipients in the United States is approximately 39 months.
Fever, malaise, hypertension, oliguria, and increase in serum creatinine are all manifestations of acute graft failure following renal transplant.
During the first year following successful renal transplant 30% to 60% of patients develop infections, and infections contribute to 50% of the mortality during the early posttransplant period.
Dosekun A, Foringer JR, Kone BC. Urine formation: from normal physiology to florid kidney failure. In: Miller TA, ed. Modern Surgical Care: Physiologic Foundations and Clinical Applications. 3rd ed. New York, NY: Informa Healthcare; 2006:725-765.
Humar A, Dunn DL. Transplantation. In: Brunicardi FC, Andersen DK, Billiar TR, et al, eds. Schwartz’s Principles of Surgery. 9th ed. New York, NY: McGraw-Hill; 2010:271-312.
Markmann JF, Yeh H, Naji A, Othoff KM, Shaked A, Barker CF. Transplantation of abdominal organs. In: Townsend CM Jr, Beauchamp RD, Evers BM, Mattox KL, eds. Sabiston Textbook of Surgery. 18th ed. Philadelphia, PA: Saunders Elsevier; 2008:692-733.