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MANAGEMENT AND THERAPY OF SICKLE CELL DISEASE
NIH Publication No. 95-2117, Revised December 1995 (Third Edition) National Institutes of Health, National Heart, Lung, and Blood Institute
Chapter 18--Renal
Clinical and pathologic data indicate that intravascular sickling occurs more readily in the kidney than in any other organ. A series of progressive and random pathologic events involving the kidney begins early in the first decade of life in a patient with sickle cell disease and continues throughout life. The distribution of blood flow in the kidney and the hypertonicity of the renal medulla create a situation where red blood cells containing sickle hemoglobin undergo deoxygenation in an acidic and hyperosmolar environment that causes them to sickle more easily. The combination of hypoxia, hypertonicity, and acidosis in the renal medulla leads to stasis in the vasa recta and to ischemia of the renal medulla and papillary tip. Distortion of regional blood flow, focal interstitial nephritis and fibrosis, tubular dysfunction and atrophy, and papillary necrosis result. Table 4 indicates the progressive renal events that can occur in each decade of life in association with sickle cell disease.
HYPOSTHENURIA
The earliest and most common renal defect in sickle cell disease is hyposthenuria, which is expressed as an inability of the kidney to maximally concentrate the urine. It is almost universally evident by the time the patient with SS disease reaches age 3 years. This condition results in an obligatory urinary output of greater than 2,000 ml/day--in effect, a form of nephrogenic diabetes insipidus. The resultant increased fluid requirement renders the patient much more susceptible than the normal individual to dehydration, which is a precipitating cause of vaso- occlusive crises. A liberal fluid intake should be ensured, to provide for both the obligatory urinary water loss and normal daily fluid requirement. The abnormality of the renal medulla may render the patient hyporesponsive to "loop" or osmotic diuretic agents such as furosemide or mannitol, respectively. Hyposthenuria also frequently gives rise to nocturia (enuresis in the child). When the latter occurs, other causes should also be considered. Hyposthenuria is also seen in individuals with Hb AS (see Chapter 22, Sickle Cell Trait.)
RENAL TUBULAR DYSFUNCTION
Patients with sickle cell disease are unable to acidify their urine maximally when they are subjected to acid loading, and this can sometimes lead to significant systemic acidosis. If metabolic acidosis is found in a patient with sickle cell disease, renal hydrogen ion excretion should be evaluated to determine whether it plays a role in the process. If it is present, it should be corrected by judicious therapy with sodium bicarbonate. Impaired renal tubular potassium excretion has also been described in sickle cell disease and, in some cases, can result in a tendency toward modest hyperkalemia, which is hyporesponsive to kaliuretic agents such as furosemide. Hyperkalemia can increase as patients age. When the amount is significant (K is equal to or greater than 5.5 meq), other causes should be sought. Spurious hyperkalemia may result from hemolysis and/or thrombocytosis. Table 4 Progressive Renal Events in Sickle Cell Disease
HYPERURICEMIA
About 15 percent of children and 40 percent of adults with SS disease have high-normal or elevated serum uric acid levels. This condition is due to the increase in urate production associated with accelerated erythropoiesis coupled with a decreased renal clearance of urate. Hyperuricemia in SS disease responds poorly to uricosuric agents, but the uric acid level can be lowered with the use of allopurinol. Uric acid nephropathy is rare, but if recurrent uric acid stone formation occurs, urinary alkalinization with oral sodium bicarbonate is recommended. Clinical gout is uncommon in sickle cell disease. When it is demonstrated by the presence of intracellular uric acid crystals in joint fluid, it is treated with NSAIDs and allopurinol.
GROSS HEMATURIA
Gross hematuria occurs commonly in sickle cell disease. Less commonly, it also occurs in sickle cell trait (although the larger number of AS persons make them more frequent visitors to medical facilities). The bleeding is usually painless, although clot formation in the renal pelvis or ureter can produce renal colic. It is frequently unilateral, with the left kidney being involved in 80 percent of the cases. It can show a pattern of intermittency, lowgrade chronicity, or persistence. The pathogenic mechanism is thought to be sickling in the vasa recta, which leads to stasis and ischemia, with extravasation of blood into the renal parenchyma and collecting system, or in some cases to micropapillary or macropapillary necrosis.
As with all patients who have hematuria, the differential diagnosis in patients with sickle cell disease includes papillary necrosis, glomerulonephritis, tuberculosis, tumor, stones, and urinary tract infection. Bleeding disorders should also be considered. Evaluation can require renal ultrasonography, intravenous pyelography (with adequate prehydration), cystoscopy, urine culture, and measurements of coagulation and hemostatic function. Good hydration should be maintained with a urine flow in excess of 2 to 3 ml/kg/hr to decrease the tendency to clot in the renal pelvis and ureter. In the presence of refractory hematuria, patients should be treated with epsilon aminocaproic acid (EACA) at an oral dosage of 2 to 8 g/day. The principal danger of this therapy is the formation of clots in the renal pelvis and ureter. Therefore, when EACA is used, the patient should be hospitalized and placed at bedrest, and high urine flow (> 3 ml/kg/hr) should be maintained. Ferrous sulfate should be given to correct documented iron deficiency. Transfusion can be indicated both for a falling hematocrit and for reducing the propensity for occlusion of the medullary vessels. When hematuria is chronic and severe, patients should have bedrest with high fluid intake, and exchange transfusion should be considered with or without EACA therapy. Every measure should be taken to avoid nephrectomy for hematuria in patients with sickling disorders because the contralateral kidney remains at risk for sickle cell-related complications. Nephrectomy is warranted only for a life-threatening exsanguinating hemorrhage.
RENAL PAPILLARY NECROSIS
Renal papillary necrosis is a relatively common finding in patients with sickle cell disease. It can be asymptomatic or accompanied by hematuria or proteinuria. Irregularities or "pseudodiverticuli" of the renal papillary tips seen on intravenous pyelograms (IVP) have been reported in about 50 percent of adults with sickling disorders. The etiology is identical to that described for hematuria. The disorder is usually asymptomatic and is most commonly diagnosed at the time of an IVP. It is believed that the ischemia or necrosis of the renal papillary tip as well as the associated interstitial nephritis, which can also be caused by heavy ingestion of certain analgesics (e.g., aspirin, acetaminophen, and NSAIDs ), may cause increased susceptibility of patients with sickle cell disease to pyelonephritis.
URINARY TRACT INFECTION
Asymptomatic bacteriuria and symptomatic urinary tract infections are common in sickle cell disease patients. Radiologic changes are often difficult to differentiate from interstitial nephritis due to ischemia or analgesic nephropathy. Because women with sickle cell disease may be at greater risk for pyelonephritis, frequent urinalyses and periodic urine cultures with colony counts may be useful as a routine surveillance measure. Significant bacteriuria (> 10(5)/mL) and documented pyelonephritis should be treated with appropriate antibiotic therapy, and repeat cultures should be obtained to confirm "sterilization" of the urine. Initiation of antibiotic therapy with trimethoprim-sulfa or ampicillin is recommended; on the basis of culture and sensitivity data, therapy should then be modified. Blood cultures should be obtained on febrile patients with suspected pyelonephritis. Individuals who have had a single bout of pyelonephritis should have careful long-term monitoring, including repeat urinalyses, cultures, and renal function studies. With an initial bout of pyelonephritis or with recurrence in a previously unstudied patient, an IVP should be done, possibly in consultation with a urologist, to exclude a predisposing or resultant anatomic defect in the urinary tract. In children, a voiding cystourethrogram may be indicated. Patients with persistent or recurrent pyelonephritis should be considered for long-term antibiotic therapy (see Chapter 6, Infection).
PROTEINURIA AND NEPHROTIC SYNDROME
Approximately 25 percent of adult patients with SS disease have chronic proteinuria due to hyperfiltration, glomerulopathy, and glomerular capillary hypertension. Nephrotic syndrome associated with a membranoproliferative glomerulonephritis has been described in patients with SS disease. If proteinuria persists for more than 4 weeks, it should be evaluated with 24-hour urinary protein quantitation and creatinine clearance. In the presence of prenephrosis (24-hour urine protein > 2.0 g/24 hrs or nephrotic syndrome (protein > 3.0/24 hrs, hypoalbuminemia, hyperlipidemia, and edema), the patient should be referred to a nephrologist for evaluation and possible renal biopsy. When biopsies are done, pathologic examination should include immunohistology (IgG, C1, IgM, and antirenal tubular epithelial antigen) and electron microscopy to establish the histologic diagnosis.
HYPERTENSION
Persistent elevation of diastolic blood pressure in patients with sickle cell disease usually signals underlying renal disease. It occurs in fewer than 5 percent of individuals with sickling disorders and increases with advancing age. Although the hypertension appears to be renoprival in nature, plasma renin levels are variable. Evaluation of hypertension in the patient with sickle cell disease is the same as in other individuals. Transient hypertension may occur during painful episodes and following red blood cell transfusions.
Therapy for hypertension in patients with sickling disorders differs from that used for other individuals. Diuretics generally are to be used with caution, particularly in younger patients because dehydration may provoke a vaso- occlusive crisis. The natriuretic response to loop diuretics is decreased, particularly in older patients. Initial therapy with beta-adrenergic blockers or calcium channel inhibitors is preferred, and the dosage must be individualized. In hypertensive patients with significant proteinuria, angiotensin-converting enzyme inhibitors may both control hypertension and reduce proteinuria by decreasing glomerular capillary hypertension. Due to the compensatory alterations of cardiovascular function in sickle cell disease patients, the deleterious effects of hypertension on the heart and vascular system are likely to be amplified.
When congestive heart failure is present in the hypertensive sickle cell patient, afterload reduction therapy is indicated. Because the risk of stroke is increased in sickle cell disease and arterial aneurysms of the circle of Willis may appear as early as the second decade, effective control of blood pressure is imperative.
CHRONIC RENAL FAILURE
Chronic renal failure in sickle cell disease is associated with end-stage renal disease due to one or a combination of the sickle cell nephropathies discussed above. Chronic renal failure occurs in a small percentage of patients with sickling disorders, and its prevalence in sickle cell disease appears to be greater than among the general African-American population. When it is associated with metabolic acidosis without significant hyperkalemia and with BUN levels less than 80.0 mg/mL and creatinine less than 4.0 mg/mL, patients can usually be managed with conservative measures, including oral sodium bicarbonate, oral phosphate binders such as Amphojel (registered trademark), and a low- protein diet. In this instance, BUN, creatinine, electrolytes, and acid-base balance should be carefully monitored. Drugs with altered pharmacokinetics in the presence of renal failure should either be avoided or have dosages appropriately modified.
As renal failure progresses, the patient should be referred for dialysis or possible renal transplantation. Sickle cell disease is not a contraindication for hemodialysis or renal transplantation. Sickle cell disease patients who have received renal homografts may experience more frequent pain crises due to increased hematocrit driven by erythropoietin produced by the graft kidney. Recurrent sickle cell nephropathy in the transplanted kidney has been reported. In some patients, the increased anemia found with chronic renal failure causes cardiopulmonary complications and necessitates a chronic transfusion program. Treatment with recombinant erythropoietin (EPO) improves the anemia of renal failure in nonsickle cell disease patients; however, there are no large studies of the use of EPO in Hb SS patients with renal failure. The experience with a few of these patients so far indicates that large doses of EPO (300 - 350 U/kg three times a week) may be required to induce a significant increase in hematocrit or to alleviate a transfusion requirement.
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