Sickle Cell Nephropathy (1999)

Sickle cell nephropathy is now a well characterized entity with specific manifestations, risk factors, and prognosis. This review provides an approach to understanding the mechanisms involved in the development of the nephropathy, in order to provide rational treatment for the patients. Epidemiology The presence of renal failure in sickle cell disease (SCD) ranges from 5 to 18% of the total population of SCD patients (1). Powars et al. (2), in a prospective, case-control study of patients with SCD compared with sickle cell hemoglobin C patients, documental 31 (4.2%) patients affected by renal failure. The median age at the time of renal failure was 23.1 yr. Survival time was 4 yr with a median age of death of 27 yr after the diagnosis of end-stage renal disease (ESRD) in spite of dialysis treatment. Proteinuria, hypertension, severe anemia, and hematuria were reliable predictors of chronic renal failure (2). In this series, the presence of the inherited Central African Republic βs-gene cluster haplotype in a patient with SCD increased significantly the risk of chronic renal failure (2). Recently, in a prospective survival analysis of 964 patients with sickle cell anemia in adults, Platt et al. (3) observed an 18% overall mortality in adult SCD patients with 40% of these (7.6% of the total) manifesting overt renal failure. None received a kidney transplant. By multivariate regression analysis, renal failure was identified as the major risk factor for early mortality in adult patients with SCD. Sklar et al. (4), in a population study of 368 patients, found chronic renal insufficiency in 4.6% of SCD patients that was significantly associated with proteinuria and increased age. In patients with SCD, priapism episodes (5), especially those with postpubertal presentation and tricorporal disease (corpora cavernosa and corpus spongiosa involvement), had increased risk of multiorgan failure, including kidney failure. Although there is no gender predilection for renal failure in most series, Nissenson and Port (6) analyzed and reported a marked male predominance of sickle cell nephropathy (SCN) patients in the U.S. Renal Data System database, in which few patients were offered transplantation. Pathophysiology Chronic sickling underlies several mechanisms for kidney injury. The arterial side of the renal microvasculature has a low O2 tension. The hypertonicity and low pH of the renal medulla promote the formation of hemoglobin polymers in the red cells with deformation of the sickled cells, resulting in an increase in the blood viscosity, functional venous engorgement, and interstitial edema, predisposing the renal microcirculation to ischemia and infarction (7). Obliteration of the medullary vasculature produces segmental scarring and interstitial fibrosis (structural papillectomy), resulting in the formation of dilated renal pelvic capillaries and veins. Hematuria may result from rupture of vessels from the early venous engorgement or from the dilated vessels that result from scarring. The development of collateral vessels and their abnormal orientation in the medulla interferes with the countercurrent exchange mechanism, culminating through the years in irreversible loss of medullary tonicity (7). Renal cortical blood flow and GFR are increased perhaps by the secretion of medullary vasodilator prostaglandins (Figure 1) (7).Figure 1.: Etiologic algorithm for sickle cell nephropathy.Hyperfiltration coupled with glomerular hypertrophy can lead to glomerulosclerosis (1,7,8). Once progression of the glomerular damage is evident, GFR begins to decrease, likely with some contribution from the ingestion of analgesics that can independently induce interstitial nephropathy (1). Recently, Guasch et al. (9) documented a pattern of an increased dextran permeability in the glomerular basement membrane of SCD patients, with an incremental increase in the pore radius. This would cause a nonselective proteinuria rather than the microalbuminuria associated with hyperfiltration. Bank et al. (10) showed that in a transgenic sickle cell mouse model, there is an induction of nitric oxide synthase II (NOS II) in the glomeruli and distal nephron. This enzyme may increase the synthesis of nitric oxide leading to vasodilation and contribute subsequently to hyperfiltration. Clinical Findings The clinical manifestations of these pathophysiologic processes in SCD are well defined (Figure 2). Hyposthenuria is the first clinical evidence of defective medullary tonicity. In SCD patients older than 10 yr, the maximal urinary concentration is often reduced to 400 mosmol/kg H2O. This urine concentrating capacity can be restored with multiple transfusions of normal erythrocytes, showing the reversible nature of the defect. However, in patients older than 15 yr, the process is often irreversible. Both vasopressin generation and urinary diluting capacity in SCN patients remain unchanged (1). Hyposthenuria can produce a higher than usual obligatory urine output, thereby increasing the risk of dehydration.Figure 2.: Age at onset of the renal features in sickle cell disease.Hematuria Asymptomatic hematuria is one of the most prevalent features of the disease (1,7) and occurs either in heterozygous or homozygous patients at any age. Gross hematuria may also be observed in patients with sickle cell trait, either alone or in combination with von Willebrand disease, even in the absence of extrarenal bleeding (1,7). The hematuria is usually unilateral with the left kidney four times more frequently involved than the right. This may be explained by increased venous pressure due to the greater length of the left renal vein (7). Most of the episodes are self-limited, although dramatic and prolonged periods of gross hematuria may be seen (1,8). Renal Tubular Acidosis In sickle cell trait, renal acidification is normal (1,7,8). The distal tubule of homozygous hemoglobin S (Hb-SS) patients requires a greater acidic stimulus to reach a maximum urine-to-blood hydrogen ion gradient. The acidification defect is consistent with less than maximal generation of titratable acid (7). Usually, this defect does not cause systemic metabolic acidosis (1,7). There is no proximal loss of bicarbonate. Proteinuria Proteinuria is a frequent finding in SCD, and is present in 30% of patients during long-term follow-up (7). Both proteinuria and renal insufficiency increase with age in a parallel pattern (1,7,11) Nephrotic syndrome is found in 40% of the patients with SCN (1,7). Falk and Jenette (12), summarizing the series of Falk (13), Bakir (14), Powars (2), and Sklar (4), suggested that the nephrotic syndrome in SCD is a predictor of progression to chronic renal failure. It is believed that glomerular capillary hypertension, thought to be present in sickle cell nephropathy, mediates proteinuria. This concept is supported by the decrease in protein excretion that is observed with the administration of angiotensin-converting enzyme inhibitors (13). Renal Failure Renal failure occurs with either an acute or chronic presentation. Acute nonoliguric renal failure is present in 10% of patients hospitalized with SCD (15). Frequently, a concomitant infection or rhabdomyolysis is detected with the renal failure. Less often, renal vein thrombosis and intravascular hemolysis have been reported as causes of acute renal insufficiency in SCD patients (15). Despite the sparse literature, the prognosis seems to be favorable (15). Sklar et al. (15), in a retrospective case-control study of 12 SCD patients with acute renal failure, reported an 83% patient survival with recovery of function in all patients who survived, without progression to ESRD. Usually, in sickle cell nephropathy the development of ESRD occurs between the third and fifth decades of life (1,11). However, the renal abnormalities begin at earlier ages (16). Hyperfiltration is common in young patients with SCD (16), and is closely related to glomerular hypertrophy. Proteinuria in sickle cell nephropathy is associated with glomerulosclerosis on renal biopsy, which often progresses to renal failure. The presence of the nephrotic syndrome in patients with SCN is a clinical marker for ESRD, evolving from the progression of glomerulosclerosis. It is reasonable to argue that chronic renal failure is almost always the consequence of the progression of this mechanism of renal injury in SCN, clinically manifested by proteinuria and pathologically represented by glomerular hypertrophy and focal segmental glomerulosclerosis. Hypertension The incidence of hypertension in patients with Hb-SS ranges between 2 and 6% (7) compared with the published incidence for the black population in the United States of 28%. A renal salt-losing state has been suggested to explain the rather low incidence of hypertension in patients with SCD (7), although this would suggest chronic volume depletion. A defect in vascular tone has also been suggested (17). Recently, data from the Cooperative Study of Sickle Cell Disease demonstrated that individuals with SCD have BP levels that are significantly lower than in the general population. Predictive variables of BP by a multiple regression analysis showed that in males under 18 yr, there was a positive correlation between diastolic BP and blood urea nitrogen, and a negative correlation with the estimated creatinine clearance. Systolic BP correlated with blood urea nitrogen in females over 17 yr of age. Alarmingly, values that could be considered normal or that represent mild hypertension in healthy individuals should be considered a risk for important cardiovascular complications in patients with SCD. Also, there was a positive association between BP, stroke, and increased mortality in SCD (18). Diagnosis Proteinuria Once proteinuria is detected by dipstick, it should be quantified and renal function should be assessed (1). Diseases other than sickle cell nephropathy should be considered. Sudden edema or massive proteinuria (>3 g/24 h) may initially suggest idiopathic nephrotic syndrome, although renal vein thrombosis should always be ruled out, due to the predisposition of patients with Hb-SS to experience venous thrombosis (1,7). Hematuria Before considering the diagnosis of sickle cell nephropathy, other causes of hematuria must be excluded. Renal and bladder ultrasound can identify bleeding from a stone or tumor (1). Increased echogenicity of the renal pyramids or calyceal clubbing by urography, in the absence of hypercalciuria or nephrocalcinosis, may suggest sickle cell disease (1). In patients with gross hematuria, the use of cystoscopy may identify the source of bleeding. Coagulation tests are useful to rule out the concomitant appearance of von Willebrand disease in sickle trait patients. Hyperfiltration The upper limit for a normal GFR is not certain even with inulin clearance (1). Simplified methods for nonisotopic iothalamate and para-aminohippurate measurement are now available (1), although for most clinical purposes an accurate measure of GFR is not necessary. A decrease in GFR over time in a patient with sickle cell disease, especially when accompanied by proteinuria, requires a careful follow-up (1). Pathology Glomerular enlargement was described as part of SCD in 1960 (1). In children, the finding has been reported more frequently beyond 2 yr of age (19). This pattern is more obvious in the juxtamedullary glomeruli. A difference in size has been shown when glomeruli from SCD children are compared with healthy children (19). In adults with Hb-SS, the average diameter of the glomeruli (186 ± 14.5 μm) has been found to be greater than that in glomeruli from control biopsies (137.9 ± 19.3 μm) (13). In older patients with renal involvement, progressive ischemia and fibrosis lead to obliteration of the glomeruli (1). Falk et al. (13) observed perihilar focal and segmental glomerulosclerosis in eight of 10 biopsy specimens. The sclerotic segments were adherent to Bowman's capsule with areas of hyalinosis, lipid vacuolation, and foam cells. Adjacent to the glomeruli, focal interstitial fibrosis and tubular atrophy were noted. Immunofluorescence microscopy revealed only irregular staining for IgM, C3, and C1q in sclerotic areas. No electron-dense immune complex-type deposits were seen. Some areas of subendothelial rarefaction had the appearance of basement membrane duplication. Bhathena and Sondheimer (20) in their analysis of kidney biopsies from six nephrotic patients with Hb-SS described both collapse of the capillaries and mesangial atrophy and expansion of the obliterated tuft segment by mesangial matrix in maximally hypertrophied glomeruli in focal segmental glomerulosclerosis. The mean glomerular diameter was enlarged in nephrotic Hb-SS (233.6 ± 25.3 μm) and non-SCD nephrotic patients (243.0 ± 12.5 μm) compared with control subjects (158.0 ± 12.7 μm). Some peripheral capillary loops had the appearance of duplication, others a wrinkling appearance. Bakir et al. (14) analyzed 240 patients with SCD. Twelve had the nephrotic syndrome. In nine, the glomerular lesion consisted of mesangial expansion and basement membrane duplication (nonimmune membranoproliferative glomerulonephritis [MPGN]-like lesion), and global or focal segmental glomerulosclerosis. Immunofluorescence studies in one series of four young patients with Hb-SS (1975) and glomerular disease revealed MPGN like lesions associated with Ig and complement deposition (four patients), and renal tubular epithelial antigen deposition (two patients) in a granular pattern along the glomerular basement membrane (21). In the circulation of some patients, tubular epithelial antigens and cryoprecipitable renal tubular antigen-antibody complexes were detected (21). It is uncertain whether these were attributable to SCD. The composite picture of sickle cell glomerulopathy is one of glomerular hypertrophy and focal glomerulosclerosis (13), with either an expansive or collapsing pattern (20). The basement membrane lucencies and areas of apparent duplication present a variable nonimmune MPGN-like picture (14), without the lobular appearance of immune MPGN. In a few cases, an immune complex nephropathy has been reported (21,22), although it is uncertain whether this is part of sickle nephropathy or an unusual appearance of an immune complex nephropathy modified by the presence of sickle cell disease. Medullary lesions consist of edema, focal scarring, and interstitial fibrosis with consequent atrophy and mononuclear infiltration. Renal papillary necrosis appears focally, with a few collecting ducts surrounded by an extensive area of fibrosis (1,7). Tubular hemosiderin deposits observed in biopsy specimens may play a role in the progression of the nephropathy. Magnetic resonance imaging in SCD patients shows a decrease in the renal cortical spin echo signal, suggesting defective renal cortical iron metabolism (23). In experimental models using rabbits, saccharated-iron complexes can produce the nephrotic syndrome (24). Renal Medullary Carcinoma The incidence of cancer in the sickle cell disease population is 1.74 per 1000 patient years with a mortality rate of 1.04 cases per 1000 patient years (25). This is comparable to the cancer incidence rate of 1.9 per 1000 patient years for African-Americans between 35 and 44 yr of age in 1990 (26). The existence of renal cell carcinoma in some patients with sickle cell disease was first suspected by Baron et al. (27), and later confirmed by Davis et al. (28). In their original description of 33 patients, Davis et al. (28) observed a cohort with male predominance under 25 yr of age, although both sexes were equally affected after 25 yr of age. In 25 patients in whom ethnic group data were provided, all were black. Gross hematuria and abdominal flank pain were frequent clinical symptoms. Less frequently, weight loss and a palpable mass were found. In 13 patients, the mean duration of the symptoms was 8 wk. Data available on 19 patients showed survival from the time of surgery of only 15 wk, evidence of the aggressive nature of the tumor. Gross pathology revealed involvement of the right kidney in 23 of the 33 patients. Most of the tissue sections had satellite nodules in the renal cortex with extension to the perinephric and peripelvic soft tissue, characteristics that have been used to detect the presence of tumor in radiologic studies (29). A composite description is that of a lobulated pattern with the tumor located in the renal medulla, which is firm with variable areas of necrosis and hemorrhage (30). Microscopically, the tumor presents a reticular or adenoid cystic pattern with regions of poor differentiation in a stroma with a mucinoid, myxoid, or edematous appearance. Due to the young age of most of the patients with SCD and renal cell carcinoma, it has been suggested that genetic factors may play a role (30). Avery et al. (30) performed cytogenetic testing in a sample of renal tumor tissue from a 30-yr-old black man with SCD. In the abnormal cells that were successfully karyotyped (n = 4), all had chromosome 11 monosomy and two contained anomalies on chromosome 3 (one monosomy and one translocation). The authors suggested a potential role of a chromosome 11 anomaly in patients with SCD and medullary carcinoma, due to the known location of the gene for beta globin in the terminal portion of the short arm of chromosome 11. Interestingly, allelic loss in chromosome 11 has been associated with other types of neoplasias (31). On the other hand, some cases of renal cell carcinoma and patients with syndrome and renal cell carcinoma have an association with chromosome 3 abnormalities with SCD and medullary carcinoma and radiologic that may be used for a more of the tumor. Medullary carcinoma is an aggressive and the of the disease has not been modified with and (30). of SCN is the of and control of that can renal as well as and of renal for of the disease has increased the survival of SCD patients without the use of should be by SCD patients (7). may be to the patient of the risk of Sudden death has been occurs even in sickle trait patients. Before it is that transfusions with normal red blood cells be of and should be and to can induce in Hb-SS more than in a normal the patient to the risk of a potential usually should be in adults and in children in to their size (7) to In of in patients due to multiple the use of is (1). Hematuria Most of the episodes of gross hematuria in patients with SCD However, in a few patients hematuria may be is to The use of per in with or can from the bladder and sickling and renal papillary necrosis (1). may be for blood The use of acid for may be necessary. control hematuria, low may be from per area 3 times with a incremental increase bleeding (1). and of the affected renal segment are in patients with bleeding (1). is Proteinuria The of a protein than the may of the nephropathy. However, protein is not due to failure and the low state of Hb-SS patients The use of angiotensin-converting enzyme inhibitors can the proteinuria in SCD patients with nephropathy In a with 10 patients with mild nephropathy, Falk et al. (13) showed that proteinuria by to levels after treatment BP, and renal flow not significantly and approach to patients with Renal The U.S. Renal Data System study reported SCD patients with renal failure of patients for renal insufficiency from with the SCD patients with ESRD received a kidney It is that not treatment to SCD patients with chronic renal there is a poor for (1). is by most SCD patients with ESRD. Interestingly, not have more complications than the of the dialysis population There may be an of dialysis by the low of of the by SCD patients when compared to other with ESRD Renal can be successfully performed in patients with SCD and chronic renal failure. A of renal in with SCD was in were performed in patients. were at yr, with a patient In an of the series in were performed in There was a survival of in related and in those data are to the survival in the general population at yr was the that sickle cell were most frequent in the first after the transplantation. This is associated with the in the and (7). early as 5 after in urine concentrating can be observed (7). In one of sickle cell nephropathy was suggested in a kidney yr after of the patient surgery with multiple transfusions of normal blood and the use of to increase hemoglobin the may the of In sickle cell nephropathy is an important cause of mortality in SCD patients, with specific genetic and clinical that can progression to ESRD. Chronic sickling mechanisms of kidney urine concentration and glomerular enlargement and Clinical of the manifestations of these as well as of risk factors for medullary carcinoma, can the to a rational treatment to the SCD Chronic dialysis and represent reasonable for those patients who reach ESRD.