Original Article
Prevalence and Pathologic Features of Sickle Cell Nephropathy and Response to Inhibition of Angiotensin-Converting Enzyme
N Engl J Med 1992; 326:910-915April 2, 1992
- Abstract
- Abstract
Background.
Nephropathy may develop in patients with sickle cell disease. We determined the prevalence of proteinuria and renal insufficiency in a group of patients with sickle cell disease and investigated the renal pathologic changes and the effects of an angiotensin-converting—enzyme inhibitor (enalapril) on protein excretion in patients found to have nephropathy.
Methods.
We prospectively screened 381 patients with sickle cell disease for the presence of proteinuria and renal insufficiency. Renal biopsy and measurements of glomerular filtration rate, effective renal plasma flow, and urinary protein excretion were performed in 10 patients with mild nephropathy before and after the administration of enalapril, and again two to three weeks after its discontinuation.
Results.
Of the 381 patients with sickle cell disease, 26 (7 percent) had serum creatinine concentrations above the normal range and 101 (26 percent) had proteinuria of at least 1 +. The renal lesions in the 10 patients who had biopsies consisted of glomerular enlargement and perihilar focal segmental glomerulosclerosis. The mean (±SD) glomerular area in these patients was 28.7±4.1 × 103 μm2, as compared with 15.8±4.3×103 μm2 in 10 control patients without renal disease who had died of trauma (P<0.001).
During the administration of enalapril, the mean 24-hour urinary protein excretion decreased 57 percent (range, 23 to 79 percent) below the base-line value (P<0.001 ), and it increased to 25 percent below the base-line value after enalapril was discontinued. The glomerular filtration rate and effective renal plasma flow did not change significantly.
Conclusions.
Approximately 25 percent of patients with sickle cell disease have proteinuria. Treatment with enalapril reduces the degree of proteinuria in these patients, suggesting that glomerular capillary hypertension may be a pathogenic factor in sickle cell nephropathy. (N Engl J Med 1992;326:910–5.)
Media in This Article
Figure 1
Light-Microscopical Sections of Renal-Biopsy Specimens from Patients with Sickle Cell Disease, Showing Mild (Panel A) and Moderate (Panel B) Perihilar Focal Segmental Glomerulosclerosis and Global Glomerulosclerosis (Panel C) (Jones' Silver Methenamine Stain with Hematoxylin–Eosin Counterstain, ×300).Figure 2
Glomerular Areas Measured in Renal-Biopsy Specimens from Patients with Sickle Cell Disease and Control Patients.Article Activity
- Article
DESPITE improvements in the management of sickle cell disease, morbidity and mortality from the failure of major organ systems remain a problem,1 and renal failure may occur in as many as 18 percent of affected patients.2 Although renal-replacement therapy with dialysis and renal allograft transplantation is feasible, long-term survival is poor,3 , 4 especially in patients with the nephrotic syndrome.5
The causes of renal failure in patients with sickle cell disease are not well understood. Etteldorf and others noted that the glomerular filtration rate in children with sickle cell disease was abnormally high and that it normalized during adolescence and declined further with age.6 7 8 9 Whether renal function decreases because of a glomerulopathy unique to sickle cell disease, an unwanted consequence of its medical management, or an unrelated disease process has been the subject of debate. Most investigators now believe that sickle cell disease causes nephropathy. Yet sickle cell nephropathy has been variously described as a process involving the immune complex,10 11 12 13 14 a variant of membranoproliferative glomerulonephritis,15 16 and focal segmental glomerulosclerosis.5 , 16 17 18 19 20 This controversy stems in part from the paucity of renal-biopsy data, especially for patients with early sickle cell nephropathy.
To improve our understanding of sickle cell nephropathy, we began a comprehensive prospective evaluation of patients with sickle cell disease. We asked the following questions: What is the prevalence of proteinuria and abnormal renal function in patients with sickle cell disease who have not been preselected for signs or symptoms of renal disease? What are the renal abnormalities in patients with sickle cell disease who have early renal disease? What effects does an angiotensin-converting—enzyme (ACE) inhibitor have on protein excretion and renal junction in patients with sickle cell disease and nephropathy? We posed the last question because some investigators reported that sickle cell nephropathy is primarily a consequence of glomerular hypertrophy and focal segmental glomerulosclerosis.5 , 16 17 18 19 20 It has been suggested that focal glomerulosclerosis may be a consequence of elevated intraglomerular pressure in rats with progressive renal disease,21 , 22 and in such rats, intraglomerular pressures can be lowered with an ACE inhibitor.23
Methods
Patient Selection
We sought to study all patients being followed in the sickle cell centers at the University of North Carolina and Duke University. From June 1985 to June 1991, we determined the prevalence of proteinuria and renal insufficiency in these patients by using a dipstick to test urine for the presence of protein and by measuring the serum creatinine concentrations. A 24-hour urine specimen was collected from patients with proteinuria of least 1 + to measure total protein excretion. Patients who had proteinuria (urinary protein, ≥0.5 g per day) and serum creatinine concentrations of less than 177 μmol per liter (2.0 mg per deciliter) were asked to undergo a renal biopsy and treatment with an ACE inhibitor (enalapril) for two weeks. This study was approved by the University of North Carolina and Duke University committees on the protection of human rights. All patients gave written informed consent for the biopsy and for treatment with the ACE inhibitor.
Renal Analysis
Ten patients who fulfilled the criteria for proteinuria and minimal renal dysfunction agreed to have a renal biopsy. None had other systemic diseases. One had mild hypertension. These patients were admitted to the General Clinical Research Center, where percutaneous renal biopsies were performed under ultrasonographic guidance. The tissue was processed for light, immunofluorescence, and electron microscopy according to standard techniques.24 In addition, computerized morphometric analysis with a Zeiss Videoplan (Carl Zeiss, New York) was performed to determine the mean area and diameter of the glomeruli.25 Video images of glomeruli were outlined on a magnetic measuring tablet, and the data were collected and analyzed by the Videoplan computer. The size of the glomeruli in the 10 patients was compared with that in kidney tissue from 10 age-matched control patients (mean age, 34.8 years) who had died of trauma and had no clinical or pathological evidence of renal disease. Only glomeruli with no evidence of sclerosis were measured. The size of the glomerular tufts was analyzed, and not the dimensions of Bowman's capsule. In each specimen, a minimum of 10 glomeruli were measured (range, 10 to 33; mean, 20).
Measurement of Glomerular Filtration Rate and Effective Renal Plasma Flow
After the renal biopsy, a 24-hour urine specimen was collected. A dietitian assessed the protein and caloric intake of each patient's diet. The patients were instructed to continue their usual diet for the remainder of the study. The glomerular filtration rate was measured by determining the rate of clearance of continuously infused inulin (Iso-Tex Diagnostics, Friendswood, Tex.),26 and effective renal plasma flow was measured by determining the rate of clearance of para-aminohippuric acid. Inulin was given initially as a bolus injection and then as a continuous infusion. The calculation of the inulin dose was based on the formula of Cockcroft and Gault,27 and the dose was compared with the measured creatinine clearance. Forty-five minutes was allowed for equilibration, and then urine was collected for four 45-minute periods. Blood samples were collected before and after each period. Each patient drank 500 ml of water before the infusions began and an amount of water equivalent to the hourly urine output during the infusions.
Effect of an ACE Inhibitor on Proteinuria and Renal Function
After the base-line studies, the 10 patients took enalapril orally in a dose (5 to 10 mg per day) that did not induce a decrease in systemic blood pressure. After two weeks of treatment, 24-hour urinary protein excretion, glomerular filtration rate, effective renal plasma flow, and blood pressure were measured again. Treatment was then discontinued, and the same studies were performed a third time two to three weeks later. Complete data on urinary protein excretion and inulin clearance were available for all patients. In two patients, para-aminohippuric acid clearances from one study were not interpretable because of technical problems, and one patient declined to have effective renal plasma flow measured.
Biochemical Analysis
Urinary protein was measured with a dipstick (Miles, Elkhart, Ind.). The protein content in the 24-hour urine samples was assessed with the use of Coomassie blue (normal value, ≤150 mg per day). Serum creatinine concentrations were measured with a Hitachi 736 or an Ektachem 400 analyzer. The upper limit of normal at the University of North Carolina Hospitals is 106 μmol per liter for women and 133 μmol per liter for men; at Duke University it is 124 μmol per liter. Urinary and plasma levels of inulin were measured with a standard anthrone assay.28 , 29 Para-aminohippuric acid was measured electrophotometrically by the method of Braton and Marshall as modified by Smith et al.30 The glomerular filtration rate and effective renal plasma flow were calculated from the clearance of inulin and para-aminohippuric acid. The mean (±SD) glomerular filtration rate in 12 normal subjects was 1.7±0.2 ml per second, and the mean effective renal plasma flow was 8.8±1.5 ml per second. The filtration fraction was calculated by dividing the glomerular filtration rate by the effective renal plasma flow. The mean arterial pressure was calculated as the diastolic pressure + 1/3(systolic pressure — diastolic pressure).
Statistical Analysis
We used repeated-measures analysis of variance to compare the three measurements of glomerular filtration rate, effective renal plasma flow, 24-hour urinary protein excretion, and mean arterial blood pressure. Bonferroni's adjustment for the alpha level was made to control the Type I error rate. The results of all tests except the 24-hour urinary protein excretion were normally distributed; the natural logarithms were used for urinary protein excretion.
Repeated-measures analysis of variance does not include missing data. In order to consider results for the two patients with missing values for effective renal plasma flow (and filtration fraction), the values at each time point were tested with paired Student's t-tests.
The Pearson chi-square test was used to test for an association between the diagnosis (hemoglobin SS disease or non—hemoglobin SS disease) and classification of serum creatinine and urinary protein concentrations (abnormal or normal). The mean area and diameter of the glomeruli in the control patients and the patients with sickle cell disease were compared with the Wilcoxon rank-sum test.
Results
Demographic Data
Serum creatinine and urinary protein were measured in 310 adults (age, ≥17 years) and 71 children. There were 177 male and 204 female patients. Hemoglobin electrophoresis revealed that 71 percent of the patients had hemoglobin SS disease, 17 percent hemoglobin SC disease, 11 percent hemoglobin S—B+-thalassemia or hemoglobin S—B0-thalassemia, and 1 percent hemoglobin S—other hemoglobinopathies. None of the patients had hemoglobin AS (sickle cell trait).
Twenty-six adults (7 percent), but none of the children, had elevated serum creatinine concentrations. Thirteen of these patients had a serum creatinine concentration of 177 μmol per liter or less, six patients had values between 185 and 530 μmol per liter, and seven patients had end-stage renal disease treated with dialysis. Among the 381 patients, 282 had no proteinuria or only trace proteinuria; 47 had proteinuria of 1 +, 28 of 2 +, 16 of 3 +, and 10 of 4 +. Thus, 26 percent of the patients had proteinuria of at least 1 + and 14 percent of at least 2 +. Similar proportions of patients with hemoglobin SS disease and patients with other hemoglobinopathies had elevated serum creatinine concentrations (P = 0.231). However, proteinuria of at least 1 + was more common among patients with hemoglobin SS disease than among patients with other hemoglobinopathies (31 percent vs. 16 percent, P = 0.002). Among the 101 patients with proteinuria, 83 had hemoglobin SS disease, 4 had hemoglobin SC disease, and 14 had either hemoglobin S—B+-thalassemia or hemoglobin S—B0-thalassemia. Twenty-four-hour urine samples were available for 44 patients with proteinuria. In these patients, protein excretion ranged from 0.03 to 10.8 g per day, with a mean (±SD) of 1.7±2.5. Urinary protein excretion exceeded 2.5 g per day in 12 patients, and these patients all had other features of the nephrotic syndrome.
Analysis of Renal-Biopsy Specimens
All 10 patients who underwent renal biopsy had homozygous SS disease. Protein excretion in this group ranged from 0.8 to 10.8 g per day (mean, 2.4 g) (Table 1Table 1
Characteristics of 10 Patients with Sickle Cell Disease, Proteinuria, and Minimal Renal Dysfunction.*). Daily protein excretion was 2.2 g or less in 9 of the 10 patients, whereas it was 10.8 g per day in 1 patient.The most prominent pathologic changes in these patients were glomerular enlargement, perihilar focal segmental glomerulosclerosis, and hemosiderosis. Light microscopy showed that the nonsclerotic glomeruli were enlarged, with an increase in the total number of cross-sectioned capillary lumens accompanied by a commensurate increase in epithelial, endothelial, and mesangial cells (Fig. 1Figure 1
Light-Microscopical Sections of Renal-Biopsy Specimens from Patients with Sickle Cell Disease, Showing Mild (Panel A) and Moderate (Panel B) Perihilar Focal Segmental Glomerulosclerosis and Global Glomerulosclerosis (Panel C) (Jones' Silver Methenamine Stain with Hematoxylin–Eosin Counterstain, ×300).). The mean (±SD) glomerular area was significantly larger in the patients with sickle cell disease than in the 10 control patients (28.7±4.1×103 vs. 15.8±4.3×103 μm2, P<0.001) (Fig. 2Figure 2Glomerular Areas Measured in Renal-Biopsy Specimens from Patients with Sickle Cell Disease and Control Patients.). In addition, the diameter of the glomeruli was significantly greater in the patients with sickle cell disease than in the control patients (186±14 vs. 138±19 μm, P<0.001).The biopsy specimens showed perihilar focal and segmental glomerulosclerosis in 8 of the 10 patients with sickle cell disease (Fig. 1, Table 1). This was sometimes accompanied by global sclerosis. In the two specimens with no focal and segmental glomerulosclerosis, global sclerosis was present in 22 percent and 11 percent of glomeruli. The 10 biopsy specimens had a mean of 27 percent segmentally and globally sclerotic glomeruli, with a range of 7 percent (Patient 5) to 67 percent (Patient 9). The sclerotic segments were typically adherent to Bowman's capsule and usually contained foci of hyalinosis, lipid vacuolation, and foam cells. All biopsy specimens had some degree of focal interstitial fibrosis and tubular atrophy; it was mild in six, moderate in three, and severe in one. This focal tubulointerstitial injury could often be identified adjacent to glomeruli with segmental or global sclerosis. All specimens also contained sickled red cells (resulting from in vitro sickling) in vessel lumens and hemosiderin granules within the cytoplasm of renal tubular cells.
Immunofluorescence microscopy showed irregular immunostaining for IgM, C3, and C1q in areas of sclerosis. The nonsclerotic segments either did not stain or showed trace or small amounts (1 + on a scale of 0 to 4 +) of mesangial staining for IgM (5 of 10 patients) and C3 (3 of 10 patients). No staining for IgG or IgA was seen.
The biopsy specimens from the patients with sickle cell disease showed focal effacement of visceral epithelial foot processes on electron microscopy, and sickle cell hemoglobin tactoids were present within erythrocytes. No biopsy specimens had immune complex—type electron-dense deposits. Six biopsy specimens
showed a slight degree of focal electron-lucent expansion of the subendothelial zone with occasional mesangial interposition into this zone, but no substantial accumulation of new electron-dense matrix material. These changes might represent early lesions that could evolve into the more extensive capillary-wall changes that are sometimes seen in patients with advanced sickle cell nephropathy and resemble membranoproliferative glomerulonephritis.15 , 16 The sclerotic segments had increased amounts of matrix material, scattered lipid vacuoles, occasional vacuolated cells, and irregular accumulations of electron-dense material corresponding to the foci of hyalinosis seen on light microscopy.
Response to Enalapril
The rate of urinary protein excretion decreased in all 10 patients at the end of the two-week period of treatment with enalapril (P<0.001) (Fig. 3Figure 3
Urinary Protein Excretion in 10 Patients with Sickle Cell Disease at Base Line, after Two Weeks of Enalapril, and at Follow-up, Two to Three Weeks after Enalapril Was Stopped.). The mean decrement was 57 percent below base line (range, 23 to 79 percent). When measured again two to three weeks after treatment with enalapril was discontinued, the mean protein excretion was 75 percent of the base-line value (P = 0.168). In three patients, however, protein excretion continued to decrease. The decrease was most pronounced in the patient whose protein excretion was 10.8 g per day at base line.The decrease in proteinuria during the administration of enalapril was not the consequence of a decrease in systemic arterial pressure. Repeated-measures analysis of the mean systemic arterial pressure in each patient before, during, and after the administration of enalapril revealed no differences between treatment periods (P = 0.786). The means of the mean systemic arterial pressures were 90.3±4.5, 88.8±3.8, and 88.8±3.0 mm Hg, respectively. The mean glomerular filtration rate did not change during or after treatment with enalapril (P = 0.341) (Fig. 4Figure 4
Glomerular Filtration Rate and Effective Renal Plasma Flow at Base Line, after Two Weeks of Enalapril, and at Follow-up, Two to Three Weeks after Enalapril Was Stopped.). Effective renal plasma flow was measured in nine patients, and the values did not change significantly during the period of enalapril treatment or after its cessation (P = 0.149) (Fig. 4). Similarly, there were no significant changes in the filtration fraction at any time (P = 0.344).Discussion
We found that 26 percent of 381 patients with sickle cell disease had proteinuria of at least 1 +. Renal insufficiency, ranging from mild to end-stage disease, was found in slightly fewer than 7 percent of the patients. These results are similar to those reported by Bakir et al. in a retrospective study of 240 adult patients.5 In addition, Halankar et al. noted that 70 percent of their patients had proteinuria.31
Our observations in patients with sickle cell disease who have early renal dysfunction suggest that sickle cell nephropathy is a consequence of glomerular hypertrophy and focal and segmental glomerulosclerosis. The immunofluorescence-microscopy studies do not support the contention that sickle cell nephropathy is an immune complex—mediated glomerulonephritis. It has also been proposed that this nephropathy may be a consequence of a toxin, such as iron, administered during blood transfusions.32
Our findings extend and confirm the observations of previous investigators that the fundamental lesion in sickle cell disease is focal segmental glomerulosclerosis in the setting of glomerular hypertrophy.16 17 18 19 20 Bernstein and Whitten were the first to document glo-
merular enlargement in patients with sickle cell disease, and they also observed focal glomerular sclerosis.17
It is possible that the focal segmental glomerulosclerosis that develops in the setting of glomerular enlargement in sickle cell disease is physiologically analogous to that which develops in rodents after subtotal nephrectomy.20 , 21 In these animals, an increase in pressure in the remaining hypertrophied glomeruli may result in glomerular sclerosis. This glomerular hypertension, with its resulting destruction of nephrons, is attenuated by controlling glomerular capillary hypertension with agents that decrease efferent glomerular arteriolar vasoconstriction (e.g., ACE inhibitors).23
The possibility that this pathogenic mechanism causes nephropathy in sickle cell disease is supported by the presence of glomerular hypertrophy with focal segmental glomerulosclerosis and by the observation that enalapril quickly, and for the most part reversibly, decreased protein excretion in patients with these pathologic abnormalities. The decrease in protein excretion was not accompanied by a decrease in arterial pressure or changes in the glomerular filtration rate, effective renal plasma flow, or filtration fraction. Decreases in protein excretion during the administration of an ACE inhibitor also occur in patients with other glomerular diseases.33 34 35 36
Our study does not explain why glomerular hypertrophy develops in patients with sickle cell disease. Glomerular hypertrophy occurs in the setting of hypoxemia — for example, in patients with cyanotic congenital heart disease37 , 38 — and is associated with obesity and the sleep apnea syndrome.25 The intermittent hypoxemia that is a consequence of sickling may be a sufficient stimulus for glomerular hypertension and hypertrophy. Another possibility is that ischemia in the medullary region of the kidney results in glomerular hypertrophy. In support of this possibility, de Jong et al. have demonstrated that the vasa recta are almost completely absent in the kidneys of patients with sickle cell disease and that medullary ischemia results in increased renal production of prostaglandins, which leads in turn to vasodilation of afferent glomerular arterioles and to glomerular hypertension.39 An additional possibility is that patients with sickle cell disease may have increased serum viscosity.40 Garcia et al. have noted that an increase in viscosity may increase the severity of the glomerulopathy associated with subtotal nephrectomy.41
Our short-term results suggest that a prospective trial to determine whether treatment with ACE inhibitors can prevent renal insufficiency in patients with sickle cell nephropathy is warranted. Whether long-term therapy with ACE inhibitors can lower protein excretion persistently and prevent the development of renal insufficiency remains to be determined.
Supported by grants from the University of North Carolina-Duke Comprehensive Sickle Cell Center (5P60 HL28391–09), the Verne S. Caviness General Clinical Research Center (RR00046), and the National Center for Research Resources General Clinical Research Center Program of the National Institutes of Health (M01–RR30).
We are indebted to Susan Hogan and Dr. Keith E. Muller for invaluable statistical expertise and to Dr. Melvin Seek for his help with the early phases of the project.
Source Information
From the Departments of Medicine (R.J.F., E.O., A.J.) and Pathology (J.C.J.). University of North Carolina at Chapel Hill, and the Departments of Pediatrics and Medicine (J.S., G.P.), Duke University, Durham, N.C. Address reprint requests to Dr. Falk at the Department of Medicine, Division of Nephrology. CB #7155, 3034 Old Clinic Bldg., Chapel Hill, NC 27599.
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