Renal abnormalities in sickle cell disease
2000; Elsevier BV; Volume: 57; Issue: 1 Linguagem: Inglês
10.1046/j.1523-1755.2000.00806.x
ISSN1523-1755
AutoresPhuong‐Thu T. Pham, Phuong‐Chi T. Pham, Alan Wilkinson, Susie Q. Lew,
Tópico(s)Iron Metabolism and Disorders
ResumoRenal abnormalities in sickle cell disease. Sickle cell nephropathy is indicated by sickled erythrocytes, with the consequent effects of decreased medullary blood flow, ischemia, microinfarct and papillary necrosis. Impaired urinary concentrating ability, renal acidification, hematuria, and potassium secretion are also found. There may be a causal relationship between an increase in nitric oxide synthesis and experimental sickle cell nephropathy, and some studies have indicated that the progression of sickle cell nephropathy is hemodynamically mediated. Although there are many studies showing that proteinuria, nephrotic syndrome, chronic progressive renal failure, and acute renal failure syndromes are the outcome of this disease, the pathogenic mechanism(s) and potential therapies remain to be elucidated. Survival of patients with sickle cell nephropathy who progress to end-stage renal disease (ESRD) is equal to non-diabetic ESRD patients, and graft survival rates are also similar for those who undergo renal transplantation. This article presents a historical review of the glomerular and tubular disorders associated with sickle cell nephropathy, and reviews therapeutic indications to slow its progression. Further research is needed. Renal abnormalities in sickle cell disease. Sickle cell nephropathy is indicated by sickled erythrocytes, with the consequent effects of decreased medullary blood flow, ischemia, microinfarct and papillary necrosis. Impaired urinary concentrating ability, renal acidification, hematuria, and potassium secretion are also found. There may be a causal relationship between an increase in nitric oxide synthesis and experimental sickle cell nephropathy, and some studies have indicated that the progression of sickle cell nephropathy is hemodynamically mediated. Although there are many studies showing that proteinuria, nephrotic syndrome, chronic progressive renal failure, and acute renal failure syndromes are the outcome of this disease, the pathogenic mechanism(s) and potential therapies remain to be elucidated. Survival of patients with sickle cell nephropathy who progress to end-stage renal disease (ESRD) is equal to non-diabetic ESRD patients, and graft survival rates are also similar for those who undergo renal transplantation. This article presents a historical review of the glomerular and tubular disorders associated with sickle cell nephropathy, and reviews therapeutic indications to slow its progression. Further research is needed. Sickle cell disease may result in both renal functional disturbances and anatomical alterations. The description of renal complications spans this century, starting with “increased urine volume of low specific gravity” by Herrick in 1910, who was also the first to describe sickle cell disease1.Herrick J.B. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.Arch Intern Med. 1910; 6: 517-520Crossref Scopus (458) Google Scholar. With the increasing longevity of patients with sickle cell disease, Davis, Mostofi, and Sesterhenn in 1995 reported renal medullary carcinoma as “another example of renal disease associated with sickle cell disorders”2.Davis Jr, C.J. Mostofi F.K. Sesterhenn I.A. Renal medullary carcinoma: The seventh sickle cell nephropathy.Am J Surg Pathol. 1995; 19: 1-11Crossref PubMed Scopus (384) Google Scholar. This review provides an overview of the spectrum of renal abnormalities encountered in sickle cell nephropathy, possible mechanisms involved, and treatment options for both pre–end-stage renal disease (ESRD) and ESRD. Table 1 summarizes the numerous pathophysiologic changes of the kidneys in patients with sickle cell disorders.Table 1Renal syndromes and functional abnormalities in sickle cell disordersAbnormalityCommentsReferencesHematuria10% bilateral, left 4× more than right6.Statius van Eps L.W. Sickle cell disease and the kidney,.Oxford Textbook of Clinical Nephrology. edited by Cameron S, Davison AM, Grunfeld JP, Kerr D, Ritz E. Oxford University Press, New York1992: 700-720Google Scholar, 27.Mostofi F.K. Vorder Brugge C.F. Diggs L.W. Lesions in kidneys removed for unilateral hematuria in sickle cell disease.Arch Pathol. 1957; 63: 336-351PubMed Google Scholar, 28.Crone R.I. Jefferson S.C. Pileggi V.J. Lowry E.C. Gross hematuria in sickle cell trait.Arch Intern Med. 1957; 100: 587-603Crossref Scopus (12) Google ScholarProteinuriaHigh association with increased age30.Falk R.J. Jennette J.C. Sickle cell nephropathy.Adv Nephrol. 1994; 23: 133-147PubMed Google Scholar,40.Sklar A.H. Campbell H. Caruana R.J. Lightfoot B.O. Gaier J.G. Milner P. A population study of renal function in sickle cell anemia.Int J Artif Organs. 1990; 13: 231-236PubMed Google ScholarIncreased glomerular filtration (GFR)? prostaglandin mediated, ? nitric oxide15.Allon M. Lawson L. Eckman J.R. Delaney V. Bourke E. Effects of nonsteroidal anti-inflammatory drugs on renal function in sickle cell anemia.Kidney Int. 1988; 34: 500-506Abstract Full Text PDF PubMed Scopus (69) Google Scholar, 16.De Jong P.E. De Jong-van Den Berg T.W. Sewrajsingh G.S. Schouten H. Donker A.J.M. Statius van Eps L.W. The influence of indomethacin on renal haemodynamics in sickle cell anemia.Clin Sci. 1980; 59: 245-250Crossref PubMed Scopus (42) Google Scholar, 24.Bank N. Aynedjian H.S. Qiu J.H. Osei S.Y. Ahima R.S. Fabry M.E. Nagel R.L. Renal nitric oxide synthases in transgenic sickle cell mice.Kidney Int. 1996; 50: 184-189Abstract Full Text PDF PubMed Scopus (76) Google ScholarIncreased renal plasma flow? prostaglandin mediated15.Allon M. Lawson L. Eckman J.R. Delaney V. Bourke E. Effects of nonsteroidal anti-inflammatory drugs on renal function in sickle cell anemia.Kidney Int. 1988; 34: 500-506Abstract Full Text PDF PubMed Scopus (69) Google Scholar,16.De Jong P.E. De Jong-van Den Berg T.W. Sewrajsingh G.S. Schouten H. Donker A.J.M. Statius van Eps L.W. The influence of indomethacin on renal haemodynamics in sickle cell anemia.Clin Sci. 1980; 59: 245-250Crossref PubMed Scopus (42) Google ScholarAcute renal failureCase reports; occurring in the setting of precipitating factors46.Kelly C.J. Singer I. Acute renal failure in sickle cell disease.Am J Kidney Dis. 1986; 8: 146-150Abstract Full Text PDF PubMed Scopus (8) Google Scholar, 47.Devereux S. Knowles S.M. Rhabdomyolysis and acute renal failure in sickle cell anemia.Br Med J. 1985; 290: 1707Crossref PubMed Scopus (1) Google Scholar, 48.Hassell K.L. Eckman J.R. Lane P.A. Acute multiorgan failure syndrome: A potentially catastrophic complication of sickle cell pain episodes.Am J Med. 1994; 96: 155-162Abstract Full Text PDF PubMed Scopus (154) Google Scholar, 49.Pham P.T. Lew S.Q. Balow J.E. Sickle cell nephropathy during the postpartum period in a patient with systemic lupus erythematosus.Am J Kidney Dis. 1997; 30: 879-883Abstract Full Text PDF PubMed Scopus (10) Google ScholarChronic renal insufficiencySeverity appeared to be age-related29.Falk R.J. Scheinman J. Phillips G. Orringer E. Johnson A. Jennette J.C. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin converting enzyme.N Engl J Med. 1992; 326: 910-915Crossref PubMed Scopus (225) Google Scholar, 30.Falk R.J. Jennette J.C. Sickle cell nephropathy.Adv Nephrol. 1994; 23: 133-147PubMed Google Scholar, 31.Bakir A.A. Hathiwala S.C. Ainis H. Hryhorczuk D.O. Rhee H.L. Levy P.S. Dunea G. Prognosis of the nephrotic syndrome in sickle glomerulopathy.Am J Nephrol. 1987; 7: 110-115Crossref PubMed Scopus (76) Google ScholarDecreased concentrating abilityUosm 400–450 mOsm/kg under water deprivation4.Statius van Eps L.W. De Jong P.E. Sickle cell disease,.Diseases of the Kidney. 6th ed), edited by Schrier RW, Gottschalk C. Little Brown, Boston1997: 2201-2219Google Scholar, 5.Statius van Eps L.W. Schouten H. Ter Harr Romeny-Wachter C.C.H. La Porte-Wijsman L.W. The relation between age and renal concentrating capacity in sickle cell disease and hemoglobin C disease.Clin Chim Acta. 1970; 27: 501-511Crossref PubMed Scopus (39) Google Scholar, 6.Statius van Eps L.W. Sickle cell disease and the kidney,.Oxford Textbook of Clinical Nephrology. edited by Cameron S, Davison AM, Grunfeld JP, Kerr D, Ritz E. Oxford University Press, New York1992: 700-720Google ScholarRenal tubular acidosis (RTA)Incomplete form of RTA7.Battle D. Itsa Rayoungyen K. Arruda J.A. Kurtzman N.A. Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies.Am J Med. 1982; 72: 188-192Abstract Full Text PDF PubMed Scopus (71) Google Scholar, 8.De Fronzo R.A. Taufield P.A. Black H. McPhedran P. Cooke C.R. Impaired renal tubular potassium secretion in sickle cell disease.Ann Intern Med. 1979; 90: 310-316Crossref PubMed Scopus (73) Google Scholar, 9.Goossens J.P. Statius van Eps L.W. Schouten H. Giterson L. Incomplete renal tubular acidosis in sickle cell disease.Clin Chim Acta. 1972; 41: 149-156Crossref PubMed Scopus (28) Google Scholar, 10.Ho Ping Kong H. Alleyne G.A.O. Studies on acid excretion in adults with sickle cell anemia.Clin Sci. 1971; 41: 505-518Crossref PubMed Scopus (20) Google ScholarImpaired potassium secretionAldosterone independent8.De Fronzo R.A. Taufield P.A. Black H. McPhedran P. Cooke C.R. Impaired renal tubular potassium secretion in sickle cell disease.Ann Intern Med. 1979; 90: 310-316Crossref PubMed Scopus (73) Google Scholar,13.Allon M. Renal abnormalities in sickle cell disease.Arch Intern Med. 1990; 150: 501-504Crossref PubMed Google ScholarIncreased glomerular permselectivitySize selectivity defect found in patients with renal insufficiency21.Guasch A. Cua M. Mitch W.E. Early detection and the course of glomerular injury in patients with sickle cell anemia.Kidney Int. 1996; 49: 786-791Abstract Full Text PDF PubMed Scopus (83) Google ScholarAltered ultrafiltration coefficient? Variable with GFR21.Guasch A. Cua M. Mitch W.E. Early detection and the course of glomerular injury in patients with sickle cell anemia.Kidney Int. 1996; 49: 786-791Abstract Full Text PDF PubMed Scopus (83) Google Scholar,23.Schmitt F. Martinez F. Brillet G. Giatras I. Choukroun G. Girot R. Bachir D. Galacteros F. Lacour B. Grunfeld J.P. Early glomerular dysfunction in patients with sickle cell anemia.Am J Kidney Dis. 1998; 32: 208-214Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Open table in a new tab The hypoxic, acidotic, and hyperosmolar environment of the inner medulla are known to promote sickling of erythrocytes with resultant impairment in renal medullary blood flow, ischemia, microinfarct, and papillary necrosis. Microradioangiographic studies in patients with sickle cell disease showed a significantly reduced number of vasa recta, abnormal dilation, or obliteration of the remaining medullary capillaries with consequent loss in the countercurrent multiplication and exchange system of the inner medulla3.Alleyne G.A.O. Statius van Eps L.W. Addac S.K. Nicholson G.D. Schouten H. The kidney in sickle cell anemia (editorial review).Kidney Int. 1975; 7: 371-379Abstract Full Text PDF PubMed Scopus (39) Google Scholar,4.Statius van Eps L.W. De Jong P.E. Sickle cell disease,.Diseases of the Kidney. 6th ed), edited by Schrier RW, Gottschalk C. Little Brown, Boston1997: 2201-2219Google Scholar. Clinically, patients demonstrate an inability to concentrate urine. In young children with sickle cell anemia (SCA), it has been observed that maximal urine osmolality can be increased by multiple blood transfusions. However, with repeated sludging causing thrombosis, progressive infarction, and necrosis of the papillae and inner medulla, the capacity to improve renal concentrating ability is progressively lost with age, and the defect is irreversible after the age of 154.Statius van Eps L.W. De Jong P.E. Sickle cell disease,.Diseases of the Kidney. 6th ed), edited by Schrier RW, Gottschalk C. Little Brown, Boston1997: 2201-2219Google Scholar, 5.Statius van Eps L.W. Schouten H. Ter Harr Romeny-Wachter C.C.H. La Porte-Wijsman L.W. The relation between age and renal concentrating capacity in sickle cell disease and hemoglobin C disease.Clin Chim Acta. 1970; 27: 501-511Crossref PubMed Scopus (39) Google Scholar, 6.Statius van Eps L.W. Sickle cell disease and the kidney,.Oxford Textbook of Clinical Nephrology. edited by Cameron S, Davison AM, Grunfeld JP, Kerr D, Ritz E. Oxford University Press, New York1992: 700-720Google Scholar. Maximum urinary osmolality of 400 to 450 mOsm/kg is typically seen under water-deprived conditions in adult patients with SCA. In heterozygotes, more gradual and smaller degrees of impairment are seen4.Statius van Eps L.W. De Jong P.E. Sickle cell disease,.Diseases of the Kidney. 6th ed), edited by Schrier RW, Gottschalk C. Little Brown, Boston1997: 2201-2219Google Scholar, 5.Statius van Eps L.W. Schouten H. Ter Harr Romeny-Wachter C.C.H. La Porte-Wijsman L.W. The relation between age and renal concentrating capacity in sickle cell disease and hemoglobin C disease.Clin Chim Acta. 1970; 27: 501-511Crossref PubMed Scopus (39) Google Scholar, 6.Statius van Eps L.W. Sickle cell disease and the kidney,.Oxford Textbook of Clinical Nephrology. edited by Cameron S, Davison AM, Grunfeld JP, Kerr D, Ritz E. Oxford University Press, New York1992: 700-720Google Scholar. In addition to defects in urinary concentrating ability, other renal functions that are primarily accomplished in the renal medulla, including renal acidification and potassium secretion, are also found to be impaired in sickle cell patients. The former is manifested as an incomplete form of distal renal tubular acidosis (RTA). Under normal conditions, these patients do not manifest acidosis; however, in the setting of mild renal insufficiency, hyperchloremic metabolic acidosis has been described7.Battle D. Itsa Rayoungyen K. Arruda J.A. Kurtzman N.A. Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies.Am J Med. 1982; 72: 188-192Abstract Full Text PDF PubMed Scopus (71) Google Scholar. Sickle cell patients are unable to lower their urine pH to less than 5.3 following ammonium chloride loading8.De Fronzo R.A. Taufield P.A. Black H. McPhedran P. Cooke C.R. Impaired renal tubular potassium secretion in sickle cell disease.Ann Intern Med. 1979; 90: 310-316Crossref PubMed Scopus (73) Google Scholar,9.Goossens J.P. Statius van Eps L.W. Schouten H. Giterson L. Incomplete renal tubular acidosis in sickle cell disease.Clin Chim Acta. 1972; 41: 149-156Crossref PubMed Scopus (28) Google Scholar. A blunted increase in urinary excretion of titratable acid in these patients compared with control subjects has been shown by different investigators8.De Fronzo R.A. Taufield P.A. Black H. McPhedran P. Cooke C.R. Impaired renal tubular potassium secretion in sickle cell disease.Ann Intern Med. 1979; 90: 310-316Crossref PubMed Scopus (73) Google Scholar, 9.Goossens J.P. Statius van Eps L.W. Schouten H. Giterson L. Incomplete renal tubular acidosis in sickle cell disease.Clin Chim Acta. 1972; 41: 149-156Crossref PubMed Scopus (28) Google Scholar, 10.Ho Ping Kong H. Alleyne G.A.O. Studies on acid excretion in adults with sickle cell anemia.Clin Sci. 1971; 41: 505-518Crossref PubMed Scopus (20) Google Scholar. Ammonium excretion was found to be either normal or decreased8.De Fronzo R.A. Taufield P.A. Black H. McPhedran P. Cooke C.R. Impaired renal tubular potassium secretion in sickle cell disease.Ann Intern Med. 1979; 90: 310-316Crossref PubMed Scopus (73) Google Scholar,10.Ho Ping Kong H. Alleyne G.A.O. Studies on acid excretion in adults with sickle cell anemia.Clin Sci. 1971; 41: 505-518Crossref PubMed Scopus (20) Google Scholar. This is not seen in patients with the sickle cell trait11.Oster J.R. Lee S.M. Lespier L.E. Pellegrini E.L. Vaamonde C.A. Renal acidification in sickle cell trait.Arch Intern Med. 1976; 136: 30-35Crossref PubMed Scopus (13) Google Scholar. Hyperkalemia has not been reported to occur in sickle cell disease patients unless there is renal function impairment7.Battle D. Itsa Rayoungyen K. Arruda J.A. Kurtzman N.A. Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies.Am J Med. 1982; 72: 188-192Abstract Full Text PDF PubMed Scopus (71) Google Scholar,8.De Fronzo R.A. Taufield P.A. Black H. McPhedran P. Cooke C.R. Impaired renal tubular potassium secretion in sickle cell disease.Ann Intern Med. 1979; 90: 310-316Crossref PubMed Scopus (73) Google Scholar or stress such as volume contraction during a sickle cell crisis7.Battle D. Itsa Rayoungyen K. Arruda J.A. Kurtzman N.A. Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies.Am J Med. 1982; 72: 188-192Abstract Full Text PDF PubMed Scopus (71) Google Scholar. Like the urinary acidification defect, the defect in potassium secretion is not clinically apparent under normal conditions. De Fronzo et al have demonstrated impaired potassium secretion in the presence of an intact renin-aldosterone axis, suggesting the presence of a primary defect in the renal tubular secretion of potassium8.De Fronzo R.A. Taufield P.A. Black H. McPhedran P. Cooke C.R. Impaired renal tubular potassium secretion in sickle cell disease.Ann Intern Med. 1979; 90: 310-316Crossref PubMed Scopus (73) Google Scholar. It is probable that the abnormality in potassium metabolism could be due to the result of ischemic damage to the segment of the distal nephron responsible for potassium excretion; however, the exact mechanism of decreased potassium excretion has not been well elucidated. Selective aldosterone deficiency as well as reports of hyporeninemia hypoaldosteronism have been described7.Battle D. Itsa Rayoungyen K. Arruda J.A. Kurtzman N.A. Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies.Am J Med. 1982; 72: 188-192Abstract Full Text PDF PubMed Scopus (71) Google Scholar,12.Yoshino M. Amerian R. Brautbar N. Hyporeninemic hypoaldosteronism in sickle cell disease.Nephron. 1982; 31: 242-244Crossref PubMed Scopus (6) Google Scholar. Despite impaired potassium secretion, the serum potassium level does not increase during potassium loading. This finding suggests an increased intracellular shift of potassium, probably caused by β;2 adrenergic stimulation13.Allon M. Renal abnormalities in sickle cell disease.Arch Intern Med. 1990; 150: 501-504Crossref PubMed Google Scholar. In contrast to defects in distal nephron abnormalities, proximal tubular functions were found to be supranormal. This is evidenced by an increased reabsorption of phosphorus and β;-microglobulins and increased secretion of uric acid and creatinine4.Statius van Eps L.W. De Jong P.E. Sickle cell disease,.Diseases of the Kidney. 6th ed), edited by Schrier RW, Gottschalk C. Little Brown, Boston1997: 2201-2219Google Scholar,13.Allon M. Renal abnormalities in sickle cell disease.Arch Intern Med. 1990; 150: 501-504Crossref PubMed Google Scholar. Alterations in renal hemodynamics were noted in sickle cell disease patients but not in subjects with the sickle cell trait. Increased glomerular filtration rate (GFR) and renal plasma flow (RPF) have been well described in patients with sickle cell disease14.Etteldorf J.N. Tuttle A.H. Clayton G.W. Renal function studies in pediatrics.Am J Dis Child. 1952; 83: 185-191PubMed Google Scholar, 15.Allon M. Lawson L. Eckman J.R. Delaney V. Bourke E. Effects of nonsteroidal anti-inflammatory drugs on renal function in sickle cell anemia.Kidney Int. 1988; 34: 500-506Abstract Full Text PDF PubMed Scopus (69) Google Scholar, 16.De Jong P.E. De Jong-van Den Berg T.W. Sewrajsingh G.S. Schouten H. Donker A.J.M. Statius van Eps L.W. The influence of indomethacin on renal haemodynamics in sickle cell anemia.Clin Sci. 1980; 59: 245-250Crossref PubMed Scopus (42) Google Scholar putatively related to compensatory hypersecretion of vasodilator prostaglandins in response to sickling. Indomethacin treatment has been shown to produce significant decreases in GFR in these patients but not in control subjects15.Allon M. Lawson L. Eckman J.R. Delaney V. Bourke E. Effects of nonsteroidal anti-inflammatory drugs on renal function in sickle cell anemia.Kidney Int. 1988; 34: 500-506Abstract Full Text PDF PubMed Scopus (69) Google Scholar,16.De Jong P.E. De Jong-van Den Berg T.W. Sewrajsingh G.S. Schouten H. Donker A.J.M. Statius van Eps L.W. The influence of indomethacin on renal haemodynamics in sickle cell anemia.Clin Sci. 1980; 59: 245-250Crossref PubMed Scopus (42) Google Scholar. Both GFR and RPF are normal during adolescence but are frequently subnormal after the age of 4017.Etteldorf J.N. Smith J.D. Tuttle A.H. Diggs L.W. Renal hemodynamic studies in adults with sickle cell anemia.Am J Med. 1955; 18: 243-248Abstract Full Text PDF PubMed Scopus (56) Google Scholar,18.Morgan A.G. Serjeant G.R. Renal function in patients over 40 with homozygous sickle-cell disease.Br Med J. 1981; 282: 1181-1183Crossref PubMed Scopus (25) Google Scholar. Progressive renal insufficiency in these patients has been ascribed to hyperfiltration-mediated sclerosis of the glomerular capillaries19.Tejani A. Phadke K. Adamson O. Nicastri A. Chen C.K. Sen D. Renal lesions in sickle cell nephropathy in children.Nephron. 1985; 39: 352-355Crossref PubMed Scopus (57) Google Scholar,20.De Jong P.E. Statius van Eps L.W. Sickle cell nephropathy: New insights into its pathophysiology (editorial review).Kidney Int. 1985; 27: 711-717Abstract Full Text PDF PubMed Scopus (74) Google Scholar. In a recent study to determine the cause of progressive renal insufficiency in patients with SCA, Guasch, Cua, and Mitch found an association between renal insufficiency and a decrease in ultrafiltration coefficient21.Guasch A. Cua M. Mitch W.E. Early detection and the course of glomerular injury in patients with sickle cell anemia.Kidney Int. 1996; 49: 786-791Abstract Full Text PDF PubMed Scopus (83) Google Scholar. In addition, there is an inverse correlation between ultrafiltration coefficient and glomerular permselectivity, as assessed by the fractional clearances of albumin and IgG. It is of interest that the ultrafiltration coefficient was also found to be reduced in albuminuric patients with normal GFR. This latter finding appears to support the observation of Powars et al that proteinuria and the nephrotic syndrome were significant preazotemic predictors of chronic renal failure22.Powars D.R. Elliott-Mills D.D. Chan L. Niland J. Hiti A.L. Opas L.M. Johnson C. Chronic renal failure in sickle cell disease: Risk factors, clinical course, and mortality.Ann Intern Med. 1991; 115: 614-620Crossref PubMed Scopus (252) Google Scholar. In a more recent study, Schmitt et al found enhanced macromolecule trafficking, decreased glomerular size selectivity, and a dramatic increase in ultrafiltration coefficient (Kf) in proteinuric patients with SCA23.Schmitt F. Martinez F. Brillet G. Giatras I. Choukroun G. Girot R. Bachir D. Galacteros F. Lacour B. Grunfeld J.P. Early glomerular dysfunction in patients with sickle cell anemia.Am J Kidney Dis. 1998; 32: 208-214Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar. Although the latter finding seems to be in apparent contradiction to the results obtained by Guasch et al, Schmitt et al argued that the patients studied by Guasch et al had more advanced glomerular dysfunction, including a lower mean GFR and a higher degree of proteinuria. The authors speculated that proteinuria and an increase in Kf may represent very early changes that act synergistically to trigger the development of glomerulosclerosis. At later stages, these early changes are no longer detected, and even a decrease in Kf may contribute to the decrease in GFR23.Schmitt F. Martinez F. Brillet G. Giatras I. Choukroun G. Girot R. Bachir D. Galacteros F. Lacour B. Grunfeld J.P. Early glomerular dysfunction in patients with sickle cell anemia.Am J Kidney Dis. 1998; 32: 208-214Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar. Of interest, over the past few decades since the discoveries of the multifold functions of nitric oxide (NO) in animal and human physiology, the causal relationship between increase NO synthesis and glomerular hyperfiltration has been described in experimental models of sickle cell nephropathy. Bank et al have shown that inducible NO synthase (NOS II) is increased in the glomeruli and distal nephron of transgenic sickle cell mice but not in control mice24.Bank N. Aynedjian H.S. Qiu J.H. Osei S.Y. Ahima R.S. Fabry M.E. Nagel R.L. Renal nitric oxide synthases in transgenic sickle cell mice.Kidney Int. 1996; 50: 184-189Abstract Full Text PDF PubMed Scopus (76) Google Scholar. The investigators further demonstrated that urinary excretion of the products of NO (NO2S + NO3) and GFR is significantly higher in the transgenic sickle cell mouse model compared with controls. It is hypothesized that NOS II may increase the synthesis of NO leading to vasodilation, which, in turn, may contribute to renal hyperperfusion. In a more recent study by the same group of investigators, the exposure of the transgenic sickle cell mice to chronic hypoxia has led to several important observations25.Bank N. Kiroycheva M. Ahmed F. Anthony G.M. Fabry M.E. Nagel R.L. Singhal P.C. Peroxynitrite formation and apoptosis in transgenic sickle cell mouse kidneys.Kidney Int. 1998; 54: 1520-1528Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar. Specifically, the authors have shown that hypoxia could result in inducible NO synthase (iNOS) activation, superoxide radical and peroxynitrite (ONOO-) formation. Two consequences of these reactions appear to be nitration of tyrosine residues of some renal proteins and enhanced apoptosis ultimately leading to structural damage. Ischemia/reperfusion-mediated apoptosis has previously been shown to induce tubulointerstitial changes, loss of functioning nephrons, and eventual scarring. Hematuria is a common finding in both sickle cell trait and disease. Abel and Brown first described the relationship between sickle cell disease and hematuria in 194826.Abel M.S. Brown C.R. Sickle cell disease with severe hematuria simulating renal neoplasm.JAMA. 1948; 136: 624-625Crossref PubMed Scopus (27) Google Scholar. The cause of the hematuria is probably related to the pathologic events in the inner medulla and renal papillae of patients with sickle cell disease. Sickling of erythrocytes in the vasa recta results in increased blood viscosity, microthrombi formation, and ischemic necrosis, which, in turn, could cause structural changes leading to hematuria4.Statius van Eps L.W. De Jong P.E. Sickle cell disease,.Diseases of the Kidney. 6th ed), edited by Schrier RW, Gottschalk C. Little Brown, Boston1997: 2201-2219Google Scholar,6.Statius van Eps L.W. Sickle cell disease and the kidney,.Oxford Textbook of Clinical Nephrology. edited by Cameron S, Davison AM, Grunfeld JP, Kerr D, Ritz E. Oxford University Press, New York1992: 700-720Google Scholar. In 21 sickle cell kidneys removed because of protracted hematuria and the possibility of renal neoplasm, Mostofi et al found severe stasis in peritubular capillaries that were most marked in the medulla27.Mostofi F.K. Vorder Brugge C.F. Diggs L.W. Lesions in kidneys removed for unilateral hematuria in sickle cell disease.Arch Pathol. 1957; 63: 336-351PubMed Google Scholar. Extravasation of blood predominantly in the collecting tubules was observed. Hematuria may originate from either kidney, although a preponderance of left-sided renal bleeding has been observed6.Statius van Eps L.W. Sickle cell disease and the kidney,.Oxford Textbook of Clinical Nephrology. edited by Cameron S, Davison AM, Grunfeld JP, Kerr D, Ritz E. Oxford University Press, New York1992: 700-720Google Scholar, 27.Mostofi F.K. Vorder Brugge C.F. Diggs L.W. Lesions in kidneys removed for unilateral hematuria in sickle cell disease.Arch Pathol. 1957; 63: 336-351PubMed Google Scholar, 28.Crone R.I. Jefferson S.C. Pileggi V.J. Lowry E.C. Gross hematuria in sickle cell trait.Arch Intern Med. 1957; 100: 587-603Crossref Scopus (12) Google Scholar. Unlike hematuria, proteinuria is more commonly encountered in patients with homozygous (hemoglobin SS) sickle cell disease than in other hemoglobinopathies29.Falk R.J. Scheinman J. Phillips G. Orringer E. Johnson A. Jennette J.C. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin converting enzyme.N Engl J Med. 1992; 326: 910-915Crossref PubMed Scopus (225) Google Scholar. Proteinuria occurred in 20 to 30% of patients with sickle cell disease30.Falk R.J. Jennette J.C. Sickle cell nephropathy.Adv Nephrol. 1994; 23: 133-147PubMed Google Scholar, although a higher incidence has also been reported. Nephrotic syndrome is now well recognized, although its frequency in sickle cell nephropathy has not been well studied. Renal failure occurs with high frequency in patients with nephrotic syndrome31.Bakir A.A. Hathiwala S.C. Ainis H. Hryhorczuk D.O. Rhee H.L. Levy P.S. Dunea G. Prognosis of the nephrotic syndrome in sickle glomerulopathy.Am J Nephrol. 1987; 7: 110-115Crossref PubMed Scopus (76) Google Scholar. A prospective study by Powars et al showed that ineffective erythropoiesis with increasingly severe anemia, hypertension, proteinuria, the nephrotic syndrome, and microscopic hematuria was a significant preazotemic predictor of chronic renal failure22.Powars D.R. Elliott-Mills D.D. Chan L. Niland J. Hiti A.L. Opas L.M. Johnson C. Chronic renal failure in sickle cell disease: Risk factors, clinical course, and mortality.Ann Intern Med. 1991; 115: 614-620Crossref PubMed Scopus (252) Google Scholar. Table 2 summarizes the major anatomic and pathologic (morphologic) changes o
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