renal failure in sickle cell anemia

SICKLE CELL DISEASE 0889-8588/96 $0.00 + 2 0

RENAL FAILURE IN SICKLE CELL ANEMIA

Wing-Yen Wong, MD, Donna Elliott-Mills, MD, and Darleen Powars, MD

End-stage renal disease (ESRD) in sickle cell anemia (SCA) is the ultimate consequence of sickle cell-induced damage to the renal micro- vasculature by sickle cells’ (Fig. 1). The arterial bed of the kidney, which has low oxygen tension and low pressure in a slow flow system, is suited to facilitate the polymerization of Hb S8, 1 5 7 37, 383 50 and microvascular occlusion.z5~ 39 Progression to ESRD in SCA starts with hwosthenuria, which leads to an increased glomerular filtration rate (GFR), resulting in glomerulosclerosis and finally end-stage renal failure. Clinical identi- fication of renal insufficiency is usually made during the third or fourth decade of life9; however, there are significant preazotemic predictors of renal insufficiency occurring years before irreversible elevations of blood urea nitrogen (BUN) and ~reat inine.~~ Results of treatment during the uremic phase have been dismal, underscoring the need for development of useful preazotemic therapeutic modalities.%

Therapy must be aimed at preventing the unrelenting progression of each specific age-related pathology to have significant clinical impact (Table 1).

AGE-ASSOCIATED RENAL PATHOPHYSIOLOGY AND TREATMENT OPTIONS

Early Childhood

Hyposthenuria is the first clinical manifestation of the sickle cell- induced obliteration of the vasa recta of the kidney r n e d ~ l l a . ~ ~ , ~ Edema

From the Department of Pediatrics, Division of Hematology, University of Southern California School of Medicine, Los Angeles, California

~

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA

VOLUME 10 NUMBER 6 DECEMBER 1996 1321

1322 WONG et a1

PATHOPHYSIOLOGY AGE GROUP

Figure 1. Hemoglobin S-induced progression of end-stage renal disease in sickle cell anemia, broken down by age group.

in the medullary vasculature is followed by focal scarring, interstitial fibrosis, and destruction of the counter-current mechanism necessary for concentration of urine and electrolyte balance. Patients exhibit the beginning of an incomplete form of distal renal tubular acidosis’; however, systemic acidosis is rarely seen except in cases of severe dehydration and stress.”

Hyposthenuria results in a concentrating capacity of about 400 to 450 mOsm/kg and an obligatory urinary output of as much as 2000 mL/m2/day in infants to 4000 mL/m2/day in adults, causing the patient to be particularly susceptible to dehydration.* The increased urine output is associated with nocturia, often manifesting as enuresis. This condition persists throughout life and should not be viewed as a psychogenic problem.

Medications such as imipramine and intranasal DDAVP have been used with questionable success.24 If DDAVP is prescribed, the lower potency product (0.01%) must be used. Intranasal DDAVP at higher potency (0.15%) is reserved for use in patients with mild hemophilia A or von Willebrand disease, and it is not routinely used for nocturnal enuresis owing to the danger of hyponatremia and water intoxication. Owing to the end-organ damage in sickle renal failure (SRF), the efficacy of DDAVP is doubtful, and its routine use for sickle cell-related enuresis is not currently recommended. If an effect is obtained, however, the patient must be monitored closely for fluid and serum sodium abnormalities periodically while using DDAVP. The efficacy of tricyclic agents such as imipramine or protriptyline in decreasing enuretic episodes in

RENAL FAILURE IN SICKLE CELL ANEMIA 1323

Table 1. AGE-SPECIFIC THERAPEUTIC INTERVENTION DURING THE PROGRESSION OF SICKLE RENAL FAILURE (SRF)

Age-Specific Defect Intervention Strategy

Early Childhood Microenvironmental ischemia

and destruction of vasa recta

Nocturiddefective counter- current mechanism

Adolescence and Young Adulthood

Increased renal cortical blood with increased glomerular filtration rate (GFR)

Renal tubular acidosis (RTA)

Impaired potassium excretion

Irreversible hyposthenuria Microscopic hematuria Proteinuria

Nephrotic syndrome

Adulthood Decreased urate clearance

Decreased cortical blood flow

Hypertension and decreased GFR

Ineffective erythropoiesis with increasingly severe anemia

Renal tubular siderosis

Renal osteodystrophy

Glomerulosclerosis (ESRD)

Encourage oral fluids

Imipramine, protriptyline, and DDAVP are controversial and potentially hazardous (see text)

Increase oral fluids to 150 mL/kg/24 hrs

Oral sodium bicarbonate, calcium carbonate if RTA

No added potassium to intravenous fluids unless

Encourage oral fluids No specific intervention required Angiotensin-converting enzyme (ACE) inhibitors

(enalapril, captopril) Management with diuretics

present by serum electrolyte abnormalities

serum potassium is low

Allopurinol if serum uric acid level persistently

ACE inhibitors; loop diuretics not useful

Beta-blockers (propranolol, timolol), ACE inhibitors, calcium channel inhibitors (verapamil or diltiazem) (see cautions in text); diuretics not indicated

Erythropoietin at 1000 to 2000 U/kg twice a week; RBC transfusion

Iron chelation (deferoxamine) during RBC transfusion therapy

Supplementation with calcium carbonate and vitamin D (calcitriol); oral phosphate binders (aluminum hydroxide)

Hemodialysis or peritoneal dialysis; kidney transplantation

elevated or clinical gout present

children with SCA is controversial. An electrocardiogram must precede their use and must be repeated annually to detect any conduction abnormalities during treatment. We do not recommend their use for enuresis in patients with sickle cell anemia.

Most children with SCA are, as expected, hyporesponsive to "loop" diuretics such as furosemide. Its use in this age group is usually not indicated, but if used the patient must be monitored for fluid and electrolyte abnormalities.

1324 WONG et a1

Adolescence

Ongoing medullary ischemia culminates in irreversible hyposthenuria, which cannot be affected by transfusion therapy." Management consists of encouraging oral fluids and avoidance of mild diuresis- inducing agents such as caffeine. The impaired renal tubular potassium excretion during this stage of life is associated with a moderate tendency toward hyperkalemia that is clinically manifest only in the presence of coexistent renal failure.*

During late childhood and adolescence, the loss of vasa recta is complete, with an increased renal cortical blood flow and an increased GFR.@' Medullary ischemia apparently enhances the secretion of vasodi- latory prostaglandins, causing increases in renal blood flow, at first shunting selectively to the juxtamedullary nephrons, and then to the inner cortical nephrons.'l In time, the enlargement and increased vascu- larity includes the glomeruli of the entire cortex, resulting in an increased GFR. The alteration in cortical function may occur in part as a compensatory mechanism for the defective salt and water conservation in the medulla. The supranormal GFR is maintained by a prostaglandin- mediated me~hanism.~, Permanently increased glomerular blood flow and increased GFR have been postulated to be destructive to glomeruli in other diseases, ultimately resulting in renal insufficiency. l3

Glomerular enlargement and arteriolar dilatation consistent with the increase in renal blood flow and GFR are the anatomic manifestations coincident with the hemodynamic changes. Prostaglandin-synthetase inhibitors have been suggested as a therapeutic agent with the potential of preventing hyperfiltration, thus maintaining a near-normal GFR.I2 At this point, such therapy would be experimental, and clinical efficacy needs to be further documented.

Serum calcium and parathyroid hormone (PTH) levels are altered in children and young adults with SCA in the absence of clinically evident renal disease.53 Fourteen percent of patients have a serum calcium below the normal range, and 31% have a PTH above the normal range. Dietary intake of calciumland vitamin D was adequate. Many SCA patients have a hypocalcemic tendency, perhaps related to impaired intestinal absorption of calcium and vitamin D.47 Superimposed renal insufficiency during adolescence leads to renal osteodystrophy and bone demineralization. Oral calcium carbonate and vitamin D can slow the progression of renal osteoporosis in this select group of patients.

Asymptomatic microscopic hematuria is one of the most prevalent manifestations of SCA.4O The hematuria is a result of the medullary ischemia leading to a structural papillectomy with formation of dilated renal pelvic capillaries and veins. There is rupture of these vessels and resultant hematuria. Additionally, microscopic hematuria was found to be significantly more frequent (P<0.006) in patients who developed ESRD.57 Occasionally the hematuria becomes clinically evident. Blood loss is usually minimal, resolving with bed rest and hydration, and it does not require transfusion.


Before 1980, renal papillary necrosis (RPN) syndrome was a rela- tively commonly reported complication in patients with all forms of sickle cell disease.16 RPN was often asymptomatic and incidently found on intravenous pyelography or Abnormal intravenous pyelograms have been reported in about 50% of Hb SS adults with all forms of sickling disorders (73% in a study of Hb SC patients who were said to have had "asymptomatic" IU"). It is now believed that the syndrome of asymptomatic papillary necrosis was a manifestation of the progressive medullary interstitial ischemia induced by heavy ingestion of analgesics such as phenacetin and possibly acetaminophen.60, A few reports from Africa are still being published that incriminate excessive analgesia use.l0 Asymptomatic papillary blunting is rarely diagnosed today because intravenous pyelograms have been supplanted by renal ultrasonography or computed tomography. On the rare occasion of painful passage of necrotic papillary tissue, hospitalization with intravenous hydration is recommended. Ultrasonography can usually identify an obstructed ureter that would require rapid urologic intervention. Anal- gesia should consist of unequivocally non-nephropathic agents such as morphine. Epsilon-aminocaproic acid and triglycyl vasopressin have been used in some instances of persistent gross hematuria, but the complications of clot formation, obstruction, and progressive vaso-occlusion may pose additional hazards to the patient.35, 36 We do not recommend using these medications in every patient with hematuria, because most cases resolve within 1 to 3 days with only strict bed rest and hydration.

Persistent increasing proteinuria is the clear harbinger of glomerular insufficiency and renal failure as is seen in diabetes mellitus.", 65, 69

Intraglomerular hypertension with sustained elevations of pressure and flow are considered to be the prime etiology of the hemodynamic changes and subsequent proteinuria.6, 22, 32, 33, 67 If proteinuria persists for greater than 4 to 8 weeks, angiotensin-converting enzyme (ACE) inhibitors are recommended (such as enalapril at 5 to 10 mg/day given as a ~ ing le~dose ) .~~ ACE inhibitor therapy has been shown to lower urinary protein excretion, supporting the concept that glomerular capillary hypertension is the pathogenic mechanism for the proteinuria.22, 59 ACE inhibitors may decrease the aldosterone activity and precipitate hyperkalemia in those patients who already have marginally increased serum potassium levels. The long-term benefit of such therapy needs to be defined. Chronic cough with chest pain, a side effect of ACE inhibitors, may lead to the erroneous diagnosis of acute chest syndrome.

Nephrotic syndrome, with a 24-hour urine protein of greater than 2 g /day, edema, hypoalbuminemia, and hyperlipemia, may be a manifestation of progressive renal insufficiency.3o* 66 In our previous 40% of patients who eventually developed ESRD had nephrotic syndrome early in their clinical course. No data are available to support the efficacy of steroid therapy in the management of nephrotic syndrome in SCA patients.43 Carefully monitored use of diuretics is indicated to control edema.

1326 WONG et a1

Adulthood

The increased GFR observed during adolescence gradually de- creases during the third and fourth decades of life as glomerular conges- tion and enlargement give way to progressive ischemia and Unselected autopsy studies on kidneys from patients with Hb SS show clear age-related damage, with fibrosis and obliteration of glomeruli; in many of these patients renal insufficiency was not clinically rec- ~gnized.~, l7 The glomerular destruction appears similar to that observed with aging but on a markedly accelerated basis, beginning in the patients with SCA during the second and third decades of life.6,19

The contribution of long-term analgesic use in inducing interstitial nephropathy and renal papillary necrosis and leading to sickle renal failure is not clear.60 The majority of SRF patients who have already developed ESRD are between 30 and 50 years of age. Most were given analgesics including phenacetin as children. In our study, the SCA patients who developed ESRD had no more painful crises than did their counterparts or the control groups, but information regarding long- term analgesic use was not available.60 The use of nonsteroidal anti- inflammatory agents (NSAIDs) in non-SS patients has been associated with renal insufficiency, hyperkalemia, hypertension, and renal papillary necrosis.57

As glomerular damage progresses and the GFR begins to decrease, the use of NSAIDs is of concern, because they may increase the rate of progression to end-stage renal disease, thus decreasing the time to dialysis.12 NSAIDs should be used only sparingly in the adult patient whose pain is effectively controlled by these medications, at no more than a 5-day course per month, with close monitoring of renal function.

Hypertension is a major prelude to SRF and occurs in the same time frame with severe proteinuria and h e m a t ~ r i a . ~ ~ Control of hypertension is critical because it is well recognized to delay progression to ESRD.4lr 42 Management of hypertension is similar to that employed for other adults without SCA except that diuretics are less effective and are potentially hazardous.45 Additional considerations for the use of antihypertensive agents may include the increased efficacy of calcium channel blockers in black patients, although they may increase any existing proteinuria. Beta-blockers are contraindicated in patients with congestive heart failure or with iron overload affecting the myocardium. ACE inhibitors such as enalapril are effective agents and, as stated previously, may have the added benefit of decreasing pro te in~r ia .~~

Renal osteodystrophy in SCA patients is associated with severe pain, vascular necrosis of the femoral heads, and collapsing vertebral bodies5, 34* Oral calcium carbonite and vitamin D (calcitriol) should be given at the first sign of decreased serum calcium or of renal insufficiency. In the later stages, some patients can continue to improve calcium balance by supplementation with oral phosphate binders (for example, calcium carbonate or Amph~jel) .~~, 34. 61

Supportive red cell transfusions are required in almost all adults


with renal failure and anemia. Iron overload from chronic red cell transfusions leads to renal tubular siderosis, which occurs rapidly and enhances interstitial nephritis and renal tubular defects.'* Iron chelation therapy such as deferoxamine (DFO) given at the same time as the red cell transfusions should be considered. The dose of DFO depends on the extent of iron overload and the degree of renal failure, because the kidney is the route to excretion of DFO. Recombinant erythropoietin (Epo) has been valuable in the management of non-SCA patients with ESRD and significantly raises the hemoglobin concentration, decreasing the anemia-related symptomatology.*l This response seems to be rela- tively blunted in patients with SCA. Even doses of Epo as large as 1000 to 2000 U/kg twice a week subcutaneously may be ineffe~tive.~~ The increased blood viscosity as the absolute numbers of sickle erythrocytes increase may result in hypertension?*

The development of ESRD is associated with a number of clinical and laboratory identifiable indicators of decreased cortical blood flow and decreased GRF. Blood urea nitrogen (BUN) and serum creatinine are irreversibly elevated. Lifetime increased uric acid production caused by the accelerated erythropoietic rate, associated with a decreased urate clearance, results in a mildly elevated serum uric acid. Hyperuricemia in patients with SCA has not resulted in a marked increase in the incidence of uric acid nephropathy or gout, h~wever .~, Allopurinol with oral sodium bicarbonate for urinary alkalinization can be used to decrease serum urate levels and improve gouty arthritis, if present. Control of hypertension coupled with the use of ACE inhibitors that have the additional benefit of exerting potentially favorable hemodynamic effects have been demonstrated to slow the rate of progression of renal failure. Aggressive dietary management with emphasis on restriction of phos- phorous and protein is also important?O Finally, avoidance of nephro- toxic agents and appropriate dosing of renally metabolized or excreted agents are beneficial. Patients with proteinuria, nephrotic syndrome, or hypertension should be referred to a nephrologist for complete evalua- tion and renal biopsy, if indicated. If the mechanisms responsible for the progr-sive loss of renal function were well understood, it would be possible to design specific interventions that would delay or abort the process.

ESRD eventually requires maintenance hemodialysis or peritoneal dialysis.26 Hemodialysis is selected in 82% of patients with sickle cell anemia, and they do not have more complications as compared with the dialysis population as a Peritoneal dialysis and renal transplantation are used less frequently in SCA patients as compared with other subgroups with ESRD, reflecting the underuse of these modalities in this patient population. Mean survival time for patients with SCA after thk diagnosis of ESRD is 4 years despite dialysis.58

Kidney transplantation has been performed in patients with SCA, and l-year graft survival is reported to be equivalent to that of the non-SCA population at 62% to 82%.27 When the donor kidney is en- grafted, the hemoglobin concentration risesI4 and painful crisis may

1328 WONG et a1

recur.62 Hyposthenuria returned in one patient 5 months after kidney t ran~plant .~~ As long as the sickle red cells circulate through the kidney, the cycle of damage is likely to be reinstituted.

SUMMARY AND CONCLUSION

ESRD is a major complication in young adults with sickle cell anemia.49 As more patients with sickle cell anemia reach the third and fourth decades of life, the incidence of clinically apparent renal insufficiency will increase. As we understand the pathophysiology of renal damage and the effects of various therapies on the sickle renal vasculature, we can tailor specific management without further compromising already impaired renal function. Diagnostic clues must be recognized prior to the onset of irreversible damage, with appropriate intervention initiated at each age group.

Bone marrow transplantation (BMT) is the only available cure for SCA at the present time. The demonstration that several distinct haplotypes of the ps gene cluster on chromosome 11 influence the clinical expression of sickle cell anemia51, 57, 58 may be useful in delineating children who are at high risk for severe disease, and hence candidates for such hazardous therapeutic interventions as BMT prior to onset of clinically discernable disease. Current' BMT preparative regimens can produce renal cortical and pulmonary toxicity, posing a patient selection problem in those cases in which the vasculopathy of the major organs is at an early stage and might be potentially repairable. Gene therapy without toxic preparative regimens is the ultimate answer. The challenge for the near future is the development of effective early therapeutic intervention during childhood and young adulthood.

References

1. Alleyne GAO, Statius van Eps LW,rAddae SK, et a1 The kidney in sickle cell anemia.

2. Allon M Renal abnormalities in sickle cell disease. Arch Intern Med 150:501-504, 1990 3. Allon M, Lawson L, Eckman JR, et al: Effects of nonsteroidal anti-inflammatory drugs

on renal function in sickle cell anemia. Kidney Int 34:500-506, 1988 4. Aluoch J R Renal and electrolyte profile in steady state sickle disease: Observations in

patients with sickle cell disease in The Netherlands. Trop Geogr Med 41:128-132,1989 5. Andress DL, Sherrard DJ: The osteodystrophy of chronic renal failure. In Schrier RW,

Gottschalk CW (eds): Diseases of the Kidney, ed 5, vol 3. Boston, Little, Brown, 1993,

6. Bernstein J, Whitten C F A histologic appraisal of the kidney in sickle cell anemia. Arch l'athol 70:25-36, 1960

7. Bileckot R, Ntsiba H, Mbongo JA, Gt a1 Epidemiological and clinical aspects of gout in equatorial Africa. Apropos of 60 cases followed in the Department of Rheumatology of the Teaching Hospital Center in Brazzaville. Revue Du Rheumatisme Et Des Mala- dies Osteo-articulaires 58:863-867, 1991

8. Briehl RW Rheology of hemoglobin S gels: Possible correlation with impaired microvascular circulation. Am J l'ediatr Hematol/Oncol 5:390-400, 1983

Kidney Int 7:371-379, 1974

pp 2759-2788


9. Cruz IA, Hosten AO, Dillard MG, Castrol OL: Advanced renal failure in patients with sickle cell anemia: Clinical course and prognosis. J Natl Med Assoc 74:1103-1109, 1982

10. Dahniya MH, Szmigielski W, Reddy CK, et al: Renal papillary necrosis in Kuwait. Trop Geogr Med 44.331-337, 1992

11. de Jong PE, de Jong-van den Berg LTW, Schouten H, et al: The influence of indomethacin on renal acidification in normal subjects and in patients with sickle cell anemia. Clin Nephrol 19259-264, 1983

12. de Jong LTW PE, de Jong-Van Den Berg LTW, Sewrajsingh GS, et al: The influence of indomethacin on renal haemodynamics in sickle cell anaemia. Clin Sci 59245-250,1980

13. De-Paepe ME, Trudel M The transgenic SAD mouse: A model of human sickle cell glomerulopathy. Kidney Int 461337-1345, 1994

14. Donnellv PK, Edmunds ME, OReillv K Renal transplantation in sickle cell disease. Lancet i10229, 1988

15. Eaton WA, Hofrichter J: Hemoglobin S gelation and sickle cell disease. Blood 70:1245- 1266, 1987

16. Eknoyan G, Qunibi WY, Grissom RT, et al: Renal papillary necrosis: An update. Medicine 61:55-73, 1982

17. Elfenbein IB, Patchefsky A, Schwartz W, Weinstein AG: Pathology of the glomerulus in sickle cell anemia with and without nephrotic syndrome. Am J Pathol77357-347,1974

18. Ellis TJ: Glomerular lesions and the nephrotic syndrome in rabbits given saturated iron oxide intravenously. J Exp Med 103:127-145,1956

19. el Nahas AM: Growth factors and glomerulosclerosis. Kidney Int 36515-520, 1992 20. England BK, Mitch WE: Mechanisms of progression renal insufficiency. In Massry SG,

Glassock RJ (eds): Textbook of Nephrology, ed 3, vol 2. Baltimore, Williams and

21. Eschbach JW, Egrie JC, Downing MR, et a1 Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. N Engl J Med 31673-78, 1987

22. Falk RJ, Scheinman J, Phillips G, et a1 Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N Engl J Med 326910-915, 1992

23. Ferder LQ Inserra F, Daccordi H, et al: Effects of enalapril on renal parameters in patients with CRF. Drugs 39 (supp12):40-46, 1990

24. Figueroa TE, Benaim E, Griggs ST, Hvizdala EV: Enuresis in sickle cell disease. J Urol

25. Francis RB Jr, Johnson CS Vascular occlusion in sickle cell disease: Current concepts and unanswered questions. Blood 771405-1414,1991

26. Friedman EA, Rao TKS, Sprung CL, et al: Uremia in sickle-cell anemia treated by maintenance hemodialysis. N Engl J Med 291:431435, 1974

27. Gonzalez-Carrillo M, Rudge CJ, Parsons V, et a1 Renal transplantation in sickle cell disease. Clin Nephrol 18209-210, 1982

28. Haddy TB: Erythropoietin in sickle cell disease. Relation of erythropoietin levels to crisis and other complications. Am J Pediatr Hematol/Oncol4:191-196, 1982

29. Hamdy NAT, Kanis JA, Beneton MNC, et a1 Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure. Br Med J 310:358-363, 1995

30. Hatch FE, Azar SH, Ainsworth TE, et al: Renal circulatory studies in young adults with sickle cell anemia. J Lab Clin Med 76:632-640, 1970

31. Herings RMC, de Boer A, Stricker BH Ch, et al: Hypoglycemia associated with use of inhibitors of angiotensin converting enzyme. Lancet 345~195-1198, 1995

32. Hostetler TH, Olson JL, Rennke HG, et a1 Hyperfiltration in remnant nephrons: A potentially adverse response to renal ablation. Am J Physiol241:F85-F93, 1981

33. Hostetler TH, Rennke HG, Brenner BM The case of intrarenal hypertension in the initiafion and progression of diabetic and other glomerulopathies. Am J Med 72375- 390, 1982

Wilkins, 1995, pp 1261-1269

153:1987-1989, 1995

34. Hruska KA, Teitelbaum SL Renal osteodystrophy. N Engl J Med 333:166-174, 1995 35. Immergent M, Stevenson T The use of epsilon aminocaproic acid in the control of

36. John EG, Schade SG, Spigos DG, et al: Effectiveness of triglycyl vasopressin in persis- hematuria associated with hemoglobinopathies. J Urol 93:110, 1965

1330 WONG et a1

tent hematuria associated with sickle cell hemoglobin. Arch Intern Med 140:1589- 1593, 1980

37. Johnson CS, Stuart J: Rheology of the sickle cell disorders. Baillieres Clin Hematol

38. Kaul DK, Fabry ME, Nagel RL: Microvascular sites and characteristics of sickle cell adhesion to vascular endothelium in shear flow conditions: Pathophysiological impli- cations. Proc Natl Acad Sci USA 863356-3360, 1989

39. Kurantsin-Mills J, Klug PP, Lessin LS Vaso-occlusion in sickle cell disease: Pathophysi- ology of the microvascular circulation. Am J Pediatr Hematol/Oncol 10357-372, 1988

40. Lucas WM, Bullock WH: Hematuria in sickle cell disease. J Urol 83:733-741, 1960 41. Maki DD, Ma JZ, Louis TA, Kasiske BL Long-term effects of antihypertensive agents

on proteinuria and renal function. Arch Intern Med 1551073-1080, 1995 42. Mayer JH, Heider C, Pevey K, Ford RF: The effect of treatment on the vascular

deterioration associated with hypertension with particular emphasis on renal function. Am J Med 24:177-192, 1958

43. McCoy RC: Ultrastructural alterations in the kidney of patients with sickle cell disease and the nephrotic syndrome. Lab Invest 21:85-95, 1969

44. McNally PG, Burden AC, Swift PGF, et al: The prevalence and risk factors associated with the onset of diabetic nephropathy in juvenile-onset (insulin-dependent) diabetics diagnosed under the age of 17 years in Leicestershire 193&1985. Q J Med 76831-844, 1990

1~747-775, 1987

45. The Medical Letter. Drugs for Hypertension, vol 37, 1995, pp 45-50 46. Miner DJ, Jorasky DK, Perloff LJ, et al: Recurrent sickle cell nephropathy in a trans-

planted kidney. Am J Kidney Dis 10306-313,1987 47. Mohammed S, Addae S, Suleiman S, et al: Serum calcium, parathyroid hormone, and

vitamin D status in children and young adults with sickle cell disease. Ann Clin Biochem 30:4551, 1993

48. Morgan AG, Serjeant GR: Renal function in patients over 40 with homozygous sickle cell-disease. Br Med J 282:1181-1183, 1981

49. Morgan AG, Shah DJ, Williams W: Renal pathology in adults over 40 with sickle cell disease. West Ind Med J 36:241-250, 1987

50. Mozzarellia A, Hofrichter J, Eaton WA: Delay time of hemoglobin S polymerization prevents most cells from sickling in vivo. Science 237:500-506, 1987

51. Nagel RL, Ranney HM: Genetic epidemiology of structural mutations of the beta- globin gene. Semin Hematol 27342-359, 1990

52. Nagel RL, Vichinsky E, Shah M, et al: F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: A double-blind study. Blood 81:9- 14, 1993

53. Nduke N, Ekeke GI: Serum calcium and protein in haemoglobin-SS patients. Folia Haematol (Leipz) 114508-511, 1987

54. Nissenson AR, Port FK Outcome of end-stage renal disease in patients with rare causes of renal failure. I. Inherited and metabolic disorders. Q J Med 73:10551062,1989

55. Odita JC, Ugbodaga CI, Okafor LA, et al: Urographic changes in homozygous sickle cell disease. Diagnostic Imaging 52:259-263, 1983

56. Oster JR, Lespier LE, Lee SM, et a1 Renal acidification in sickle cell disease. J Lab Clin Med 88389-401, 1976

57. Powars DR, Meiselman H, Fisher TC, et al: Beta-S-gene cluster haplotypes modulate hematologic and hemorrheologic expression in sickle cell anemia. Am J Pediatr Hema- tol/Oncol 16:5561, 1994

58. Powars DR, Elliott-Mills DD, Chan L, et al: Chronic renal failure in sickle cell disease: Risk factor, clinical course and mortality. Ann Intern Med 115:614-620, 1991

59. Rodicio JL, Alcazar JM, Ruilope LM Influence of converting enzyme inhibition on glomerular filtration rate and proteinuria. Kidney Int 38590-594, 1990

60. Sandler DP, Smith JC, Weingerg CR, et al: Analgesic use and chronic renal disease. N Engl J Med 3201238-1243,1989

61. Sherrod DJ, Hercz G, Pei Y, et a1 The spectrum of bone disease in end-stage renal fa i lurean evolving disorder. Kidney Int 43436-432, 1993


62. Spector D, Zachary JB, Sterioff S, Millan J: Painful crises following renal transplantation in sickle cell anemia. Am J Med 64:835-839, 1978

63. Statius van Eps LW, Pinedo-Veels C, de Vries GH, de Konig J: Nature of the concentrating defect in sickle cell nephropathy: Micro-angiographic studies. Lancet k450-452, 1970

64. Statius van Eps LW, Schorten H, La Ponto-Wijsman LW, Struyker Boudier A M The influence of red blood cell transfusions on the hyposthenuria and renal hemodynamics of sickle cell anemia. Clin Chim Acta 17449-461, 1967

65. Strauss J, Zilleruelo G, Abitbol C: The kidney and hemoglobin S. Nephron 43941- 245, 1986

66. Sweeney MJ, Dobbins WT, Etteldorf JN: Renal disease with elements of the nephrotic syndrome associated with sickle cell anemia. J Pediatr 60:42-50, 1962

67. Tejani A, Phadke K, Adamson 0, et al: Renal lesions in sickle cell nephropathy in children. Nephron 39:352-355, 1985

68. Vaamonde CA: Renal papillary necrosis in sickle cell hemoglobinopathies. Semin Nephrol448-64, 1984

69. Williams PS, Fass G, Bone JM: Renal pathology and proteinuria determine progression in untreated mild/moderate chronic renal failure. Q J Med 67345354, 1988

Address reprint requests to

Wing-Yen Wong, MD LAC + USC Medical Center

Department of Pediatrics 1240 North Mission Road, RmL911

Los Angeles, CA 90033

renal failure in sickle cell anemia

Documents