| Abstract|| |
Chronic renal failure develops in 4-18% of patients with sickle cell anemia. Hemodialysis and kidney transplant are viable options in the management of end-stage renal disease in patients with sickle cell disease (SCD). Information on kidney disease among Saudi patients with SCD is non-existing. In this report, the clinical course of two adult males with end-stage sickle cell nephropathy from Eastern Saudi Arabia is described. Literature on renal replacement therapy in sickle cell anemia (SCA) is discussed.
Keywords: Sickle cell anemia, End-stage sickle cell nephropathy, Hemodialysis, Kidney transplantation, Saudi Arabia.
|How to cite this article:|
Al-Mueilo SH. Renal Replacement Therapy in End-Stage Sickle Cell Nephropathy: Presentation of Two Cases and Literature Review. Saudi J Kidney Dis Transpl 2005;16:72-7
|How to cite this URL:|
Al-Mueilo SH. Renal Replacement Therapy in End-Stage Sickle Cell Nephropathy: Presentation of Two Cases and Literature Review. Saudi J Kidney Dis Transpl [serial online] 2005 [cited 2020 Oct 30];16:72-7. Available from: https://www.sjkdt.org/text.asp?2005/16/1/72/32952
| Introduction|| |
Survival of patients with sickle cell anemia (SCA) has improved substantially since the initial description of the disorder.  This improvement reflects advances in general medical care, wider use of prophylactic antibiotics, immunization in childhood, better blood transfusion support, and increased knowledge and experience with the specific complications or crises of SCA. With advancing age, complications related to organ damage become a major problem in these patients. Chronic renal failure (CRF) develops in 4-18% of patients with sickle cell disease and is an important cause of morbidity and mortality. ,,, The prevalence increases with advancing age, reaching rates of 20 to 33% in those over 40 years of age.  Proteinuria, hypertension, microscopic hematuria and ineffective erythropoiesis with worsening anemia are important predictors of risk for the development of CRF in SCA.  The frequency of the Central African Republic (CAR) βs-gene cluster haplotype is significantly increased in patients with CRF compared with patients who do not have CRF, suggesting a genetic predilection for the risk of developing renal failure in SCA.  On the other hand, coinheritance of microdeletions in one or two of the four α-globin genes in SCA patients is associated with a lower prevalence of macroalbuminuria. 
Both hemodialysis and kidney transplantation can be successfully utilized in the management of end-stage renal disease resulting from sickle cell nephropathy. ,,,,,,,
The hemodialysis course in patients with SCA is associated with profound anemia often requiring multiple blood transfusions, despite high dose erythropoietin therapy. The anemia may improve following successful kidney transplantation.  Earlier reports had suggested that, with kidney transplantation, both graft and patient survival rates in SCA are inferior to those seen in non-SCA patients. , More recent surveys are, however, more encouraging.  Rates of painful episodes often increase following renal transplantation.  This is attributed to the increased blood viscosity that results from the elevation in hemoglobin.
Patients from the Kingdom of Saudi Arabia (KSA) with SCA originating from the eastern province of the Kingdom tend to have a milder course when compared with their counterparts from Africa, North America and even Southwestern region of KSA. , To my knowledge, there are no reports describing features of sickle cell renal disease among the Saudi population. In this report, the clinical course of two males from Eastern Saudi Arabia, who developed end-stage renal disease secondary to sickle cell nephropathy, who were treated at the King Fahd Hospital of the University (KFHU), Alkhobar, Saudi Arabia is described.
A 43-year-old Saudi male originally from the Al-Hasa region, is a known case of sickle cell anemia since childhood. Hemoglobin electrophoresis showed sickle hemoglobin (Hb S) to be 63%, fetal hemoglobin (Hb F) was 36% and hemoglobin A2 was 1%. He first presented to the ophthalmology department at KFHU in March 1987 at 37 years of age for repair of left retinal detachment. At the time, he was noted to be normotensive, with urine analysis showing 1+ proteinuria with 2-3 white blood cells (WBC) and no blood. Blood urea measured 5.7 mmol/l, serum creatinine was 132.6 umol/l, serum potassium was 5 mmol/l, and serum bicarbonate (HCO3) was 25 mmol/l. The hemoglobin (Hb) and hematocrit (Hct) were 10.6 gm/dl, and 31.6% respectively. The patient presented six years later in March 1993 with lower limb edema and exertional dyspnea of eight months duration. Physical examination revealed blood pressure (BP) of 190/110 mmHg, jugular venous pressure (JVP) of 13 cm H2O, bibasilar fine inspiratory crepitations in both lungs, muffled first heart sound (S1) with pansystolic grade III/VI murmur at the apex, hepatomegaly with liver span of 17 cm, positive ascites and lower limb and sacral edema. Investigations showed Hb 5 gm/dl, Hct 13.6%, WBC 17,800 cells/micro liter, Reticulocyte count 22.4%, Blood urea 36.8 mmol/l, serum creatinine 857 umol/l, potassium (K) 5.3 mmol/l, HCO3 12 mmol/l, calcium (Ca) 1.9 mmol/l, phosphate (PO4) 2.5 mmol/l, uric acid 785 umol/l, total protein 57 g/l and serum albumin of 27 g/l. Urinalysis showed moderate blood and protein excretion of 10.3 g/day. Chest X ray showed cardiomegaly with minimal pulmonary congestion. Electrocardiogram revealed left bundle branch block. Echocardiogram showed globally thickened left ventricle, left ventricular ejection fraction (LVEF) 40%, dilated left atrium, moderate mitral valve and tricuspid valve regurgitation. Ultrasound abdomen showed slightly enlarged liver with multiple gallstones. Both kidneys were smallish with increased parenchymal echotexture. The diagnosis of end-stage sickle cell nephropathy was made and a left forearm arteriovenous fistula (AVF) was created. Hemodialysis was initiated and administered three times per week via temporary catheter awaiting fistula maturation. Three units of packed red blood cells were transfused and captopril, calcium carbonate, and 1, 25 dihydroxycholecalciferol were prescribed. Erythropoietin (EPO) 4000 units was given subcutaneously three times per week. This was later increased to 6000 units three times per week. The patient's course was characterized by progressive bilateral hip pain and limitation due to avascular necrosis of the femoral heads. Bilateral total hip replacement was considered, but poor general condition precluded such procedure. Parathyroid hormone (PTH) was 845 pmol/l (normal 0-95) with concomitant serum calcium of 3.35mmol/l. In spite of EPO therapy, patient's Hb was mostly 6 to 7 gm/dl. Packed red cells were transfused at a rate of about one to two units per one to two months. In June 1996, the patient was admitted to the hospital with history of deepening jaundice, anorexia and abdominal pain. Physical examination revealed severe jaundice, raised JVP, hepatomegaly with liver span of 27 cm, ascites and lower limb edema. Investigations showed total bilirubin 220.6 umol/l, direct bilirubin 154 umol/l, total protein 66 g/l, serum albumin 26 g/l, alkaline phosphatase 307 u/l, aspartate amino transferase (AST) 131 u/l, lactate dehydrogenase (LDH) 426 u/l and gamma glutamate transaminase (GGT) 267 u/l. Serum total bilirubin peaked at 855 umol/l with direct bilirubin of 665 umol/l. Prothrombin time and partial thromboplastin times were prolonged by nine and 19 seconds respectively. Hepatitis B surface antigen and hepatitis C virus antibody were negative. Abdominal sonography showed enlarged but homogenous liver and multiple cholelithiasis. Endoscopic retrograde cholangiopancreatography (ERCP) showed normal common bile duct. Clinical impression was hepatic crisis and the patient was managed conservatively. Liver function improved and patient was discharged home in July 8, 1996. In August 1996 and 41 months after initiating maintenance hemodialysis, the patient died suddenly at home. The family reported that the patient had increasing back pain for one day before the final event.
A 40-year-old Saudi male from Qatif presented to KFHU in February 1989 at 33 years of age with left knee pain. The patient was a known case of sickle cell disease (Hb S 66%, Hb F 33.5%, Hb A2 0.5%) and G6PD deficiency. The patient had undergone splenectomy at 23 years of age for hypersplenism. Examination revealed BP 150/95, palpable liver 4 cm below costal margin with liver span of 14 cm and an old scar of splenectomy. Hb was 10.3 g/dl and Hct was 31.5%. Blood urea was 8.6 mmol/l, serum creatinine 159.1 umol/l, sodium 136 mmol/l, K 3.9 mmol/l and LDH was 367 u/l. Urine analysis showed protein excretion of 4.95 g/day and creatinine clearance was 48 ml/min. Ultrasound of the abdomen revealed increased parenchymal echotexture of both kidneys. Right kidney measured 9 by 2.9 cm, left kidney measured 10.7 by 4.6 cm. Antinuclear antibody was negative and complement levels (C3 and C4) were normal. With gradual decline of renal function, Hb decreased to a level of around 7 g/dl. Predialysis EPO therapy was initiated in January 1996 at a dose of 4000 u subcutaneously three times per week. This resulted in a rise of Hb to a level of 9 to 9.8 g/dl without need of blood transfusion. Renal function declined further and in July 1996 at 40 years of age, the patient was placed on regular hemodialysis three times per week through a previously created right wrist AVF. At onset of dialysis, BUN was 51.77 mmol/l, serum creatinine 1069 umol/l, K 4.7 mmol/l, HCO3 22 mmol/l and serum albumin 36 g/l. Echocardiogram showed normal left ventricular size and function. The patient's course on hemodialysis was uneventful except for one episode of mild painful crisis after the first hemodialysis session. The patient underwent a successful living related HLA identical sickle cell negative kidney transplant at another hospital in November 1997, sixteen months after the onset of maintenance hemo-dialysis. Six and a half years post transplantation; the patient enjoys an excellent graft function with blood urea of 8.57 mmol/l and serum creatinine of 115 umol/l. Hb is stable around 10.7 gm/dl. Post-transplantation, the patient experiences infrequent, mild painful episodes at a rate of about one episode every one to two years, easily managed at home with simple analgesics. He never required hospital admissions for such episodes. His current immunosuppression regimen consists of prednisolone 5 mg/day and cyclosporin 50 mg twice a day. He also takes atenolol 50 mg daily for blood pressure control.
| Discussion|| |
Young patients with SCA have glomerular hypertrophy, increased glomerular filtration rate (GFR) and renal plasma flow (RPF).  Hyperfiltration along with glomerular hypertrophy can result in glomerulosclerosis. In SCD patients, advancing age is associated with decrease in renal hemodynamics to normal levels, proteinuria occurs in 20 to 30%, and renal failure develops in 4 to 18% culminating in end-stage renal disease in some of these patients. Renal biopsy in early sickle cell nephropathy reveals a pattern of glomerulomegaly and focal segmental and global glomerulosclerosis in most cases with sickle cell nephropathy. ,,
Saudi patients originating from the eastern province with SCA, when compared with American or Jamaican blacks, tend to have lower rate of serious complications, no leg ulceration, higher mean hemoglobin levels, higher mean Hb F, lower reticulocyte count, and lower childhood mortality.  Microdeletions in one or two of the four α-globin genes are commonly seen in patients with SCA from Eastern Saudi Arabia.  Additionally, the Asian βs-gene cluster haplotype is prevalent among these patients.  Based on these clinical and genetic parameters, it is reasonable to expect lower rate of sickle renal failure in this group of SCA patients. However, no prospective clinical data is available to support such assumption. Preliminary retrospective analysis of the medical records of 170 adult patients with SCA followed-up regularly at KFHU, revealed the prevalence rate of CRF to be 4.7% (personal unpublished data). CRF in this study was defined as a serum creatinine persistently greater than 132.6 umol/l for > 3 months. Patients with CRF were significantly older (44.4 + 15.5 vs. 24.3 + 9 yr, p<0.001), and had significantly lower Hb level (6.9 + 1.9 vs. 9.1 + 1.4 g/dl, p 0.014) than those without CRF. There was no significant difference in the level of Hb F between the two groups.
Both maintenance hemodialysis and kidney transplantation are viable options in the management of end-stage sickle cell nephropathy. Nissenson et al.  had evaluated the outcome of end-stage renal disease in 77 patients with SCA treated largely with in-center hemodialysis. The 30-month survival was 59%, statistically not different from the survival rate of 66% encountered in the control group of non-diabetic ESRD patients. Renal transplantation was performed in only 5% of these patients compared to 13% in non-diabetic patients at two years.  Chatterjee had surveyed 34 kidney transplants in 30 patients with sickle cell disease or trait. One-year graft and patient survival were 67% and 87% respectively. Seven of the nine grafts placed in SCA patients (77.8%) were functional at one year. Seven of the nine SCA patients experienced sickle cell crises during the first year post-transplantation.  A follow-up survey by the same author reported a one-year patient survival rate of 88%. One-year graft survival was 82% and 62% in living donor and cadaveric transplant recipients respectively.  Ojo et al.  had evaluated transplant data supplied by United Network for Organ Sharing (UNOS) and United States Renal Data System (USRDS) covering the period 1984-1996. They compared the kidney transplant outcome of 82 patients with sickle cell nephropathy as the primary cause of ESRD with 22,565 patients with other causes of ESRD. The incidence of delayed graft function, early acute rejection and the mean serum creatinine at discharge were similar between the two groups. There was no difference in the 1-year cadaveric graft survival (SCN: 78% vs. Other-ESRD: 77%). However, the 3-year cadaveric graft survival tended to be lower in the SCN group (48% vs. 60%). There was a trend toward improved survival in the SCN transplant recipients compared to their dialysis counterparts who are placed on the waiting list. In comparison to other ESRD patients, the adjusted mortality risk in the SCN group was higher both at one and three years.
Sickle cell nephropathy is primarily a consequence of glomerular hypertrophy and focal segmental glomerular hypertrophy and sclerosis. Early recognition of the disorder and instituting measures to reduce intraglomerular pressure might help prevent or ameliorate disease progression. Microalbuminuria, defined as albumin excretion of 30 to 300 mg per day, has been recognized as an early marker of glomerular damage.  Foucan et al. administered captopril (up to 25 mg/day) to 12 adult SCA patients with microalbuminuria, normal blood pressure and normal renal function. At six months, there was a significant 37% reduction in the microalbuminuria among the captopril group, whereas microalbuminuria increased by 17% in the placebo group. One patient in the placebo group progressed to overt proteinuria during the third month.  Falk et al. treated 10 patients with SCA and clinical proteinuria (protein excretion 0.8 to 10.8 g/day) with enalapril 5 to 10 mg/day for two weeks. At the end of the two-week period of treatment, proteinuria decreased by a mean of 57% without significant change in systemic arterial pressure.  Whether the reduction in urinary protein excretion with angiotensinconverting enzyme inhibitors can delay the development of progressive renal failure in SCA patients remains to be established.
The two patients in this report show variability in organ damage among SCA patients. The first patient not only sustained end-stage sickle cell nephropathy, but also had significant retinal, cardiac and hepatic involvement. In addition, he experienced progressive femoral head osteonecrosis. Secondary hyperparathyroidism and osteomalacia may have contributed to this progression. The presence of multiple organ-system failures most certainly contributed to the patient's sudden death. The fact that this patient experienced painful episode before death may also be of significance. Platt and colleagues investigated the circumstances of death in 209 adult patients with sickle cell disease. Among these patients, 18% of the deaths occurred in patients with overt organ failure, predominantly renal. Thirty-three percent were clinically free of organ failure but died during an acute sickle crisis. 
By contrast, the second patient had a very satisfactory course during hemodialysis and after kidney transplantation. The worsening anemia with onset of end-stage renal disease was easily controlled with reasonable doses of EPO. There was no increased rate of painful crises following kidney transplantation. The reported increased risks of such episodes following kidney transplantation may not be applicable to our population with very high levels of fetal hemoglobin. The donor being HLA identical to the patient, allowed minimizing the immunosuppressive regimen and therefore decreasing the risk of infections. It has been reported that infections, predominantly septicemia, accounted for 23.3% of deaths following kidney transplantation in patients with SCA. 
In conclusion, end-stage sickle cell nephropathy is amenable to hemodialysis and kidney transplantation. Outcome is largely determined by the magnitude of organ-system failures. Renal replacement therapy including kidney transplantation should be offered to these patients following the same general guidelines applicable to non-sickle cell disease patients.
| References|| |
|1.||Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease: Life expectancy and risk factors for early death. N Engl J Med 1994;330:1639-44. [PUBMED] [FULLTEXT]|
|2.||Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: Risk factors, clinical course, and mortality. Ann Intern Med 1991;115:614-20. [PUBMED] |
|3.||Falk RJ, Scheinman J, Phillips G, Orringer E, Johnson A, Jennette JC. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensinconverting enzyme. N Engl J Med 1992; 326:910-5 [PUBMED] |
|4.||Sklar AH, Campbell H, Caruana RJ, Lightfoot BO, Gaier JG, Milner PA population study of renal function in sickle cell anemia. Int J Artif Organs 1990;13:231-6. |
|5.||Morgan AG, Serjeant GR. Renal function in patients over 40 with homozygous sicklecell disease. Br Med J 1981;282:1181-3. |
|6.||Guasch A, Zayas CF, Eckman JR, Muralidharan K, Zhang W, Elsas L. Evidence that microdeletions in the alpha globin gene protect against the development of sickle cell glomerulopathy in humans. J Am Soc Nephrol 1999; 10:1014-9. |
|7.||Nissenson AR, Port FK. Outcome of end stage renal disease in patients with rare causes of renal failure. Inherited and metabolic disorders. Q J Med 1989;73:1055-62. |
|8.||Ojo AO, Govarets TC, Schmouder RL, et al. Renal transplantation in end-stage sickle cell nephropathy. Transplantation 1999;67(2):291-5. |
|9.||Breen CP, Macdougall IC. Improvement of erythropoietin-resistant anaemia after renal transplantation in patients with homozygous sickle-cell disease. Nephrol Dial Transplant 1998;13:2949-52. [PUBMED] [FULLTEXT]|
|10.||Barber WH, Deierhoe MH, Julian BA. Renal transplant in sickle cell anemia and sickle cell disease. Clin Transpl 1987;1:169-75. |
|11.||Chatterjee SN. National study on natural history of renal allografts in sickle cell disease or trait. Nephron 1980;25:199-201. [PUBMED] |
|12.||Perrine RP, Pembrey ME, John P, Perrine S, Shoup F. Natural history of sickle cell anemia in Saudi Arabs. A study of 270 subjects. Ann Intern Med 1978;88(1):1-6. |
|13.||Padmos MA, Roberts GT, Sackey K, et al. Two different forms of homozygous sickle cell disease occur in Saudi Arabia. Br J Haematol 1991;79:93-8. [PUBMED] |
|14.||Bakir AA, Hathiwala SC, Ainis H, et al. Prognosis of the nephrotic syndrome in sickle glomerulopathy. Am J Nephrol 1987;7: 110-5. |
|15.||Bhathena DB, Sondheimer JH. The glomerulopathy of homozygous sickle hemoglobin (SS) disease: morphology and pathogenesis. J Am Soc Nephrol 1991;1:1241-52. [PUBMED] |
|16.||Chatterjee SN. National study in natural history of renal allograft in sickle cell disease or trait: a second report. Transplant Proc 1987;19 (Suppl 20):33-5. |
|17.||Aoki RY, Saad ST. Microalbuminuria in sickle cell disease. Braz J Med Biol Res 1990;23:1103-6. [PUBMED] |
|18.||Foucan L, Bourhis V, Bangou J, Merault L, Etienne-Julan M, Salmi RL. A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia. Am J Med 1998;104:339-42. |
Samir H Al-Mueilo
King Fahd Hospital of the University, PO Box 40154, Alkhobar 31952