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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 4  |  Page : 751-757
End-stage renal disease in patients with sickle cell disease

1 Specialty Medicine Department, Nephrology Section, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
2 Cancer Institute, Cancer Care Unit, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
3 Department of Internal Medicine, King Fahd Hospital of the University, Dammam University, Alkhobar, Saudi Arabia

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Date of Web Publication21-Jul-2017


Sickle cell nephropathy is a severe complication of sickle cell disease (SCD) that has a wide range of manifestations, from asymptomatic microalbuminuria to end-stage renal disease (ESRD). The data on patients with SCD who develop ESRD are scarce. The aim of this study was to explore the course of patients with SCD who developed ESRD and received renal replacement therapy (RRT). The course of patients with SCD who developed ESRD and started dialysis at two centers in the Eastern Province of Saudi Arabia was retrospectively analyzed. Parameters included age at initiation of dialysis, survival until death or kidney transplantation, hospitalization due to pain crisis, disease-related parameters, and requirement for blood transfusion. Sixteen patients with SCD developed ESRD and started RRT with either hemodialysis or peritoneal dialysis. The mean age at initiation of dialysis was 46.6 years. The majority of patients (10 out of 16) were resistant to erythropoiesis-stimulating agents (ESA) and required blood transfusion repeatedly. Pain crises were infrequently encountered. Median survival was 54 months. Four patients received kidney transplantation with good outcome. In conclusion, most patients with SCD who developed ESRD were resistant to ESA and required repeated blood transfusion. The rate of hospitalization due to pain crisis was relatively low. Survival on dialysis was comparable to that of patients with no SCD, and the post-transplant course was relatively benign.

How to cite this article:
Alkhunaizi AM, Al-Khatti AA, Al-Mueilo SH, Amir A, Yousif B. End-stage renal disease in patients with sickle cell disease. Saudi J Kidney Dis Transpl 2017;28:751-7

How to cite this URL:
Alkhunaizi AM, Al-Khatti AA, Al-Mueilo SH, Amir A, Yousif B. End-stage renal disease in patients with sickle cell disease. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2020 May 31];28:751-7. Available from: http://www.sjkdt.org/text.asp?2017/28/4/751/211341

   Introduction Top

Sickle cell disease (SCD) is associated with a wide spectrum of structural and functional renal abnormalities including hematuria, proteinuria, papillary necrosis, urinary concentration defect, renal tubular acidosis, renal insufficiency, medullary carcinoma, and end-stage renal disease (ESRD).[1] The data on patients with SCD who develop ESRD are scarce. There is a large population of patients with SCD in the Kingdom of Saudi Arabia (KSA), concentrated mainly in the eastern and southwestern regions. Patients in the eastern region have the Asian beta globin haplotype and have less severe disease compared to patients with African haplotypes. The aim of this study was to explore the course of patients with SCD in Eastern Saudi Arabia who developed ESRD and received renal replacement therapy (RRT) in the form of hemodialysis (HD) or peritoneal dialysis (PD).

   Methods Top

The computer database of Johns Hopkins Aramco Healthcare (JHAH) was used to extract patients’ information. Patients with ESRD were identified among patients with SCD who were registered at JHAH from January 2003 until May 2016. In addition, medical records of patients with SCD who developed ESRD and received medical care at King Fahd Hospital of the University (KFHU) from March 1993 to May 2016 were included in the study. Information about the total number of patients with SCD who were registered and received their medical care at KFHU was not available. Only patients who started RRT with either HD or PD were included in the study. Patients with SCD who developed ESRD and were not started on RRT were excluded from the study.

The diagnosis of SCD was confirmed using the standard laboratory methods of hemoglobin (Hb) electrophoresis. The two genotypes encountered and considered as having SCD were homozygous SS and compound heterozygous sickle beta zero thalassemia (Sβ0). Different parameters were evaluated including hepatitis status, presence of diabetes mellitus, hypertension (HTN), cardiovascular and cerebrovascular comorbidities, need for blood transfusion, requirement of erythropoiesis-stimulating agents (ESA) using Epoetin alfa (EPO) (Eprex®, Jannsen-Cilag) or equivalents, serum ferritin level, hospitalization for pain crisis, and survival. Pain crisis was defined as any episode of musculoskeletal pain necessitating hospitalization. Resistance to EPO was defined as a weekly requirement of more than 12,000 units of Eprex® or equivalents. Numerical data were expressed as a mean ± standard deviation. Survival on dialysis was calculated from the date of the first dialysis until the time of death or transplantation. Kaplan–Meier analysis was used to calculate the patients’ survival. Patients who received kidney transplantation were censored at the time of kidney transplantation. Approval for the study was obtained from the Institutional Review Board at JHAH before the study began.

   Results Top

Between January 2003 and May 2016, a total of 942 patients with SCD were registered at JHAH. Over the same time period, 763 patients developed ESRD and were started on RRT. Among the patients who started RRT, 11 patients carried the diagnosis of SCD (1.17% of patients with SCD and 1.44 % of patients with ESRD).

In addition, five patients with SCD received dialysis at KFHU between March 1993 and May 2016; two had been previously published.[2]

All patients had either HbSS or S-thalassemia and none had HbSC or HbSD. Among the 16 patients included in our study, ten were female and six were male. The diagnosis of sickle cell nephropathy (SCN) was biopsy proven in six patients. Eleven patients received in center HD three times/week and five patients were treated with automated PD. The demographics of these patients are shown in [Table 1]. Most patients required high doses of EPO, averaging 28,375 units/week. One patient was completely unresponsive to EPO and was placed on a regular blood transfusion program. Iron overload was commonly observed with high serum ferritin averaging 2543 ng/mL (normal range for adults 21.8–274.6 ng/mL).
Table 1: Demographics of patients.

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Only one patient received iron chelation therapy with poor result most likely due to poor adherence. Pain episodes were encoun-tered infrequently, and most patients had fewer hospitalizations for pain crises following the initiation of dialysis. One patient experienced several episodes of pain after splenectomy which resulted in a decrease in the rate of blood transfusion. Median survival on dialysis was 54 months ([Table 2] and [Figure 1]). Nine patients died over the study period. The main cause of death was sepsis with multiorgan failure (six patients). Other causes included acute chest syndrome (one patient), liver failure (one patient), and sudden death (one patient) [Figure 2].
Table 2: Outcome and survival of patients.

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Figure 1: Kaplan–Meier survival curve.

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Figure 2: Cause of death.
MOF: Sepsis with multiorgan failure, ACS: Acute chest syndrome.

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Four patients underwent successful kidney transplantation. One patient lost her graft eight years post-transplantation due to chronic allograft nephropathy while one patient died with a functioning graft 20 years post-transplantation. The other two patients are enjoying good allograft function three and four years after transplantation. Both are receiving hydroxyurea with no side effects. Acute rejection episode within the 1st year was diagnosed in one patient and was successfully treated. Polyomavirus nephropathy was diagnosed in one patient. None of the other patients developed opportunistic infections. Frequent pain episodes requiring hospitalization among the transplant recipients were experienced by one patient.

   Discussion Top

Data about patients with SCD who progress to ESRD are very scarce. Most patients with SCD die at a young age before they develop ESRD. There are only a few studies with a small number of patients that have addressed the course of SCD patients with ESRD over the past three decades. With the improvement in medical care, the life expectancy of patients with SCD is expected to increase leading to an increase in organ dysfunction.[3] Among the many organs affected by SCD, SCN is a severe complication that has a wide range of manifestations including asymptomatic microalbuminuria, impaired urinary concentrating ability, tubular dysfunction, hematuria, overt proteinuria, nephrotic syndrome, renal impairment, and ESRD.[4],[5],[6] SCD is found mainly in the eastern and southwestern regions of the KSA.[7],[8] Patients in the eastern region have less severe disease, owing to the presence of the Asian beta globin haplotype, as compared to those in the southwestern region, who have the Benin haplotype.[9] Patients in the eastern region typically have high levels of fetal Hb with a mean level of 21%. This is believed to be protective against the complications of SCD.[10],[11] We have previously estimated the prevalence of proteinuria among our sickle cell population to be 8.4%, which is much lower than what has been reported in other populations with SCD.[1],[12] Based on this observation, we believe that the risk of developing ESRD in our sickle cell population is less than in other populations. This is supported by our finding that only 1.17% of our patients with SCD developed ESRD and were started on renal replacement. Similarly, patients with SCD who developed ESRD constituted only a small percentage (1.44%) of the total ESRD population treated at JHAH despite the high prevalence of SCD in this region. Renal involvement is associated with increased mortality among patients with SCD.[13],[14] Whether the course of patients with SCD who develop ESRD and undergo dialysis in this area is different than that in other populations has not been previously evaluated. The median survival of our cohort was 54 months. This is not different than the overall survival of our general ESRD population that has an annual mortality rate of 8%.[15] It is important to note that, in our cohort, the age of patients with SCD who developed ESRD was younger than the general dialysis population (mean age 46.6 compared to 60 years).[15] In other series, the reported outcome of SCD patient with ESRD has been variable. Nissenson and Port evaluated the outcome of 77 mainly African American patients with ESRD secondary to SCD who were treated with HD.[16] The 30-month survival rate was 59%, which is comparable to the nondiabetic ESRD population. Powars et al reported on the outcome of SCD patients in the United States who developed ESRD.[17] In that cohort, 4.2% of patients with SCD developed ESRD at a young age of 23 years and had a median survival on dialysis of four years. They had an early onset of hematuria, proteinuria, renal impairment, HTN, and ineffective erythropoiesis. In another report, Abbott et al reported on the characteristics and survival of SCD patients with ESRD who were included in the United States Renal Data System between 1992 and 1997. In their report, the mean age at presentation with ESRD was 41 years, and there was an adjusted increased risk of mortality (hazard ratio 1.52).[18] More recently, McClellan et al had shown a high one-year mortality of 26% among patients with ESRD due to SCN with a hazard ratio for death of 2.8 compared to those without SCD.[19] There are no reports comparing the efficacy of HD to PD. HD has the advantage of having a vascular access that can be used for standard and exchange blood transfusion. Most of our patients elected HD and only five were maintained on PD. Among our five patients who were on PD, one had undergone cholecystectomy and open splenectomy and another patient had undergone cholecystectomy. Despite the concern that previous abdominal surgeries may interfere with the ability to perform effective dialysis due to intra-abdominal adhesions, the course of our patients who received PD was relatively uneventful and all maintained adequate dialysis with good clearance. Two of the five patients eventually underwent successful kidney transplantation. Although the number of patients who underwent PD was small, we believe that both HD and PD are viable options, and the choice between the two modalities should be a personal preference unless there is a medical contraindication that precludes one of the choices.

Most of the patients with SCD who developed ESRD and received dialysis were female with a ratio of 10:6 reflecting the demographics of the SCD patients at JHAH, which serves the Saudi Aramco (SA) population. JHAH provides medical care to the employees and their dependents who include their spouses, children, and parents. Male employees comprise the main bulk of the workforce at SA. Candidates with SCD may not pass the preemployment physical evaluation, and therefore employees with SCD are under-represented and do not reflect the proportion of people with SCD in the community. This may explain the female predominance in our cohort.

Pain crises among our patients were encountered infrequently. This may be related to the high demand for blood transfusion due to resistance to ESA, which results in a decrease in the percentage of HbS in these patients rendering them less likely to develop the sickling process. Carbamylation of HbS in the uremic milieu that results in increased affinity to oxygen may also explain the decreased tendency to sickling.[20],[21] Response to EPO was generally poor and the average weekly requirement was much larger than what is normally needed by the rest of our dialysis population (23,500 and 7000 units/week, respectively). One of our patients had no response to large doses of EPO (56,000 units/week) and was later placed on a regular blood transfusion program. Disappointing response to ESA was reported in SCD patients with ESRD.[22],[23],[24] The cause of poor response to ESA is most likely related to reduced red cell life span. Other postulated mechanisms include abnormal bone marrow responsiveness to ESA and ineffective erythropoiesis.[23] Correction of anemia following kidney transplantation indicates that uremia has a detrimental effect on erythropoiesis.[23] Besides the high costs of ESA, administering large doses of ESA is associated with side effects, in particular, induction and worsening of HTN. Patients who do not respond to ESA may have no option but to receive regular blood transfusion taking into account the potential side effects associated with blood transfusion such as iron overload, acquiring blood-borne pathogens, and allosensitization, especially in those patients who are potential kidney transplantation candidates. Correction of uremia with kidney transplantation leads to restoration of endogenous erythropoietin production and bone marrow responsiveness to ESA and correction of anemia.[23] Our limited experience with kidney transplantation was encouraging. All kidney transplant recipients had a favorable course with no major complications. The concern of developping frequent pain crises as a result of correction of anemia post-transplantation materialized in one patient while the other three patients did not experience any increase in pain crises. Similar to the general dialysis population, kidney transplantation should be considered the treatment of choice for patients with SCD and ESRD. The favorable outcome of patients with SCD has been demonstrated earlier among African American kidney transplant recipients with SCD.[25] The use of hydroxyurea postkidney transplant appears to be safe.

Our study has several limitations associated with a retrospective study. The number of patients included was small and may not be fully representative of the local SCD patients with ESRD. Due to the sample size, we could not perform a multivariate analysis to assess the effect of patients’ comorbidities on the overall survival. This, however, is one of the largest series ever published that explored the course of patients with SCD and ESRD, and the findings shed light on the overall prognosis and complications of SCD patients who develop ESRD and receive RRT.

In conclusion, in Eastern Saudi Arabia, patients with SCD who developed ESRD and received RRT did reasonably well, and their survival was comparable to that of the general dialysis population. Both HD and PD are viable options for RRT. Similar to the general dialysis population, kidney transplantation is the modality of choice for SCD patients with ESRD and should be offered to all suitable candidates. Considering the low risk of developing ESRD among patients with SCD, a multicenter prospective study with a larger number of patients will be better to explore the course of these patients.

   Acknowledgment Top

The authors acknowledge the use of Johns Hopkins Aramco Healthcare and King Fahd Hospital of the University facilities for research data used in this article. Opinions expressed in this article are those of the authors and not necessarily of JHAH or KFHU.

Conflict of interest: None declared.

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Correspondence Address:
Ahmed M Alkhunaizi
Specialty Medicine Department, Nephrology Section, Johns Hopkins Aramco Healthcare, Saudi Aramco, P. O. Box 10955, Dhahran 31311
Saudi Arabia
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PMID: 28748876

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