Kidney Failure Outcomes in Children and Young Adults with Sickle Cell Disease in the United States Renal Data System

Abstract

Background:

Children and young adults with sickle cell disease (SCD) develop kidney disease early in childhood with some patients progressing to require dialysis and kidney transplantation. The prevalence and outcomes of children with kidney failure (chronic kidney stage 5) due to SCD is not well described. This study aimed to assess the outcome of children and young adults with SCD with chronic kidney failure compared to matched children and young adults without SCD- kidney failure in a large national database.

Methods:

Utilizing the United States Renal Data System (USRDS) we retrospectively examined kidney failure outcomes in children and young adults with SCD from 1998 – 2019.

Results:

We identified 97 patients with SCD that developed kidney failure and identified 96 matched controls with median age of 19 years (IQR 17, 21) at time of kidney failure diagnosis. SCD patients had significantly shorter survival (8.4 years vs. 14.0 years, p < 0.001) and had a longer waiting time to their first transplant when compared to matched non-SCD-Kidney Failure patients (12.1 years vs. 7.3 years, p < 0.001).

Conclusions:

Children and young adults with SCD-Kidney Failure have a significantly higher mortality when matched to non-SCD-Kidney Failure children and experience a longer mean time to kidney transplant.

Introduction

Sickle cell disease (SCD) is an inherited hematologic disorder that causes progressive damage in many organs, including the kidneys. The prevalence of albuminuria, an early manifestation of chronic kidney disease, in children is high with around 10–30% of pediatric patients with the severe form of sickle cell disease (compromising of homozygous SCD [HbSS] and sickle β⁰ thalassemia [HbSβ⁰]) developing albuminuria and many patients transition from hyperfiltration to a normal filtration rate in kidney function during adolescence(1). The literature on progression to kidney failure in children is limited. A 1995 study from the National American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) identified that only 0.5% and 0.2% of pediatric patients that progressed to require either dialysis or kidney transplantation, respectively, were in patients with SCD(2). However, this data does not represent the true burden of disease as only US centers belonging to the collaborative entered their patient data and adoption. Importantly, since 1995, the acceptance of SCD modifying therapies has markedly improved and may impact the incidence of kidney failure in pediatric SCD.

Childhood survival in the United States has improved for patients with SCD due to interventions that reduce acute mortality from infections and use of disease modifying agents; with this improved survival, mortality from chronic end-organ damage is increasing (3). Kidney failure (chronic kidney disease stage 5) has had an increasing contribution to mortality in adults with SCD (3, 4). In adults with kidney failure who initiate dialysis, one-year mortality is approximately three times higher individuals with SCD than those without SCD (4). Further, the risk of death in the first year of dialysis could be attenuated by more than 6 months with pre-dialysis nephrology care (4). In pediatric individuals with SCD-kidney failure, the survival outcomes and risk for premature death is not well established; this information is necessary to provide guidance for care teams. We performed a study to quantify the relative survival and time to transplantation of children with kidney failure with and without SCD using the United States Renal Data System (USRDS) registry.

Patients and Methods/Materials and Methods

We conducted a retrospective cohort study of children and young adults with a diagnosis of SCD-kidney failure (KD) who had their first kidney failure service aged 21 years and younger, between the years of 1998–2017 using data from the US Renal Data System (USRDS)(5). The USRDS is a national data system that collects information on individuals with kidney failure in the United States. We performed propensity matching for year of initial kidney failure service, age, sex, race, and ethnicity between patients with SCD- Kidney Failure and non-SCD-Kidney Failure. Unmatched characteristics included first kidney failure event modality type, pre- kidney failure nephrology care duration, and comorbidities (congestive heart failure, cerebrovascular disease, and hypertension).

Demographics and initial therapy were compared between unmatched and matched groups using Chi-square or Fisher exact testing, as appropriate. Kaplan-Meier survival curves were created for the matched groups comparing survival and time to transplant between SCD- Kidney Failure and non-SCD- Kidney Failure. The log-rank test was used to test the difference between the survival of these two matched groups. All statistical analysis was performed in SPSS (Version 27.0; IBM Corp, Armonk, NY). A p value of < 0.05 was considered significant. This study was approved by the institutional review board at the University of Tennessee Health Science Center at Memphis and USRDS. Per USRDS requirements all categories with fewer than 11 patients were censored.

Results

We identified 97 (0.03%) children and young adults with SCD diagnosed with kidney failure and 31,536 children and young adults with non-SCD-Kidney Failure from 1998–2017 (Supplementary Table 1). Patients with SCD- Kidney Failure were primarily young adults, with a median age of 19 years [IQR 17, 21]. Male patients comprised 67% of patients with SCD- Kidney Failure.

Propensity matching identified 96 pairs with exact matches for initial kidney failure year of service, age, sex, race, and ethnicity. We identified statistically significant differences between SCD- Kidney Failure patients and unmatched non-SCD- Kidney Failure patients for age, Black race, Hispanic ethnicity, first kidney failure event modality type, pre- Kidney Failure nephrology care, congestive heart failure, hypertension, and cerebrovascular disease. After matching, due to censoring patient numbers that were fewer than 11 per category no further associations were assessed.

The mean survival time after kidney failure diagnosis for children with SCD- Kidney Failure patients (Figure 1a) was significantly shorter than matched non-SCD- Kidney Failure patients (8.4 years (95% Confidence Interval (CI) 7.0–9.8 years) vs. 14.0 years (95% CI 12.4– 15.5 years), p < 0.001). SCD- Kidney Failure patients experienced a longer mean time before receiving transplant (Figure 1b) than matched non-SCD- Kidney Failure patients (12.1 years (95% CI 10.3–13.8 years vs. 7.3 years (95% CI 5.6–8.9 years), p <0.001).

Figure 1.

Comparison between year of service, age, sex, race, and ethnicity-matched patients with SCD-Kidney Failure and non-SCD-Kidney Failure. A) Kaplan-Meier mean survival time after kidney failure diagnosis, 8.4 years vs. 14.0 years, p <0.001and B) Kaplan-Meier time to transplantation, 12.1 years vs. 7.3 years, p < 0.001.

Discussion

This study further highlights disparities in health outcomes and access to transplant for children and young adults with SCD- Kidney Failure. First, children and young adults with SCD- Kidney Failure have worse survival than matched individuals with non-SCD- Kidney Failure. Second, SCD individuals experience longer wait times for kidney transplant than matched controls. Third, children, and young adults with SCD- Kidney Failure had overall higher mortality. The recent American Society of Hematology guidelines for the management of SCD suggests early referral for renal transplant and highlights the need for studies to evaluate disparities in access to care for SCD patients with kidney failure (6). This study provides additional evidence to support the need to further understand and address the reasons for this marked healthcare disparity.

Kidney transplantation in children is well-recognized to provide a long-term survival advantage in all patients with kidney failure however racial disparities in transplantation can lead to unequitable transplantation rates(7). Two adult SCD studies suggest that transplantation is associated with a decrease in mortality (8, 9). However, in this study, the time from the development of kidney failure kidney transplant remained longer for patients with SCD. This disparity is further highlighted by findings that these individuals have a higher mortality within the first and subsequent years after developing kidney failure. Therefore, children, and young adults with SCD should not be precluded from early referral to access to kidney transplantation. A study published in 2021, examined the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplant Network (OPTN) database, found that patient and allograft survival in SCD kidney recipients did not improve between recent era (2010–2019) and early era (2000–2009). However, the authors note that these findings should not discourage kidney transplantation due to the overall survival benefits that transplantation confers(10). Several of these more recent studies point towards graft loss secondary to poorly controlled SCD-related disease. Strategies to reduce post-transplant complications due to SCD should therefore be evaluated. Disease modifying agents such as hydroxyurea, is both effective in reducing the concentration of sickle hemoglobin and decreasing albuminuria in children and adults with SCD and could be continued post-transplant(11) (12). Initiating automated blood transfusion in adult recipients during and after kidney transplantation has also demonstrated the ability to improve allograft and patient outcomes (8). The mammalian target of rapamycin (mTOR) pathway has been identified as a regulator of red blood cell growth and proliferation(13); one case report found use of mTOR inhibitor, everolimus, post-transplant improved fetal hemoglobin and decreased SCD pain(14). Lastly, allogenic hematopoietic stem cell transplantation remains the only curative therapy for SCD, but this can be limited by the cost, suitable matched donors as well as significant morbidity(15). An approach of dual stem cell and organ transplantation may be an option for patients in the foreseeable future as advances in stem cell transplantation are made. Larger prospective studies are needed to confirm these medications and modalities on allograft survival.

Our study has several limitations inherent to a retrospective study of administrative data. We can only identify associations between SCD status and mortality/transplantation but cannot speak directly to causal relationships between delayed transplantation and mortality. We only identified SCD-Kidney Failure and cannot calculate the prevalence or incidence of Kidney Failure within the SCD population at large. Additionally, due to the limited number of participants within the SCD-Kidney Failure cohort and the small number of patients in many subgroups, we were unable to further stratify the data. We have limited information about care prior to developing kidney failure particularly regarding the use and duration of disease modifying therapies prior to development of kidney failure and transfusions post-transplant. Future studies need to evaluate approved therapies for treatment of SCD to understand how these interventions influence the progression of kidney disease.

It is vital that the transplant community identify and reduce the barriers to kidney transplantation in children and young adults with SCD-Kidney Failure. Future research should consider qualitative assessment of the barriers to transplantation among kidney transplant centers. Equitable access to transplantation may mitigate the decreased survival seen in this study. The risk of SCD-related kidney disease must be balanced with improvement in the quality of life and possible improved survival when compared to those who remain on dialysis. Use of hydroxyurea, mTOR inhibitors and exchange transfusions need to be further studied in the post-transplant period. However, in the immediate future, nephrology centers can start to work towards improving access to transplantation and establishing sickle cell specific transplant protocols to improve post-transplant allograft survival by working with their hematology colleagues and sharing protocols.

Supplementary Material

Supplementary Material

Supplementary Table 1. Unmatched and propensity-matched analysis of patients with sickle-cell disease-related end-stage kidney disease (SCD-Kidney Failure) and non-SCD-Kidney Failure.

Abbreviations

KD

Kidney Failure

SCD

Sickle Cell Disease

USRDS

United States Renal Data System