Patients with sickle cell disease (SCD) experience increased morbidity and early mortality, due in part to organ damage, including end stage kidney disease (ESKD)1. Decline in kidney function is progressive with initial hyperfiltration, followed by decline in glomerular filtration rate (GFR) and eventual ESKD in adults. Individuals with SCD experience a more rapid decline in GFR than the general African American population and this rapid decline is associated with increased mortality 2,3. Prior studies suggest the one-year mortality rate after initiating dialysis is higher in patients with SCD but early care by a nephrologist may decrease mortality4. Additionally, individuals with ESKD due to SCD (SCD-ESKD) are less likely to receive an arteriovenous fistula (AVF) when initiating hemodialysis (HD)5,6 despite studies demonstrating improved survival when dialyzed with an AVF or graft 7,8. Finally, referral for transplantation and transplantation rates are lower among individuals with SCD-ESKD despite the improved survival benefit of kidney transplantation9–11.
It is important to characterize the mortality, and disparities experienced by patients with SCD-ESKD. This data can highlight the need to improve clinical care, monitor kidney disease progression, and develop therapies to prevent SCD-ESKD. Despite improvement in care over the last two decades, the prognosis of SCD-ESKD remains uncertain. This study aimed to characterize the outcomes of individuals with SCD-ESKD from 1998–2017 enrolled in the United States Renal Data System (USRDS) registry. We hypothesized that survival of patients with SCD-ESKD has improved over the course of the last two decades.
We performed an IRB approved retrospective analysis using the USRDS database from 1998–2017. Data including age, sex, race, ethnicity, primary diagnosis, outcome dates, first ESKD treatment modality, and comorbid conditions (atherosclerotic heart disease, congestive heart failure, cerebrovascular disease, diabetes mellitus, peripheral vascular disease, and hypertension) were abstracted from the patient profile using Centers for Medicare and Medicaid Services (CMS) Medical Evidence Form 2278.
Age was summarized by mean (standard deviation), median (interquartile range), and by number and percentage within age groups. Sex, ethnicity, first ESKD modality, dialysis access, duration of pre-ESKD nephrology care, and co-morbid conditions were summarized by number and percentage (Table 1). Groups were divided first by SCD status and then by Black race. Adjusted (Figure 1) and unadjusted (Supplemental Figure) survival and time-to-transplant were calculated using Cox proportional hazards regression model, overall and by year of first ESKD event. For survival, adjusted values were adjusted for age, sex, ethnicity, Black race, initial treatment modality, hemodialysis access type, pre-ESKD nephrology care, and comorbidities. For transplant, due to small numbers in the temporal analysis, adjustment was restricted to demographic variables including age (on a continuous scale), sex, ethnicity, and black race.
Table 1.
Baseline characteristics of patients with end-stage kidney disease (ESKD), with and without sickle cell disease (SCD), and by Black or non-Black race
| SCD |
Non-SCD |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Black |
Non-Black |
Black |
Non-Black |
Unadjusted OR SCD vs. non-SCD | Adjusted† OR SCD vs. non-SCD | |||||
| Number of Patients | 1879 | 139 | 598726 | 1593335 | ||||||
|
| ||||||||||
| Age (years) | ††0.57 (0.55, 0.58) *** | ††0.62 (0.60, 0.64) *** | ||||||||
| Mean (SD) | 43.2 (13.3) | 48.9 (16.8) | 58.4 (15.5) | 63.8 (15.7) | ||||||
| Median (IQR) | 44 (34, 52) | 49 (37, 60) | 59 (48, 70) | 66 (55, 76) | ||||||
| Age Group | ||||||||||
| <18 | 32 | 1.7% | <11 | N/A | 4812 | 0.8% | 16762 | 1.1% | ||
| 18–30 | 345 | 18.4% | 13 | 9.4% | 23696 | 4.0% | 41084 | 2.6% | ||
| 31–40 | 405 | 21.6% | 25 | 18.0% | 50556 | 8.4% | 75084 | 4.7% | ||
| 41–50 | 539 | 28.7% | 34 | 24.5% | 95458 | 15.9% | 159613 | 10.0% | ||
| 51–60 | 383 | 20.4% | 30 | 21.6% | 141139 | 23.6% | 295856 | 18.6% | ||
| 61–70 | 130 | 6.9% | 18 | 12.9% | 142396 | 23.8% | 398127 | 25.0% | ||
| 71–80 | >11 | N/A | <11 | N/A | 101024 | 16.9% | 396473 | 24.9% | ||
| >80 | <11 | N/A | <11 | N/A | 39645 | 6.6% | 210336 | 13.2% | ||
| Male Sex | 973 | 51.8% | 76 | 54.7% | 307684 | 51.4% | 923885 | 58.0% | 1.18 (1.09, 1.29) *** | 1.17 (1.07, 1.27) *** |
| Hispanic Ethnicity | 19 | 1.0% | 42 | 30.2% | 8959 | 1.5% | 296665 | 18.6% | 0.15 (0.10, 0.22) *** | 0.95 (0.72, 1.24) |
| First ESRD Event Modality Type | ||||||||||
| Hemodialysis | 1638 | 87.2% | 122 | 87.8% | 557154 | 93.1% | 1406547 | 88.3% | Reference Group | Reference Group |
| Peritoneal Dialysis | 228 | 12.1% | >11 | N/A | 35745 | 6.0% | 134963 | 8.5% | 1.58 (1.38, 1.81) *** | 1.00 (0.85, 1.17) |
| Transplant | >11 | N/A | <11 | N/A | 5104 | 0.9% | 49104 | 3.1% | 0.29 (0.17, 0.49) *** | 0.24 (0.14, 0.41) *** |
| Unknown | <11 | N/A | <11 | N/A | 723 | 0.1% | 2721 | 0.2% | ||
| Initial Hemodialysis Access | ||||||||||
| Arterio-Venous Fistula | 84 | 4.5% | <11 | N/A | 49664 | 8.3% | 149776 | 9.4% | Reference Group | Reference Group |
| Graft | 71 | 3.8% | <11 | N/A | 16811 | 2.8% | 25017 | 1.6% | 3.80 (2.81, 5.15) *** | 2.96 (2.18, 4.02) *** |
| Catheter | 836 | 44.5% | 68 | 48.9% | 294325 | 49.2% | 757059 | 47.5% | 1.82 (1.48, 2.26) *** | 1.43 (1.15, 1.78) ** |
| None/Other/Unknown | 888 | 47.3% | 57 | 41.0% | 237926 | 39.7% | 661483 | 41.5% | ||
| Pre-ESKD Nephrology Care | ||||||||||
| None | 731 | 38.9% | 46 | 33.1% | 207870 | 34.7% | 535221 | 33.6% | Reference Group | Reference Group |
| < 6 Months | 152 | 8.1% | <11 | N/A | 48983 | 8.2% | 138909 | 8.7% | 0.96 (0.80, 1.16) | 1.23 (1.01, 1.48) * |
| 6–12 Months | 228 | 12.1% | >11 | N/A | 77071 | 12.9% | 211982 | 13.3% | 0.93 (0.79, 1.10) | 1.33 (1.13, 1.58) *** |
| > 12 Months | 293 | 15.6% | 16 | 11.5% | 92485 | 15.4% | 307508 | 19.3% | 0.86 (0.74, 1.00) | 1.43 (1.22, 1.69) *** |
| Unknown | 474 | 25.2% | 52 | 37.4% | 172293 | 28.8% | 399661 | 25.1% | ||
| Co-morbid Conditions | ||||||||||
| Atherosclerotic Heart Disease | 37 | 2.0% | <11 | N/A | 46764 | 7.8% | 210243 | 13.2% | 0.16 (0.12, 0.21) *** | 0.39 (0.29, 0.54) *** |
| Congestive Heart Failure | 522 | 27.8% | 29 | 20.9% | 168701 | 28.2% | 494474 | 31.0% | 0.87 (0.76, 0.96) ** | 2.07 (1.87, 2.30) *** |
| Cerebrovascular Disease | 141 | 7.5% | <11 | N/A | 56973 | 9.5% | 136861 | 8.6% | 0.80 (0.68, 0.95) * | 1.43 (1.21, 1.71) *** |
| Diabetes Mellitus | 75 | 4.0% | <11 | N/A | 205068 | 34.3% | 526230 | 33.0% | 0.08 (0.06, 0.10) *** | 0.10 (0.08, 0.12) *** |
| Hypertension | 1313 | 69.9% | 79 | 56.8% | 515443 | 86.1% | 1280527 | 80.4% | 0.49 (0.45, 0.54) *** | 0.53 (0.48, 0.59) *** |
| Peripheral Vascular Disease | 63 | 3.4% | <11 | NA | 54733 | 9.1% | 220991 | 13.9% | 0.24 (0.18, 0.30) *** | 0.71 (0.55, 0.91) ** |
Adjusted for Age, Sex, Race, Ethnicity, Initial Treatment Modality, Access, Nephrology Care, and Comorbidities
For an increase in 10 years age
p < 0.05
p < 0.01
p < 0.001
Figure 1.
Adjusted survival† and time-to-transplant‡ comparison overall and over time between sickle cell disease patients with end stage kidney disease (SCD-ESKD) and non-sickle cell disease patients with end-stage kidney disease (non-SCD-ESKD) using Cox proportional hazard model with hazard ratio and 95% confidence intervals overall.
† Adjusted for Age, Sex, Race, Ethnicity, Initial Treatment Modality, Access, Nephrology Care, and Comorbidities
‡ Adjusted for Age, Sex, Race, Ethnicity
Between 1998 and 2017, 2,194,079 patients developed ESKD; 2018 (0.09%) had a diagnosis of SCD. The age at ESKD diagnosis was significantly lower in the SCD-ESKD group than in the non-SCD-ESKD group, both unadjusted (OR: 0.57, 95% CI: 0.55–0.58, for each 10-year increase in age) and when adjusted for sex, race, ethnicity, initial treatment modality, access, nephrology care, and comorbidities (OR: 0.62, 95% CI: 0.60–0.64, for each 10-year increase in age). Twenty percent of patients developed ESKD before the age of 30. Male patients with SCD-ESKD developed ESKD at an earlier age than female patients with SCD-ESKD (p < 0.001). Patients with SCD-ESKD had lower adjusted odds of receiving a pre-emptive kidney transplant as compared to being started on dialysis (OR 0.24, 95% CI 0.14, 0.41). Patients with SCD-ESKD were more likely to have ongoing pre-ESKD nephrology care than not having any care (<6 months: OR 1.23, 95% CI 1.01–1.48; 6–12 months: OR 1.33 95% CI. 1.13–1.58; and >12 months: OR 1.43 95% CI 1.22–1.69). The unadjusted hazard ratio of mortality following first ESKD event was higher among SCD-ESKD patients than non-SCD-ESKD patients (HR: 1.21, 95% CI: 1.15–1.27). This hazard of mortality effect was much larger after adjusting for age, sex, ethnicity, Black race, initial treatment modality and comorbidities (HR: 2.68, 95% CI: 2.55–2.83). Over the nineteen-year study period, the adjusted hazard of mortality improved by 35% (HR 0.65, 95% CI 0.64–0.66) for non-SCD-ESKD and by 30% (HR 0.70, 95% CI 0.58–0.84) for SCD-ESKD. These values were not significantly different between the groups. The unadjusted rate of receiving a transplant was lower among SCD-ESKD patients than non-SCD-ESKD patients by 29% (OR: 0.71, 95% CI: 0.62–0.83). This relative transplant rate was even smaller after adjusting for age, sex, ethnicity, and Black race (HR: 0.49, 95% CI: 0.29–0.84). Over the study period, the adjusted rate of transplant decreased for the non-SCD-ESKD (HR 0.81, 95% CI 0.80–0.82), but this decrease was not statistically significant for the SCD-ESKD group (HR 0.75, 95% CI 0.43–1.32).
Patients with SCD continue to develop ESKD earlier in life, have a higher risk of death, and lower transplant rate than non-SCD-ESKD patients. When adjusting for age, this disparity in survival was magnified as SCD-ESKD patients have a 2.7 times higher hazard of mortality. In contrast to a prior study4, we found that despite the increase in pre-ESKD nephrology care, mortality remained elevated. It remains alarming that patients with SCD-ESKD were less likely to receive a kidney transplant as compared to non-SCD-ESKD patients. Data remains conflicting as to whether SCD patients have lower overall and graft survival than non-SCD patients; this should not preclude patients from transplant11–13.
This retrospective study has some limitations. We could not assess the stage of CKD at time of referral. USRDS reports active medications, but we could not evaluate the effect of SCD modifying or renoprotective therapies on progression to ESKD. Large prospective cohort studies are needed to determine the impact of therapies on progression of kidney disease.
This study confirms that patients with SCD who develop ESKD continue to experience disparities in renal outcomes. As patients with SCD-ESKD are at high risk of all-cause mortality, it is important to ensure comprehensive SCD care centers that includes both pediatric and adult hematologists14. Ongoing research should identify risk factors for ESKD progression, ensure implementation of monitoring for kidney disease, and determine therapies that prevent the development of ESKD.
Supplementary Material
Supplementary Figure 1. Unadjusted survival and time-to-transplant comparison overall and over time between sickle cell disease patients with end stage kidney disease (SCD-ESKD) and non-sickle cell disease patients with end-stage kidney disease (non-SCD-ESKD) using Cox proportional hazard model with hazard ratio and 95% confidence intervals overall.
Acknowledgements:
We thank the USRDS for approving our study and giving us the opportunity to carry out this study.
Funding Sources:
RZ receives research funding from the NIH/NHLBI K23HL157554
Footnotes
Disclosures: RZ: No COI; JW: No COI; MY: No COI; KIA: No relevant COI related to this manuscript, but has served on advisory boards for Novartis, Global Blood Therapeutics, Novo Nordisk, Roche and Forma Therapeutics; JL: Consultant for Novartis, Agios and Forma Therapeutics for studies unrelated to this manuscript.
Contributor Information
Jeffrey C. Winer, Department of Pediatrics, Division of Academic Hospital Medicine, University of Tennessee Health Science Center, Memphis, TN.
Marianne E. Yee, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, and Department of Pediatrics, Emory University School of Medicine, Atlanta GA.
Kenneth I. Ataga, Center for Sickle Cell Disease, University of Tennessee Health Science Center Memphis, TN.
Jeffrey D. Lebensburger, Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL.
Rima S. Zahr, Division of Pediatric Nephrology and Hypertension, University of Tennessee Health Science Center Memphis, TN.
Data Sharing:
This study was approved by the institutional review board at the University of Tennessee Health Science Center at Memphis and the USRDS. Data is made available by contacting the USRDS.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Figure 1. Unadjusted survival and time-to-transplant comparison overall and over time between sickle cell disease patients with end stage kidney disease (SCD-ESKD) and non-sickle cell disease patients with end-stage kidney disease (non-SCD-ESKD) using Cox proportional hazard model with hazard ratio and 95% confidence intervals overall.
Data Availability Statement
This study was approved by the institutional review board at the University of Tennessee Health Science Center at Memphis and the USRDS. Data is made available by contacting the USRDS.