Renal Function Is Preserved after Hematopoietic Stem Cell Transplantation for Sickle Cell Disease
Authors: Limerick Emily , Jeffries Neal , Diamantidis Clarissa , Lokhnygina Yuliya , Hsieh Matthew M. , Fitzhugh Courtney D. 
Published: February 2021

Chronic kidney disease (CKD) is a common complication and a significant contributor to morbidity and mortality for patients with sickle cell disease (SCD). Hematopoietic stem cell transplantation (HSCT) is a curative strategy for SCD and potentially life-saving therapy. Though HSCT can reverse the SCD phenotype, acute and chronic kidney dysfunction may be an unintended consequence. The incidence of acute kidney injury (AKI) and the effect of different HSCT regimens on progression or amelioration of CKD in adults with SCD have not previously been reported.
This cohort study analyzes prospectively collected data from 106 patients transplanted for SCD at the National Institutes of Health (NIH) Clinical Center, including HLA-matched sibling (N=71) and haploidentical HSCT (N=26) where nonmyeloablative conditioning was given, as well as gene therapy (N=9), where a myeloablative regimen was employed. Patients' renal function was assessed at baseline and annually thereafter for up to 3-years.
We sought to define 1) the prevalence of CKD before and after HSCT 2) the incidence of CKD after HSCT 3) estimated glomerular filtration rate (eGFR) trends after HSCT 4) urine albumin to creatinine ratio (UACR) change after HSCT and 5) the incidence of AKI within 100 days of HSCT. We defined and staged AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria (stage 1: 1.5-1.9 times baseline serum creatinine increase or ≥0.3 mg/dl increase; stage 2: 2-2.9 times baseline; stage 3: 3 times baseline, increase in creatinine to ≥4.0 mg/dl, or initiation of renal replacement therapy).
The baseline prevalence of CKD was 6% when defined conservatively (eGFR &lt;60 ml/min/1.73m2); this prevalence did not change significantly post-HSCT. When using a more comprehensive definition of CKD (urine albumin to creatinine ratio (UACR) ≥30 mg/g OR eGFR &lt;60 ml/min/1.73m2), 48% had CKD at baseline, 62% at 1 year, 55% at 2 years, and 55% at 3 years (with p=0.02, 0.26, 0.54 for longitudinal model comparing post-HCST prevalence to baseline). The incidence of CKD any time after HSCT was 1% and 11% according to each of these CKD definitions, respectively. 25% of participants had follow-up of ≤2 years, median follow-up was 3 years.
The median eGFR remained within the normal range throughout the follow-up period but declined annually: the baseline median eGFR was 139.7 ml/min/1.73m2 and declined by 7.6, 11.6, and 20.9 ml/min/1.73m2 each year post-HSCT (p&lt;0.0001). In an adjusted regression analysis, there was no association of gender, engraftment status, transplant regimen, or conditioning agent- specifically use of pentostatin, total body irradiation, or post-transplant cyclophosphamide- with worsening eGFR (p&gt;0.05 for each variable). This eGFR trend represents an improvement in renal function toward the normal range: there was a statistically significant decrease in hyperfiltration (eGFR ≥150 ml/min/1.73m2), which was present in 34% patients at baseline but steadily declined to 12% by 3 years post-HSCT (p = 0.0006 for adjusted longitudinal model). There was a corresponding increase in patients with normal eGFR (60-149 ml/min/1.73m2) from 60% at baseline to 80% at 3 years post-HSCT.
UACR showed an increase in the year following transplant that subsequently dissipated. Median UACR at baseline was 24.3 mg/g with annual follow-up median values of 62.2, 38.9 and 36.2 mg/g (p-values of 0.007, 0.41, and 0.69 for comparison to baseline from regression model of log transformed UACR).
In our cohort, 58% of patients experienced AKI in the first 100 days post-HSCT; which is consistent with previous data. 77% of those were mild, stage 1; 13% were moderate, stage 2; and 10% were severe, stage 3 AKI.
This study demonstrates that HSCT in patients with SCD is not associated with a significant increase in CKD incidence or prevalence at 2 and 3 years post-HSCT. While there is a substantial decline in eGFR from baseline to each annual follow-up, the proportion of patients whose eGFR was in the normal range increased and the prevalence of hyperfiltration decreased. The stability of UACR after an initial increase at the 1-year time point further suggests that even more mild renal damage may stabilize after transplant. Finally, AKI occurred in over half of the patients in our cohort, though the preponderance developed mild AKI.

Disclosures
Diamantidis: United Health Group: Membership on an entity's Board of Directors or advisory committees.