When Cure Meets Susceptibility: APOL1 ‐Associated Kidney Injury After Gene Therapy for Sickle Cell Disease

To the Editor,

1.

Allogeneic hematopoietic stem cell transplant (HCT) is a curative option for individuals with sickle cell disease (SCD). However, many patients lack matched donors, making gene therapy (GT) or haploidentical HCT feasible alternatives. Although long‐term outcomes following GT appear promising, data on organ‐level sequelae, including renal effects, are sparse. In the non‐HCT setting, renal manifestations of SCD, collectively termed sickle cell nephropathy (SCN), operate on a spectrum. Early features, such as glomerular hyperfiltration (estimated glomerular filtration rate [eGFR] > 130 mL/min/1.73 m² in women and > 140 mL/min/1.73 m² in men) [1] and pathological albuminuria or proteinuria (urine albumin to creatinine [UAC] ratio > 0.03 mg/mg or urine protein to creatinine [UPC] ratio > 0.2 mg/mg respectively) [2] often go undetected and may represent early progression toward chronic kidney disease (CKD). CKD affects 26.5% of children and > 50% of adults over 40 years, with renal disease causing 18% of SCD‐related deaths [2, 3]. SCN can also cause progressive glomerular injury, most commonly focal segmental glomerulosclerosis (FSGS) [4]. In contrast, post‐HCT renal function is generally preserved, with a very low incidence of new‐onset CKD (~2.8%) [5].

In this context, individuals with SCD may coinherit genetic modifiers such as variants in APOL1, MYH9, and HMOX that increase the risk of nephropathy, with high‐risk APOL1 variants being the most common [6]. The APOL1 gene encodes apolipoprotein L1, a protein expressed in multiple kidney cell types [7, 8]. Among individuals of African ancestry, inheritance of high‐risk APOL1 variants, most commonly the G1 and G2 alleles in a homozygous or compound heterozygous pattern, are associated with an increased risk of CKD [7]. These variants are believed to have arisen under selective pressure against African trypanosomiasis, as APOL1‐mediated lytic activity against Trypanosoma species confers protection from infection but predisposes carriers to kidney injury [9]. APOL1‐associated kidney disease encompasses several histologic phenotypes, including FSGS [10]. Approximately 13% of individuals of African ancestry carry two high‐risk APOL1 alleles [11]. Among individuals with SCD, 11% harbor high‐risk APOL1 variants, conferring a sevenfold increased risk of CKD, earlier onset of nephropathy, and glomerular proteinuria [6, 8].

We report on a patient who developed diffuse glomerulosclerosis leading to CKD post‐GT and was later found to have high‐risk APOL1 gene variants, thus highlighting a potentially underrecognized risk in patients with SCD considering curative therapies. We are currently evaluating two additional patients with SCD and known high‐risk APOL1 mutations for potential GT. Through these parallel case descriptions, we discuss the rationale for offering GT despite the presence of high‐risk APOL1 variants.

The index patient is a now 23‐year‐old male with hemoglobin (Hb) SS disease complicated by recurrent vaso‐occlusive crisis (VOC) despite treatment with hydroxyurea and crizanlizumab. Due to the lack of matched donors, he proceeded to GT on the EDIT‐301 trial (NCT04853576) which employs CRISPR‐Cas12a editing of the HBG1/2 promoters to induce fetal hemoglobin (HbF) [12]. He had no evidence of CKD, chronic proteinuria, or hypertension prior to GT. One month pre‐GT, his eGFR_Cr was 88 mL/min/1.73 m² (trial inclusion criteria eGFR > 70 mL/min/1.73 m²) with elevated UPC at 2.84 mg/mg (normal < 0.2 mg/mg) with a normal serum albumin (3.6 g/dL). As isolated proteinuria was not a trial exclusion criterion, he proceeded to GT following myeloablative conditioning with busulfan (cumulative AUC of 82.3 mg h/L) and infusion of autologous edited peripheral blood stem cells. Post‐GT increases in UPC were noted without other clinical or laboratory evidence for transplant‐associated thrombotic microangiopathy (TA‐TMA). He engrafted neutrophils and platelets on day (D) + 26 and D + 35, respectively. At discharge (D + 29), eGFR_Cr was 135 mL/min/1.73 m² with persistent proteinuria (UPC 4.05 mg/mg). By D + 98, his eGFR_Cr declined to 85 mL/min/1.73 m². Prophylactic acyclovir was the only nephrotoxic medication administered for 6 months post‐GT. Over the ensuing 5 months post‐GT, his creatinine progressively increased in parallel with worsening hypertension (Figure 1A,B). He was transitioned from amlodipine, text a calcium channel blocker, to losartan, an angiotensin receptor blocker (ARB) D + 239 for persistent proteinuria and gingival hyperplasia. He then switched back to amlodipine on D + 267 after an acute kidney injury during a VOC in the background of chronic pain. By D + 307, he progressed to CKD stage 3b. A kidney biopsy on D + 331 demonstrated diffuse and segmental glomerulosclerosis involving approximately 70% of glomeruli, as well as tubular atrophy with interstitial inflammation and fibrosis (Figure 2). Blood infectious disease testing including viral reactivation was negative, with an absence of viral cytopathic changes on the renal biopsy. The absence of clinical features suggestive of autoimmune disease, coupled with normal IgG, C3, and C4 levels and a lack of immune complex deposition on histopathology, ruled out an autoimmune etiology. Blood genetic testing revealed heterozygous G1/G2 high‐risk APOL1 variants. He was started on empagliflozin; a sodium‐glucose co‐transporter 2 inhibitor (SGLT2) on D + 407 for persistent proteinuria. At 19 months post‐GT, he remains free of VOCs, with a hemoglobin of 14.5 mg/dL and an HbF/HbS/HbA2 of 57.2%/42.1%/0.7%. His last eGFR_Cr was 39 mL/min/1.73 m² consistent with CKD stage 3b. His rapidly progressive kidney disease places him at high risk for progression to end stage kidney disease potentially needing a renal transplantation in the future.

FIGURE 1.

Trends in eGFRcr and urine protein to creatinine ratio in the Index patient (A, B), Patient 2 (C, D), and Patient 3 (E, F).

FIGURE 2.

Kidney biopsy of index case. (A) hematoxylin and eosin (H&E) sections (100X) demonstrate globally sclerosed glomeruli (arrows) in a background of interstitial fibrosis highlighted by extensive blue staining on the trichrome stain (inset). (B) H&E section (400×) demonstrates a normal glomerulus with dilatation of surrounding proximal tubules. (C) H&E section (400×) demonstrates a glomerulus with diffuse glomerulosclerosis and associated interstitial sclerosis and tubular atrophy in the lower and left compared to intact proximal tubules in the upper right. (D) H&E section (400×) demonstrates glomerulus with segmental sclerosis (arrow) and interstitial inflammation in the lower right. (E) Electron micrograph demonstrates extensive glomerular basement membrane thickening and collapse with podocyte foot process effacement (arrow).

At our center, we are currently evaluating two siblings with HbSS from West Africa, who were found to carry high‐risk APOL1 variants during evaluation for SCN. Neither has an HLA‐matched or suitable haploidentical donor. The older sibling is a 15‐year‐old male with mild kidney disease, suggested by baseline hyperfiltration, and proteinuria treated with losartan since age 12 (Figure 1C,D); he was found to have heterozygous G1/G2 high‐risk APOL1 variants at age 13. The younger sibling is a 6‐year‐old female with more advanced kidney disease, marked by hyperfiltration, and severe proteinuria (Figure 1E,F); requiring losartan and empagliflozin to decrease proteinuria; she was identified to have heterozygous G1/G2 high‐risk APOL1 variants at age 4. After a risk–benefit assessment and informed shared decision‐making with the family, we plan to proceed with GT in the older sibling, while future treatment of the younger sibling may be considered as pediatric eligibility for GT expands commercially.

Our series highlights an important consideration for patients with SCD considering GT or HCT: unrecognized high‐risk APOL1 variants in patients with SCD may impact renal outcomes. Screening for genetic variants predisposing to nephropathy as a potential “second hit” in SCD is currently not routinely recommended, including in patients with isolated proteinuria. However, given the overlapping ancestral origins of SCD and APOL1 mutations, Kormann et al. proposed that assessment of APOL1 polymorphisms in individuals with SCD may help identify those at increased risk for renal complications [8, 13]. In a longitudinal study (n = 111), Rashkin et al. demonstrated that after the age of 10, individuals with SCD and G1/G2 APOL1 risk variants exhibited higher baseline eGFR but a steeper decline over time, along with increased odds of accelerated eGFR loss [14]. These findings suggest that genetic risk stratification and early renal surveillance may identify patients at highest risk for progressive kidney injury who could benefit from proactive renoprotective strategies such as early initiation of angiotensin converting inhibitors (ACE) inhibitors, ARBs, and SGLT2 inhibitors to control proteinuria, as well as emerging APOL1‐channel drug inhibitors prior to definitive treatment [15].

To our knowledge, there are no published reports of patients with SCD and APOL1 mutations who have undergone GT or HCT likely reflecting under recognition of this association. Although rapid CKD progression in P#1 may have been impacted by busulfan (traditionally not nephrotoxic) and acyclovir exposure as 3rd hits, causality cannot be established and progression may have occurred regardless of GT. In hindsight, GT was still appropriate for P #1, although it was likely performed too late to preserve renal function; its benefits: elimination of vaso‐occlusive events, improved end‐organ outcomes, and enhanced quality of life likely outweigh the risk of progressive SCD and premature mortality. Earlier GT may favorably modify SCN by interrupting hemolysis‐driven renal injury, supported by evidence that cell‐free heme induces IFN‐I–mediated inflammation [16] Disruption of the hemolytic cycle through GT thus represents a critical therapeutic advantage that informed our consideration of GT for patients #2 and #3.

In patients with SCD who harbor high‐risk APOL1 variants, the choice between GT and HCT requires careful consideration of kidney‐specific risks. Kidney injury during HCT may result from exposure to chemotherapy, nephrotoxic medications, including immunosuppressants (e.g., tacrolimus), infections, hemodynamic stress, and inherent SCD‐specific susceptibility to endothelial injury and TA‐TMA [5, 17]. Post‐HCT, early declines in kidney function and increased rates of acute kidney injury are seen, with many studies demonstrating a long‐term reduction in glomerular hyperfiltration with preservation of renal function [5, 18].

Allogeneic HCT may also facilitate subsequent kidney transplantation from the same donor, provided the donor does not carry APOL1 risk variants, thereby potentially obviating the need for long‐term post‐transplant immunosuppression [19]. However, this approach depends on an uncomplicated HCT course and appropriate donor availability. In contrast, GT, which utilizes busulfan without immunosuppression, represents a less nephrotoxic approach.

In conclusion, our report underscores the potential contribution of high‐risk APOL1 variants to renal injury in patients with SCD undergoing transformative therapies, particularly as the use of GT continues to expand [20]. Gene therapy should not be withheld in patients with SCN or APOL1 risk variants; rather, comprehensive pretreatment renal assessment and counseling are critical to identify at‐risk individuals and guide individualized monitoring and early nephroprotective strategies.

Author Contributions

E.G. and L.M. collected data and wrote the initial version of the manuscript. O.N.R.B., S.M., A.V., S.Cr., R.A.‐A. contributed to the care of the patient, provided scientific input and edited the manuscript. S.Ch. provided scientific input and edited the final version of the manuscript. H.G.R., contributed to the care of the patient, designed the concept, helped with collection of data, wrote the initial version of the manuscript and edited the final version of the manuscript.

Funding

The authors have nothing to report.

Ethics Statement

The manuscript was reviewed and approved by the Nationwide Children's Ethics Committee and Institutional Review Board, which waived the requirement for informed consent due to the retrospective nature of the study and use of anonymized and deidentified data.

Conflicts of Interest

Evelyn Gartstein, Lauren McNaughton Shamlal Mangray report no conflicts of interest. Hemalatha Rangarajan: Vertex Therapeutics (consultancy November 2024), Medexus (consultancy June 2024), and Beam Therapeutics (consultancy February 2026). Sonali Chaudhury: Advisory Board—Vertex, Genetix, Alexion. O.N. Ray Bignall: No Conflicts of Interest. Anthony Villella: Vertex endpoint adjudication committee. Susan Creary: No Conflicts of Interest. Rolla Abu‐Arja: No Conflicts of Interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.