Association of Collapsing Glomerulopathy with Donor Apolipoprotein L1 Risk Variants in Kidney Allografts from Black Donors

Visual Abstract

Abstract

Key Points

• Kidneys from donors with two apolipoprotein L1 (APOL1) risk variants are associated with a higher risk of collapsing glomerulopathy compared with donors with no risk variants.

• Kidneys with one APOL1 risk variant are associated with intermediate risk of collapsing glomerulopathy.

• Kidneys from donors with two, but not with one, APOL1 risk variants, have inferior graft survival compared with donors with no risk variants.

Introduction

Collapsing glomerulopathy (CG) in the kidney allograft is an infrequent complication, encountered more often in recipients of kidneys from Black donors. Despite its poor prognosis, the genetic susceptibility of this complication remains incompletely understood.

Methods

We performed a retrospective study from two major North American transplant centers. We assessed 47 recipients of kidney allografts from Black donors that developed CG and were followed for a median of 2.9 years after transplantation. Donor apolipoprotein L1 (APOL1) genotypes were available in 44 patients with CG and compared with 560 recipients of kidneys from Black donors who did not develop CG.

Results

Transplant recipients with CG were 55% of Black race and 40% female, and CG developed at a median of 9.5 months post-transplantation. Donors harboring zero, one, and two APOL1 kidney-risk variants (KRVs) comprised 16%, 41%, and 43% of CG cases and 45%, 43%, and 12% of controls, respectively. Combining cases and controls, receipt of a kidney from donors with two KRVs was associated with a higher risk of CG compared with donors with zero KRVs (adjusted odds ratio=12.51 [95% confidence interval, 4.83 to 32.39], P < 0.001). Receipt of a kidney with one KRV was also associated with a higher risk of CG compared with donors with no KRVs, although with lower effect than those with two KRVs (adjusted odds ratio=3.39 [1.36 to 8.46], P = 0.009). Recipients of kidneys from donors with two KRVs, but not with one KRV, had lower graft survival when compared with donors with zero KRVs (adjusted hazard ratio=1.49 [1.03 to 2.16], P = 0.04).

Conclusions

Although the association of CG in the kidney allograft with donor APOL1 KRVs suggests possible dose-dependent effects, lower graft survival was only observed in recipients of kidneys with two KRVs. Identification of additional risk factors for CG may improve utilization of kidneys from Black donors, including these with APOL1 KRVs.

Introduction

Although collapsing glomerulopathy (CG) in kidney allografts is infrequent, it has devastating effects on graft survival.^1–4 Compared with recipients of kidneys from White donors, those who receive kidneys from Black donors have higher probability of developing CG.⁵

The gene encoding apolipoprotein L1 (APOL1) is expressed in kidney tissue, including podocytes.^6–8 The frequency of APOL1 kidney-risk variants (KRVs) in the US Black population approximates 13% with two APOL1 KRVs (G1/G1, G1/G2, G2/G2), defining “high-risk genotypes.” The remaining variants have been traditionally labeled as “low-risk genotypes,” comprising approximately 39% with one KRV (G1/G0, G2/G0) and approximately 48% with zero KRVs (G0/G0).^9,10 In vitro dose-dependent effects of APOL1 KRVs are observed,¹¹ and a study in West Africans suggests higher risk of kidney disease with one KRV.¹² However, these findings could not be confirmed in CG of the native kidney, where over 75% of CG cases are encountered in patients with two KRVs.^13–16 In contrast to the native kidneys, some reports suggest that CG in the setting of kidney transplantation may not have similar strong association with donor APOL1 high-risk genotypes^17–19; nevertheless, this has not been critically analyzed.

Although HLAs have emerged as important immunogenetic risk factors in many native kidney diseases,^20–23 their role in CG of the kidney allograft has not been systematically examined.

We hypothesized that CG in the kidney allograft has a distinct association with donor APOL1 KRVs, where the presence of even one APOL1 KRV in donors may be sufficient for the development of CG in the allografts in a subset of patients. To address this, we examined a cohort of allograft CG in recipients of kidneys from Black donors at two large North American transplant centers (Columbia University Irving Medical Center [CUIMC, New York, NY] and Wake Forest University School of Medicine [WFUSM, Winston-Salem, NC]). To test relevant genomic correlates, CG cases were compared with recipients of kidneys from Black donors who did not develop CG.

Methods

To understand the association between CG and kidney APOL1 KRVs, we performed a case-control study focusing on subsets of cohort of recipients of allografts from Black donors (workflow depicted in Figure 1). This study was performed under the approved guidelines of the institutional review boards of CUIMC and WFUSM, in accordance with the Declaration of Helsinki and Principles of the Declaration of Istanbul.

Figure 1.

Diagram of the study design. All patients included (with CG and with no CG) are recipients of kidneys from Black donors. Ags, antigens; APOL1, apolipoprotein L1; CG, collapsing glomerulopathy; CUIMC, Columbia University Irving Medical Center; PH, proportional hazard; WFUSM, Wake Forest University School of Medicine.

CG was defined according to the Columbia classification of focal segmental glomerulosclerosis,²⁴ and each case was confirmed by two kidney pathologists. Kidney transplant recipients of allografts from Black donors between 2005 and 2018 who developed CG were identified retrospectively from the electronic medical records of CUIMC and WFUSM (N=42). To increase the sample size, we included all previously identified CG cases that received kidney allografts from Black donors before 2005 (N=4; one in 2001, two in 2003, and one in 2004) and in 2019 (N=1). In total, 47 cases were included, 18 of which were published previously¹⁷ (current report with extended follow-up). WFUSM cases included only recipients of deceased donor kidneys.

Demographic, clinical, and laboratory parameters were extracted from medical records. Histologic parameters were evaluated according to the Banff criteria for kidney allograft pathology,²⁵ and acute T-cell–mediated rejection was defined by the presence of Banff grades 1A–3. Death censored graft failure was defined as re-initiation of KRT and/or retransplantation.

Controls for APOL1 KRVs and HLA Antigens

1. To determine the association of CG in the kidney allograft with donor APOL1 KRVs, donor APOL1 genotyping in CG (available in N=44) was compared with recipients of kidney allografts from Black donors between 2005 and 2018 who did not develop CG (with no kidney allograft biopsies showing CG) but had donor APOL1 genotyping (N=560, 216 from CUIMC and 344 from WFUSM). All WFUSM CG cases and controls without CG received kidneys from deceased donors (Supplemental Table 1).

2. To examine the association of CG with HLA antigens, serologic and/or molecular typing for HLA-A, HLA-B, HLA-DR, and HLA-DQ in recipients and donors of patients with CG (N=47) were compared with patients who received kidney allografts from Black donors but did not develop CG and who had HLA typing available in both recipients and donors (N=373; all from CUIMC because WFUSM patients data lacked these data; Supplemental Table 1).

Donor APOL1 Genotyping

For recipients of kidney allografts from Black donors, donor DNA was extracted from whole blood (N=481, including 27 CG [17 CUIMC, ten WFUSM] and 454 control subjects receiving kidneys from Black donors and not developing CG [110 CUIMC, 344 WFUSM]) or formalin-fixed paraffin-embedded postreperfusion biopsies or rarely from non-inflamed allograft biopsies (N=123, 17 CG and 106 non-CG; all from CUIMC; details in Supplemental Material). Donor APOL1 variants were characterized as having no KRVs (G0/G0), one KRV (G1/G0, G2/G0), or two KRVs (G1/G1, G1/G2, G2/G2).

Statistical Analysis

Statistical analysis was performed using Prism 10 (GraphPad Inc., San Diego, CA) and SPSS Statistics 29 (IBM, Armonk, NY). Semiquantitative and continuous values were presented as mean±SD and median and interquartile range (IQR, 25th and 75th percentile), respectively, and compared using the Mann–Whitney U test. Categorical variables were presented as percentages and compared using the Fisher exact test. The association between donor APOL1 KRVs and CG was evaluated using logistic regression, which was adjusted for medical sites, recipient demographics (age, sex, and Black race), donor demographics (age and sex; all donors were of Black race according to study design), and allograft source (deceased versus living). Graft survival in cases and controls was separately assessed by the Kaplan-Meier method and compared using the log rank test. Subjects were censored at graft failure, patient death, or last available serum creatinine. Multivariable Cox proportional hazards (PHs) models were used to test donor APOL1 KRVs against the outcome of time-to-graft failure after adjustment for the following variables: CG, sites, recipient and donor demographics, and allograft source. Individuals with missing data on tested variables were excluded from corresponding analyses.

Results

Demographic, Clinical, and Pathologic Features

Forty-seven kidney transplant recipients who had at least one kidney allograft biopsy with CG were identified. Recipients had a median age of 48 years and included 40% women, 55% self-identified Black, 30% with native kidney failure attributed to hypertension, and 74% who received their allograft from deceased donors (Table 1). Selection criteria required all donors to self-identify as being of Black race. The median donor age was 39 years, and 40% of the donors were female (Table 1).

Table 1.

Demographic and clinical characteristics of collapsing glomerulopathy in the kidney allograft

Characteristic	n=47
Recipient age at transplantation (yr)	48 (38–60)
Recipient sex, female (%)	19/47 (40%)
Recipient race, Black (%)	26/47 (55%)
Donor age at transplantation (yr)	39 (27–52)
Donor sex, female (%)	19/47 (40%)
Allograft source, deceased donor (%)	35/47 (74%)
Donor APOL1 KRVsa	Low-risk genotypes: 25/44 (57%)
	High-risk genotypes: 19/44 (43%)
Etiology of native kidney failure
Hypertension attributed	14/47 (30%)
GN	12/47 (25%)
FSGS	9/47 (19%)
Diabetes	8/47 (17%)
Other	4/47 (9%)
Post-transplant interval to CG (d)	284 (88–644)
Serum creatinine at biopsy (mg/dl)b	3.6 (2.6–5.7)
eGFR (ml/min per 1.73 m 2 )	17 (10–28)
eGFR <30 ml/min per 1.73 m2	37/47 (79%)
Urine protein/creatinine ratio at biopsy (g/g)c	3.4 (1.2–6.8)
Urine protein/creatinine ratio ≥3.5 g/g	22/44 (50%)
Serum albumin (g/dl)d	3.1 (2.4–3.6)
Serum albumin ≤3.5 g/dl	28/43 (65%)
Nephrotic syndrome (urine protein/creatinine ≥3.5 g/g and serum albumin ≤3.5 g/dl)e	18/44 (41%)
Potential clinical risk factors (one or more)f	28/47 (60%)
Active rejection	18/47 (38%)
	Ten TCMR
	Five AMR
	Three mixed
Viral infection	7/47 (15%; four CMV, two EBV, one SARS-CoV-2)
Acute vaso-occlusion	7/47 (15%)
Rapamycin maintenance at diagnosis	3/47 (6%)

AMR, antibody-mediated rejection; APOL1, apolipoprotein L1; CG, collapsing glomerulopathy; CMV, cytomegalovirus; EBV, Epstein-Barr virus; FSGS, focal segmental glomerulosclerosis; KRV, kidney risk variant; SARS-COV-2, severe acute respiratory syndrome coronavirus 2; TCMR, T-cell–mediated rejection.

^aApolipoprotein L1 genotypes not available in three donors.

^bThree patients were on dialysis at time of biopsy with serum creatinine 3.6, 5.2, and 3.3 mg/dl, respectively.

^cProteinuria not available in three patients. In six different patients, only a spot urine protein was available at biopsy. For statistical purposes, quantification of proteinuria <20 mg/dl (trace), 30 mg/dl (1+), 100 mg/dl (2+), 300 mg/dl (3+), or >1000 mg/dl (4+) in these patients was estimated as 0.3, 0.5, 1, 2, and 3.5 g/g, respectively.

^dSerum albumin not available in four patients.

^eData sufficient to confirm or exclude the presence of nephrotic syndrome not available for three patients.

^fFive patients had more than one risk factor: one patient had three risk factors (active rejection, acute vaso-occlusion, and rapamycin maintenance) and four patients had two risk factors, including active rejection and viremia (n=2), active rejection and rapamycin maintenance (n=1), and viremia and acute vaso-occlusion (n=1).

Allograft biopsies with CG were obtained a median of 9.5 (IQR, 2.9–21.5) months after transplantation. At the time of biopsy, the median serum creatinine was 3.6 mg/dl. The median eGFR, obtained using the 2021 non–race-based CKD Epidemiology Collaboration equation,²⁶ was 17 (10–28) ml/min per 1.73 m² and 79% had eGFR<30 ml/min per 1.73 m² at biopsy. Less than half of the patients (41%) had nephrotic syndrome. One or more of the previously identified clinical correlates for CG in the kidney allograft^17,27 were noted in 60% of these patients, the most common of which was active rejection (38%), while the least common was rapamycin maintenance (6%) (Table 1). Notably, two of three patients with CG on rapamycin had concurrent active rejection.

Donor APOL1 genotyping was available for 44 recipients with CG and included 19 (43%) with two KRVs, 18 (41%) with one KRV, and 7 (16%) with no KRVs (Figure 2A).

Figure 2.

Donor APOL1 KRVs in patients with and without CG. (A) Donor APOL1 KRVs in patients with and without CG. Donor two KRVs: 19/44 (43%) CG versus 65/560 (12%) non-CG, P < 0.001. Donor one KRV: 18/44 (41%) CG versus 242/560 (43%) non-CG, P = 0.87. Donor zero KRVs: 7/44 (16%) CG versus 253/560 (45%) non-CG, P < 0.001. (B) Association between CG and donor APOL1 KRVs in recipients of kidney allograft from Black donors. The plot describes odds ratio and CI. The analysis was adjusted for medical site, recipient demographics (age, sex, Black race), donor demographics (age, sex), and allograft source (deceased versus living). CI, confidence interval; KRV, kidney risk variant.

Five hundred and sixty recipients of kidney allograft from Black donors who did not develop CG were included as controls. These recipients had a median age of 53 years and included 44% women, 55% self-identified Black, and 83% who received their allograft from deceased donors (Supplemental Table 1). The median donor age was 42 years, and 48% of the donors were female. Donor APOL1 genotyping revealed 65 (12%) donors with two KRVs, 242 (43%) with one KRV, and 253 (45%) with no KRVs (Figure 2A).

Association with APOL1 KRVs

Among all cases and controls, logistic regression revealed that recipients of kidneys from Black donors with two APOL1 KRVs were more likely to develop CG compared with those who received kidneys with no KRVs (adjusted odds ratio [OR]=12.51 [4.83 to 32.39], P < 0.001). The presence of one KRV in donors was also associated with the development of CG (adjusted OR=3.39 [1.36 to 8.46], P = 0.009) compared with those who received kidneys with no KRVs (Figure 2B and Table 2).

Table 2.

Multivariable logistic regression analysis of collapsing glomerulopathy in the kidney allograft

Variables	Multivariable (n=604, N Events=44)
	aOR (95% CI)	P Value
Donor APOL1 KRVs
Donor 0 KRV	1 (Reference)	Reference
Donor 1 KRV	3.39 (1.36 to 8.46)	0.009
Donor 2 KRVs	12.51 (4.83 to 32.39)	<0.001
Medical site (CUIMC)	8.33 (3.52 to 19.71)	<0.001
Recipient age at transplant (per each year)	0.99 (0.96 to 1.01)	0.24
Recipient female sex	0.85 (0.43 to 1.68)	0.65
Recipient Black race	1.38 (0.64 to 3.01)	0.41
Donor age at transplant (per each year)	1.00 (0.98 to 1.03)	0.90
Donor female sex	0.93 (0.46 to 1.85)	0.83
Allograft from deceased donor	2.19 (0.84 to 5.73)	0.11
Constant	0.006	<0.001

APOL1, apolipoprotein L1; CI, confidence interval; CUIMC, Columbia University Irving Medical Center; KRV, kidney risk variant;

aOR, adjusted odds ratio.

To confirm the association of donor APOL1 KRVs with CG, we performed three additional logistic regression analyses (Supplemental Table 2). The first coded donor APOL1 KRVs under a recessive model (two KRVs versus others) and confirmed significant association of donor two KRVs with CG (adjusted OR=6.06 [3.04 to 12.09], P < 0.001). The second coded donor APOL1 KRVs under a dominant model (one or two KRVs versus zero KRV) and also confirmed significant association with CG (adjusted OR=5.43 [2.32 to 12.68], P < 0.001). The third treated donor APOL1 KRVs as an additive (dose-dependent) model (0, 1, and 2) and similarly revealed significant association of donor KRVs with CG (adjusted OR per allele=3.56 [2.23 to 5.68], P < 0.001). The additive model showed the highest goodness-of-fit as assessed by Nagelkerke R squared (0.23 for additive model, 0.21 for recessive model, and 0.19 for dominant model).

The breakdown of APOL1 genotyping in CG and non-CG controls is presented in Supplemental Figure 1. The presence of either G1 or G2 in the donor was associated with higher risk of CG (donor G1/Gx: adjusted OR=4.29 [2.12 to 8.67], P < 0.001, donor G2/Gx: adjusted OR=4.01 [1.95 to 8.24], P < 0.001; Supplemental Table 2).

Outcome

Patients who developed CG were followed for a median of 2.9 (IQR, 1.6–5.9) years post-transplantation. During follow-up, graft failure developed in 34 of 47 (72%) patients at a median of 12.9 (IQR, 3.7–58) months after CG and 28.3 (IQR, 17.4–57.9) months after transplantation.

When CG cases were grouped based on the number of donor APOL1 KRVs, no significant difference in post-transplant graft survival was observed (Figure 3A). However, significant differences were observed when patients were grouped by the presence of donor high-risk (two KRVs) versus low-risk (one or zero KRV) genotypes (hazard ratio [HR]=2.05 [0.98 to 4.31], P = 0.04; Figure 3B), and these results were also confirmed when CG was treated as time-varying covariate in Cox PH analysis (HR: 2.29 [1.12 to 4.7], P = 0.02). Notably, these effects were NS in the controls, who showed no differences in post-transplant graft survival when grouped on the basis of the number of donor APOL1 KRVs or high-risk versus low-risk genotypes (Figure 3, C and D).

Figure 3.

Death-censored allograft survival. (A) Death-censored graft survival in CG stratified by donor KRVs (P = 0.12). Donor one KRV versus zero KRVs: 1.00 (0.34–2.92), P = 0.99. Donor two KRVs versus one KRV: 1.88 (0.87–4.06), P = 0.10. Donor two KRVs versus zero KRVs: 2.07 (0.86–4.98), P = 0.14. (B) Death-censored graft survival in CG stratified by donor two KRVs versus zero or one KRVs: HR=2.05 (0.98–4.31), P = 0.04. (C) Death-censored graft survival in non-CG controls stratified by donor KRVs (P = 0.36). Donor one KRV versus zero KRVs: 0.98 (0.72–1.34), P = 0.91. Donor two KRVs versus one KRV: 1.32 (0.83–210), P = 0.21. Donor two KRVs versus zero KRVs: 1.35 (0.85–2.15), P = 0.16. (D) Death-censored graft survival in non-CG stratified by donor two KRVs versus zero or one KRVs: HR=1.34 (0.86–2.09), P = 0.15. HR, hazard ratio.

In the combined analysis adjusted for case/control studies, receiving kidneys from Black donors with two APOL1 KRVs was associated with higher risk of graft failure when compared with donors with no KRVs (adjusted HR=1.49 [1.03 to 2.16], P = 0.04), while receiving kidneys from donors with one KRV was not (Table 3). Notably, in this analysis, CG was also independently associated with poorer graft survival (adjusted HR=4.05 [2.62 to 6.28], P < 0.01). Other independent risk factors included older donor age (adjusted HR=1.02 [1.01 to 1.03], P = 0.001) and receiving allografts from deceased donors (adjusted HR=1.78 [1.05 to 3.02], P = 0.03; Table 3). These findings were robust to inclusion of CG as a time-varying covariate (Supplemental Table 3).

Table 3.

Multivariable Cox proportional hazards analysis of death censored graft survival

Variables	Multivariable (n=604), N Events=224
	aHR (95% CI)	P Value
Donor APOL1 KRVs
Donor 0 KRV	1 (Reference)	Reference
Donor 1 KRV	0.90 (0.66 to 1.21)	0.47
Donor 2 KRVs	1.49 (1.03 to 2.16)	0.04
Development of CG	4.05 (2.62 to 6.28)	<0.001
Medical site (CUIMC)	0.69 (0.48 to 0.99)	0.04
Recipient age at transplant (per each year)	0.99 (0.98 to 1.00)	0.21
Recipient female sex	1.02 (0.78 to 1.32)	0.91
Recipient Black race	1.03 (0.78 to 1.36)	0.86
Donor age at transplant (per each year)	1.02 (1.01 to 1.03)	0.001
Donor female sex	1.19 (0.91 to 1.56)	0.20
Allograft from deceased donor	1.78 (1.05 to 3.02)	0.03

aHR, adjusted hazard ratio; APOL1, apolipoprotein L1; CI, confidence interval; CG, collapsing glomerulopathy; CUIMC, Columbia University Irving Medical Center; KRV, kidney risk variant.

Finally, given the poor prognosis of CG, histologic variables associated with postbiopsy graft survival were analyzed. Cox PH multivariable analysis showed that higher Banff scores for interstitial fibrosis (0–3; adjusted HR=1.75 [1.16 to 2.62], P = 0.007) and transplant glomerulopathy (0–3; adjusted HR=3.37 [1.07 to 10.66], P = 0.04) were associated with lower graft survival (Table 4).

Table 4.

Univariable and multivariable Cox proportional hazards analyses of the association of histologic variables in collapsing glomerulopathy with postbiopsy death censored graft survival

Variables	Univariable (n=47, N Events=34)		Multivariable (n=47, N Events=34)
	HR (95% CI)	P Value	HR (95% CI)	P Value
Global glomerulosclerosis (%)	4.27 (0.61 to 29.84)	0.14
Interstitial inflammation (i0-3)	0.98 (0.69 to 1.38)	0.90
Tubulitis (t0–3)	0.86 (0.61 to 1.22)	0.40
Intimal arteritis (v0–3) a	1.48 (0.83 to 2.65)	0.19
Peritubular capillaritis (ptc0–3)	1.25 (0.89 to 1.75)	0.21
Transplant glomerulitis (g0–3)	1.46 (0.99 to 2.15)	0.05	1.15 (0.75 to 1.77)	0.52
Transplant glomerulopathy (cg0–3)	4.66 (1.49 to 14.57)	0.008	3.37 (1.07 to 10.66)	0.04
Interstitial fibrosis (ci0–3)	1.88 (1.27 to 2.79)	0.002	1.75 (1.16 to 2.62)	0.007
Tubular atrophy (ct0–3)b	1.84 (1.23 to 2.76)	0.003
Arteriosclerosis (cv0–3) a	1.27 (0.87 to 1.85)	0.22
Arteriolar hyalinosis (ah0–3)	0.98 (0.68 to 1.41)	0.91
C4d score (C4d0–3) c	1.07 (0.75 to 1.53)	0.72

aHR, adjusted hazard ratio; CI, confidence interval.

^aData on intimal arteritis and arteriosclerosis were not available for three allograft biopsies, given the limited arterial sampling.

^bFor multivariable analysis, only variables with P < 0.10 were considered. Given the colinearity, only interstitial fibrosis and not tubular atrophy was included in multivariable analysis.

^cData on C4d score were not available for four allograft biopsies.

Association with HLA Antigens

In recipients with CG, the most frequently encountered HLA antigens were A2 (38%), A30 (23%), B53 (23%), B35 (21%), DR13 (36%), DR11 (30%), DQ6 (44%), and DQ7 (37%), whereas the most frequently encountered HLA antigens in donors were A30 (26%), A2 (26%), B44 (19%), B53 (19%), DR15 (28%), DR13 (28%), DQ6 (51%), and DQ2 (40%; Supplemental Table 4). No significant differences were observed in recipient or donor HLA antigens between patients with CG compared with their counterparts who received kidney allografts from Black donors but did not develop CG (Supplemental Table 4).

Discussion

CG in the kidney allograft is an infrequently encountered and poorly understood lesion, that is associated with poor graft survival. The current report represents the largest collection of cases of CG in allografts from Black donors genotyped for APOL1 KRVs.

APOL1 is expressed in the kidney, including podocytes^6–8 and APOL1 KRVs typically exhibit kidney disease risk effects under an autosomal recessive model.⁷ Although an in vitro study revealed dose-dependent toxic effects of APOL1 KRVs¹¹ and a recent large study demonstrated modestly higher odds of having CKD and biopsy-proven focal segmental glomerulosclerosis in West Africans with one KRV compared with those without KRV,¹² most studies demonstrate association of CG in native kidneys with two KRVs but not one KRV. For example, more than 75% of Black patients with CG developing in the settings of HIV-associated nephropathy,¹³ coronavirus disease 2019,^14,15 or IFN treatment¹⁶ possess APOL1 high-risk genotypes (two KRVs). Nevertheless, cases of CG in the kidney allograft have been described in recipients of kidneys with one APOL1 KRV.^17–19 This led us to hypothesize that, in contrast to the native kidney, the kidney allograft may represent a unique situation in which APOL1 KRVs exhibit a more apparent dosage effect (additive model for risk). This could be explained by the presence of fewer functioning nephrons in the kidney allograft and exposure to multiple types of toxic and immunologic insults.

The present report demonstrates that most CG cases were encountered in recipients of kidneys from donors with two (43%) or one APOL1 KRVs (41%). As expected, the presence of two KRVs was strongly associated with higher risk of developing CG compared with donors with no KRVs (adjusted OR=12.51, P < 0.001). However, the presence of only one KRV was also associated with higher risk of CG, although with a lower OR (adjusted OR=3.39, P = 0.009). Together, these findings provide initial support for the concept of dose effects of donor APOL1 KRVs that can predispose the kidney allograft to the development of CG.

Only a minority of CG cases were encountered in donors with no KRVs (16%). This finding is not surprising. In the native kidney, a small proportion of CG is encountered in patients of European ancestry,²⁸ who are very unlikely to carry APOL1 KRVs.¹⁰ Similarly, in the transplant settings, we reported that CG can be encountered in recipients of kidneys from White donors¹⁷ but at significantly lower frequency than among those receiving kidneys from Black donors.⁵

In line with previous observations showing an association of donor APOL1 high-risk genotypes (two KRVs) with worse graft survival,²⁹ our data revealed that recipients of kidneys from donors with two KRVs, but not with one KRV, had lower graft survival when compared with donors with no KRVs. However, our data also demonstrated that CG was an independent risk factor for graft failure. Further analyses showed that patients with CG who received kidneys with two KRVs had worse graft survival than those who received kidneys with zero or one KRVs. However, in contrast to patients with CG, recipients of kidneys with two KRVs who did not develop CG had comparable graft survival with those who received kidneys with one or zero KRVs. Although the sample size is relatively small, our findings suggest that early graft failure risk for allografts with two KRVs is largely attributable to CG.

Regarding other potential immunogenomic contributors, HLA antigens have emerged as important risk factors in several glomerular diseases.^20–23 However, this report revealed that the frequency of the commonly encountered HLA antigens in recipients and donors with CG was similar to controls who did not develop CG.

The findings in this report are subject to several limitations, including its retrospective nature, relatively small sample size, and inability to correct for variable proportions of African admixture of kidney donors. Although we may have overestimated the risk for donors with one KRV due to our case-control sampling, the additive model of inheritance of KRVs demonstrated higher goodness-of-fit than recessive or dominant models of inheritance, providing additional support for our hypothesis. Another limitation is the lack of recipient APOL1 KRVs. Studies reported conflicting results regarding the association of recipient APOL1 high-risk genotypes and increased risk of graft failure.^30–32 Furthermore, this study necessitated pooling data across two large academic centers, and this might have introduced some heterogeneity by site for the observed associations. For example, we had higher ratio of CG cases to controls at CUIMC, which is likely due to missing APOL1 genotype data in a larger subset of controls. To control for site-specific effects, including differences in treatments, exposures, and site-specific data missingness patterns, adjustments for medical sites were included in all our multivariable analyses.

In summary, this report describes the largest cohort of CG in the kidney allograft and addresses the role of donor KRVs in this complication. Among recipients of kidneys from Black donors genotyped for APOL1, the presence of two KRVs was associated with high risk of developing CG and higher risk of graft failure compared with those with no KRVs. The presence of one KRV in donors was also associated with risk for developing CG compared with those with no KRVs but had no significant effect on graft survival. Future studies may benefit from focusing on larger genetically characterized cohorts that account for the interplay between donor and recipient APOL1 KRVs. Such studies would have the potential to improve utilization of kidneys from Black donors.

Supplementary Material

cjasn-20-1268-s001.pdf ^{(1.6MB, pdf)}

cjasn-20-1268-s002.pdf ^{(265.3KB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C330.

Funding

I. Batal: Nelson Family Foundation. B.I. Freedman: National Institutes of Health (R01-MD009055). K. Kiryluk: National Institutes of Health (R01-DK136765). L. Liu: National Institutes of Health (K01-DK137031).

Author Contributions

Conceptualization: Ibrahim Batal, Vivette D. D’Agati, Barry I. Freedman, Kevin L. Gardner, Syed A. Husain, Krzysztof Kiryluk, Alejandra M. Mena Gutierrez, Alexei V. Mikhailov, Simone Sanna-Cherchi, Francesca Zanoni.

Data curation: Ibrahim Batal, Lanny T. DiFranza, Barry I. Freedman, Syed A. Husain, Satoru Kudose, Tze Y. Lim, Lili Liu, Glen S. Markowitz, Alejandra M. Mena Gutierrez, Alexei V. Mikhailov, Sumit Mohan, Rachel A. Nuccitelli, Lloyd E. Ratner, Dominick Santoriello, Miroslav Sekulic, Michael B. Stokes, Elena-Rodica Vasilescu, Francesca Zanoni.

Funding acquisition: Ibrahim Batal.

Supervision: Ibrahim Batal, Barry I. Freedman, Kevin L. Gardner, Krzysztof Kiryluk.

Writing – original draft: Ibrahim Batal.

Writing – review & editing: Vivette D. D’Agati, Lanny T. DiFranza, Barry I. Freedman, Syed A. Husain, Krzysztof Kiryluk, Satoru Kudose, Tze Y. Lim, Lili Liu, Glen S. Markowitz, Alejandra M. Mena Gutierrez, Alexei V. Mikhailov, Sumit Mohan, Rachel A. Nuccitelli, Lloyd E. Ratner, Simone Sanna-Cherchi, Dominick Santoriello, Miroslav Sekulic, Michael B. Stokes, Elena-Rodica Vasilescu, Francesca Zanoni.

Data Availability Statements

Original data generated for the study will be made available upon reasonable request to the corresponding author. Observational Data. Protected Health Information.

Supplemental Material

This article contains the following supplemental material online at http://links.lww.com/CJN/C331.

Supplemental Methods

Supplemental Figure 1. Detailed donor APOL1 genotyping in patients with and without CG.

Supplemental Table 1. Demographic data on recipients of kidney allografts from Black donors who did not develop CG in comparison with cases with CG.

Supplemental Table 2. Multivariable logistic regression analyses of CG in the kidney allograft using different models of KRVs.

Supplemental Table 3. Multivariable Cox PH analysis of death censored graft survival.

Supplemental Table 4. Frequency of HLA antigens in patients with CG and patients who received kidney allografts from Black donors but did not develop CG.

Supplemental References