Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts

Abstract

Collapsing focal segmental glomerulosclerosis (cFSGS) in the native kidney is associated with heavy proteinuria and accelerated renal failure. However, cFSGS in the renal allograft is less well characterized. Here we report clinico-pathologic features and APOL1 donor risk genotypes in 38 patients with de novo post-kidney transplant cFSGS. Recipients were 34% female and 26% African American. Concurrent viral infections and acute vaso-occlusion (including thrombotic microangiopathy, cortical necrosis, atheroembolization, and cardiac arrest with contralateral graft thrombosis) were present in 13% and 29% of recipients, respectively. Notably, 61% of patients had concurrent acute rejection and 47% received grafts from African American donors, of which 53% carried APOL1 high-risk genotypes. These frequencies of acute rejection and grafts from African American donors were significantly higher than in our general transplant population (35% and 16%, respectively). Patients had a median serum creatinine of 5.4 mg/dl, urine protein/creatinine 3.5 g/g, and 18% had nephrotic syndrome. Graft failure occurred in 63% of patients at an average of eighteen months post-index biopsy. By univariate analysis, donor APOL1 high-risk genotypes, post-transplant time, nephrotic syndrome, and chronic histologic changes were associated with inferior graft survival while acute vaso-occlusion was associated with superior graft survival. Donor APOL1 high-risk genotypes independently predicted poor outcome. Compared to native kidney cFSGS, post-transplant cFSGS had more acute vaso-occlusion but less proteinuria. Thus, de novo cFSGS is associated with variable proteinuria and poor prognosis with potential predisposing factors of African American donor, acute rejection, viral infection and acute vaso-occlusion. Additionally, donor APOL1 high-risk genotypes are associated with higher incidence and worse graft survival.

Keywords: APOL1 genotypes; African Americans; acute rejection; acute vasoocclusion; collapsing glomerulopathy; kidney transplantation.

Figure 1:. Representative photo-micrographs of post-KTx cFSGS and accompanying histologic lesions

(A) A glomerulus showing features of cFSGS in an allograft biopsy. Note the glomerular tuft collapse and the prominence of epithelial cells (Jones’ Methenamine Silver stain; original magnification x600) (B) An allograft with cortical necrosis involving most of the low power view image and ~25% of total sampled cortex (hematoxylin and eosin, original magnification x100) (C) An allograft with thrombotic microangiopathy. The arteriole displays near occlusion of its lumen and shows segmental fibrinoid necrosis (arrows). cFSGS is seen in the adjacent glomerulus (hematoxylin and eosin stain, original magnification x400) (D) An allograft with arterial athero-emboli manifested as empty needle-shape spaces (because of the dissolving of cholesterol during preparation) that are surrounded by giant cells (arrow) (periodic acid–Schiff stain, original magnification x400) (E) An allograft with grade 1B acute T cell ediated rejection. Note the interstitial inflammation and severe tubulitis (arrow) (periodic acid–Schiff stain, original magnification x400). (F) An allograft with antibody-mediated rejection showing diffuse C4d staining in peritubular and glomerular capillaries (immunofluorescence C4d staining, original magnification x100).

Figure 2:. Comparison of demographic data in cases with post-KTx cFSGS and the general transplant population at Columbia University Medical Center

Demographic information were compared between our cohort and all patients who underwent kidney transplantation at CUMC between 2006 and 2009 including crossmatch positive and ABO-incompatible patients (n=773). Acute rejection in general transplant cohort was calculated during a follow-up of 59 ±32 months from transplantation while it was only considered at that time of index biopsy in the de novo post-KTx cFSGS cohort. (* P<0.05; for more detailed analysis, please refer to Supplemental Table 1).

Figure 3:. Graft survival in post-KTx cFSGS

(A) Kaplan–Meier curve for post-biopsy cumulative kidney allograft survival in patients with de novo post-KTx cFSGS (n=38) (B) Curves for patients who had short term partial response vs. these who had persistent dysfunction (P<0.001) (C) Curves for patients who had absence or persistence of cFSGS on follow-up biopsies are also shown (P<0.001).

Figure 4:. Allograft survival in patients stratified by donor race and APOL1 genotype

Kaplan–Meier survival curves for post-biopsy cumulative kidney allograft survival in patients stratified as receiving grafts from AA donors with APOL1 high-risk genotypes, AA donors with APOL1 low-risk genotypes, and Caucasian donors (P=0.03) AA donors/APOL1 high-risk genotypes vs. AA donors/APOL1 low-risk genotypes (P=0.029) AA donors/APOL1 high-risk genotypes vs. Caucasian donors (P=0.026) AA donors/APOL1 low-risk genotypes vs. Caucasian donors (P=0.76)