Donor’s APOL1 Risk Genotype and “Second Hits” Associated With De Novo Collapsing Glomerulopathy in Deceased Donor Kidney Transplant Recipients: A Report of 5 Cases

Abstract

The presence of 2 APOL1 risk variants (G1/G1, G1/G2, or G2/G2) is an important predictor of focal segmental glomerulosclerosis (FSGS) and chronic kidney disease in individuals of African descent. Although recipient APOL1 genotype is not associated with allograft survival, kidneys from deceased African American donors with 2 APOL1 risk variants demonstrate shorter graft survival. We present a series of cases of presumed de novo collapsing FSGS in 5 transplanted kidneys from 3 deceased donors later identified as carrying 2 APOL1 risk alleles, including 2 recipients from the same donor whose kidneys were transplanted in 2 different institutions. Four of these recipients had viremia in the period preceding the diagnosis of collapsing FSGS. Cytomegalovirus and BK virus infection were present in 3 and 1 of our 5 cases, respectively, around the time that collapsing FSGS occurred. We discuss viral infections, including active cytomegalovirus infection, as possible "second hits" that may lead to glomerular injury and allograft failure in these recipients. Further studies to identify additional second hits are necessary to better understand the pathologic mechanisms of donor APOL1-associated kidney disease in the recipient.

APOL1 high‐risk genotypes and renal transplantation

“…A recent report, collating 38 cases of de novo cFSGS in kidney allografts, donor APOL1 high-risk genotype status was associated with significantly worse graft survival after the development of cFSGS in multivariable analyses, showing that the presence of the risk genotypes with cFSGS lesions also had prognostic importance. 30 A striking case report of a HLA-identical live donor kidney transplant involving a high-risk APOL1 donor, where both the recipient allograft and live donor developed FSGS post-transplantation further exemplifies the predilection toward this pathology. 38 In our unpublished data from the GoCAR study, 39…”

“…29 Analogously, in high-risk variant allograft kidneys, viral infections, specifically CMV and BK, were identified as second hits that led to the development of glomerular injury, and initiation of glomerular tuft collapse and FSGS. 30 APOL1 circulates in the serum on HDL molecules and is expressed nearly ubiquitously, but with especially high levels in the pancreas, prostate, spleen, liver, kidney, placenta, and lung. 31,32 The liver is the most important source of circulating APOL1 33 ; hence, in patients with risk genotypes, circulating mutant APOL1 originates in the liver.…”

“…44 This suggests risk modification by gene-gene or gene-environment interactions with high-risk genotype kidneys, that is, second hits. In transplantation, reports have postulated that obesity, smoking, proteinuria, hypertension, 38 BK viremia, CMV viremia, 30 donor, and recipient age 44 may be potential environmental exposures that serve as modifiers of risk for allograft loss.…”

Schistosoma mansoni infection as a trigger to collapsing glomerulopathy in a patient with high-risk APOL1 genotype

“…In agreement with this mechanism, transplant recipients without an HRG who received an HRG kidney developed de novo CG after cytomegalovirus or poliomavirus infection or antibody-mediated rejection. [ 17 , 18 ] Immune profile analysis of patients with SM revealed a role for the Th1, Th2, and Th17 lymphocytic subpopulations in the disease pathogenesis. Notably, the Th1 and Th2 profiles remain chronically activated throughout the disease process.…”

The effect of APOL1 risk variants on emergent outcomes in kidney disorders: A meta-analysis of individual participant data

“…Finally12 published articles were included in this study. These 12 articles included 20 case reports that were examined 20 patients at risk APOL1 genotype and renal dysfunction for qualitative and quantitative synthesis [13][14][15][16][17][18][19][20][21][22][23][24]. Eleven of twenty patients (11/20, 55%) were from Afro-American ethnicity, four of twenty patients (4/20, 20%) from the Caribbean, three of twenty patients from white ancestry (3/20, 15%) and one patient (1/20, 5%) from Asian and black race.…”