Collapsing Glomerulopathy Encountered in Time Zero Kidney Allograft Biopsies

Introduction

Collapsing glomerulopathy (CG) in the native kidney is typically associated with heavy proteinuria, rapid progression to kidney failure, and frequent presence of APOL1 kidney risk variants (KRVs).¹ In the kidney allograft, CG is rare, often occurring de novo, and has a poor prognosis.^2,3 A recent report suggested an association between CG in the kidney allograft and dose-dependent APOL1 KRVs in the donor.⁴

To our knowledge, no cases of donor-derived CG have been reported previously. Herein, we report 4 cases of donor-derived CG detected in postreperfusion biopsies (performed within 1 hour of transplantation), retrospectively retrieved from the pathology archives of 3 transplant centers (Columbia University Irving Medical Center [CUIMC], Brigham and Women’s Hospital, Wake Forest Baptist Medical Center).

A full protocol is provided in Supplementary Methods.

Results

Case-1

A 47-year-old Black male with native kidney failure attributed to hypertension received a kidney allograft from a deceased donor. The donor was a 48-year-old Hispanic male with a history of drug abuse, cigarette smoking, and hypertension, who expired from cardiac arrest. The donor’s terminal serum creatinine (sCr) was 1.2 md/dl and urinalysis showed 2+ protein (Table 1).

Table 1.

Cases of donor-derived collapsing glomerulopathy in the allograft kidney

Case	Native kidney failure	Cause of death	Donation type	Donor initial/terminal sCr (mg/dl)	Donor initial/ peak proteinuria	Donor demographics	Donor KRV# (genotype)	Recipient demographics	Recipient KRV# (genotype)	Follow-up
1	HTN	Cardiac arrest	DBD	0.8/1.2	1+/2+	48M Hispanic	2 (G1/G2) (from post-reperfusion biopsy)	47M Black	NA	Graft failure (20 months)
2	LN	CVA	DBD	1.2/1.1	>1000/>1000 mg/dl	24M Hispanic	1 (G1/G0) (from peripheral blood)	45F Black	2 (G2/G2) (from peripheral blood)	Graft failure (56 months)
3	DM	CVA	DBD	1.1/1.1	3+/N/A	58M Black	1 (G1/G0) (from peripheral blood)	76F White	NA (assumed no KRVs since recipient is White)	Functioning graft: sCr: 1.9 mg/dl (43 months)
4	DM	Cardiac arrest	DBD	1.4/1.0	50/300 mg/dl	63F Black	1 (G2/G0) (from post-reperfusion biopsy)	61M Black	2 (G1/G2) (from pathology samples of native tissue)	Functioning graft: sCr: 2.8 mg/dl (10 months)

CVA, cerebrovascular accident; DBD, donation after brain death; DM, diabetes mellitus; F, female; HTN, hypertension; KRV, APOL1 kidney-risk variant; LN, lupus nephritis; M, male; NA, not available; sCr, serum creatinine.

Details of APOL1 genotyping are presented in Supplementary material.

APOL1 genotyped from the tissue included performing genotyping for G2M1 variants p.(N264K) in samples with G2. No M1 variant was detected in donor #1, donor #4, and recipient #4.

The postreperfusion biopsy displayed focal segmental glomerulosclerosis (FSGS) with collapsing features in 4 of 27 glomeruli (Figure 1a), global glomerulosclerosis (GGS) in 4 of 27 glomeruli, mild tubulointerstitial scarring, and proximal tubules with focal prominent protein reabsorption droplets. Postoperative course was complicated by slow graft function. Fourteen weeks post-transplantation, an allograft biopsy performed because of an elevated sCr of 2.7 mg/dl, revealed FSGS with collapsing features in 5 of 19 glomeruli, 5 of 19 GGS, scattered tubular microcysts (Supplementary Figure S1A and B), severe tubulointerstitial scarring, and borderline changes suspicious for acute T-cell mediated rejection (borderline-TCMR). The latter was treated with steroids and sCr decreased to 2.3 mg/dl. Fourteen months post-transplantation, another allograft biopsy was performed for further increase of sCr to 4 mg/dl and urine protein-to-creatinine ratio (UPCR) of 3.4 g/g (first available post-transplant value). The biopsy again revealed FSGS with collapsing features in 2 of 23 glomeruli, 9 of 23 GGS, severe tubulointerstitial scarring, and proximal tubules focally engorged with protein reabsorption droplets (Supplementary Figure S1C and D). Between 14 and 18 months posttransplantation, UPCR values fluctuated between 2.6 to 6.0 g/g. Graft failure occurred 20 months post-transplantation and was attributed to CG. Donor APOL1 genotyping revealed 2 KRVs (G1/G2). Recipient genotyping could not be performed because of lack of residual material (Table 1).

Figure 1.

Glomeruli with collapsing features on postreperfusion biopsies. (a) Case 1 (periodic acid-schiff stain, original magnification, × 400). (b) Case 2 (Jones methenamine silver stain, original magnification, × 200). (c) Case 3 (Jones methenamine silver stain, original magnification, × 200). (d) Case 4 (Jones methenamine silver stain, original magnification, × 400).

Case-2

A 45-year-old Black female with native kidney failure from lupus nephritis received a kidney allograft from a deceased donor. The donor was a 24-year-old Hispanic male with a history of drug abuse, hypertension, and diabetes mellitus, who expired from a cerebrovascular accident. Donor’s terminal sCr was 1.1 mg/dl, urinalysis showed > 1000 mg/dl of protein (Table 1), and serum albumin was 2.0 g/dl.

The postreperfusion biopsy demonstrated FSGS with collapsing features in 3 of 25 glomeruli (Figure 1b) without GGS or significant tubulointerstitial scarring. Postoperatively, proteinuria peaked at 2 months (UPCR: 4.6 g/g) with sCr of 1.1 mg/dl. Nine months posttransplantation, sCr increased to 1.5 mg/dl although UPCR decreased to 0.2 g/g. An allograft biopsy revealed borderline-TCMR, noncollapsing FSGS in 3 of 12 glomeruli, 1 of 12 GGS, and mild tubulointerstitial scarring. The patient was treated with steroids. Forty-six months post-transplantation, sCr increased to 3.1 mg/dl and UPCR to 1.1 g/g. An allograft biopsy demonstrated severe T cell mediated rejection (Banff grade 2B), noncollapsing FSGS in 1 of 10 glomeruli, 3 of 10 GGS, and mild tubulointerstitial scarring. Despite treatment with thymoglobulin, graft failure occurred 4 years and 8 months post-transplantation and was attributed to noncompliance with medications. Donor APOL1 genotyping revealed 1 KRV (G1/G0). Recipient genotyping revealed 2 KRVs (G2/G2; Table 1).

Case-3

A 76-year-old White female with native kidney failure from diabetes mellitus received a kidney from a deceased donor. The donor was a 58-year-old Black male with a history of hypertension and obesity, who expired because of a cerebrovascular accident. Donor’s terminal sCr was 1.1 mg/dl and urinalysis showed 3+ protein (Table 1). Donor’s serum albumin was not available.

The postreperfusion biopsy revealed FSGS with collapsing features in 1 of 14 glomeruli (Figure 1c), 7 of 14 GGS, and mild tubulointerstitial scarring. A 1-month protocol biopsy (sCr, 1.6 mg/dl; UPCR, 0.7 g/g) demonstrated no FSGS, 2 of 15 GGS and mild tubulointerstitial scarring. At 12 months post-transplantation, sCr decreased to 1.3 mg/dl and UPCR decreased to 0.6 g/g. At 38 months post-transplantation, UPCR was elevated (3.1 g/g) but with a relatively stable Cr (1.5 mg/dl) after discontinuing therapy with angiotensin-converting enzyme inhibitor. Forty-three months post-transplantation, the patient was found to have metastatic breast carcinoma for which she did not receive specific treatment and the patient expired soon after with a functioning graft (sCr of 1.9 mg/dl, no UPCR value was available). Donor APOL1 genotyping revealed 1 KRV (G1/G0). Recipient genotyping was not performed in this White patient (Table 1).

Case-4

A 61-year-old Black male with native kidney failure from diabetes mellitus received a kidney from a deceased donor. The donor was a 63-year-old Black female with history of hypertension, smoking, and obesity, who expired from cardiac arrest. Donor’s terminal sCr was 1.0 mg/dl, urinalysis showed 300 mg/dl of protein, and serum albumin was 2.8 g/dl (Table 1).

The postreperfusion biopsy exhibited FSGS with collapsing features in 2 of 22 glomeruli (Figure 1d), 2 of 22 GGS, and mild tubulointerstitial scarring. Postoperative complications included slow graft function and ureteral stricture. An allograft biopsy performed 2 months post-transplantation for a rise in sCr from 3.3 mg/dl to 3.8 mg/dl and UPCR of 1g/g (first available post-transplant value) revealed no FSGS, 3 of 19 GGS and mild tubulointerstitial scarring. Another biopsy performed 6 months post-transplantation for persistent elevation of sCr (2.7 mg/dl with UPCR of 0.4 g/g) revealed borderline-TCMR, no FSGS, 7 of 21 GGS, and severe tubulointerstitial scarring. Ten months post-transplantation, the patient had a functioning graft with sCr of 2.8 mg/dl and UPCR of 0.2 g/g. Donor APOL1 genotyping revealed 1 KRV (G2/G0). Recipient genotyping revealed 2 KRV (G1/G2; Table 1).

At CUIMC, the frequency of CG was 2 of 3869 (0.05%) of postreperfusion biopsies performed during the study (2005–2025).

Discussion

Donor-derived glomerular pathology in the allograft kidney is infrequent.⁵ Incidental IgA deposits are the most encountered of these (up to 20% of donor kidneys), without significant impact on short-term graft survival.⁶ At CUIMC, donor-derived CG was exceptionally rare, identified in 0.05% of postreperfusion biopsies.

In the native kidney, CG often occurs in association with APOL1 KRVs and second hits, including infections, and autoimmunes disease that likely enhance secretion of proinflammatory cytokines, drugs, and acute vaso-occlusion.^7,8 All our donor-derived CG cases were found in kidneys from deceased donors who harbored at least 1 KRV, had a history of hypertension, and experienced an ischemic vascular event contributing to their death. No donor-derived CG is identified from donors with no APOL1 KRVs. These findings suggest a relationship between donor ischemia, probable cytokine secretion at death, APOL1 genotype, and CG in the kidneys from deceased donors.

The extremely low incidence is somewhat surprising, given the apparently high frequency of allograft kidneys from deceased donors with KRVs that have been subjected to significant ischemic injury, suggesting that these lesions may be localized and missed on a core biopsy. Additionally, the possibility of unknown modifiers cannot be excluded. Recipient genotyping could be performed in 2 of 3 Black recipients, both of which showed 2 KRVs. One recipient also had a history of systemic lupus erythematosus. Although recipients APOL1 KRVs and inflammatory environment could theoretically promote the development of CG, the contribution of recipient conditions to CG detected within an hour of transplantation is less likely.

In contrast to donors with 1 KRV that showed disappearance of CG on follow-up biopsies, only the allograft kidney harboring 2 KRVs demonstrated apparent persistence of CG on follow-up. This case rapidly progressed to graft failure, consistent with progressive APOL1 nephropathy. Notably, although recent literature in native and transplanted kidneys demonstrate dose-dependent effect of APOL1 KRVs^4,9 inferior graft survival is mainly observed in donors with 2 APOL1 KRVs.⁴

To our knowledge, this report provides the first description of donor-derived CG and expands the association of donor APOL1 KRVs with pathologic findings in the allograft kidney. Attention to donor-derived CG is warranted to understand the causes, prognosis, and role of donor KRVs, in this rare glomerulopathy.

Disclosure

BIF and Wake Forest University Health Sciences have rights to a US patent for APOL1 genotyping. BIF receives research support from AstraZeneca. IB is supported from Nelson Family faculty development award.

Supplementary Material

Supplementary file (PDF)

Supplementary Methods. Supplementary Reference. Figure S1. Follow-up kidney allograft biopsies from Case 1.