Abstract
Rationale & Objective:
Some living donor kidneys are found to have biopsy evidence of chronic scarring and/or glomerular disease at implantation, but it is unclear if these biopsy findings help predict donor kidney recovery or allograft outcomes. Our objective was to identify the prevalence of chronic histological changes and glomerular disease in donor kidneys, and their association with donor and recipient outcomes.
Study Design:
Retrospective cohort study.
Setting & Participants:
Single center, living donor kidney transplants from January 2010 to July 2022.
Exposures:
chronic histological changes, glomerular disease in donor kidney implantation biopsies.
Outcomes:
(a) for donors, single kidney eGFR increase, percent total eGFR loss, ≥40% eGFR decline from pre-donation baseline, eGFR<60ml/min/1.73m2 at 6-months post-donation; (b) for recipients, death-censored allograft survival.
Analytical Approach:
Biopsies were classified as having possible glomerular disease by pathologist diagnosis or chronic changes based on the percentage of glomerulosclerosis, interstitial fibrosis/tubular atrophy, and vascular disease. We used logistic regression to identify factors associated with the presence of chronic changes, linear regression to identify the association between chronic changes and single-kidney estimated glomerular filtration rate (eGFR) recovery, and time-to-event analyses to identify the relationship between abnormal biopsy findings and allograft outcomes.
Results:
Among 1104 living donor kidneys, 155 (14%) had advanced chronic changes on implantation biopsy, and 12 (1%) had findings suggestive of possible donor glomerular disease. Adjusted logistic regression showed that age (OR 2.44 per 10 years, 95%CI 1.98–3.01), Hispanic ethnicity (OR 1.87, 95%CI 1.15–3.05), and hypertension (OR 1.92, 95%CI 1.01–3.64), were associated with a higher odds of chronic changes on implantation biopsy. Adjusted linear regression showed no association of advanced chronic changes with single-kidney eGFR increase or relative risk of eGFR <60 ml/min/1.73m2. There were no differences in time-to-death-censored allograft failure in unadjusted or adjusted Cox proportional hazards models when comparing kidneys with chronic changes to kidneys without histological abnormalities.
Limitations:
Retrospective, absence of measured GFR.
Conclusion:
Approximately 1 in 7 living donor kidneys had chronic changes on implantation biopsy, primarily in the form of moderate vascular disease, and 1% had possible donor glomerular disease. Abnormal implantation biopsy findings were not significantly associated with 6-month donor eGFR outcomes or allograft survival.
Keywords: kidney biopsy, glomerulosclerosis, kidney donor, nephrosclerosis, hypertension
Plain Language Summary
Kidney biopsies are the gold standard test to identify the presence or absence of kidney disease. However, kidneys donated by healthy living donors—who are extensively screened for any evidence of kidney disease before donation—occasionally show findings that might be considered “abnormal”, including the presence of scarring in the kidney or findings suggestive of a primary kidney disease. We studied the frequency of abnormal” kidney biopsy findings among living donors at our center. We found that about 14% of kidneys had chronic abnormalities and 1% had findings suggesting possible glomerular kidney disease, but the presence of abnormal biopsy findings was not associated with worse outcomes for the donors or their recipients.
Introduction
Kidney transplantation is the treatment of choice for end-stage kidney disease (ESKD), with living donor transplantation providing the best outcomes.1,2 Given that living kidney donors have a small but significant increase in lifetime risk of ESKD following donation, a rigorous pre-donation evaluation aims to identify risk factors for kidney disease.3,4 Despite this extensive pre-donation workup and risk factor optimization, some donors are discovered to have chronic renal parenchymal scarring5 and others primary glomerular disease6 on biopsies performed at the time of allograft implantation. Prior investigations have demonstrated that chronic changes found on these biopsies are typically age-related and not associated with donor kidney function at the time of donation.7 However, the post-donation impact of these chronic changes for donors is less clear given the accompanying reduction in renal reserve, with mixed results of prior studies.8–11
We sought to identify the prevalence of chronic changes and possible glomerular disease in a large, diverse cohort of living kidney donors who were screened for evidence of kidney dysfunction prior to donation, to identify factors associated with the presence of chronic changes, and to describe the association of these findings with donor and recipient outcomes.
Methods
We conducted a retrospective cohort study of living donor kidney transplants at our center. We identified all living donor transplants performed from 01/01/2010–07/31/2022 (n=1295), then excluded 129 with no implantation biopsy performed (Figure S1). Of the remaining 1166, we excluded 52 that sampled ≤10 glomeruli and 10 in which there was no assessment of the tubulointerstitium or blood vessels reported, yielding a cohort of 1104 living donor kidneys with adequate implantation biopsies for analyses of the prevalence of biopsy abnormalities.
For analyses of living donor outcomes, we further excluded 300 donors that did not have a follow-up serum creatinine level 6 months post-donation, yielding a cohort of 804 donors (Figure S1).
Three of 1104 included transplants were missing all recipient follow-up data; these were excluded from recipient outcomes analyses.
Implantation Biopsies
At our center, implantation biopsies are routinely performed on transplanted kidneys following allograft reperfusion (Item S1). Biopsies were scored based on retrospective review of the biopsy interpretation report (Tables S1–S4). Percent glomerulosclerosis (GS) was calculated as the number of globally sclerotic glomeruli divided by the total number of glomeruli observed. GS was scored from 0–2: 0: GS 0%; 1: GS >0% and ≤25%; 2: GS>25%. Interstitial fibrosis and tubular atrophy (IFTA) were scored from 0–3: <5%; 1: 5%–25%; 2: 26%–50%; 3: >50%”; one kidney whose IFTA was qualitatively described as “moderate” was scored 2. Vascular disease (VD) was based on characterization of arteriosclerosis and was scored from 0–3: 0: “none”/“minimal”; 1: “mild”; 2: “moderate”; 3: “severe.” Biopsies were defined as having chronic changes if they had score≥2 on either GS, IFTA, and/or VD. Evidence of donor-derived glomerular disease was included as described in the biopsy report.
Donor and Recipient Characteristics
Donor and recipient characteristics were obtained from the medical record (Item S1).
Outcomes
For living donors, our primary donor outcome of interest was single-kidney eGFR increase at 6 months, calculated as [(eGFR6 months post-donation) – (eGFRpre-donation/2)]. Although this outcome was previously validated at 3 months post-donation as a surrogate for long-term outcomes,12 our center does not routinely check 3-month post-donation creatinine values as we attempt follow up at 6, 12, and 24 months post-transplant per Organ Procurement and Transplantation Network policy. A secondary outcome of percent total eGFR loss at 6 months was defined as [(eGFRpredonation - eGFR6 months post-donation) x 100] /[eGFRpre-donation]. Estimated glomerular filtration rate (eGFR) pre-donation and 6 months post-donation were retrospectively calculated using the CKD-EPI 2021 equation.
End of follow-up was March 15, 2023. Long-term outcomes for living donors in this cohort were not studied due to high loss to follow-up.
Statistical Analysis
Kidneys were classified into 3 mutually exclusive groups based on the presence of implantation biopsy findings as determined above: 1) No Abnormalities, 2) Chronic Changes, or 3) Possible Donor Glomerular Disease. One who met the criteria for both the chronic changes and donor glomerular disease groups was classified in the donor glomerular disease group. Descriptive statistics were used to compare donor pre-donation characteristics by group, including chi-squared tests for categorical variables and Kruskal-Wallis tests for continuous variables.
We next attempted to identify factors associated with the presence of chronic changes , excluding kidneys with glomerular disease. Model variables were determined a priori based on clinical significance: age, sex, race, weight, height, smoking history (any versus none), pre-donation urine microalbumin-to-creatinine ratio (>30 mg/g vs <30mg/g), microhematuria (present versus absent), family history of ESKD (present versus absent), and pre-donation hypertension (present versus absent). First, unadjusted models were computed for each variable. Then, we performed stepwise forward selection using a p-value threshold of 0.10 to compute an adjusted logistic regression model. No logistic regression models were calculated to determine donor factors associated with the presence of glomerular disease given the small number of kidneys in this group.
Next, we aimed to study the association between abnormal implantation biopsy findings and donor eGFR. We performed linear regression with single-kidney eGFR increase as the outcome: we first conducted unadjusted linear regression with biopsy finding group as the independent variable, then computed an adjusted model accounting for donor characteristics. Given the small number of donors in the possible glomerular disease group, these donors were excluded from adjusted analyses. Adjusted model variables were determined a priori based on clinical significance: age, sex, race, weight, height, smoking history, pre-donation eGFR, pre-donation urine microalbumin-to-creatinine ratio, microhematuria, family history of ESKD, and pre-donation hypertension. We then repeated these analyses instead calculating unadjusted and adjusted relative risk of secondary outcomes of ≥40% eGFR decline from pre-donation baseline at 6 months and 6-month post-donation eGFR<60ml/min/1.73m2 using Poisson regression with robust error variance; logistic regression was not used due to the high frequency of each of these outcomes.
Finally, we used time-to-event analyses to determine the association between chronic changes on implantation biopsy and recipient outcomes. We computed an unadjusted Cox proportional hazards model for death-censored graft failure, then computed an adjusted accounting for donor characteristics (age, sex, pre-donation eGFR, height, weight, hypertension), recipient characteristics (age, sex, height, weight, diabetes, prior organ transplant, pre-emptive transplant), and number of human leukocyte antigen mismatches. Given the small number of transplants using kidneys from donors with possible glomerular disease, these transplants were excluded from adjusted analyses.
Given a paradoxical association observed between higher donor eGFR and higher odds of chronic changes on a priori analyses, we then performed post-hoc sensitivity analyses in which we assessed donor and recipient outcomes models above using a restricted cohort of donors with pre-donation eGFR≥105 ml/min/1.73m2 (the median value). We also used stepwise forward selection with a p-value threshold of 0.1 to compute a linear regression model to assess the association between chronic changes and 6-month post-transplant recipient eGFR, excluding transplants using kidneys with possible donor glomerular disease.
Statistical significance was defined as a two-sided alpha<0.05. All analyses were performed using Stata/MP 17 (College Station, Texas).
Results
Among 1104 living donor kidneys included in the analysis (Figure S1), 155 (14%) had chronic changes on implantation biopsy and 12 (1%) had findings suggestive of possible donor glomerular disease, whereas 937 (85%) had no histologic abnormalities (Table 1). Most classifications of chronic changes were attributable to moderate/severe arteriosclerosis (Tables S1–S4). Of 12 biopsies showing possible donor glomerular disease, 8 showed IgA nephropathy.
Table 1.
Characteristics of living kidney donors in the study cohort, by implantation biopsy findings
| All | No histologic abnormalities | Chronic changes | Possible glomerular disease | |
|---|---|---|---|---|
| n | 1104 (100%) | 937 (85%) | 155 (14%) | 12 (1%) |
| Characteristics at time of donation | ||||
| Age | 44 (33–54) | 42 (32–52) | 55 (47–61) | 37 (33–49) |
| Female | 456 (41) | 398 (42) | 53 (34) | 5 (42) |
| Race/ethnicity | ||||
| Asian | 79 (7) | 67 (7) | 10 (6) | 2 (17) |
| Black, non-Hispanic | 132 (12) | 116 (12) | 14 (9) | 2 (17) |
| Hispanic/Latino | 220 (20) | 183 (20) | 34 (22) | 3 (25) |
| White, non-Hispanic | 660 (60) | 560 (60) | 95 (61) | 5 (42) |
| Other | 13 (1) | 11 (1) | 2 (1) | 0 (0) |
| Smoking | ||||
| Current | 102 (9) | 91 (10) | 11 (7) | 0 (0) |
| Former | 285 (26) | 233 (25) | 48 (31) | 4 (33) |
| Never | 717 (65) | 613 (65) | 96 (62) | 8 (67) |
| Height, cm | 168 (162–175) | 168 (162–175) | 168 (160–175) | 169 (163–177) |
| Weight, kg | 77 (65–87) | 77 (65–88) | 75 (64–87) | 71 (58–88) |
| Body mass index, kg/m2 | 26.6 (23.8–30.1) | 26.6 (23.9–30.1) | 26.3 (23.3–30.0) | 24.3 (22.8–29.5) |
| Hypertension | 58 (5) | 37 (4) | 20 (13) | 1 (8) |
| Family history of ESKD | 646 (59) | 556 (59) | 78 (50) | 12 (100) |
| Pre-donation laboratory testing | ||||
| Serum creatinine, mg/dL | 0.82 (0.71–0.94) | 0.83 (0.72–0.95) | 0.79 (0.70–0.89) | 0.81 (0.73–0.88) |
| Timed creatinine clearance, ml/mina | 130 (112–157) | 133 (115–159) | 121 (101–144) | 128 (120–158) |
| Pre-donation eGFR, ml/min/1.73m2 | 105 (91–118) | 105 (91–119) | 102 (90–111) | 111 (97–120) |
| Urinary albumin:creatinine >30 mg/g | 104 (9) | 97 (10) | 7 (5) | 0 (0) |
| Microhematuria (>3 RBC/hpf) | 82 (7) | 64 (7) | 17 (11) | 1 (8) |
| 6 month post-donation laboratory testing b | ||||
| eGFR, ml/min/1.73m2 | 64 (55–75) | 65 (56–76) | 60 (52–70) | 63 (58–74) |
| eGFR<60 ml/min/1.73m2 | 300 (37) | 235 (35) | 61 (50) | 4 (36) |
| Single-kidney eGFR increase, ml/min/1.73m2 | 13 (7–20) | 13 (8–20) | 11 (5–18) | 8 (5–18) |
| Percent reduction in total eGFR, % | 37 (31–43) | 37 (30–43) | 38 (32–45) | 42 (34–44) |
| >40% reduction in total eGFR | 311 (39) | 252 (38) | 53 (43) | 6 (55) |
All figures expressed as n(%) or median (IQR).
Abbreviations: ESKD, end-stage kidney disease; eGFR, estimated glomerular filtration rate; RBC, red blood cell
missing 480 donors
among 804 donors with 6 month follow up
Pre-donation characteristics were similar between groups other than age (no histologic abnormalities: median 42 years, chronic changes: 55, possible glomerular disease: 37, p<0.001), hypertension (4% vs 13% vs 8%, p<0.001), and family history of ESKD (59% vs 50% vs 100%, p=0.001). Pre-donation laboratory testing also demonstrated significant differences in pre-donation eGFR (no histologic abnormalities: median 105 ml/min/1.73m2, chronic changes: 102, possible glomerular disease: 111, p=0.03) and urinary albumin:creatinine ratio >30mg/g (1% vs 5% vs 0%, p=0.04).
Factors Associated with Abnormal Implantation Biopsy Findings
In unadjusted logistic regression models assessing donor factors associated with chronic changes on implantation biopsy (excluding donors with possible glomerular disease), older age and hypertension were each associated with higher odds of chronic changes, whereas family history of ESKD, urinary albumin:creatinine ratio >30 mg/g, and higher pre-donation eGFR were each associated with lower odds of chronic changes (Table 2). Adjusted logistic regression showed that age (OR 2.40 per 10 year increase, 95%CI 1.97–2.92, p<0.001), Hispanic ethnicity (ref: White, non-Hispanic, OR 1.70, 95%CI 1.08–2.69, p=0.01), and eGFR at donation (OR 1.17 per 10 min/min/1.73m2 increase, 95%CI 1.02–1.33, p=0.02) were each associated with higher odds of chronic changes on implantation biopsy (Table 2).
Table 2.
Logistic regression model of factors associated with chronic changes among 1,092 donors without evidence of glomerular disease
| Unadjusted | Adjusted | |||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p | OR | 95% CI | p | |
| Age (per 10 years) | 2.15 | 1.83–2.54 | <0.001 | 2.40 | 1.97–2.92 | <0.001 |
| Female sex | 1.42 | 0.99–1.03 | 0.05 | ‐‐ | ||
| Race/ethnicity (ref: White, non-Hispanic) | ||||||
| Black, non-Hispanic | 0.71 | 0.39–1.29 | 0.3 | ‐‐ | ||
| Hispanic | 1.1 | 0.72–1.68 | 0.7 | 1.70 | 1.08–2.69 | 0.02 |
| Asian/Other | 0.91 | 0.48–1.73 | 0.8 | ‐‐ | ||
| Smoking history | 1.16 | 0.82–1.65 | 0.4 | |||
| Hypertension | 3.60 | 2.03–6.39 | <0.001 | 1.81 | 0.97–3.39 | 0.06 |
| Height | 1.00 | 0.98–1.01 | 0.4 | ‐‐ | ||
| Weight | 1.00 | 0.98–1.01 | 0.4 | ‐‐ | ||
| Family history of ESKD | 0.69 | 0.49–0.98 | 0.04 | ‐‐ | ||
| Microhematuria | 1.68 | 0.96–2.95 | 0.07 | ‐‐ | ||
| Urinary albumin:creatinine >30 mg/g | 0.41 | 0.19–0.90 | 0.03 | 0.44 | 0.19–0.99 | 0.05 |
| Estimated GFR (per 10 ml/min/1.73m2) | 0.87 | 0.79–0.96 | 0.006 | 1.17 | 1.02–1.33 | 0.02 |
Abbreviations: ESKD, end-stage kidney disease; GFR, glomerular filtration rate; OR, odds ratio; CI, confidence interval
Adjusted model was computed using stepwise forward selection and includes all variables with effect sizes presented in the table.
Detailed descriptions of characteristics of donors with possible donor glomerular disease are presented in Table 3. Notably, all these donors had a family history of ESKD, 75% had a family member with glomerular disease, 25% had at least one urinalysis with microhematuria, and none had pre-donation urinary microalbumin:creatinine >30mg/g.
Table 3.
Summary of donors with possible glomerular disease on implantation biopsy
| Donor Number | Donor Diagnosisa | Family History of ESKD | Pre-transplant Donor or Recipient Genetic Testing | Predonation Creatinine (mg/dL) | Predonation MALB/Crb (mg/g) | Predonat ion UA | Months between donation and most recent follow-up | Most recent serum creatinine (mg/dL) | Hyperten sion at most recent follow-up? | Renal Complications | Pertinent Immunofluorescence Staining at Implantation Biopsy |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | IgA Nephropathy | Half Sibling: Hereditary nephritis | Yes-Recipient-negative for X-linked Alport’s | 0.70 | n/c | 1/1 Negative | 24 | 0.97 | no | none | Granular segmental mesangial straining for IgA (2–3+), kappa (1–2+), and lambda (2+) |
| 2c | IgA Nephropathy | Sibling: Membranous nephropathy | no | 0.73 | 4 | 1/4 with ≥3 RBC/hpf | n/a | 1.18 | n/a | none | Segmental mesangial staining for IgA (trace), kappa (trace to 1+) and tubules for IgA (1+) |
| 3 | IgA Nephropathy | Sibling: DM nephropathy | no | 0.73 | n/c | 1/4 with ≥3 RBC/hpf | 23 | 1.06 | no | none | Granular segmental mesangial staining for IgA (1–2+), lambda (trace to 1+) and kappa (trace) |
| 4 | IgA Nephropathy | Sibling: IgA Nephropathy | no | 1.08 | 15 | 2/2 Negative | 5 | 1.44 | no | none | Granular global mesangial staining for IgA (1–2+), kappa (1+), lambda (2+) and tubules for IgA (3+) |
| 5 | IgA Nephropathy | Sibling: IgA Nephropathy | no | 0.91 | n/c | 3/3 Negative | 5 | 1.42 | no | none | Granular segmental to global mesangial staining for IgA (23+), kappa (1+), and lambda (1+) |
| 6 | IgA Nephropathy | Parent and Grandparents : HTN and DM nephropathy | no | 0.69 | 1 | 4/4 Negative | 10 | 1.20 | no | none | Granular segmental mesangial staining for IgA (1+), kappa (trace), and lambda (trace) |
| 7 | IgA Nephropathy | Sibling: IgA Nephropathy | no | 0.87 | 2 | 5/5 Negative | n/a | n/a | no | none | Granular segmental mesangial staining for IgA (1–2+), kappa (trace to 1+), and lambda (trace to 1+) |
| 8 | IgA Nephropathy | Sibling: IgA Nephropathy | no | 0.75 | 3 | 2/2 Negative | 22 | 0.94 | no | none | Granular segmental to global mesangial staining for IgA (1+), kappa (trace), lambda (trace) and tubules for IgA (trace) |
| 9 | Fibrillary GN | Parent: Fibrillary GN | Yes-Recipient negative | 0.88 | 20 | 3/4 with ≥3 RBC/hpf | 33 | 1.37 | no | MALB/Cr ratio 327 mg/g at 33 months postdonation | Confluent mesangial and segmental glomerular capillary wall staining for IgG (2+), C3 (1+), C1 (1+), kappa (2+), and lambda (2+) |
| 10 | Membranous Nephropathy | Parent: Lupus nephritis | no | 0.87 | 5 | 3/3 Negative | 10 | 1.21 | no | none | Granular global glomerular capillary wall deposits staining for IgG (1+), C4d (1+), kappa (1+), and lambda (1+) |
| 11 | Immune Complex Mediated | Child: CAKUT | no | 0.84 | n/c | 2/2 Negative | 15 | 1.33 | no | none | Granular mesangial staining for IgG (2+), IgM (trace to 1+), C3 (1+), C1 (2+), kappa (1–2+), and lambda (1–2+) |
| 12 | Immune Complex Mediated | Child: Denys-Drash Syndrome | no | 0.77 | 3 | 5/5 Negative | 25 | 0.94 | no | none | Granular mesangial staining for IgG (trace to 1+), IgM (1–2+), C3 (trace), C1 (trace), kappa (1+), lambda (trace to 1+) |
All donors with IgA nephropathy had at least 1+ staining on immunofluorescence IgA staining. None had significant mesangial, endocapillary or extracapillary proliferation.
n/c= not calculable due to urine albumin below lab limit of detection.
This donor also met criteria for the chronic changes on implantation biopsy
Abbreviations: HTN, hypertension; DM, diabetes mellitus; CAKUT, congenital anomalies of the kidney and urinary tract; GN, glomerulonephritis; RBC, red blood cell
Association between Abnormal Implantation Biopsy Findings and Post-Donation Kidney Function
Characteristics of donors included versus excluded from analyses of 6-month post-donation outcomes are presented in Table S2. Among the 804 donors with 6-month follow-up labs available, median eGFR at 6 months post-donation was 65 ml/min/1.73m2 for donors with no histologic abnormalities (n=670), 60 for donors with chronic changes (n=124), and 63 for donors with possible glomerular disease (n=11) (p=0.004) (Table 1). Median single-kidney eGFR increase for each group was 13, 11, and 8 ml/min/1.73m2, respectively (Table 1, Figure 1A). There was a negative correlation between donor age and single-kidney eGFR increase for each group (Figure 1B).
Figure 1.
Single kidney increase in estimated glomerular filtration rate at 6 months following living kidney donation (A) and association between donor age single kidney increase in estimated glomerular filtrate rate at 6 months (B), by implantation biopsy findings. Lines in Panel B represent lines of best fit for each group, and shaded areas represent 95% confidence intervals.
Adjusted linear regression showed no association of chronic changes (β=0.72, 95%CI −1.36 – 2.80, p=0.5) with single-kidney eGFR increase (Table 4), nor with relative risk of total eGFR loss >40% or eGFR<60 ml/min/1.73m2 at 6 months after donation (Table 4).
Table 4.
Association between abnormal implantation biopsy findings and donor outcomes 6 months after living kidney donation
| Unadjusted | Adjusted* | |
|---|---|---|
| Outcome: Single-kidney eGFR increase (Ref: No histologic abnormalities) | ||
| Chronic changes | β = −2.3 (−4.41 to −0.20) P = 0.03 | β = 0.72 (−1.36 to 2.80) P = 0.5 |
| Possible glomerular disease | β = −4.23 (10.76 to 2.29) P = 0.2 | excluded |
| Outcome: Total eGFR loss >40% (Ref: No histologic abnormalities) | ||
| Chronic changes | RR = 1.17 (0.93 to 1.46) P = 0.2 | RR = 0.91 (0.72 to 1.15); P = 0.5 |
| Possible glomerular disease | RR = 1.45 (0.84 to 2.51) P = 0.2 | excluded |
| Outcome: 6-month eGFR <60 ml/min/1.73m2 (Ref: No histologic abnormalities) | ||
| Chronic changes | RR = 1.41 (1.15 to 1.74) P = 0.001 | RR = 1.15 (0.96 to 1.38) P = 0.1 |
| Possible glomerular disease | RR = 1.04 (0.47–2.28) P = 0.9 | excluded |
Values in parentheses are 95% CI.
Abbreviations: eGFR, estimated glomerular filtration rate; RR, relative risk; CI, confidence interval
a) Adjusted for age, sex, race, height, weight, smoking, hypertension, family history of end-stage kidney disease, albuminuria, microhematuria, pre-donation estimated glomerular filtration rate
We next conducted sensitivity analyses restricted to donors with pre-donation eGFR≥105 ml/min/1.73m2. Among 399 donors included in the donor outcomes analyses who met this threshold, there was no significant association between chronic changes on implantation biopsy and any donor outcome (Table S3).
Association between Abnormal Implantation Biopsy Findings and Allograft Outcomes
Three of the 1104 transplants included in the primary analysis were missing recipient follow-up data, including 2 using kidneys with no histologic abnormalities and 1 a kidney with chronic changes. Recipient characteristics of the remaining 1101 transplants are presented in Table S4, and were similar except for age, biological relationship to donor, and human leukocyte antigen (HLA) mismatches.
Over a median of 4.6 years (IRQ 2.5–7.5) follow-up, there were 88 graft failures (8%), that included 79 (8%) among transplants with kidneys without histologic abnormalities, 8 (5%) among those with chronic changes, and 1 (8%) among those with possible donor glomerular disease (Figure 2). There were no differences in time to death-censored graft failure in unadjusted or adjusted Cox proportional hazards models (chronic changes: adjusted HR 0.83, 95%CI 0.39–1.78, p=0.6) (Table S5).
Figure 2.
Death-censored graft failure of 1101 transplants with recipient follow up available, by biopsy implantation finding group
In a sensitivity analysis restricted to 547 included transplants using kidneys from donors with eGFR≥105 ml/min/1.73m2, there was no association between chronic changes on implantation biopsy and death-censored graft failure (Table S6). Of these transplants, 533 had 6-month recipient creatinine values available. Median 6-month post-transplant eGFR was 62 ml/min/1.73m2 (IQR 51–76) for recipients of kidneys with no histologic abnormalities, 52 (42–66) for recipients of kidneys with chronic changes, and 72 (39–106) for recipients of kidneys with possible donor glomerular disease (p<0.001). In unadjusted linear regression, chronic changes were associated with lower 6-month post-transplant eGFR (ref: no histologic changes; β −10.32, 95%CI −16.38 – −4.25, p=0.001). However, this relationship was no longer significant after accounting for only donor age (chronic changes: β −3.87, 95%CI −10.07 – −2.32, p=0.22). Using stepwise forward selection, chronic changes on implantation biopsy was not included in the adjusted model.
Discussion
In this single-center retrospective cohort study of 1104 living donor kidney transplants, we found that approximately 1 in 7 kidneys had chronic changes on implantation biopsy and 1% had possible donor glomerular disease. Donor age was associated with increased odds of having chronic changes, whereas all kidneys with possible donor glomerular disease came from donors with a family history of ESKD. However, neither type of abnormal implantation biopsy finding was associated with either lower donor GFR or adverse allograft outcomes post-transplant. Together, these findings suggest that abnormal biopsy findings in kidneys from healthy donors well-screened for kidney dysfunction are typically incidental findings that are of limited consequence to donors in the short-term or recipients in the long-term.
Although living donor kidney transplantation provides the best outcomes for the treatment for ESKD, the proportion of kidney transplants from living kidney donors has fallen in the United States. At the same time, a worsening organ shortage has resulted in the expansion of the living donor pool to include more medically complex donors.13,14 One consequence of this expansion is an increase in donors with nephrosclerosis, given that renal parenchymal scarring increases with age in healthy individuals.5,15,16 Understanding the implications of such histologic abnormalities are important for both donor and allograft management when these findings are detected as the prevalence of these findings increases with current donor selection criteria.
In adjusted analysis of associations between predonation characteristics and chronic changes, higher eGFR was paradoxically associated with presence of changes—likely due to selection bias in donor acceptance and overestimation of eGFR with age, since older donors were more likely to have nephrosclerosis. The absence of an association between lower eGFR and chronic changes is consistent with prior demonstrations that nephrosclerosis in an otherwise healthy population does not improve the ability to predict age-related decline in renal function.7,27 Importantly, albuminuria in donors also was not associated with higher odds of chronic changes on biopsy,suggesting that chronic changes on biopsy represents age-related sclerosis rather than preclinical kidney disease preceding changes in serum-creatinine measurement. Accordingly, a sensitivity analysis limited to donors with above-median pre-donation eGFR still showed no relationship between the presence of chronic changes and inferior donor 6-month eGFR outcomes, recipient death-censored graft failure, or recipient 6-month eGFR. Similarly, an analysis of 1395 living kidney donor implantation biopsies reported no association between albuminuria and nephrosclerosis despite an independent association between albuminuria and nephron hypertrophy,17 suggesting two distinct but related pathways for the development of CKD, through nephron hypertrophy and nephrosclerosis. The presence of age- and hypertension-associated chronic changes without albuminuria in our otherwise healthy living donor population presumably occurs through the well-defined mechanism of progressive arteriosclerosis mediating tissue ischemia.18 That much of these chronic changes were driven by moderate-severe vascular changes without concomitant advanced GS and IF/TA may suggest our donors fall on an earlier stage of the nephrosclerosis pathway, with fibrosis and glomerulosclerosis often understood to be further downstream consequences of parenchymal ischemia. Longer-term follow-up studies of the association of these findings with lifetime post-donation ESKD are needed to determine if chronic changes reflect pre-clinical pathologic processes that portend higher long-term risk of incident kidney disease.
Despite screening for pre-donation proteinuria and hematuria, 1% of donors in our cohort had an implantation biopsy showing possible donor glomerular disease. The significance of these biopsy diagnoses without evidence of glomerular dysfunction is unclear, especially since low-grade positive immunofluorescence may results from protein trapping and there was no association between possible glomerular disease and donor/recipient outcomes (albeit in unadjusted analyses limited by small sample size). However, these donors all had first-degree relatives with ESKD, nearly half of the donors with possible IgA nephropathy had a family member with ESKD due to IgA nephropathy, and one donor with new diagnosis of fibrillary GN donated to a family member with the same diagnosis, suggesting that at least some of these biopsies identified true subclinical pathology. The small number of cases precluded studying the impact of these biopsy findings on donor outcomes. Gaber et al. reported higher short-term risk of recipient events in kidneys with incidental IgA deposits,6 but studies are consistent in demonstrating no long-term risk of recipient graft loss or mortality in this context.6,19 Conversely, biologically related donor-recipient pairs show an increased risk of donor ESKD and recipient graft failure after accounting for HLA matching.20,21 One plausible explanation for these results is that there are common genetic predispositions to kidney disease in a subset of donor-recipient pairs.22 Complicated, polygenic risk factors can contribute to kidney failure, and as our understanding of the relationship between genetic variants and ESKD risk continues to evolve, genetic testing improve donor risk stratification. Considering our finding that all donors with possible glomerular disease had a family history of ESKD, there should be a low threshold for additional evaluation of findings such as transient hematuria or proteinuria identified during donor evaluation in candidates with such a family history, perhaps including genetic testing of both the donor candidate and affected family members. Future prospective studies might explore the impact of broader genetic screening cohorts of all donors with a family history of kidney disease.
While 14% of all living donors in this study had chronic changes on implantation biopsy, these changes were not associated with post-donation eGFR in this well-screened population. Previous investigations have demonstrated inconsistent results depending on the microstructural features studied and the outcome measures chosen.8–11 In the largest study to date, nephrosclerosis on implantation biopsy had no ability to predict eGFR postdonation.8 Beyond nephrosclerosis, implantation biopsies can provide morphometric data on glomerular and tubular microarchitecture, some of which have been associated with post-donation kidney function. Factors limiting routine assessment of these features include labor intensiveness and the necessity for biopsy interpretation by trained renal pathologists. It is possible that advances in AI-based imaging analysis will facilitate the adoption of these measurements in high-throughput clinical environments where they then may be validated more broadly.23 In the interim, the findings of our study and others suggest that, when considering organs from healthy donors, focusing on chronic scarring rather than other morphometric features likely “double-counts” age and hypertension rather than providing an independent assessment of kidney quality. These findings should provide reassurance that the presence of chronic changes on implantation biopsies of kidneys from carefully screened donors should not prompt changes in either donor or recipient surveillance or management at this time.
The frequency of both chronic changes and possible glomerular disease we observed suggests a potential role for the routine performance of implantation biopsies to provide a baseline histologic assessment that allows identification of findings on subsequent allograft biopsies as new versus donor-derived. Although we found no association between chronic changes and allograft longevity, future research is needed to determine whether implantation histology can also be used to personalize allograft management, such as implementing calcineurin inhibitor-sparing protocols upon identification of donor-derived chronic changes.
Previous investigations have evaluated the associations between living donor kidney implantation biopsy findings and recipient outcomes. We have previously studied the impact of suboptimal histology on allograft survival in 427 living donor transplants, finding no adverse impact of suboptimal histology on recipient death-censored graft survival.24 Our current work expands on these results in its larger cohort size and application of more commonly used criteria for chronic changes, with similar results. On the other hand, Issa et al. found that IFTA ≥5% and presence of arteriolar hyalinosis were associated with graft failure in adjusted analyses.25 The small proportion of donors with IFTA in our cohort limits direct comparisons between that study and ours.
Strengths of our study include a large, diverse series of consecutive transplants. Limitations include that 27% of donors did not have 6-month post-donation eGFR, similar to prior studies evaluating the association between biopsy findings and kidney function recovery in living donors.8,17 Furthermore, while 3-month single kidney eGFR increase has been validated as a surrogate for ten-year post-donation eGFR,12 our reliance on 6-month single kidney eGFR—based on our center’s follow-up schedule— precludes direct comparison to studies using 3-month values. Importantly, this 6-month donor outcome is only a surrogate for the kidney outcomes of most interest: long-term post-donation kidney function and the development of kidney failure. The use of this surrogate outcome allows us to study the association between biopsy findings and post-donation kidney function in the presence of high long-term loss to follow up and the infrequency of post-donation kidney failure. However, its use also precludes our ability to comment on the true relationship between biopsy findings and long-term donor kidney function or development of kidney failure, especially since the presence of abnormal biopsy findings may alter the relationship between the surrogate outcomes and long-term outcomes of interest. For example, if possible donor glomerular disease on implantation biopsy is associated with a higher risk of the future development of clinically relevant glomerulonephritis, such a relationship may be missed in a study using 6-month outcomes that largely reflect the quality of post-donation adaptive hyperfiltration. Additionally, eGFR equations in general have lower performance in individuals with normal kidney function, and the bias and accuracy of CKD-EPI 2021 equation has not been assessed in individuals who have previously undergone living donor nephrectomy. Lastly, while we demonstrate a limited role for the biopsy assessment of a chronic changes for predicting donor and recipient renal function in living kidney donation, the generalizability of these results to findings of for-cause native kidney biopsies is limited, as living kidney donors are a highly selected population and nephrosclerosis in this context may have a different etiology than in other clinical contexts.26
In conclusion, we found that chronic changes in implantation biopsies of living donor kidney transplants were primarily associated with age and had no subsequent association with 6-month donor eGFR outcomes or recipient outcomes.. Possible donor glomerular disease was seen in 1% of implantation biopsies, all of which were kidneys from donors with family history of ESKD, but the clinical significance of these findings is uncertain. Long-term follow up is needed to determine what, if any, impact the presence of abnormal implantation biopsy findings should have on donor or recipient management.
Supplementary Material
Figure S1. Flow diagram of study cohort
Item S1. Supplemental Methods
Table S1. Implantation biopsy scoring system, and the distribution of glomerulosclerosis, interstitial fibrosis/tubular atrophy, and arteriosclerosis scores of kidneys included in the study.
Table S2. Characteristics of donors included in 6-month post-donation analysis versus those who were excluded
Table S3. Association between chronic changes on implantation biopsy and donor outcomes 6 months after living kidney donation among donors with pre-donation eGFR≥ 105 ml/min/1.73m2
Table S4. Characteristics of recipients of kidneys included in the analysis, by biopsy finding group
Table S5. Unadjusted and adjusted Cox proportional hazards model for death-censored graft failure by implantation biopsy finding group
Table S6. Unadjusted and adjusted Cox proportional hazards model for the association of chronic changes on implantation biopsy and death-censored graft failure among donors with pre-donation eGFR≥ 105 ml/min/1.73m2
Support:
SAH was supported by a Nelson Family Faculty Development Award and NIDDK grant K23DK133729. SM was supported by NIH grants DK114893, DK116066, DK126739, DK130058 and MD014161 and a Nelson Family Faculty Development Award. No funders or author institutions had any role in study design, collection, analysis or interpretation of data, writing of the manuscript, and/or the decision to submit this manuscript for publication.
Footnotes
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Financial Disclosure: The authors declare that they have no relevant financial interests.
Prior Presentation: Presented in part at the 2023 American Transplant Congress; June 6, 2023; San Diego, California.
Data Sharing:
The data underlying this article cannot be shared due to potential loss of confidentiality of individual records given the small number of donors at our center with each combination of characteristics.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. Flow diagram of study cohort
Item S1. Supplemental Methods
Table S1. Implantation biopsy scoring system, and the distribution of glomerulosclerosis, interstitial fibrosis/tubular atrophy, and arteriosclerosis scores of kidneys included in the study.
Table S2. Characteristics of donors included in 6-month post-donation analysis versus those who were excluded
Table S3. Association between chronic changes on implantation biopsy and donor outcomes 6 months after living kidney donation among donors with pre-donation eGFR≥ 105 ml/min/1.73m2
Table S4. Characteristics of recipients of kidneys included in the analysis, by biopsy finding group
Table S5. Unadjusted and adjusted Cox proportional hazards model for death-censored graft failure by implantation biopsy finding group
Table S6. Unadjusted and adjusted Cox proportional hazards model for the association of chronic changes on implantation biopsy and death-censored graft failure among donors with pre-donation eGFR≥ 105 ml/min/1.73m2
Data Availability Statement
The data underlying this article cannot be shared due to potential loss of confidentiality of individual records given the small number of donors at our center with each combination of characteristics.