Correlation of Glomerular Size With Donor-Recipient Factors and With Response to Injury

Abstract

Background: Glomerular size in renal allografts is impacted by donor-recipient factors and response to injury. In serial biopsies of patients with well-functioning grafts, increased glomerular size correlates with better survival. However, no previous study has addressed the association of glomerular size at the time of a for-cause biopsy and clinical/histopathologic markers of injury, or effect on long-term graft outcome.

Methods: Two cohorts of kidney transplant recipients enrolled in the Deterioration of Kidney Allograft Function study were evaluated. The prospective cohort (PC, n = 581): patients undergoing first for-cause kidney biopsy 1.7 ± 1.4 (mean ± SD) y posttransplant; and the cross-sectional cohort (CSC, n = 446): patients developing new-onset renal function deterioration 7.7 ± 5.6 y posttransplant. Glomerular planar surface area and diameter were measured on all glomeruli containing a vascular pole. Kidney biopsy was read centrally in a blinded fashion according to the Banff criteria.

Results: Glomerular area was significantly higher in the CSC than the PC; time from transplant to indication biopsy was associated with glomerular area in both cohorts (P values ≤ 0.001). Glomerular area was associated with indices of microvascular inflammation (glomerulitis, peritubular capillary infiltrates; P values ≤ 0.001) and segmental glomerulosclerosis (P value < 0.0001). In the CSC, higher glomerular area was associated with higher estimated glomerular filtration rate (P value ≤ 0.001) and increased graft survival after accounting for microvascular inflammation (adjusted hazard ratio = 0.967; 95% confidence interval: 0.948-0.986; hazard ratio in biopsies without evidence of diabetes or antibody mediated rejection = 0.919, 95% confidence interval: 0.856-0.987).

Conclusions: Glomerular size is associated with histopathologic features present at the time of indication biopsy and with increased graft survival in the CSC.

Trial registration: ClinicalTrials.gov NCT00270712.

Conflict of interest statement

The authors declare no conflicts of interest.

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Figures

Figure 1:

Diagram of study cohort

Figure 2:

Representative tracing of glomerular region of interest using Nikon Elements System. Glomerular area = 33 690 microns2; diameter = 207.1 microns. Scale bar = 100 microns.

Figure 3:

Summary of study findings. Factors positively associated with larger glomerular area are denoted by a blue dot; negatively associated with a red dot. Factors with a stronger association (as evaluated by p-values) have larger -log10(P) values. Black dashed line represents p-value=0.05. Gray dashed line represents threshold for significance (α=0.05) after implementing a Bonferroni correction for multiple comparisons within cohort. For Banff scores and continuous variables p-value was calculated based on Spearman’s correlation coefficient; for binary factors Wilcoxon rank sum tests. Char: Characteristics. tx=transplant. ktx=kidney transplant. SPK=simultaneous pancreas-kidney transplant. Seg scler: presence of any segmentally sclerotic glomeruli.

Figure 4:

Glomerular area (in log square microns) versus time to index biopsy. Blue=LOESS curve; Red=regression line. For the prospective cohort the regression line estimate for a 1 year increase in time from transplant biopsy is a 0.043 log micron increase in glomerular area (95% CI: 0.024 to 0.061; R2: 0.034, p-value ≤0.001). For the cross-sectional cohort the regression line estimate for a 1 year increase in time from transplant biopsy is a 0.019 log micron increase in glomerular area (95% CI: 0.012 to 0.025; R2: 0.064, p-value≤0.001)

Figure 5:

Relationship between log transformed glomerular area and eGFR. Blue=LOESS curve; Red=regression line. For the prospective cohort, the regression line estimate for a 1 log micron increase in glomerular area is a 1.38 mL/min/1.73m2 increase in eGFR (95% CI: −2.96 to 5.73 mL/min/1.73m2; R2≤0.001, p-value=0.532). For the cross-sectional cohort, the regression line estimate for a 1 log micron increase in glomerular area is a 5.17 mL/min/1.73m2 increase in eGFR (95% CI: 2.04 to 8.30 mL/min/1.73m2; R2=0.024, p-value≤0.001).

Figure 6:

Death censored graft survival by glomerular area quartiles. For the prospective cohort the quartiles were defined as: P1=biopsies with glomerular area