The Two Kidney to One Kidney Transition and Transplant Glomerulopathy

Abstract

The attrition rate of functioning allografts beyond the first year has not improved despite improved immunosuppression, suggesting that nonimmune mechanisms could be involved. Notably, glomerulopathies may account for about 40% of failed kidney allografts beyond the first year of engraftment, and glomerulosclerosis and progression to ESRD are caused by podocyte depletion. Model systems demonstrate that nephrectomy can precipitate hypertrophic podocyte stress that triggers progressive podocyte depletion leading to ESRD, and that this process is accompanied by accelerated podocyte detachment that can be measured in urine. Here, we show that kidney transplantation "reverse nephrectomy" is also associated with podocyte hypertrophy and increased podocyte detachment. Patients with stable normal allograft function and no proteinuria had levels of podocyte detachment similar to levels in two-kidney controls as measured by urine podocyte assay. By contrast, patients who developed transplant glomerulopathy had 10-to 20-fold increased levels of podocyte detachment. Morphometric studies showed that a subset of these patients developed reduced glomerular podocyte density within 2 years of transplantation due to reduced podocyte number per glomerulus. A second subset developed glomerulopathy by an average of 10 years after transplantation due to reduced glomerular podocyte number and glomerular tuft enlargement. Reduced podocyte density was associated with reduced eGFR, glomerulosclerosis, and proteinuria. These data are compatible with the hypothesis that podocyte depletion contributes to allograft failure and reduced allograft half-life. Mechanisms may include immune-driven processes affecting the podocyte or other cells and/or hypertrophy-induced podocyte stress causing accelerated podocyte detachment, which would be amenable to nonimmune therapeutic targeting. Podocytes are complex neuron-like postmitotic cells adherent to the underlying glomerular basement membrane via foot processes that must contiguously cover the filtration surface area to maintain the normal filtration barrier. Podocytes cannot divide in situ and have limited capacity for replacement. 1 This means that when podocytes are lost, or the glomerular surface area increases due to glomerular growth, the major adaptive response is by hypertrophy. At the same time, the podocyte's structural complexity means that its capacity to hypertrophy is limited. Inability to maintain contiguous coverage of the filtration surface by foot processes results in protein leak into the filtrate. If podocyte detachment exceeds hypertrophic capacity, other glomerular cells adapt by proliferating and laying down matrix resulting in glomerulosclerosis. [2][3][4][5][6]

Transplant Glomerulopathy

“…Podocytes, with their complex structure that includes foot processes and slit diaphragms, are a vital element of the glomerular filtration barrier to protein. Not surprisingly, Yang et al 9 found that transplantation of a single kidney resulted in an approximately 20% increase in glomerular volume and podocyte volume by 3 months posttransplantation, with a similar, corresponding decrease in podocyte nuclear density within glomeruli. However, somewhat surprisingly, they found that although the transplant patients had only a single functioning kidney, their urinary podocin/creatinine ratio (UPod/Cr; an estimate of podocyte excretion) at 3 months post-transplantation was on average approximately 6-fold higher than that of control patients with two kidneys and normal renal function, and this remained elevated beyond 5 years post-transplantation.…”

“…However, somewhat surprisingly, they found that although the transplant patients had only a single functioning kidney, their urinary podocin/creatinine ratio (UPod/Cr; an estimate of podocyte excretion) at 3 months post-transplantation was on average approximately 6-fold higher than that of control patients with two kidneys and normal renal function, and this remained elevated beyond 5 years post-transplantation. Yang et al 9 also found that although acute rejection (mainly TCMR), acute tubular injury, calcineurin inhibitor toxicity, and BK virus nephropathy were not associated with a significant increase in UPod/Cr above levels seen in transplant recipients with biopsies showing no histologic lesions, TG was associated with an additional 5-to 10-fold increase in UPod/Cr, signifying a marked acceleration of podocyte detachment from GBMs.…”

“…Proteinuria was not different in C4d-positive and C4d-negative cases, but levels of .1 g/d or $21 by dipstick were associated with a trend toward worse graft survival. 8 In this context, the article in this issue of JASN by Yang et al 9 from the laboratory of Roger Wiggins at the University of Michigan represents an interesting and unique approach to the study of TG. The authors examine podocyte density and related glomerular parameters in renal allograft biopsies taken at different times post-transplantation in patients with and without TG, and correlate these findings with urinary excretion of podocytes and of protein.…”

“…10 Notably, the marked glomerular hypertrophy seen in late TG is not simply a matter of time post-transplantation, because biopsies without TG or other glomerulopathy performed at similar times post-transplantation showed only modest glomerular enlargement (1.2-fold) compared with 3-month protocol biopsies. 9 Whether this difference in late TG and late non-TG biopsies is the result of immunologic effects in the former is currently unclear.…”

From Patient to Dish and Back Again

“…4,5 Recent studies determining absolute podocyte numbers and density also show in humans that, should any regenerative mechanism for podocytes exist within the glomerulus, it cannot be very effective. 6 …”