The two kidney to one kidney transition and transplant glomerulopathy: a podocyte perspective.
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.
Departments of Internal Medicine.
Yan
Y
Yang
Pathology, and.
Jeffrey B
JB
Hodgin
Departments of Internal Medicine.
Farsad
F
Afshinnia
Departments of Internal Medicine.
Su Q
SQ
Wang
Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
Larysa
L
Wickman
Departments of Internal Medicine.
Mahboob
M
Chowdhury
Departments of Internal Medicine.
Ryuzoh
R
Nishizono
Departments of Internal Medicine.
Masao
M
Kikuchi
Departments of Internal Medicine.
Yihung
Y
Huang
Departments of Internal Medicine.
Milagros
M
Samaniego
Departments of Internal Medicine, rwiggins@umich.edu.
Roger C
RC
Wiggins
D000222:Adaptation, Physiological; D000328:Adult; D000818:Animals; D064592:Autografts; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D005923:Glomerulosclerosis, Focal Segmental / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000401:mortality / Q000503:physiopathology / Q000601:surgery*; D016030:Kidney Transplantation / Q000009:adverse effects / Q000379:methods*; D008297:Male; D008875:Middle Aged; D050199:Podocytes / Q000378:metabolism / Q000473:pathology*; D011183:Postoperative Complications / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D012189:Retrospective Studies; D018570:Risk Assessment; D015996:Survival Rate
glomerulosclerosis; podocyte; proteinuria; transplantation