Evolution and pathophysiology of renal-transplant glomerulosclerosis.
BACKGROUND
Glomerulosclerosis (GS) is characteristic of chronic allograft nephropathy and graft failure; however, its natural history and pathophysiology are poorly defined.


METHODS
We evaluated 959 prospective protocol kidney-transplant biopsies from 120 recipients taken regularly up to 10 years after transplantation for evidence of glomerular injury.


RESULTS
GS exhibited a nonlinear triphasic time course. An intense but limited peak of damage in the first month was associated with cold ischemia (P<0.05) and calcineurin nephrotoxicity (P<0.001). GS then occurred as a late consequence of earlier immune-mediated tubular damage (9.3+/-6.6%, P<0.01 vs. no damage), suggesting delayed sclerosis of atubular glomeruli. Subsequent progressive GS occurred beyond 4 years, associated with increasing arteriolar hyalinosis from calcineurin inhibitor nephrotoxicity (r=0.33, P<0.001). From 5 years after transplantation, 32.4+/-22.2% of glomeruli were globally sclerosed, and segmental GS and periglomerular fibrosis increased by 4.0+/-9.3% and 8.4+/-14.2% per year, respectively. Severe arteriolar hyalinosis resulted in greater GS on sequential biopsies (P<0.001), consistent with vascular narrowing causing glomerular ischemia. Chronic glomerulopathy scores were relatively mild. Glomerular loss was patchy, with a high coefficient of variation of 633%. Isotopic glomerular filtration rate correlated best with Banff chronic interstitial fibrosis (r=-0.30, P<0.001) and chronic glomerulopathy scores (r=-0.23, P<0.001) rather than the percentage of sclerosed glomeruli (r=-0.12, P<0.05). Renal function gradually fell with time, and the hyperfiltration index increased from 1.14+/-0.42 at 3 months to 1.83+/-1.40 by 7 to 10 years after transplantation.


CONCLUSIONS
In summary, GS is a time-dependent response to glomerular injury from early ischemia, immune-mediated tubular loss, and late calcineurin nephrotoxicity.
Department of Renal Medicine, University of Sydney, Westmead Hospital, Westmead, Australia. brian_nankivell@wsahs.nsw.gov.au
Brian J
BJ
Nankivell
Richard J
RJ
Borrows
Caroline L S
CL
Fung
Philip J
PJ
O'Connell
Richard D M
RD
Allen
Jeremy R
JR
Chapman
D001706:Biopsy; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D003928:Diabetic Nephropathies / Q000601:surgery; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D005923:Glomerulosclerosis, Focal Segmental / Q000453:epidemiology* / Q000473:pathology; D006801:Humans; D015994:Incidence; D016030:Kidney Transplantation / Q000473:pathology* / Q000502:physiology*; D016035:Pancreas Transplantation / Q000473:pathology; D011183:Postoperative Complications / Q000503:physiopathology*; D012189:Retrospective Studies; D013997:Time Factors