Evolution and pathophysiology of renal-transplant glomerulosclerosis

Transplantation. 2004 Aug 15;78(3):461-8. doi: 10.1097/01.tp.0000128612.75163.26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy
  • Diabetes Mellitus, Type 1 / surgery
  • Diabetic Nephropathies / surgery
  • Follow-Up Studies
  • Glomerular Filtration Rate
  • Glomerulosclerosis, Focal Segmental / epidemiology*
  • Glomerulosclerosis, Focal Segmental / pathology
  • Humans
  • Incidence
  • Kidney Transplantation / pathology*
  • Kidney Transplantation / physiology*
  • Pancreas Transplantation / pathology
  • Postoperative Complications / physiopathology*
  • Retrospective Studies
  • Time Factors