Elsevier

Seminars in Nephrology

Volume 27, Issue 2, March 2007, Pages 195-207
Seminars in Nephrology

Histopathology of Diabetic Nephropathy

https://doi.org/10.1016/j.semnephrol.2007.01.012Get rights and content

Summary

The clinical manifestations of diabetic nephropathy, proteinuria, increased blood pressure, and decreased glomerular filtration rate, are similar in type 1 and type 2 diabetes; however, the renal lesions underlying renal dysfunction in the 2 conditions may differ. Indeed, although tubular, interstitial, and arteriolar lesions are ultimately present in type 1 diabetes, as the disease progresses, the most important structural changes involve the glomerulus. In contrast, a substantial subset of type 2 diabetic patients, despite the presence of microalbuminuria or proteinuria, have normal glomerular structure with or without tubulointerstitial and/or arteriolar abnormalities. The clinical manifestations of diabetic nephropathy are strongly related with the structural changes, especially with the degree of mesangial expansion in both type 1 and type 2 diabetes. However, several other important structural changes are involved. Previous studies, using light and electron microscopic morphometric analysis, have described the renal structural changes and the structural-functional relationships of diabetic nephropathy. This review focuses on these topics, emphasizing the contribution of research kidney biopsy studies to the understanding of the pathogenesis of diabetic nephropathy and the identification of patients with a higher risk of progression to end-stage renal disease. Finally, evidence is presented that the reversal of established lesions of diabetic nephropathy is possible.

Section snippets

Morphometric Analysis and Structural-Functional Relationships

The relationships between structural abnormalities and kidney function are best defined using light and electron microscopic morphometric analysis. The critical lesion in T1DM is mesangial expansion, morphometrically termed mesangial fractional volume (Vv [Mes/glom]) (the fraction of the cross-sectional area of the glomerular tuft made up by mesangium); this is the electron microscopically estimated structural parameter that best correlates with all functional parameters in T1DM.9, 17 Indeed, a

Role of Podocytes in DN

The glomerular filtration barrier is composed of fenestrated endothelium, GBM, podocyte foot processes, and slit diaphragms. Compromise of one or more elements of this filtration complex leads to proteinuria.41 Podocyte detachment from GBM, from apoptosis, necrosis, or loss of adhesive interaction may play a central role in the pathogenesis of several proteinuric diseases; in fact proteinuria in glomerular disorders ultimately is associated with foot process effacement, flattening, and

Risk Factors for DN

Although it is clear that genetic factors modulate DN risk and that some patients escape this complication despite decades of poor glycemic control, it also is clear that hyperglycemia is a necessary precondition for DN lesions and renal functional disturbances to develop. Important support for this concept derives from research kidney biopsy studies in identical twins discordant for T1DM. The kidneys of all of the nondiabetic members of these twin pairs were normal structurally, and in each

Reversibility of DN Lesions

Pancreas transplantation offers the opportunity to test the effects of long-term normoglycemia to prevent, halt, or reverse DN lesions. Pancreas transplantation, performed at the time of renal transplant or within a few years after kidney transplant, prevents or slows the development of early diabetic glomerulopathy lesions in the renal allograft.71, 72, 73

The possibility of diabetic renal lesion reversal was addressed by long-term studies of the native kidneys of T1DM recipients of pancreas

Acknowledgments

The authors thank Patricia L. Erickson for assistance in manuscript preparation.

References (78)

  • W. Kriz et al.

    Progression of glomerular disease: is the podocyte the culprit?

    Kidney Int

    (1998)
  • E.N. Ellis et al.

    Observation of glomerular epithelial cell structure in patients with type I diabetes mellitus

    Kidney Int

    (1987)
  • M.W. Steffes et al.

    Glomerular cell number in normal subjects and in type 1 diabetic patients

    Kidney Int

    (2001)
  • V.A. Luyckx et al.

    Low birth weight, nephron number and kidney disease

    Kidney Int

    (2005)
  • K. Borch-Johnsen et al.

    Is diabetic nephropathy an inherited complication?

    Kidney Int

    (1992)
  • B.I. Freedman et al.

    Familial predisposition to nephropathy in African-Americans with non-insulin-dependent diabetes mellitus

    Am J Kidney Dis

    (1995)
  • R. Trevisan et al.

    Insulin-dependent diabetic sibling pairs are concordant for sodium-hydrogen antiport activity

    Kidney Int

    (1999)
  • P. Fioretto et al.

    Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys

    Lancet

    (1993)
  • P. Fioretto et al.

    Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients

    Kidney Int

    (2006)
  • P. Fioretto et al.

    Cyclosporine associated lesions in native kidneys of diabetic pancreas transplant recipients

    Kidney Int

    (1995)
  • M. Mauer et al.

    Diabetic nephropathy

  • E.T. Bell

    Renal vascular disease in diabetes mellitus

    Diabetes

    (1953)
  • R. Østerby

    Early phases in the development of diabetic glomerulopathy

    Acta Med Scand

    (1975)
  • R. Østerby

    Morphometric studies of the peripheral glomerular basement membrane in early juvenile diabetes IDevelopment of initial basement membrane thickening

    Diabetologia

    (1972)
  • P. Fioretto et al.

    Glomerular structure in non-proteinuric insulin-dependent diabetic patients with various levels of albuminuria

    Diabetes

    (1994)
  • S.M. Mauer et al.

    Structural functional relationships in diabetic nephropathy

    J Clin Invest

    (1984)
  • R. Østerby et al.

    Quantitative studies of glomerular ultrastructure in type 1 diabetics with incipient nephropathy

    Diabet Nephropathy

    (1984)
  • R.J. Falk et al.

    Polyantigenic expansion of basement membrane constituents in diabetic nephropathy

    Diabetes

    (1983)
  • Y. Kim et al.

    Differential expression of basement membrane collagen chains in diabetic nephropathy

    Am J Pathol

    (1991)
  • A. Katz et al.

    An increase in the cell component of the cortical interstitium antedates interstitial fibrosis in type 1 diabetic patients

    Kidney Int

    (2002)
  • B. Najafian et al.

    Atubular glomeruli and glomerulotubular junction abnormalities in diabetic nephropathy

    J Am Soc Nephrol

    (2003)
  • B. Najafian et al.

    Glomerulotubular junction abnormalities are associated with proteinuria in type 1 diabetes

    J Am Soc Nephrol

    (2006)
  • M.L. Caramori et al.

    Cellular basis of diabetic nephropathy: 1Study design and renal structural-functional relationships in patients with long-standing diabetes

    Diabetes

    (2002)
  • G.W. Lipkin

    More than one kind of type 2 diabetes with renal disease do not have diabetic nephropathy

    J Am Soc Nephrol

    (1994)
  • V. Gambara et al.

    Heterogeneous nature of renal lesions in type II diabetes

    J Am Soc Nephrol

    (1993)
  • P. Ruggenenti et al.

    The nephropathy of non-insulin dependent diabetes: predictors of outcome relative to diverse patters of renal injury

    J Am Soc Nephrol

    (1998)
  • S. Olsen et al.

    Non-diabetic renal disease in NIDDM proteinuric patients may be rare in biopsies from clinical practice

    Diabetologia

    (1996)
  • P. Fioretto et al.

    Patterns of renal injury in type 2 (non-insulin dependent) diabetic patients with microalbuminuria

    Diabetologia

    (1996)
  • B. Najafian et al.

    Clustering of type 1 and type 2 diabetic patients based on diabetic nephropathy structural-functional relationships

    J Am Soc Nephrol

    (2005)
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    The natural history studies discussed here also were supported by the Juvenile Diabetes Research Foundation. Many of the other studies reported here were supported by National Institutes of Health grant awards (PO1-DK13083, RO1-DK054638, and RO1-DK51975).

    1

    Dr. Fioretto was a Juvenile Diabetes Research Foundation Fellow and Career Development Award recipient while performing some of the research reviewed herein.

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