The tubulointerstitium in early diabetic nephropathy: Prime target or bystander

Dhruv K. Singh, Ken Farrington

Research output: Contribution to journalReview articlepeer-review

6 Citations (Scopus)


Diabetic nephropathy (DN) is a major microvascular complication of diabetes and a leading cause of end-stage renal disease (ESRD) worldwide. DN is classically understood as a glomerular disease. However, this understanding is currently being contested with recent studies suggesting a pivotal role of the tubulointerstitium in the initiation and progression of DN. We performed a review of the current literature as detailed below. The literature suggests that chronic hyperglycemia may orchestrate several structural and functional abnormalities of the tubulointerstitium before significant glomerular changes. Abnormalities such as increased advanced glycation end products, oxidative stress, cytokine activation, inflammatory markers, and enhanced hypoxic milieu may result in progressive tubulointerstitial damage as reflected by dysfunction of tubular protein receptors such as megalin and loss of charge-dependent tubular protein reabsorption, resulting in higher excretion of tubular injury markers such as N-acetyl - glucosaminidase (NAG) and retinol-binding protein (RBP), and overflow microproteinuria in the presence of intact glomerulus and before the onset of microalbuminuria. In addition, people with diabetes may have higher excretion of NAG and RBP and low levels of tubular hormones such as erythropoietin and 1,25-dihydroxyvitamin D, before the onset of microalbuminuria, suggesting that tubulointerstitial changes are present before the onset of microalbuminuria. These abnormalities are highly suggestive of DN being of tubular, rather than glomerular origin.

Original languageEnglish
Pages (from-to)185-190
Number of pages6
JournalInternational Journal of Diabetes in Developing Countries
Issue number4
Publication statusPublished - 1 Oct 2010


  • 1,25-dihydroxyvitamin D
  • Cubulin
  • diabetic nephropathy
  • erythropoietin
  • megalin
  • microalbuminuria
  • NAG
  • RBP
  • tubular dysfunction


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