Renal Complications in Chronic Diabetic Minipigs

Authors

Roth, S., Liu, J., Bouchard, G.F., Stricker-Krongrad, A.

Abstract

Renal complications as a consequence of chronic diabetes is considered a leading cause of chronic kidney diseases in humans and it is currently estimated that diabetic nephropathy is affecting more than 7 million people in the U.S.

Objective: Assess kidney pathophysiology in chronic insulin-dependent diabetic Yucatan miniature swine.

Methods: Type I diabetes was induced in Yucatan miniature swine and animal were maintained on a daily insulin regimen for more than 3.5 years. Clinical (BUN and creatinine) and urine chemistries were conducted using a Beckman Coulter AU480. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured in conscious
diabetic and normal control animals. RBF was measured by the rate of elimination of circulating iodohippurate and GFR was measured by the rate of elimination of circulating iohexol in each animal over the course of 4 hours post-injection of each marker. Circulating concentrations of the markers was quantified by specific ELISAs. In addition, kidneys from chronic diabetic minipigs were dissected, fixed in 10% NBF, processed and stained with hematoxylin and eosin, or Periodic acid Schiff. 

Results: BUN ranged from 19 to 23 mg/dL and creatinine ranged from 1.10 to1.47 mg/dL, no significant abnormalities were noted in albuminuria. RBF was remarkably increased in the diabetic minipig when compared to normal animals: 240.9 +/- 59.9 versus 103.7 +/- 8.6 mL/min, respectively. GFR was moderately increased: 36.3 +/- 5.0 versus 17.6 +/- 1.7 mL/min, respectively. Gross kidney findings ranged from normal (majority of animals) to moderately shrunken, lobulated with white foci (in one animal). Histopathologic findings ranged from little to mild aberrations (majority of animals) to severe interstitial fibrosis, severe glomerular sclerosis and tubular nephrosis in one animal.

Conclusions: Chronic diabetes in Yucatan miniature swine manifests with a renal pathophysiological tableau corresponding to the hyperfiltration phase of early diabetic kidney disease (increased glomerular hydrostatic pressure and increased glomerular filtration rate in absence of increased albumin secretion rate). This corresponds well to the 50% elevation in GFR seen early in type 1 human diabetes and in some type 2 diabetic patients. This indicates that the diabetic miniswine could provide a good model to test preventative approaches for progressive kidney therapies, using GFR hyperfiltration as a marker of early renal damage.

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