Model of Chronic Renal Failure in Miniature Pigs
Lynn R. Willis*1, Rajash K. Handa1, Ryan F. Paterson2, Ramsey L. Kuo2, Samuel C. Kim2, William W. Tinmouth2, and Bret A. Connors3.
1Department of Pharmacology and Toxicology, Indiana University School of Medicine, 2Methodist Institute for Kidney Stone Disease, 3Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana
We have examined the feasibility of 5/6-nephrectomy as a model of chronic renal failure in 7 male Gottingen minipigs (12 weeks old; 9.2±0.6 kg BW). Pre-surgery plasma creatinine (Cr; 0.68±0.11 mg/dl), BUN (5.4±1.3 mg/dl), hematocrit (Hct; 37.9±2.8%) and plasma potassium (K; 3.96±0.3 mEq/l) were measured by venipuncture under brief anesthesia 1 week prior to surgery. On day 0, the pigs were anesthetized for complete unilateral nephrectomy and removal of both poles of the contralateral kidney (open flank incisions for each), to leave a remnant approximately1/6 total renal mass.
After recovery, 3 pigs had to be euthanized for unrelenting uremia and weight loss within 11-23 days after surgery. In the remaining 4 animals, the plasma markers stabilized through 98-133 days of follow-up. Terminal body weight was 11.9±2.1 kg. Terminal plasma markers were: Cr, 1.54±0.73 mg/dl; BUN, 25.2±5.5 mg/dl; Hct, 27.6±4.3; K, 3.88±0.29 mEq/L. On the last day of the protocol, 3 pigs were anesthetized and prepared for clearance measurement of GFR, para-aminohippurate clearance (CPAH) and PAH extraction (EPAH). GFR was 146±32 ml/min/gm-remnant, CPAH was 1004±332 ml/min/gm-remnant, and EPAH was 82.7±3.0%. Remnant kidneys were perfused in situ and removed, weighed and prepared for histology. Mean remnant weight (n=4) was 41.3±14.4 g, double the estimated weight of the remnant at surgery (19.3±1.0 g), and approximately 50% of the pre-surgical total renal mass. The latter is consistent with our finding of GFR approximately half that for intact binephric pigs of similar size.
These studies show the 5/6-nephrectomy model as stable for 3 to 4 months, with moderate uremia (Cr, 2-2.5 times baseline; BUN 5x baseline). Remnant kidneys extracted PAH from blood as efficiently as intact kidneys, accounting for the relatively high CPAH. More severe uremia (Cr 4-5 times baseline; BUN >30 times baseline) decreased longevity to 2-3 weeks.