Recombinant human growth hormone exacerbates chronic puromycin aminonucleoside nephropathy in rats

Abstract

Growth failure is a cardinal feature of chronic renal failure in children. Administration of recombinant human growth hormone (rhGH) ameliorates this problem but may adversely affect the kidney and hasten the progression to end-stage renal disease. We conducted experiments to examine the impact of rhGH on the severity of chronic puromycin aminonucleoside (PAMN) nephropathy in rats. The glomerulopathy was induced by serial injections of PAMN over a 12 week period. Experimental animals (N = 6) received rhGH, 0.5 mg per dose, three times weekly, while control rats (N = 6) received hormone vehicle. rhGH had no effect on weight gain, hematocrit, or blood pressure in rats with the experimental renal disease. Urinary protein excretion increased approximately 50% in rhGH-treated rats with chronic PAMN nephropathy compared to untreated animals between four to eight weeks of the observation period. After 12 weeks, the inulin clearance was significantly lower in rhGH-treated rats, 0.26 ± 0.05 versus 0.50 ± 0.06 ml/min/100 g body wt in control PAMN animals, P < 0.05. Compared to untreated rats with PAMN nephropathy, administration of rhGH increased the extent of segmental glomerulosclerosis from 11 ± 3 to 46 ± 9% (P < 0.005) and elevated the tubulointerstitial injury score from 0.5 ± 0.1 to 1.4 ± 0.4 (P < 0.05). Furthermore, glomerular hypertrophy was enhanced in animals with chronic PAMN nephropathy given rhGH, as evidenced by a larger glomerular planar area, 9.2 ± 0.3 x 10-3 versus 11.9 ± 0.5 x 10-3 mm2, P < 0.005. The renal cortical malondialdehyde content was higher in rhGH-treated rats with chronic PAMN nephropathy, 2.33 ± 0.13 versus 1.78 ± 0.06 nmol/mg protein in untreated animals with glomerular disease, P < 0.05. In normal rats with intact kidneys, rhGH administration (N = 4) increased glomerular filtration rate and glomerular planar area without altering blood pressure, proteinuria, renal cortical malondialdehyde content, or glomerular or tubulointerstitial damage, compared to untreated animals (N = 4). We conclude that administrailon of rhGH to rats with chronic PAMN nephropathy exacerbates the severity of the renal functional and structural injury in response to the epithelial cell toxin. These data suggest that caution should be exercised when prescribing rhGH for the treatment of short stature in children with chronic renal failure, especially those with glomerulopathies and persistent, severe nephrotic range proteinuria.