Effects of perindopril and hydrochlorothiazide on the long-term progression of lithium-induced chronic renal failure in rats.
Administration of lithium in the diet to new-born rats induces chronic renal failure associated with hypertension, proteinuria and irreversible tubulo-interstitial morphological changes. In the present study we induced chronic renal failure by administration of lithium for 16 weeks to new-born rats, and examined the spontaneous course of this nephropathy and the effects of antihypertensive treatment with either perindopril (12 mg/kg diet) or hydrochlorothiazide (500-1000 mg/kg diet) during a 24 weeks follow up period without lithium. In the placebo group, progression to terminal uraemia occurred in all rats with severe renal failure (initial Purea > 15 mM) (10 of 18). Rats with mild-moderate renal failure (Purea 9-15 mM) showed no deterioration in renal function despite persistent systolic hypertension and irreversible structural renal changes. Perindopril normalized the blood pressure in all rats but did not prevent the progression to terminal uraemia (8 to 18). Hydrochlorothiazide partially controlled the hypertension and accellerated the progression of uraemia without increasing the mortality (7 of 17). Irrespective of treatments, the predominant quantitative structural changes (e.g. decreased volume of proximal tubular cells) showed significant correlations with the degree of renal dysfunction, but not with systolic blood pressure in the surviving rats. It is concluded that progression of lithium-induced nephropathy to terminal uraemia occurs when the nephrotoxic insult results in a more than 50% reduction of the glomerular filtration rate, judged from Purea levels. The failure of effective antihypertensive treatment with an angiotension-converting enzyme inhibitor to modify the progression suggests that in this model, systemic or glomerular hypertension may not be an important pathophysiological factor. The structural and functional deterioration observed in Li-uraemic rats during treatment with hydrochlorothiazide remains unexplained.
Christensen
S
S
Department of Pharmacology, Panum Institute, University of Copenhagen, Denmark.
Shalmi
M
M
Hansen
A K
AK
Marcussen
N
N
D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D007677:Kidney Function Tests; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D008094:Lithium / Q000008:administration & dosage / Q000633:toxicity* / Q000652:urine; D008297:Male; D020913:Perindopril; D011247:Pregnancy; D051381:Rats; D012964:Sodium / Q000652:urine; D013054:Spectrophotometry, Atomic; D014508:Urea / Q000097:blood; D014511:Uremia / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology
D000959:Antihypertensive Agents; D007211:Indoles; D006852:Hydrochlorothiazide; D014508:Urea; D008094:Lithium; D012964:Sodium; D003404:Creatinine; D020913:Perindopril