Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats.
Patients with renal insufficiency develop secondary hyperparathyroidism. Monotherapy with active vitamin D or calcimimetics ameliorates secondary hyperparathyroidism. We compared kidney damage in subtotally nephrectomized (SNX) rats treated with active vitamin D (calcitriol) or the calcimimetic R-568. Male Sprague-Dawley SNX and sham-operated (sham-op) rats were randomized into the following treatment groups: SNX + R-568, SNX + calcitriol, SNX + vehicle, sham-op + R-568, sham-op + calcitriol, and sham-op + vehicle. Albuminuria and blood pressure were monitored and kidneys were examined using morphometry, immunohistochemistry, quantitative RT-PCR, and in situ hybridization. Parathyroid hormone concentrations were lowered to the same extent by the two interventions, although phosphorus and the calcium-phosphorus product were reduced only by R-568 treatment. SNX rats developed marked albuminuria, which was significantly reduced in ad libitum- and pair-fed animals treated with R-568 and animals treated with calcitriol. Mean glomerular volume (6.05 +/- 1.46 vs. 2.70 +/- 0.91 mm(3)), podocyte volume (831 +/- 127 vs. 397 +/- 67 microm(3)), the degree of foot process fusion (mean width of foot processes = 958 +/- 364 vs. 272 +/- 35 nm), and glomerular basement membrane thickness (244 +/- 6 vs. 267 +/- 23 nm), as well as desmin staining, were significantly higher in vehicle-treated SNX than sham-operated animals. These changes were ameliorated with R-568 and calcitriol. In SNX, as well as sham-operated, animals, expression of the calcium-sensing receptor (protein and mRNA) was upregulated by treatment with the calcimimetic, but not calcitriol. Calcitriol and R-568 were similarly effective in ameliorating kidney damage.
Piecha
Grzegorz
G
Institute of Pathology, Univ. of Heidelberg, Im Neuenheimer Feld 220/221, D-69120 Heidelberg, Germany. g.piecha@gmx.de
Kokeny
Gabor
G
Nakagawa
Kumiko
K
Koleganova
Nadezda
N
Geldyyev
Aman
A
Berger
Irina
I
Ritz
Eberhard
E
Schmitt
Claus Peter
CP
Gross
Marie-Luise
ML
D000419:Albuminuria; D000814:Aniline Compounds / Q000627:therapeutic use*; D000818:Animals; D002117:Calcitriol / Q000627:therapeutic use*; D002118:Calcium / Q000819:agonists; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate; D006962:Hyperparathyroidism, Secondary / Q000209:etiology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D009392:Nephrectomy; D010627:Phenethylamines; D011437:Propylamines; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000235:genetics
D000814:Aniline Compounds; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; D002117:Calcitriol; D002118:Calcium