Combination treatment with an ET(A)-receptor blocker and an ACE inhibitor is not superior to the respective monotherapies in attenuating chronic transplant nephropathy in a 'Fisher-to-Lewis' rat model.
BACKGROUND
Specific endothelin A (ET(A))-receptor blockade and ACE inhibition attenuate chronic transplant nephropathy (CTN) in the 'Fisher-to-Lewis' rat model. It is unknown (i) which of both pharmacological interventions attenuates CTN more effectively and (ii) whether combination therapy exerts additive nephroprotection.


METHODS
We compared (i) the effects of specific ET(A)-receptor blockade with LU 302146 (30 mg/kg bw/day) and ACE inhibition with trandolapril (0.3 mg/kg bw/day) and (ii) the effect of a combination therapy of both drugs on the development of CTN. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Untreated 'Fisher-to-Lewis' allografts served as controls (TX). All animals received low-dose cyclosporin A (1.5 mg/kg body weight) for 10 days post-transplant to inhibit early acute rejection episodes. The duration of the experiment was 36 weeks. Blood pressure (BP) was measured every other week by tail plethysmography. Indices of glomerulosclerosis (GS), tubulointerstitial and vascular damage, number of glomeruli, total glomerular volume and mean glomerular volume were measured using morphometric and stereological techniques, respectively. Albuminuria, blood chemistry and haematology were measured at the end of the experiment.


RESULTS
LU 302146 did not affect systolic BP. In contrast, trandolapril and combination treatment significantly reduced systolic BP. Histological signs of CTN were almost completely prevented by LU 302146 and trandolapril as compared to TX, e.g. GS=0.8+/-0.08 and 0.9+/-0.20 vs 1.8+/-0.21* (arbitrary unit; *P<0.001 vs treated groups). Allograft weight was significantly lower in treated vs TX animals. Trandolapril and combination therapy, but not LU 302146 alone, abrogated glomerular hypertrophy, i.e. mean glomerular volume: TX 2.22+/-0.43, trandolapril 1.61+/-0.38**, LU 302146 2.22+/-0.11, trandolapril+LU 302146 1.78+/-0.28* (microm(3); *P<0.05 vs control and LU 302146, **P<0.01 vs control and LU 302146). Albuminuria was lower in treated compared to TX animals. Combination therapy did not confer additional benefit compared to the respective monotherapies.


CONCLUSIONS
We conclude that ET(A)-receptor blockade abrogates GS, tubulointerstitial and vascular damage in the 'Fisher-to-Lewis' model of CTN to a similar extent as ACE inhibition. However, only ACE inhibition inhibits glomerular hypertrophy. In contrast to ACE inhibition, the effect of ET(A)-receptor blockade is independent of BP. This finding is consistent with the notion that ET(A)-receptor mediated events play a partly BP-independent role in the genesis of CTN. Combination therapy exerts no additive nephroprotection.
Adams
Judith
J
Department of Urology, Ruperto Carola University, Heidelberg, Germany.
Odoni
Giulio
G
Ogata
Hiroaki
H
Viedt
Christiane
C
Amann
Kerstin
K
Ritz
Eberhard
E
Orth
Stephan R
SR
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D007211:Indoles / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D044022:Receptor, Endothelin A
D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D007211:Indoles; D044022:Receptor, Endothelin A; C052035:trandolapril