Sevelamer hydrochloride attenuates kidney and cardiovascular calcifications in long-term experimental uremia.
BACKGROUND
In chronic renal failure (CRF), hyperphosphatemia and an elevated calcium-phosphate product are associated with vascular calcification and increased cardiovascular morbidity and mortality. Previous data have demonstrated that 3-month treatment of uremic rats with sevelamer was associated with less nephrocalcinosis compared to calcium carbonate (CaCO3), despite similar control of serum phosphorus, calcium-phosphorus product (Ca x P product), and secondary hyperparathyroidism. There was no evidence of aortic calcification after 3 months of uremia (J Am Soc Nephrol 13:2299-2308, 2002). The present studies explore the influence of sevelamer and CaCO3 on cardiovascular and kidney calcifications in long-term experimental uremia over 6 months.


METHODS
Normal and 5/6 nephrectomized rats (U) were fed a high phosphorus (HP) diet for 6 months. Two phosphate binders, CaCO3 and sevelamer, were administered and their influence on hyperphosphatemia, secondary hyperparathyroidism, kidney/myocardial/aortic calcification, and renal function was compared.


RESULTS
All uremic rats began the study with the same degree of renal failure. Sevelamer was as effective as CaCO3 in reducing serum phosphorus, Ca x P product, and attenuating secondary hyperparathyroidism. Despite similar serum cholesterol levels, rats in the U-HP + sevelamer group had markedly lower calcium deposition in the myocardium and aorta (myocardium, 72 +/- 4 microg/g wet tissue; aorta, 736 +/- 156 microg/g wet tissue) compared to rats in either the U-HP + CaCO3 group (myocardium, 179 +/- 48, P < 0.05; aorta, 1308 +/- 343, P < 0.05) or the U-HP group (myocardium, 98 +/- 10, NS; aorta, 2150 +/- 447, P < 0.05). Dual immunohistochemical analysis for calcium and endothelial cell markers demonstrated that myocardial calcium deposition was intravascular within capillaries. Furthermore, calcium deposition in the kidney of uremic rats treated with sevelamer (582 +/- 111 microg/g wet tissue) was lower than that found in uremic rats treated with CaCO3 (1196 +/- 180 microg/g wet tissue). Sevelamer-treated rats had less deterioration in renal function with an associated lower serum creatinine, higher creatinine clearance, and less proteinuria. There was no difference in overall mortality between the three experimental groups.


CONCLUSIONS
In long-term experimental CRF, in addition to controlling serum phosphorus and secondary hyperparathyroidism as efficiently as CaCO3, treatment with the phosphate-binder sevelamer attenuates vascular and kidney calcification.
Cozzolino
Mario
M
Renal Division, Department of Internal Medicine, Washington University School of Medicine. St. Louis, Missouri 63110, USA.
Staniforth
Mark E
ME
Liapis
Helen
H
Finch
Jane
J
Burke
Steven K
SK
Dusso
Adriana S
AS
Slatopolsky
Eduardo
E
D000818:Animals; D001011:Aorta / Q000473:pathology*; D001835:Body Weight / Q000187:drug effects; D002114:Calcinosis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D002118:Calcium / Q000097:blood / Q000652:urine; D002119:Calcium Carbonate / Q000494:pharmacology; D003404:Creatinine / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology*; D005260:Female; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D007668:Kidney / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D010280:Parathyroid Glands / Q000473:pathology; D010281:Parathyroid Hormone / Q000097:blood; D016226:Phosphorus, Dietary / Q000097:blood / Q000494:pharmacology / Q000652:urine; D011073:Polyamines; D011095:Polyethylenes / Q000494:pharmacology*; D011507:Proteinuria / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000069603:Sevelamer; D013997:Time Factors; D014511:Uremia / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*
D004852:Epoxy Compounds; D010281:Parathyroid Hormone; D016226:Phosphorus, Dietary; D011073:Polyamines; D011095:Polyethylenes; D000069603:Sevelamer; D003404:Creatinine; D002119:Calcium Carbonate; D002118:Calcium