Lipid nephrotoxicity: new concept for an old disease.

The prevalence of obesity in the United States remains high, exceeding 30% in most states. As this trend continues unhindered, we will continue see a persistent rise in obesity-related metabolic effects­hypertension, dyslipidemia, diabetes mellitus, and atherosclerosis. These diseases are also the leading causes of chronic kidney diseases and end-stage renal disease. The lipid nephrotoxicity hypothesis, proposed over three decades ago, suggested that proteinuria, decreased albumin levels, and the resultant hyperlipidemia may cause a glomerulosclerosis similar to atherosclerosis. More recent studies have demonstrated the role of oxidized high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles in the progression of kidney disease. Elucidation of the role of lipid-lowering therapies and the concomitant improvement in tubulointerstitial and glomerular diseases is a further evidence of the role of lipids in renal injury. Synergistic effects of lipid-lowering drugs and blockers of the renin-angiotensin-aldosterone system (RAAS) in renal protection have also been documented. Dyslipidemia in renal disease is usually characterized by elevated LDL cholesterol, low HDL cholesterol, and high triglycerides. After an initial glomerular injury, likely to be inflammatory, a series of self-perpetuating events occur. Increased glomerular basement permeability leads to loss of lipoprotein lipase activators, which results in hyperlipidemia. Circulating LDL has a charge affinity for glycoaminoglycans in the glomerular basement membrane and further increases its permeability. Substantial amounts of filtered lipoprotein cause proliferation of mesangial cells. Proximal tubules reabsorb some of the filtered lipoprotein, and the remainder is altered during passage through the nephron. If intraluminal pH is close to the isoelectric point of the apoprotein, luminal apoprotein will precipitate, causing tubulointerstitial disease. This review shows the evidence for the role of lipids in development of chronic renal disease, the pathophysiology of lipid nephrotoxicity, and strategies available to clinicians to slow the progression of disease.

Effects of additive therapy with spironolactone on proteinuria in diabetic patients already on ACE inhibitor or ARB therapy: results of a randomized, placebo-controlled, double-blind, crossover trial.

INTRODUCTION: Aldosterone seems to have deleterious effects on the kidneys. Many animal studies and a few clinical trials have shown that suppression of aldosteroneby aldosterone receptor blockers ameliorates these effects. METHOD: In a double-blind crossover study, patients with diabetic nephropathy who were already receiving either angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) were given spironolactone or matching placebo with 1 month of washout in between. Blood pressure (BP), serum creatinine, serum potassium, and spot urine protein/creatinine were measured at the beginning and end of each study period. RESULTS: Mean systolic BP on spironolactone went down from 153.64 (+/-25.95) at the beginning to 141.60 (+/-16.54) at the end of study (P = 0.01). Diastolic BP during spironolactone therapy did not change significantly. The urine protein/creatinine increased from 1.24 (+/-1.13) to 1.57 (+/-2.13) on placebo (P = 0.35) and decreased from 1.80 (+/-1.78) to 0.79 (+/-0.99) during spironolactone therapy (P = 0.004). In other words proteinuria increased by 24% during the placebo treatment period but decreased by half (57%) during the active treatment. Serum potassium increased from 4.29 (+/-0.47) to 4.64 (+/-0.55) during spironolactone therapy (P = 0.002), no significant change with placebo. Whereas serum creatinine did not change on placebo, it increased from 1.35 (+/-0.54) to 1.56 (+/-0.62) on spironolactone (P = 0.006). Glomerular filtration rate decreased from 61.91 (+/-23.4) to 53.94 (+/-23.58) on spironolactone (P = 0.0001) but not on placebo. CONCLUSIONS: Addition of a modest dose of spironolactone to a regimen of ACEI or ARB in patients with diabetic proteinuria causes further reduction in proteinuria and also lowers the systolic BP. As with ACEI or ARB, spironolactone modestly reduces the glomerular filtration rate and raises serum potassium.