Statin induced proteinuria: renal injury or renoprotection?

Meticulous blood pressure control, particularly with antiproteinuric medications, such as ACE inhibitors and angiotensin receptor blockers (ARBs), have proven to be effective in slowing the progression of kidney disease and are pillars in the modern management of chronic kidney disease (CKD). However, despite careful attention to blood pressure lowering and the use of ACEi and/or ARBs, progression of renal disease remains the rule. Furthermore, blood pressure control and renin angiotensin system (RAS) blockade has not been successful in reducing the extremely high incidence of cardiovascular disease in patients with CKD. Thus, an unfulfilled need exists for reducing progression of renal and cardiovascular disease patients with CKD. HMG-CoA reductase inhibitors (statins) represent a particularly attractive class of medications for CKD patients. Statins have dramatically improved cardiovascular outcomes in patients without significant kidney disease and may prove to have similar effects in patients with kidney disease. However, careful attention should be paid to some new data on the renal effects of statins. Preclinical studies done with all statins have shown to produce renal tubular degeneration in high doses (1). Proteinuria commonly occurs with high dose statin therapy. Although this adverse effect has long been recognized, the phenomenon resurfaced as a result of clinical trials conducted with a highly potent statin, rosuvastatin. With the highest dose of rosuvastatin tested in clinical trials (80 mg) a high incidence of proteinuria and hematuria was seen and was accompanied by isolated cases of renal failure some of which were associated with myopathy (2). The 80 mg dose of rosuvastatin was not approved by the FDA for clinical use. Nevertheless, an interest into the mechanism of this phenomenon of proteinuria was kindled. Receptor mediated endocytosis (RME) is the process that is responsible for albumin uptake in proximal tubular cells. RME of proteins in the proximal tubules occurs via megalin and cubulin receptors (3) requires the presence of prenylated GTP binding proteins. Statins reduce the activity of mevalonate, which is required for the generation of isoprenoid pyrophosphates. Isoprenoid pyrophosphates are required for prenylation of GTP binding proteins and can impair RME. Sidaway et al. performed experiments in cell cultures of proximal tubular cells derived from the opossum kidney to test the hypothesis that statins reduce RME by reduced prenylation of GTP binding proteins (4). The following set of observations made by Sidaway et al. support the hypothesis that statins reduce albumin uptake by RME (4). First, there was a dose dependent reduction in RME. Second, the degree of inhibition in RME was related to the in vitro inhibition of HMG-CoA reductase that was related to the lipophilicity of the statin. Thus, the IC50 of simvastatin in reducing cholesterol synthesis was 1/50th that of pravastatin, and predictably simvastatin produced greater impairment in RME. Third, the reduction in RME was not related to binding of albumin to the receptor but receptor mediated albumin endocytosis and was shared by other proteins such as 2-microglobulin. What was the mechanism of reduction in RME? The authors provide evidence that impairment of prenylation of GTP-binding proteins may be etiologically related to reduced RME. Inhibition of RME was associated with the time-dependent appearance of unprenylated Rap1A, a GTP-binding protein. Second, the impairment in RME was reversed by the addition of mevalonate and by the addition of the isoprenoid, geranylgeranyl pyrophosphate. Third, RME was impaired independently by reduction of prenylation induced by the addition of farnesyl and geranylgeranyl transferase inhibitors. Finally, addition of cholesterol did not correct the impairment in RME providing further evidence that RME was not impaired due to reduction in cholesterol synthesis but as a direct result of prenylation of GTP-binding proteins. Whether the above phenomenon is replicated in human kidney cells was evaluated by Verhulst et al (5). In primary cultures of human kidney cells harvested from the intact kidney region of cancerous kidneys, the authors demonstrated RME by microscopy, flow cytometry, and spectrofluorometry in the proximal tubular cells that was inhibited in a dose-dependent way by statins (simvastatin rosuvastatin pravastatin) without altering cell viability. Mevalonate reversed the impairment of RME induced by statins. These data provide a mechanism for the occurrence of proteinuria with rosuvastatin. Gel electrophoresis of urine in patients receiving rosuvastatin showed a “tubular pattern”, which was confirmed by increased levels of low-molecularweight proteins such as 1-microglobulin, 2-microglobulin, and retinal binding proteins, that also undergo RME (1). Back titration showed greatest reductions in low-molecular-weight Correspondence to Dr. Rajiv Agarwal, VAMC, 111N, 1481 West 10 Street, Indianapolis, IN 46202. Phone: 317-554-0000 x2241; Fax: 317-554-0298; E-mail: [email protected]