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Proteinuria and cholesterol reduction are independently associated with less renal function decline in statin-treated patients; a post hoc analysis of the PLANET trials.

ABSTRACT: BACKGROUND:Statins have shown multiple effects on different renal risk factors such as lowering of total cholesterol (TC) and lowering of urine protein:creatinine ratio (UPCR). We assessed whether these effects of statins vary between individuals, the extent of discordance of treatment effects on both TC and UPCR within an individual, and the association of responses in TC and UPCR with estimated glomerular filtration rate (eGFR) decline. METHODS:The PLANET I and II (Renal effects of Rosuvastatin and Atorvastatin in Patients Who Have Progressive Renal Disease) trials examined effects of atorvastatin and rosuvastatin on proteinuria and renal function in patients with proteinuria. We post hoc analysed 471 therapy-adherent proteinuric patients from the two trials and assessed the individual variability in UPCR and TC response from 0 to 14?weeks and whether these responses were predictive of eGFR decline during the subsequent 9?months of follow-up. RESULTS:UPCR and TC response varied between individuals: mean UPCR response was -1.3% (5th-95th percentile -59.9 to 141.8) and mean TC response was -93.9?mg/dL (-169.1 to -26.9). Out of 471 patients, 123 (26.1%) showed a response in UPCR but not in TC, and 96 (20.4%) showed a response in TC but not in UPCR. eGFR (mL/min/1.73 m2) did not decrease significantly from baseline in both UPCR responders [0.4; 95% confidence interval (CI) -1.6 to 0.9; P?=?0.54] and TC responders (0.3; 95% CI -1.8 to 1.1; P?=?0.64), whereas UPCR and TC non-responders showed a significant decline in eGFR from baseline (1.8; 95% CI 0.6-3.0; P?=?0.004 and 1.7; 95% CI 0.5-2.9; P?=?0.007, respectively). A lack of response in both parameters resulted in the fastest rate of eGFR decline (2.1; 95% CI 0.5-3.7; P?=?0.01). These findings were not different for rosuvastatin or atorvastatin. CONCLUSIONS:Statin-induced changes in cholesterol and proteinuria vary between individuals and do not run in parallel within an individual. The initial fall in cholesterol and proteinuria is independently associated with a reduction in eGFR decline. This highlights the importance of monitoring both cholesterol and proteinuria after initiating statin therapy.

SUBMITTER: Idzerda NMA

PROVIDER: S-EPMC6775475 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Proteinuria and cholesterol reduction are independently associated with less renal function decline in statin-treated patients; a post hoc analysis of the PLANET trials.

Idzerda Nienke M A NMA Pena Michelle J MJ Parving Hans-Henrik HH de Zeeuw Dick D Heerspink Hiddo J L HJL

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20191001 10

<h4>Background</h4>Statins have shown multiple effects on different renal risk factors such as lowering of total cholesterol (TC) and lowering of urine protein:creatinine ratio (UPCR). We assessed whether these effects of statins vary between individuals, the extent of discordance of treatment effects on both TC and UPCR within an individual, and the association of responses in TC and UPCR with estimated glomerular filtration rate (eGFR) decline.<h4>Methods</h4>The PLANET I and II (Renal effects ...[more]

PMID: 30184238

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Project description:Administered at maximal dosages, the most common statins--atorvastatin, simvastatin and rosuvastatin--lower low-density lipoprotein cholesterol (LDLC) by an average of 37-57% in patients with primary hypercholesterolemia. We hypothesized novel genetic underpinnings for variation in LDLC levels in the context of statin therapy.Genotyping of 384 SNPs in 202 volunteers from a lipid outpatient clinic was accomplished and LDLC levels obtained from chart records. The SNPs were distributed across 222 genes representing physiological pathways such as general metabolism, cholesterol biochemistry, cardiovascular function, inflammation, neurobiology and cell proliferation. We discovered significant associations with LDLC levels for the rs34274 SNP (p < 0.0002) and for rs2241220 (p < 0.008) in the acetyl-coenzyme A carboxylase beta (ACACB) gene. When corrected for multiple testing, the false-discovery rate associated with rs34274 was 0.076 (significance threshold: 0.10) and for rs2241220 the false-discovery rate was 0.93 (not significant). The acetyl coenzyme A carboxylase beta enzyme synthesizes malonyl coenzyme A, an essential substrate for hepatic fatty acid synthesis and an inhibitor of fatty acid oxidation.The SNPs were in weak linkage disequilibrium (D = 0.302). Minor alleles at these sites demonstrate opposing influences on LDLC; the C>T substitution at rs34724 is a risk marker and the C>T substitution at rs2241220 a protective marker for LDLC levels. These SNPs hypothetically influence enzymatic activity through different mechanisms, rs34274 through the PII promoter and rs2241220 via alteration of the protein's responsiveness to allosteric influence.Physiogenomic evidence suggests a novel link between LDLC levels and the regulation of fatty acid metabolism. The findings complement previously discovered novel SNP relationships to myalgia (pain) and myositis (serum creatine kinase activity). By genotyping for myositis, myalgia and LDLC levels, a physiogenomic model may be developed to help clinicians maximize effectiveness and minimize side effects in prescribing statins.

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Proteinuria and cholesterol reduction are independently associated with less renal function decline in statin-treated patients; a post hoc analysis of the PLANET trials.

Publications

Proteinuria and cholesterol reduction are independently associated with less renal function decline in statin-treated patients; a post hoc analysis of the PLANET trials.

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