Dyslipidemia after Kidney Transplant Fasika M. Tedla, MD, MSc Medical Director of Transplantation Assistant Professor of Medicine SUNY Downstate Medical Center

Outline Background Basics of lipoprotein biology Pathophysiology Outcomes of treatment Non-dialysis CKD Dialysis Transplant Future directions Summary

Prevalence of Cardiovascular Disease in CKD USRDS 2016 ADR

Cardiovascular Disease in CKD USRDS 2016 ADR 4

Background 1850’s:- “…plates of cholesterine” – Virchow 1901 :- Nerking suggested lipids exist in plasma bound to protein 1950’s:- Biochemical pathway, lipoprotein quantitation Framingham and other association studies J-curve 1980’s: Cholesterol reduction with sequesterants ?reduction in cardiovascular mortality 1990’s - present HMG-CoA reductase inhibitors (statins) in tertiary prevention Statins in secondary prevention Extension to subpopulations, lower targets

Lipoprotein Biology

Lipoprotein Biology

Lipoprotein Biology

The “HDL” Hypothesis Barter et al. N Engl J Med. 2007;357(21):2109-22.

Lipid Profile in CKD Hemodialysis patients Pre-dialysis CKD Triglycerides (H) Total Cholesterol (L/N) LDL (V, but usually L/N) HDL (L) Pre-dialysis CKD Similar to HD (if no proteinuria) Progression to HD pattern with declining GFR de Boer et al. Clin J Am Soc Nephrol. 2008;3(1):125-32.

Mechanism of Dyslipidemia in CKD

Lipoprotein (a) [Lp(a)] Modified LDL Higher affinity to macrophages Homologous to plasminogen Impairs fibrinolysis Variable size Levels determined by genetics Stable over time Associated with CAD Levels of larger moieties increase in CKD

HDL Changes in CKD Vaziri N. Kidney Int. 2009;76(4):437-44. Holzer M. J Am Soc Nephrol. 2015;26(9):2267-76. Bakillah A. Mediators Inflamm. 2015;2015:352356.

Changes After Transplant Complex factors Proteinuria Graft dysfunction New-onset or worsening diabetes Immunosuppressants Sirolimus > Cyclosporine > tacrolimus Mechanism unknown Impaired activity of lipases Overall Lipid profile similar to non-CKD patients Lp(a) levels decline HDL function may improve

Effect of Statin Therapy: non-dialysis CKD Study of Heart and Renal Protection (SHARP) 9,200 patients, ~ 1/3 on HD Simvastatin + ezetimibe vs placebo 10 outcome: major atherosclerotic event (coronary event or death, ischemic stroke or revascularization) 11.3% vs 13.4% Similar side effects Subgroup analysis No difference in MI or coronary death No difference in HD patients (but so if adjusted for reduction in LDL-C) Baigent C et al. Lancet. 2011;377(9784):2181.

Effect of Statin Therapy: non-dialysis CKD Outcome No. Stud. No. Subj. RR/MD All cause M 21 18762 0.81 CV mort. 20 18746 0.8 CV events 5 19363 0.75 Proteinuria (g/24h) 6 311 -0.73 CrCl 11 548 NS LFTs 10 2282 CK 2299 Navaneethan et al. Cochrane Database Syst Rev. 2009;(2):CD007784.

Effect of Statin Therapy: Hemodialysis Wanner et al. N Engl J Med 2005;353(3):238-48.

Effect of Statin Therapy: Hemodialysis Fellstrom et al. N Engl J Med. 2009;360(14):1395-407.

Effect of Statin Therapy: Renal Transplant Recipients Holdaas et al. Lancet. 2003 Jun 14;361(9374):2024-31.

Effect of Statin Therapy: Renal Transplant Recipients Holdaas et al. Am J Transplant. 2005;5(12):2929-36.

Treatment Guidelines KDIGO: NKF/K-DOQI/AST: not recently updated Treatment for Non-dialysis CKD ≥ 50 18-59 with known stroke or CAD or 10-yr risk >10% Dialysis Continue for dialysis patients already on treatment Do not start NKF/K-DOQI/AST: not recently updated symptomatic coronary disease or stroke after HD start? Non-obstructive CAD or carotid disease identified on testing? KDIGO 2013

Future Directions Reason for lack of effect in HD: ?agent, duration, subpopulation, target ?CV death due to arrhythmia/CHF What is the target for lipid lowering in CKD? β-lipoproteins? metabolic pathways other than cholesterol e.g. MTP, HDL pathway, PPAR-α agonists Effect of treatment in modern era? Newer ISx Longer dialysis vintage

Summary Lipoprotein, not simply cholesterol level, associated with atherosclerosis Both quantitative and qualitative lipoprotein abnormalities Treatment of Dyslipidemia of benefit in non-dialysis CKD Probably of benefit to renal transplant recipients No evidence for benefit in hemodialysis patients Statins are safe in CKD or after transplant