Conversion from Tacrolimus to Cyclosporine A Improves Glucose Tolerance in HCV-Positive Renal Transplant Recipients.

BACKGROUND:Calcineurin-inhibitors and hepatitis C virus (HCV) infection increase the risk of post-transplant diabetes mellitus. Chronic HCV infection promotes insulin resistance rather than beta-cell dysfunction. The objective was to elucidate whether a conversion from tacrolimus to cyclosporine A affects fasting and/or dynamic insulin sensitivity, insulin secretion or all in HCV-positive renal transplant recipients. METHODS:In this prospective, single-center study 10 HCV-positive renal transplant recipients underwent 2h-75g-oral glucose tolerance tests before and three months after the conversion of immunosuppression from tacrolimus to cyclosporine A. Established oral glucose tolerance test-based parameters of fasting and dynamic insulin sensitivity and insulin secretion were calculated. Data are expressed as median (IQR). RESULTS:After conversion, both fasting and challenged glucose levels decreased significantly. This was mainly attributable to a significant amelioration of post-prandial dynamic glucose sensitivity as measured by the oral glucose sensitivity-index OGIS [422.17 (370.82-441.92) vs. 468.80 (414.27-488.57) mL/min/m2, p = 0.005), which also resulted in significant improvements of the disposition index (p = 0.017) and adaptation index (p = 0.017) as markers of overall glucose tolerance and beta-cell function. Fasting insulin sensitivity (p = 0.721), insulinogenic index as marker of first-phase insulin secretion [0.064 (0.032-0.106) vs. 0.083 (0.054-0.144) nmol/mmol, p = 0.093) and hepatic insulin extraction (p = 0.646) remained unaltered. No changes of plasma HCV-RNA levels (p = 0.285) or liver stiffness (hepatic fibrosis and necroinflammation, p = 0.463) were observed after the conversion of immunosuppression. CONCLUSIONS:HCV-positive renal transplant recipients show significantly improved glucose-stimulated insulin sensitivity and overall glucose tolerance after conversion from tacrolimus to cyclosporine A. Considering the HCV-induced insulin resistance, HCV-positive renal transplant recipients may benefit from a cyclosporine A-based immunosuppressive regimen. TRIAL REGISTRATION:ClinicalTrials.gov NCT02108301

The Impact of PNPLA3 rs738409 SNP on Liver Fibrosis Progression, Portal Hypertension and Hepatic Steatosis in HIV/HCV Coinfection - Fig 2

<p><b>A:</b> Proportion of patients with METAVIR F3/F4 according to PNPLA3-SNP. <b>B:</b> Fibrosis progression rate according to PNPLA3-SNP. <b>C:</b> Levels of aminotransferases according to PNPLA3 genotype. <b>D:</b> Portal pressure (HVPG) according to PNPLA3 genotype. <b>E:</b> Hepatic steatosis (assessed by CAP) according to PNPLA3 genotype. <b>F:</b> Levels of y-glutaryl transaminases according to PNPLA3 genotype. Abbreviations: PNPLA3 (patatin-like phospholipase domain-containing protein 3), SNP (single nucleotide polymorphism), HVPG (hepatic venous pressure gradient), CAP^™ (Controlled Attenuation Parameter).</p

Metabolic parameters before and three months after conversion.

<p>Determination of plasma glucose (A), serum insulin (B) and C-peptide (C) levels by OGTTs performed prior to (full symbols) and three months after (blank symbols) the conversion from taxrolimus to cyclosporine A. Data are expressed as median (IQR). + indicates p <0.05 (in detail for plasma glucose levels: p = 0.012 at 0min, p = 0.025 at 30 min, p = 0.059 at 60 min, p = 0.022 at 90 min, p = 0.028 at 120 min).</p

Correlation analyses.

<p>Scatter plots showing the correlation between tacrolimus trough levels and fasting insulin levels before conversion from tacrolimus to cyclosporine A.</p

Trend flow chart.

<p>Trend flow chart.</p

Factors independently associated with advanced fibrosis (F3/F4).

<p>Factors associated with advanced fibrosis in HIV/HCV coinfection in an univariable as well as a multivariable analysis; factors in univariable analysis are shown as mean ± SD or number (percentage) of patients; on the right side all factors included in the multivariable analysis are shown, factors written in bold remained in the final model; Abbreviations: UVA (univariable analysis), MVA (multivariable analysis).</p><p>Factors independently associated with advanced fibrosis (F3/F4).</p

Patient characteristics according to PNPLA3 genotypes.

<p>Patient characteristics (demographic data, data on HIV/HCV coinfection, IL28B-genotype, data on liver fibrosis, hepatic steatosis, liver stiffness, fibrosis progression rate and hepatic venous pressure gradient) according to PNPLA3 (patatin-like phospholipase domain-containing protein 3)-risk allele; continuous variables shown as mean ± SD or median (IQR); Abbreviations: SNP (single nucleotide polymorphism), IVDU (intravenous drug-use), MSM (men having sex with men), CAP^™ (Controlled Attenuation Parameter), HVPG (hepatic venous pressure gradient).</p><p>Patient characteristics according to PNPLA3 genotypes.</p

Virological response to PEGIFN/RBV by PNPLA3-SNP and IL28B-SNP.

<p>Virologic response rates (rapid virological response, complete early virological response and sustained virological response) to PEGIFN/RBV by PNPLA3-SNP and IL28B-SNP; reported as number (percentage) of patients; Abbreviations: PNPLA3 (patatin-like phospholipase domain-containing protein 3), IL28B (interleukin 28B), RVR (rapid virological response), cEVR (complete early virological response), SVR (sustained virological response).</p><p>Virological response to PEGIFN/RBV by PNPLA3-SNP and IL28B-SNP.</p

Patient flowchart showing the number of HIV/HCV coinfected patients referred to the Medical University of Vienna, the number of patients included / excluded from the study and the number of patients undergoing assessment of hepatic fibrosis and steatosis as well as portal pressure and the number of patients treated with PEGIFN/RBV; Abbreviations: TE (transient elastography), HVPG (hepatic venous pressure gradient), CAP^™ (Controlled Attenuation Parameter).

<p>Patient flowchart showing the number of HIV/HCV coinfected patients referred to the Medical University of Vienna, the number of patients included / excluded from the study and the number of patients undergoing assessment of hepatic fibrosis and steatosis as well as portal pressure and the number of patients treated with PEGIFN/RBV; Abbreviations: TE (transient elastography), HVPG (hepatic venous pressure gradient), CAP^™ (Controlled Attenuation Parameter).</p