Jeffrey S. Zaltzman

A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group.

BACKGROUNDnThe safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study.nnnMETHODSnBetween September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons.nnnRESULTSnThe mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P<0.05). Serum creatinine and creatinine clearance did not change in either treatment group throughout the study. Biopsy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histologically proven acute rejection in an additional three patients (0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA (P=NS). Serum creatinine rose transiently in 35 patients (9.8%) receiving ConCsA and 138 patients (18.7%) receiving MeCsA (P<0.05) and resolved either spontaneously or after a reduction in the cyclosporine dose. One graft was lost in the MeCsA group due to irreversible rejection, and seven patients died, three in the group receiving ConCsA and four of those receiving MeCsA (P=NS). Absorption of cyclosporine was more rapid and complete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug (P<0.001). There was close correlation between area under the time-concentration curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, making AUC over the first 4 hr a good predictor of total cyclosporine exposure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 and 6, whereas there was no change in those who continued on ConCsA. A limited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, particularly for patients receiving MeCsA (r2=0.94 MeCsA vs. r2=0.89 ConCsA).nnnCONCLUSIONSnMeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.

Reduced Incidence of New-Onset Diabetes Mellitus after Renal Transplantation with 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors (Statins)

Statins have anti‐inflammatory effects, modify endothelial function and improve peripheral insulin resistance. We hypothesized that statins influence the development of new‐onset diabetes mellitus in renal transplant recipients. The records of all previously non‐diabetic adults who received an allograft in Toronto between January 1, 1999 and December 31, 2001 were reviewed with follow‐up through December 31, 2002. All patients receiving cyclosporine or tacrolimus, mycophenolate mofetil and prednisone were included. New‐onset diabetes was diagnosed by the Canadian Diabetic Association criteria: fasting plasma glucose ≥7.0 mmol/L or 2‐h postprandial glucose ≥11.1 mmol/L on more than two occasions. Statin use prior to diabetes development was recorded along with other variables. Cox proportional hazards models analyzing statin use as a time‐dependent covariate were performed. Three hundred fourteen recipients met study criteria, of whom 129 received statins. New‐onset diabetes incidence was 16% (n = 49). Statins (p = 0.0004, HR 0.238[0.109–0.524]) and ACE inhibitors/ARB (p = 0.01, HR 0.309[0.127–0.750]) were associated with decreased risk. Prednisone dose (p = 0.0001, HR 1.007[1.003–1.010] per 1 mg/d at 3 months), weight at transplant (p = 0.02, HR 1.022[1.003–1.042] per 1 kg), black ethnicity (p = 0.02, HR 1.230[1.023–1.480]) and age ≥45 years (p = 0.01, HR 2.226[1.162–4.261]) were associated with increased diabetes. Statin use is associated with reduced new‐onset diabetes development after renal transplantation.

Accurate measurement of impaired glomerular filtration using single-dose oral cimetidine☆☆☆

To improve the validity of a timed creatinine clearance as a measure of glomerular filtration rate (GFR), we investigated whether a single 800-mg dose of oral cimetidine was sufficient to inhibit tubular secretion of creatinine (TScr). Forty-five 3-hour timed creatinine clearances (Clcr) with single 800-mg dose oral cimetidine (TCC) in 17 renal transplant recipients with marked renal function impairment (creatinine 2.0 to 7.1 mg/dL) were compared with simultaneous [125I]-iothalamate GFR (Cliothal). For comparison, 13 timed Clcr without cimetidine (TC), and 36 24-hour Clcr were performed. The TCC was the most accurate: the ratio (mean +/- SD) of TCC:Cliothal was 1.12 +/- 0.02, compared with 1.33 +/- 0.08 for Clcr:Cliothal and 1.53 +/- 1.02 for TC:Cliothal. The difference between Cliothal and TCC was small over the range of GFRs tested (mean +/- 2 SD), 0.9 +/- 2.5 mL/min/1.73 m2. The intraclass correlation (R) for within-subject reproducibility of the TCC in five subjects was 0.8 (95 percent CI; 0.5, 0.9), and in 11 subjects who had at least three GFR determinations over 24 weeks, the TCC was as responsive to change in GFR as Cliothal. There was an inverse relationship between fractional excretion of cimetidine and GFR (r2 = -0.70), suggesting increased tubular secretion of cimetidine with decreasing GFR. In conclusion, a single 800-mg oral dose of cimetidine was effective in inhibiting TScr such that the TCC was an accurate, reproducible, and responsive test of GFR.

Association of Uric Acid With Inflammation, Progressive Renal Allograft Dysfunction and Post-Transplant Cardiovascular Risk

Hyperuricemia is common after kidney transplantation. Although its risk factors are well established, its relation to inflammation, progressive renal dysfunction, and cardiovascular events is unknown. In this study, 405 stable renal transplant recipients with > or = 3 uric acid (UA) and C-reactive protein measurements from January 2005 to April 2008 were identified to determine the relations between UA and C-reactive protein and between UA and the rate of decrease in the estimated glomerular filtration rate (eGFR; using the Modification of Diet in Renal Disease equation) and cardiovascular events. Hyperuricemia was defined as UA >7.1 mg/dl (420 micromol/L) in men and >6.1 mg/dl (360 micromol/L) in women. The prevalence of hyperuricemia was 44% (180 of 405). Hyperuricemia was negatively associated with eGFR (p <0.0001) and positively associated with diuretic use (p = 0.013), time since transplantation (p = 0.014), and triglycerides (p = 0.04). Although UA was correlated with C-reactive protein (p = 0.003), adjustment for eGFR rendered this relation nonsignificant (p = 0.225). The slope of eGFR was +0.144 +/- 0.85 ml/min/1.73 m(2)/month (95% confidence interval 0.032 to 0.257) in those with normal UA levels and -0.091 +/- 0.93 ml/min/1.73 m(2)/month (95% confidence interval -0.235 to +0.054) in patients with hyperuricemia (p = 0.003). There were 17 cardiovascular events in the patients with hyperuricemia and 4 in those with normal UA levels (p = 0.001). In conclusion, hyperuricemia is associated with a decrease in renal allograft function and may be an independent cardiovascular risk factor in transplant recipients. Further studies are needed to establish its role in post-transplantation cardiovascular disease.

The role of dietary cations in the blood pressure of renal transplant recipients

Abstract:u2002 Background:u2002 The role of dietary cations in hypertension has been evaluated in the general population and selected subgroups, but its contribution to blood pressure (BP) elevations in patients with functional renal allografts has not been critically examined.

Metabolic syndrome definitions and components in predicting major adverse cardiovascular events after kidney transplantation

Metabolic syndrome (MetS) associates with cardiovascular risk post‐kidney transplantation, but its ambiguity impairs understanding of its diagnostic utility relative to components. We compared five MetS definitions and the predictive value of constituent components of significant definitions for major adverse cardiovascular events (MACE) in a cohort of 1182 kidney transplant recipients. MetS definitions were adjusted for noncomponent traditional Framingham risk factors and relevant transplant‐related variables. Kaplan–Meier, logistic regression, and Cox proportional hazards analysis were utilized. There were 143 MACE over 7447 patient‐years of follow‐up. Only the World Health Organization (WHO) 1998 definition predicted MACE (25.3 vs 15.5 events/1000 patient‐years, P = 0.019). Time‐to‐MACE was 5.5 ± 3.5 years with MetS and 6.8 ± 3.9 years without MetS (P < 0.0001). MetS was independent of pertinent MACE risk factors except age and previous cardiac disease. Among MetS components, dysglycemia provided greatest hazard ratio (HR) for MACE (1.814 [95% confidence interval 1.26–2.60]), increased successively by microalbuminuria (HR 1.946 [1.37–2.75]), dyslipidemia (3.284 [1.72–6.26]), hypertension (4.127 [2.16–7.86]), and central obesity (4.282 [2.09–8.76]). MetS did not affect graft survival. In summary, although the WHO 1998 definition provides greatest predictive value for post‐transplant MACE, most of this is conferred by dysglycemia and is overshadowed by age and previous cardiac disease.

A comparison of the effects of C2-cyclosporine and C0-tacrolimus on renal function and cardiovascular risk factors in kidney transplant recipients.

Background. There are few data directly comparing the effects of two-hour postingestion monitored cyclosporine (C2-CsA) vs. trough-monitored tacrolimus (C0-Tac) on renal function and cardiovascular risk factors. Methods. We studied 378 (202 C2-CsA vs. 176 C0-Tac) incident kidney transplant recipients in Toronto, Canada, from August 1, 2000 and December 31, 2003. Outcomes included changes in estimated glomerular filtration rate (eGFR at 1 and 6 months by modification of diet in renal disease four-variable equation), mean arterial pressure (MAP), total cholesterol (TC), and new-onset diabetes mellitus (NODM) at six months posttransplant. The independent effect of treatment/monitoring strategies on continuous outcomes and time-to-NODM was modeled using linear and Cox regression, respectively. Results. Mean eGFR was 59.5 vs. 62.9 ml/min at one month and 50.6 vs. 61.2 ml/min at six months for C2-CsA vs. C0-Tac, respectively. Multiple linear regression revealed the slope of eGFR to be 0.93 ml/min/month lower in C2-CsA patients. This was equivalent to an adjusted average eGFR difference of 4.64 ml/min between months one and six posttransplant. There was no significant difference in average MAP and TC. In a stepwise multivariable Cox model and a propensity score analysis, there was no significant association between the type of treatment/monitoring strategy and time-to-NODM. Conclusions. There was a greater decline in eGFR for patients on C2-CsA (vs. C0-Tac) between one and six months posttransplant. However, MAP, TC, and the risk of NODM were comparable in both treatment/monitoring groups. The long-term impact of short-term reductions in eGFR as a function of the type of treatment/monitoring strategy requires further study.

Microalbuminuria post-renal transplantation: relation to cardiovascular risk factors and C-reactive protein

Abstract:u2002 Microalbuminuria predicts graft loss and all‐cause mortality in renal transplant recipients. In the general population, it clusters with both traditional cardiovascular risk factors and elevated C‐reactive protein (CRP). Our objective was to define the relationship between microalbuminuria and these risk factors in stable renal transplant recipients. We identified 222 stable recipients who were minimum twou2003months post‐transplant and provided three urine albumin‐to‐creatinine ratio (ACR) measurements, excluding those with recent illness and proteinuria. Microalbuminuria was defined as averaged ACRu2003≥u20032.0 in men and 2.8u2003mg/mmol in women (Canadian Diabetes Association 2003). Risk factors associated with microalbuminuria were determined by multivariate logistic regression analysis. Averaged ACR correlated to CRP (Ru2003=u20030.21, pu2003=u20030.001). Prevalence of microalbuminuria was 48% (108/222). Patients with microalbuminuria had higher CRP (7.01u2003±u20038 vs. 3.21u2003±u20033u2003mg/L, pu2003<u20030.0001) and systolic BP (129u2003±u200317 vs. 123u2003±u200312u2003mmHg, pu2003=u20030.004). Microalbuminuria was associated with increasing CRP [odds ratio 1.129 per 1u2003mg/L (95% CI 1.058–1.204), pu2003=u20030.0002], SBP [1.248 per 10u2003mmHg (1.023–1.522), pu2003=u20030.029] and smoking [1.938 (1.023–3.672), pu2003=u20030.042]. Post‐transplant microalbuminuria is prevalent and is associated with elevated CRP, elevated BP, and smoking. Its relationship to these factors suggests it may be an indicator of graft and patient health.

A randomized cross-over comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily tacrolimus on renal function in healthy volunteers.

Calcineurin inhibitor nephrotoxicity remains an issue for transplant recipients. The pharmacokinetic profile (PK) of the once‐daily tacrolimus extended release (Tac‐ER) includes equivalent exposure [AUC(0–24 h)] but lower Cmax versus twice‐daily tacrolimus immediate release (Tac‐IR). We hypothesized that the unique PK profiles would result in pharmacodynamic differences in renal function. Nineteen healthy male subjects were allocated to once‐daily Tac‐ER and twice‐daily Tac‐IR in a prospective, randomized, two period, cross‐over study. Tacrolimus was titrated to achieve trough levels of 8–12 ng/ml. Twenty four hours ERPF and GFR estimated by para‐aminohippurate and sinistrin clearance were performed at baseline and at the end of each 10‐day dosing period. Mean Tac C0 was 11.0 ± 2.2 and 11.3 ± 1.8 ng/ml for Tac‐ER and Tac‐IR, respectively. The mean Effective 24 h renal plasma flow (ERPF) was significantly higher with Tac‐ER compared with Tac‐IR (658 ± 127 vs. 610 ± 93 ml/min/1.73 m2, P = 0.046). There was a trend to a greater mean GFR over 24 h for Tac‐ER at 114.5 ± 13.6 ml/min/1.73 m2 compared with 108.9 ± 9.7 ml/min/1.73 m2 for Tac‐IR, P = 0.116. Under controlled physiological conditions, ERPF was significantly improved with Tac‐ER compared with Tac‐IR, likely owing to the differing PKs of these tacrolimus preparations (ClinicalTrials.gov Identifier: NCT01681134).

Seasonal Variation of Serum Lipid Levels in Stable Renal Transplant Recipients

Background/Aims: Seasonal variation in lipid levels is well described in the general population, but has not been examined in renal transplant recipients (RTR). We sought to determine whether seasonal differences exist in RTR, a group at high risk for hyperlipidemia. Methods: We reviewed our population of 920 adults, identifying primary allograft recipients with survival ≧1 year, stable function, and ≧1 pair of post-6 months ‘winter’ (December 21 to March 20) plus ‘summer’ (June 21 to September 22) fasting lipid measurements within the same year. Correlations between factors affecting lipids and lipid level change were followed by multiple linear regression analysis. Results: 243 patients contributed 344 pairs. When most recent seasonal pair (n = 243) and all pairs (n = 344) were separately analyzed, no seasonal total cholesterol difference (winter vs. summer) was seen (5.08 vs. 5.05 mmol/l, p = 0.80; 5.11 vs. 5.09 mmol/l, p = 0.81 respectively). Opposing variation was seen between hyperlipidemic and nonhyperlipidemic patients (0.08 vs. –0.18 mmol/l for winter minus summer, p = 0.02). In multivariate analysis, seasonal cholesterol variation was predicted by level (p < 0.0001) and hemoglobin change (p = 0.01), while triglyceride variation was predicted only by level (p = 0.01). Conclusion: RTR do not exhibit seasonal variation in lipids, unlike the general population. Factors unique to RTR such as immunosuppressive therapies may act to suppress any seasonal effects.