Comparison of the effects of standard vs low-dose prolonged-release tacrolimus with or without ACEi/ARB on the histology and function of renal allografts.

Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.

Development of end stage renal disease following an acute cardiac event.

We determined the rate and risk factors for end-stage renal disease (ESRD) in consecutive patients discharged after a cardiac event in a large, unbiased Canadian cohort that receives universal health coverage. A total of 8236 adults hospitalized over a 2 year period were followed for up to 7.5 years and the incidence of ESRD and mortality determined. Of these, 113 reached ESRD (stage 5). Patients with moderate (stage 3) and severe (stage 4) renal insufficiency were more likely to develop ESRD than those patients at stage 1 or 2. However, patients with moderate renal insufficiency were 78.6 times more likely to die than to develop ESRD. Absolute rates of progression to ESRD per 100-patient years were 0.08 at stages 1 and 2, 0.17 at stage 3 and 4.27 at stage 4. Age, diabetes, hypertension and congestive heart failure also predicted ESRD. We found that patients with stage 4 disease are at high risk of ESRD after a cardiac admission while those at stage 3 are far more likely to die than to develop ESRD.

Outcomes of acute coronary syndrome in a large Canadian cohort: impact of chronic renal insufficiency, cardiac interventions, and anemia.

BACKGROUND: Chronic renal insufficiency (CRI) has been identified as an important risk factor for cardiac events. Studies in the United States reported decreased survival and decreased use of surgical and medical interventions after myocardial infarction in patients with CRI. METHODS: We studied the impact of renal function on health outcomes in a Canadian cohort of consecutive patients admitted with acute coronary syndrome (ACS) between October 1997 and October 1999. The study design is an observational cohort of 5,549 adult patients who survived to discharge with a discharge diagnosis of ACS. Renal function is classified into 4 levels: (1) normal, glomerular filtration rate (GFR) greater than 80 mL/min/1.73 m2 (>1.33 mL/s); (2) mild CRI, GFR of 60 to 80 mL/min/1.73 m2 (1.00 to 1.33 mL/s); (3) moderate CRI, GFR of 30 to 59 mL/min/1.73 m2 (0.50 to 0.98 mL/s); and (4) severe CRI, GFR less than 30 mL/min/1.73 m2 (<0.50 mL/s). The primary outcome is death. RESULTS: Advanced and moderate CRI independently predicted death (hazard ratio, 1.06; 95% confidence interval [CI], 1.01 to 1.12; and hazard ratio, 1.23; 95% CI, 1.18 to 1.29). Severe anemia (hemoglobin level < 9.0 g/dL [<90 g/L]) also was an independent risk factor for death (hazard ratio, 1.38; 95% CI, 1.18 to 1.61). Use of beta-blockers (hazard ratio, 0.91; 95% CI, 0.86 to 0.97), acetylsalicylic acid (hazard ratio, 0.90; 95% CI, 0.84 to 0.97), lipid-lowering therapy (hazard ratio, 0.84; 95% CI, 0.78 to 0.89), and medical thrombolysis (hazard ratio, 0.89; 95% CI, 0.81 to 0.97) were associated with reduced risk for death. Medical interventions with beta-blockers, acetylsalicylic acid, lipid-lowering therapy, and thrombolysis and surgical intervention were significantly less likely to be used in patients with CRI. CONCLUSION: Despite universal access to health care, Canadian patients with CRI are more likely to die after a cardiac event and less likely to receive important interventions.

Generic immunosuppression in solid organ transplantation: a Canadian perspective.

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

Similar outcomes for Canadian renal transplant recipients followed up in transplant centers and satellite clinics.

BACKGROUND: A significant proportion of long-term care for renal transplant recipients (RTRs) in Canada is provided by community nephrologists in satellite clinics (SCs). The outcomes of RTRs followed up in SCs have not been formally compared with those followed up in transplant centers (TCs). METHODS: This multicenter retrospective study from 13 TCs and SCs across Canada compared patient and graft outcomes in RTRs with a functioning graft more than or equal to 18 months. Data were abstracted at 6 to 18 months posttransplantation, and at last visit (if >18 months). Patients were stratified in a 1:1 ratio between TCs and SCs, and by a 3:1 ratio between cyclosporine A and tacrolimus. The primary outcome was change (Δ) in Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR) from 6 to 18 months posttransplantation (ΔeGFRM18-6). Secondary outcomes included the prevalence of hyperlipidemia, diabetes, and hypertension. RESULTS: A total of 264 RTRs followed at TCs and SCs demonstrated broad similarity in baseline recipient and donor characteristics. ΔeGFRM18-6 were similar for TCs versus SCs and better for tacrolimus versus cyclosporine A (P=0.022). There was no difference in lipid levels between TCs and SCs during 6 to 18 months, although low-density lipoprotein cholesterol was lower in SCs versus TCs at most recent visit (2.6 vs. 2.3 mmol/L; P=0.003). Fasting blood glucose levels were similar in TCs and SCs. Comparable target blood pressure levels were achieved, and the prevalence of hypertension was similar for both TCs and SCs at all time points. CONCLUSION: Short-term graft and patient outcomes are similar in TC and SC RTRs, supporting the feasibility of follow-up patient care outside major TCs.