Post-transplant outcomes in recipients of living donor kidneys and intended recipients of living donor kidneys.

BACKGROUND: Long-term kidney transplant survival at the population level is consistently favorable, but this survival varies widely at an individual level due to both recipient and donor factors. The distinct contribution of recipient and donor factors to individual post kidney transplant outcome remains unclear. Comparing outcomes in deceased donor (DD) recipients with potential but non-actualized living donors (DD1) to those recipients with actualized living donors (LD), and to DD recipients without potential living donors (DD0) may provide transplant candidates with more information about their own post-transplant prognosis. METHODS: We conducted an observational retrospective cohort study of kidney transplant candidates presenting to our centre for evaluation between 01/01/06 and 31/12/18, and who also received a transplant during that time. Patients were followed to 31/08/2019. Candidates were classified as DD0, DD1, or LD based on whether they had an identified living donor at the time of initial pre-transplant assessment, and if the donor actualized or not. Primary outcome was 5-year death-censored graft survival, adjusted for common pre- and post-transplant donor and recipient risk factors. Secondary outcomes analyzed included patient survival and graft function. RESULTS: There were 453 kidney transplant recipients (LD = 136, DD1 = 83, DD0 = 234) who received a transplant during the study period. DD0 and DD1 did not differ in key donor organ characteristics. The 5-year death censored graft survival of DD1 was similar to LD (p = 0.19). DD0 graft survival was inferior to LD (p = 0.005), but also trended inferior to DD1 (p = 0.052). By multivariate Cox regression analysis, LD demonstrated similar 5-year graft survival to DD1 (HR for graft loss 0.8 [95% CI 0.25-2.6], p = 0.72) but LD graft survival was superior to DD0 (HR 0.34 [0.16-0.72], p = 0.005). The 5-year patient survival in DD1 was similar to LD (p = 0.26) but was superior to DD0 (p = 0.01). CONCLUSIONS: DD recipients with potential but non-actualized living donors exhibit similar mid-term graft and patient survival compared to LD recipients. Having an identified living donor at the time of pre-transplant assessment portends a favorable prognosis for the recipient.

Safety and efficacy of prophylaxis for Pneumocystis jirovecii pneumonia involving trimethoprim-sulfamethoxazole dose reduction in kidney transplantation.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for anti-Pneumocystis jirovecii pneumonia (PcP) prophylaxis in kidney transplant recipients (KTR). Post-transplant management balances preventing PcP with managing TMP-SMX-related adverse effects. TMP-SMX dose reduction addresses adverse effects but its implications to incident PcP are unclear. METHODS: We performed a retrospective review of all patients transplanted between 2011 and 2015 prescribed daily single strength TMP-SMX for twelve months post-transplantation as PcP prophylaxis. Actual TMP-SMX dose and duration, adverse effects, number of dose reductions and reasons, and PcP events were captured. Multivariate logistic regression analyses for risk factors associated with dose reduction were performed. RESULTS: Of 438 KTR, 233 (53%) maintained daily TMP-SMX and 205 (47%) sustained ≥1 dose reduction, with the point prevalence of a reduced dose regimen being between 18 and 25%. Median duration for daily TMP-SMX was 8.45/12 months, contributing 4137 patient-months daily TMP-SMX and 1110 patient-months with a reduced dose. PcP did not occur in any patients. There were 84 documented dose reductions for hyperkalemia and 102 for leukopenia, with 12 and 7 patients requiring TMP-SMX cessation. In multivariate analysis, a living donor transplant protected against hyperkalemia (Odds Ratio 0.46, 95% CI 0.26-0.83, p < 0.01) while acute rejection risked leukopenia (Odds Ratio 3.31, 95% CI 1.39-7.90, p = 0.006). CONCLUSIONS: TMP-SMX dose reduction is frequent in the first post-transplant year but PcP does not occur. To limit the need for TMP-SMX dose reduction due to adverse effects, a clinical trial comparing daily to thrice weekly single strength TMP-SMX in de-novo KTR is justified.

The Impact of Total Gastrectomy on Pharmacokinetics in Kidney Transplant Immunosuppressive Drug Regimes: A Case Study.

BACKGROUND: Ensuring reliable gastrointestinal drug absorption of orally administered immunosuppressive medications posttransplant is critical to ensuring graft survival. METHODS: A 66-year-old man of East Asian origin with a previous total gastrectomy was evaluated for living donor kidney transplantation. Pretransplant pharmacokinetic testing was performed to determine the most appropriate posttransplant medication strategy. The Gastrointestinal Quality of Life Index and Gastrointestinal Rating Scale questionnaires were administered to gauge immunosuppressive medication-related side effects in the absence of a stomach. RESULTS: The patient's ability to absorb cyclosporin, tacrolimus (Tac), enteric-coated mycophenolate sodium (EC-MPS) and sirolimus (SRL) in oral dosage forms was well-preserved. Compared to nongastrectomy reference populations, the rate and extent of absorption of SRL and mycophenolic acid from EC-MPS were similar. The absorption of Tac and cyclosporin was greater than expected. Mycophenolate mofetil did not provide mycophenolic acid absorption as well as EC-MPS. The patient had worsened gastrointestinal symptoms with mycophenolate mofetil or EC-MPS in combination with Tac and cyclosporin, but this was not seen with isolated SRL. CONCLUSIONS: This case demonstrates that commonly used postkidney transplantation immunosuppressive regimes may be prescribed after total gastrectomy as long as their limitations are noted.

Commercial kidney transplantation is an important risk factor in long-term kidney allograft survival.

Transplant tourism, a form of transplant commercialization, has resulted in serious short-term adverse outcomes that explain reduced short-term kidney allograft survival. However, the nature of longer-term outcomes in commercial kidney transplant recipients is less clear. To study this further, we identified 69 Canadian commercial transplant recipients of 72 kidney allografts transplanted during 1998 to 2013 who reported to our transplant center for follow-up care. Their outcomes to 8 years post-transplant were compared with 702 domestic living donor and 827 deceased donor transplant recipients during this period using Kaplan-Meier survival plots and multivariate Cox regression analysis. Among many complications, notable specific events included hepatitis B or C seroconversion (7 patients), active hepatitis and/or fulminant hepatic failure (4 patients), pulmonary tuberculosis (2 patients), and a type A dissecting aortic aneurysm. Commercial transplantation was independently associated with significantly reduced death-censored kidney allograft survival (hazard ratio 3.69, 95% confidence interval 1.88-7.25) along with significantly delayed graft function and eGFR 30 ml/min/1.73 m(2) or less at 3 months post-transplant. Thus, commercial transplantation represents an important risk factor for long-term kidney allograft loss. Concerted arguments and efforts using adverse recipient outcomes among the main premises are still required in order to eradicate transplant commercialization.

Reduction in new-onset diabetes mellitus after renal transplant with erythropoietin-stimulating agents: a retrospective cohort study.

BACKGROUND: Studies have shown that erythropoietin-stimulating agents (ESAs) protect mice against the development of diabetes through direct effects on pancreatic ß cells. However, the effect of ESAs on the incidence of diabetes in humans has not been well studied. It is unknown whether exposure to ESAs is associated with a reduced incidence of new-onset diabetes after transplant (NODAT). OBJECTIVE: The objective of this study is to examine the relationship between ESA exposure post-renal transplant and the development of NODAT. DESIGN: We performed a single center, retrospective cohort analysis. PATIENTS: We compared patients who received a first live or deceased donor renal allograft, with any exposure to an ESA vs. those without such exposure and who developed NODAT and who did not. Patients with a prior history of diabetes mellitus or multi-organ transplant, including a second renal transplant were excluded. MEASUREMENTS AND METHODS: NODAT was defined based on the 2008 Canadian Diabetes Association criteria. Multivariate logistic regression analysis was performed to determine factors independently associated with NODAT. RESULTS: One hundred thirty-two (29 %) patients were exposed to an ESA, four of which developed NODAT compared to 128 who did not develop NODAT (p < 0.0001). Of those not exposed to an ESA, 15 % (48/319) developed NODAT. By Fisher's exact test, exposure to an ESA at any time post-transplant reduced the risk of developing NODAT; odds ratio (OR) = 0.08, 95 % confidence interval (CI) (0.018-0.352), p = 0.0008. Older age; OR = 1.41, 95 % CI (1.036-1.933), p < 0.02, higher random blood sugar at discharge; OR = 1.30, 95 % CI (1.077-1.57), p < 0.006 and deceased donor; OR 2.18 CI (1.009-4.729), p = 0.04 were associated with an increased risk of NODAT. LIMITATIONS: The limitations of this study include its retrospective nature, single center, and homogenous population; thus, generalizability of the results must be approached with caution. CONCLUSION: ESA exposure may be associated with a reduced incidence of NODAT in the post-renal transplant population. The role of ESA in preventing NODAT requires further investigation.

MISE EN CONTEXTE: Des études ont démontré que les agents stimulant l'érythropoïèse (ASE) protègent les souris contre le développement du diabète par leur action directe sur les cellules bêta du pancréas. Toutefois, l'effet des ASE sur l'incidence du diabète chez l'humain n'a pas fait l'objet d'études approfondies. On ignore toujours si l'exposition aux ASE est associée à une réduction de l'incidence de l'apparition du diabète sucré post-transplantation (DSPT). OBJECTIFS DE L'ÉTUDE: Cette étude visait à évaluer la relation entre l'exposition aux ASE à la suite d'une greffe de rein et la survenue du DSPT. MODÈLE D'ÉTUDE: Il s'agit d'une étude de cohorte rétrospective qui s'est tenue dans un seul centre. PARTICIPANTS: Nous avons comparé les cas de patients qui recevaient une première allogreffe de rein, d'un donneur vivant ou décédé. Les comparaisons ont porté sur la présence ou l'absence d'une exposition aux ASE à la suite de la transplantation et sur le fait de développer ou non un DSPT conséquemment. Les patients ayant un historique de diabète sucré ou ayant subi une transplantation multiorganes dans le passé, y compris une deuxième greffe de rein, ont été exclus de l'étude. MÉTHODOLOGIE: La manifestation d'un DSPT a été déterminée selon des critères établis par l'Association Canadienne du Diabète en 2008. L'analyse par régression logistique multivariée a été utilisée pour déterminer les facteurs indépendamment liés au DSPT. RÉSULTATS: Sur les 132 patients (29 %) exposés aux ASE à la suite de la greffe, seuls quatre ont développé un DSPT (p < 0,000 1). Des patients qui n'avaient pas été exposés aux ASE, 15 % (48/319) ont développé un DSPT. Selon le test exact de Fisher, l'exposition à un ASE, peu importe le moment après la transplantation, a eu pour effet de réduire le risque de développer un DSPT [rapport de cote (RC) = 0,08 ; intervalle de confiance (IC) à 95 % (0,018-0,352), p = 0, 000 8]. Parmi les facteurs associés à un risque élevé de développer un DSPT, on note l'âge avancé du patient [RC = 1,41 ; IC à 95 % (1,036-1,933), p < 0,02], une glycémie aléatoire plus élevée à la sortie de l'hôpital [RC = 1,30 ; IC à 95 % (1,077-1,57), p < 0,006] et la transplantation d'un greffon provenant d'un donneur cadavérique [RC = 2,18 ; IC à 95 % (1,009-4,729), p = 0.04]. LIMITES DE L'ÉTUDE: Cette étude est limitée par sa nature rétrospective et par le fait qu'elle ait été menée à l'intérieur d'un seul centre et au sein d'une population homogène. Par conséquent, la généralisabilité des résultats doit être abordée avec prudence. CONCLUSIONS: L'exposition aux ASE pourrait être associée à une réduction de l'incidence du DSPT au sein de la population des receveurs d'une greffe de rein. Le rôle des ASE dans la prévention du DSPT exige des recherches plus poussées.

The role of CYP3A5 polymorphism and dose adjustments following conversion of twice-daily to once-daily tacrolimus in renal transplant recipients.

BACKGROUND: Tacrolimus is available as twice-daily Prograf® (Tac-BID) and the once-daily formulation, Advagraf® (Tac-OD). Although therapeutically equivalent, some transplant recipients require dose adjustments to achieve similar tacrolimus trough concentrations [Tac C0] after conversion between formulations. Tacrolimus is primarily metabolized by cytochrome P450 3A5 (CYP3A5). We sought to determine whether genetic polymorphisms in the CYP3A5 enzyme; CYP3A5 *1/*1 and CYP3A5 *1/*3 (expressers) compared to CYP3A5 *3/*3 (non-expressers) could account for discrepancies in dose requirements following conversion from Tac-BID to Tac-OD. METHODS: A cohort of 60 renal transplant recipients (RTR) from our larger conversion study of 496 patients underwent additional testing for CY3A5 genetic polymorphisms. Analysis included demographics, tac dosing and [Tac C0] pre- and post-conversion and dosing changes relative to CYP3A5 genotypes. CYP3A5 genetic polymorphisms were identified through analysis of genomic DNA. RESULTS: Conversion from tac bid to tac OD in this cohort required a mean (SD) dose increase from 3.1 (1.0) mg/day to 3.8 (1.3) mg/day (p = 0.007), to achieve similar [Tac C0]. The *1/*3 expresser group required a greater percentage dose adjustment (56.7 %) in converting from Tac-BID to Tac-OD as compared to the *3/*3 non-expresser group (26.6 %). Similar findings were observed with the both expresser groups combined (*1/*1 &*1/*3). The expressers were significantly more highly represented in the East Asian cohort. CONCLUSIONS: The CYP3A5 expresser polymorphism necessitates an increase in dosing upon conversion from Tac-BID to Tac-OD, with the expresser genotypes contributing significantly to this finding. Given the variability in frequency of CYP3A5 genotypes in various ethnic groups, future studies should account for both isoenzyme polymorphism and ethnicity in optimizing dosing requirements. TRIAL REGISTRATION: Clinical trials.gov identifier: NCT01884480.

Lithium-Induced Minimal Change Disease and Acute Kidney Injury.

CONTEXT: Lithium carbonate is a psychiatric medication commonly used in the treatment of bipolar disorder. It has been implicated in inducing nephrogenic diabetes inspidus, chronic tubulointerstitial nephropathy, and acute tubular necrosis. We describe a case of lithium-induced minimal change disease (MCD) and acute kidney injury (AKI). CASE REPORT: A 32-year-old female with a medical history of bipolar disorder treated with chronic lithium therapy presented with anasarca, fatigue, and tremors. Work-up revealed supra-therapeutic lithium levels, hypoalbuminemia, and significant proteinuria. The patient was treated conservatively with fluids and discontinuation of lithium therapy. Subsequently, she developed significant AKI and persistent proteinuria. She underwent a renal biopsy that demonstrated effacement of podocyte foot processes consistent with lithium-induced MCD. This was treated with corticosteroids, which decreased the proteinuria and resolved all the patient's symptoms. CONCLUSION: Lithium-induced MCD is a rare disease that affects patients of all ages. It is often associated with therapeutic lithium and is typically resolved with discontinuation of lithium. In some cases, concurrent AKI may result due to vascular obstruction from hyperalbuminuria and associated renal interstitial edema. Corticosteroids may be needed to reduce the proteinuria and prevent progression to chronic kidney disease. As such, patients on lithium therapy may benefit from monitoring of glomerular function via urinalysis to prevent the onset of nephrotic syndrome.

IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer.

IL-15 has pivotal roles in the control of CD8(+) memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-γ production, the different in vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-γ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-γ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-γ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-γ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion in vitro, a crucial step in adoptive T cell therapy.

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 clinical and pathological variant of acute transplant glomerulopathy.

Acute transplant glomerulopathy transplant glomerulopathy (TG) is a common cause of late renal allograft loss. We describe a unique case of a renal transplant recipient who developed rapid-onset nephrotic-range proteinuria and acute kidney injury secondary to C4d negative acute TG. Two courses of intravenous Rituximab resulted in significant improvement in proteinuria and allograft function. In the setting of acute nephrotic-range proteinuria postrenal allograft, both renal biopsy with electron microscopy and screening for de novo donor-specific antibody should be performed to distinguish atypical presentations of TG from other diagnoses.

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 m(2) , 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 m(2) compared with 108.9 ± 9.7 ml/min/1.73 m(2) 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).

A prospective cohort conversion study of twice-daily to once-daily extended-release tacrolimus: role of ethnicity.

BACKGROUND: Tacrolimus is a widely used calcineurin inhibitor in kidney transplantation. It is available as twice-daily Prograf® (Tac-BID) and once-daily Advagraf® (Tac-OD). Although therapeutically equivalent, some patients require dose adjustments to achieve similar trough concentrations [C0] after conversion. Tacrolimus exposure is affected by ethnicity in the de novo setting but the role of ethnicity in determining dose requirements and adjustments after conversion is unknown. METHODS: In this study, 496 renal transplant recipients (RTRs) were prospectively converted from Tac-BID to Tac-OD, with dose adjustments targeted to achieve similar [C0] at 12 months post-conversion. Renal function, acute rejection and Tac dose adjustments by ethnicity were analyzed. RESULTS: There were similar numbers of recipients from living and deceased donors. The mean transplant duration was 7 years. Of the RTRs, 60% were Caucasian and 40% were identified as belonging to an ethnic minority. There was no change in estimated renal function (eGFR) post-conversion to Tac-OD. At 12 months, 35/488 (7%) RTRs were receiving a reduced dose, 101/488 (21%) required a dose increase of which 77 (16%) were receiving at least a 30% increase in dose over baseline. The percentage of those in ethnic groups requiring a dose increase of >30% varied from 8.0% for South Asians to 27.5% for East Asians (P = 0.03), despite East Asians having a similar baseline dose of Tac-BID (3.59 mg/day) compared to the entire cohort (3.53 mg/day). CONCLUSIONS: Ethnicity may play an important role in dosing requirements when converting from Tac-BID to Tac-OD, unrelated to baseline dose. Further investigation is required to determine the reasons for ethnic variability when patients are converted between tacrolimus preparations.

A pilot study of reduced dose cyclosporine and corticosteroids to reduce new onset diabetes mellitus and acute rejection in kidney transplant recipients.

BACKGROUND: New onset diabetes mellitus (NODM) and acute rejection (AR) are important causes of morbidity and risk factors for allograft failure after kidney transplantation. METHODS: In this multi-center, open label, single-arm pilot study, 49 adult (≥18 years of age), low immunologic risk, non-diabetic recipients of a first deceased or living donor kidney transplant received early steroid reduction to 5 mg/day combined with Thymoglobulin® (Genzyme Transplant, Cambridge, MA, USA) induction, low dose cyclosporine (2-hour post-dose (C2) target of 600 to 800 ng/ml) and mycophenolic acid (MPA) therapy. RESULTS: Six months after transplantation, two patients (4%) developed NODM and one patient (2%) developed AR. Four patients had impaired fasting glucose tolerance based on 75-g oral glucose tolerance testing (OGTT). There was one patient death. There were no episodes of cytomegalovirus (CMV) infection or BK virus nephritis. In contrast, in a historical cohort of n = 27 patients treated with Thymoglobulin induction, and conventional doses of cyclosporine and corticosteroids, the incidence of NODM and AR was 18% and 15%. CONCLUSIONS: The pilot study results suggest that Thymoglobulin induction combined with early steroid reduction, reduced cyclosporine exposure and MPA, may reduce the incidence of both NODM and AR in low immunological risk patients. A future controlled study enriched for patients at high risk for NODM is under consideration. TRIAL REGISTRATION: ClinicalTrials.gov: http://NCT00706680.

A comparison of the extended-release and standard-release formulations of tacrolimus in de novo kidney transplant recipients: a 12-month outcome study.

BACKGROUND: Limited comparative data are available on the outcomes between extended-release and standard-release tacrolimus when used de novo in kidney transplant recipients (KTRs). METHODS: We identified KTRs transplanted at our institution during 2009-10 routinely prescribed extended-release tacrolimus and compared them with those transplanted during 2008-09 prescribed standard-release tacrolimus. Graft function (eGFR by MDRD-7 equation) at 12 months post-transplant (primary outcome); new-onset diabetes and other cardiovascular risk factors, BK viremia incidence, acute rejection, and graft survival to 12 months (secondary outcomes) were compared by intent-to-treat analysis. Time-to-steady-state concentration and number of dose adjustments required to attain steady state were recorded. RESULTS: There were no important demographic differences between the extended-release (N = 106) and standard-release (N = 95) cohorts. The estimated glomerular filtration rate (eGFR) at 12 months was similar (58.8 ± 17 versus 59.2 ± 18 mL/min/1.73 m(2), P = 0.307). There was no difference in new-onset diabetes (17 versus 20%, P = 0.581), BK viremia (10 versus 7%, P = 0.450), acute rejection (7 versus 16%, P = 0.067) or graft survival (97 versus 95%, P = 0.301). Time-to-steady state was similar (9.2 ± 1.1 versus 8.1 ± 4.7 days, P = 0.490) although extended-release patients required fewer adjustments to attain steady state (1.2 ± 1.7 [0-8] versus 1.7 ± 1.5 [0-7], P = 0.030) but a similar dose (7.2 ± 2.4 [2-17] versus 7 ± 2.7 [2-16] mg/day, P = 0.697). CONCLUSION: De novo KTRs prescribed extended-release or standard-release tacrolimus demonstrate similar 12-month outcomes.

South Asian ethnicity as a risk factor for major adverse cardiovascular events after renal transplantation.

BACKGROUND AND OBJECTIVES: South Asians (SAs) comprise 25% of all Canadian visible minorities. SAs constitute a group at high risk for cardiovascular disease in the general population, but the risk in SA kidney transplant recipients has never been studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cohort study of 864 kidney recipients transplanted from 1998 to 2007 and followed to June 2009, we identified risk factors including ethnicity associated with major cardiac events (MACEs, a composite of nonfatal myocardial infarction, coronary intervention, and cardiac death) within and beyond 3 months after transplant. Kaplan-Meier methodology and multivariate Cox regression analysis were used to determine risk factors for MACEs. RESULTS: There was no difference among SAs (n = 139), whites (n = 550), blacks (n = 65), or East Asians (n = 110) in baseline risk, including pre-existing cardiac disease. Post-transplant MACE rate in SAs was 4.4/100 patient-years compared with 1.31, 1.16, and 1.61/100 patient-years in whites, blacks, and East Asians, respectively (P < 0.0001 versus each). SA ethnicity independently predicted MACEs along with age, male gender, diabetes, systolic BP, and prior cardiac disease. SAs also experienced more MACEs within 3 months after transplant compared with whites (P < 0.0001), blacks (P = 0.04), and East Asians (P = 0.006). However, graft and patient survival was similar to other groups. CONCLUSIONS: SA ethnicity is an independent risk factor for post-transplant cardiac events. Further study of this high-risk group is warranted.

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

BACKGROUND: Calcineurin inhibitor nephrotoxicity remains an issue for recipients of solid organ transplants. After cyclosporine A (CsA) microemulsion administration, effective renal plasma flow (ERPF) and glomerular filtration rate(GFR) are decreased coincident with the maximal concentration (Cmax) of CsA. The pharmacokinetic (PK) profile of the once-daily formulation of tacrolimus extended release (Tac ER) includes an equivalent AUCPK 0-24 hr and a lower Cmax versus twice-daily Tac immediate release. METHODS: Eighteen healthy subjects were allocated once-daily Tac ER and twice-daily CsA in a prospective, randomized,open-label, two-period, two-sequence single crossover study. CsA was targeted to C2 of 700 to 1400 ng/mL, and Tac ER was targeted to C0 of 5 to 10 ng/mL. Pharmacodynamic (PD) assessments were conducted preexposure, and PD and PK were assessed during a 6-hr postdose period after 10-day exposure. RESULTS: The achieved mean C(o) Tac and CsA were 6.4 +/- 1.16 and 201 +/- 57 ng/mL, respectively. At Cmax, the change in ERPF was +30 +/- 127 vs. -70 +/- 96 mL/min/1.73 m2 relative to baseline for Tac ER and CsA (P=0.0085). The ERPF and GFR AUC (PD 0-6) hr were 3645 +/- 887 vs. 3210 +/- 582 mL/1.73 m2 (P=0.027) and 604 +/- 98 vs. 543+/- 79 mL/1.73 m2(P=0.023) for Tac ER versus CsA, respectively. Both systolic and diastolic blood pressures were significantly greater with exposure to CsA compared with Tac ER. CONCLUSIONS: Acute reductions in ERPF and GFR are attenuated with Tac ER compared with CsA and may correlate with the differing PK profiles of these calcineurin inhibitors.

Hypocomplementaemic immune complex tubulointerstitial nephritis.

We report a rare cause of rapidly progressive renal failure associated with low complement, positive ANA but negative anti DS-DNA. A renal biopsy demonstrated tubulointerstitial nephritis with positive immunoglobulin staining involving the interstitium and tubular basement membrane but glomerular sparing. A review of the literature and differential diagnosis are discussed.

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

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 two months post-transplant and provided three urine albumin-to-creatinine ratio (ACR) measurements, excluding those with recent illness and proteinuria. Microalbuminuria was defined as averaged ACR > or =2.0 in men and 2.8 mg/mmol in women (Canadian Diabetes Association 2003). Risk factors associated with microalbuminuria were determined by multivariate logistic regression analysis. Averaged ACR correlated to CRP (R = 0.21, p = 0.001). Prevalence of microalbuminuria was 48% (108/222). Patients with microalbuminuria had higher CRP (7.01 +/- 8 vs. 3.21 +/- 3 mg/L, p < 0.0001) and systolic BP (129 +/- 17 vs. 123 +/- 12 mmHg, p = 0.004). Microalbuminuria was associated with increasing CRP [odds ratio 1.129 per 1 mg/L (95% CI 1.058-1.204), p = 0.0002], SBP [1.248 per 10 mmHg (1.023-1.522), p = 0.029] and smoking [1.938 (1.023-3.672), p = 0.042]. 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.