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.

Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for the management of blood pressure in CKD.

The KDIGO (Kidney Disease: Improving Global Outcomes) 2012 clinical practice guideline for the management of blood pressure (BP) in chronic kidney disease (CKD) provides the structural and evidence base for the Canadian Society of Nephrology (CSN) commentary on this guideline's relevancy and application to the Canadian health care system. While in general agreement, we provide commentary on 13 of the 21 KDIGO guideline statements. Specifically, we agreed that nonpharmacological interventions should play a significant role in the management of hypertension in patients with CKD. We also agreed that the approach to the management of hypertension in elderly patients with CKD should be individualized and take into account comorbid conditions to avoid adverse outcomes from excessive BP lowering. In contrast to KDIGO, the CSN Work Group believes there is insufficient evidence to target a lower BP for nondiabetic CKD patients based on the presence and severity of albuminuria. The CSN Work Group concurs with the Canadian Hypertension Education Program (CHEP) recommendation of a target BP for all non-dialysis-dependent CKD patients without diabetes of ≤140 mm Hg systolic and ≤90 mm Hg diastolic. Similarly, it is our position that in diabetic patients with CKD and normal urinary albumin excretion, raising the threshold for treatment from <130 mm Hg systolic BP to <140 mm Hg systolic BP could increase stroke risk and the risk of worsening kidney disease. The CSN Work Group concurs with the CHEP and the Canadian Diabetic Association recommendation for diabetic patients with CKD with or without albuminuria to continue to be treated to a BP target similar to that of the overall diabetes population, aiming for BP levels < 130/80 mm Hg. Consistent with this, the CSN Work Group endorses a BP target of <130/80 mm Hg for diabetic patients with a kidney transplant. Finally, in the absence of evidence for a lower BP target, the CSN Work Group concurs with the CHEP recommendation to target BP<140/90 mm Hg for nondiabetic patients with a kidney transplant.

Adiponectin in renal disease--a review of the evidence as a risk factor for cardiovascular and all-cause mortality.

Adiponectin, an adipokine, was discovered in 1995. The initial evidence led to the study of adiponectin as a determinant of insulin sensitivity and blood glucose levels. The literature then evolved to reports of the inverse association of adiponectin with incident Type 2 diabetes mellitus and coronary heart disease. Shortly thereafter, reports of a positive association with heart failure and mortality appeared and were replicated. We review here the basic science evidence and clinical studies of the role of renal function and kidney disease as a determinant of adiponectin.

Ambulatory blood pressure monitoring in solid organ transplantation.

Solid organ transplant recipients are at an increased risk for hypertension and cardiovascular disease. To assist in their management, 24-h ambulatory blood pressure monitoring (ABPM) has become increasingly used in both clinical research settings and practice. ABPM has been used to better define post-transplant hypertension incidence and prevalence in different solid organ transplantation populations. ABPM provides additional information on cardiovascular risk beyond that obtained by clinic-based readings, based on its ability to assess 24-h blood pressure (BP) load, detect nocturnal non-dipping, and predict target organ damage. It has provided some assurance about the safety of living kidney donation. Information from ABPM can be used to guide living kidney donor selection, and because ABPM-related data has been correlated with clinically important kidney and heart transplant recipient outcomes, it may be a valuable adjunct in their management. Despite these advantages, barriers to wider use of ABPM include expense, clinical inertia in hypertension management, lack of prospective clinical trial data, and clinical problems that compete with hypertension for attention such as acute or chronic allograft dysfunction. The increasing amount of research and clinical use for ABPM may allow for closer assessment and intervention to help address the increased cardiovascular risk faced by many solid organ transplant recipients.

Cardiac MRI assessment of the right ventricle pre-and post-kidney transplant.

Worsening renal function in chronic kidney disease correlates with worsening right ventricular (RV) systolic function. We evaluated the association between kidney transplantation (KT) and RV structure and systolic function, and the relationships between RV and left ventricular (LV) changes, blood pressure, and specific cardiac biomarkers, in patients with end-stage kidney disease using cardiac magnetic resonance imaging (CMR). In this prospective, multi-centre, cohort study, 39 adult patients on dialysis receiving KT and 42 patients eligible for, but not yet receiving KT, were recruited. CMR was performed at baseline, and repeated at 12 months. Among 81 patients (mean age 51 years, 30% female), RV end-diastolic volume index (RVEDVi), end-systolic volume index (RVESVi), mass index (RVMi), and ejection fraction (RVEF) did not change significantly within either the dialysis or KT group over 12 months (all p ≥ 0.10). There were no significant differences in the 12-month changes of these parameters between the dialysis and KT groups (all p ≥ 0.10). RVMI demonstrated positive correlations with NT-proBNP and systolic blood pressure, but not GDF-15, at baseline and at 12 months. Changes in RVEDVi, RVESVi, and RVEF were positively correlated with changes in LVEDVi, LVESVi, and LVEF, respectively over 12 months (Spearman r = 0.72, 0.52, and 0.41; all p < 0.001), but not mass index (Spearman r = 0.20, p = 0.078). In conclusion, there were no significant changes in RV mass, volumes, or systolic function 12 months after KT, as compared with continuation of dialysis. The associations between RV and LV remodeling may suggest similar underlying pathophysiologic mechanisms.

Twenty four-hour ambulatory blood pressure profiles 12 months post living kidney donation.

Summary Small blood pressure (BP) elevations may occur post kidney donation. This prospective study determined 24-h ambulatory BP (ABP) and other cardiovascular risk factor changes in 51 living donors over 12 months postdonation. Donors also provided 24-h urine collections for monitoring protein and creatinine clearance, 75 g oral glucose tolerance tests (OGTT), and fasting lipids. Nondipping was defined as night-day systolic (SBP) ratio >or=0.9. Baseline and 12-month pre to postdonation comparisons were made both for dippers and nondippers. Of 51 donors, 35 were dippers and 16 nondippers. In these two groups, predonation 24-h SBP were 115.2 +/- 8 and 115.6 +/- 10 mmHg; serum creatinine (SCr) 69.3 +/- 12 and 71.1 +/- 13 micromol/l; and 24-h urine protein 0.12 +/- 0.05 and 0.09 +/- 0.03 g (all P = NS) while at 12 months, 24-h SBP were 111.4 +/- 11 and 114.3 +/- 8 mmHg (P = 0.384), SCr 97.9 +/- 16 and 97.7 +/- 21 micromol/l (P = 0.810); and 24-h urine protein 0.139 +/- 0.09 and 0.111 +/- 0.07 g/d (P = 0.360) respectively. The 24-h SBP was significantly lower in the dippers at 12 months as compared with predonation (P = 0.036). OGTT and lipid profiles remained normal in both groups. Predonation nocturnal nondipping does not carry adverse postdonation consequences over 12 months.

Pre-transplantation glucose testing for predicting new-onset diabetes mellitus after renal transplantation.

AIM: New-onset diabetes after renal transplantation (NODAT) adversely affects graft and patient survival. However, NODAT risk based on pre-transplant blood glucose (BG) levels has not been defined. Our goal was to identify the best pre-transplant testing method and cut-off values. MATERIALS AND METHODS: We performed a case-control analysis of non-diabetic recipients who received a live donor allograft with at least 6 months post-transplant survival. Pre-transplant glucose abnormalities were excluded through 75 g oral glucose tolerance testing (OGTT) and random BG (RBG) measurement. NODAT was defined based on 2003 Canadian Diabetes Association criteria. Multivariate logistic and Cox regression analysis was performed to determine independent predictor variables for NODAT. Receiver-operating-characteristic (ROC) curves were constructed to determine threshold BG values for diabetes risk. RESULTS: 151 recipients met initial entry criteria. 12 had pre-transplant impaired fasting glucose and/or impaired glucose tolerance, among who 7 (58%) developed NODAT. In the remaining 139, 24 (17%) developed NODAT. NODAT risk exceeded 25% for those with pre-transplant RBG > 6.0 mmol/l and 50% if > 7.2 mmol/l. Pre-transplant RBG provided the highest AUC (0.69, p = 0.002) by ROC analysis. Increasing age (p = 0.025), acute rejection (p = 0.011), and RBG > 6.0 mmol/l (p = 0.001) were independent predictors of NODAT. CONCLUSION: Pre-transplant glucose testing is a specific marker for NODAT. Patients can be counseled of their incremental risk even within the normal BG range if the OGTT is normal.

Nonreimbursed Costs Incurred by Living Kidney Donors: A Case Study From Ontario, Canada.

BACKGROUND: Living donors may incur out-of-pocket costs during the donation process. While many jurisdictions have programs to reimburse living kidney donors for expenses, few programs have been evaluated. METHODS: The Program for Reimbursing Expenses of Living Organ Donors was launched in the province of Ontario, Canada in 2008 and reimburses travel, parking, accommodation, meals, and loss of income; each category has a limit and the maximum total reimbursement is $5500 CAD. We conducted a case study to compare donors' incurred costs (out-of-pocket and lost income) with amounts reimbursed by Program for Reimbursing Expenses of Living Organ Donors. Donors with complete or partial cost data from a large prospective cohort study were linked to Ontario's reimbursement program to determine the gap between incurred and reimbursed costs (n = 159). RESULTS: The mean gap between costs incurred and costs reimbursed to the donors was $1313 CAD for out-of-pocket costs and $1802 CAD for lost income, representing a mean reimbursement gap of $3115 CAD. Nondirected donors had the highest mean loss for out-of-pocket costs ($2691 CAD) and kidney paired donors had the highest mean loss for lost income ($4084 CAD). There were no significant differences in the mean gap across exploratory subgroups. CONCLUSIONS: Reimbursement programs minimize some of the financial loss for living kidney donors. Opportunities remain to remove the financial burden of living kidney donors.

Role of Magnetic Resonance Elastography as a Noninvasive Measurement Tool of Fibrosis in a Renal Allograft: A Case Report.

A major reason for poor long-term kidney transplant outcomes is the development of chronic allograft injury, characterized by interstitial fibrosis and tubular atrophy. Currently, an invasive biopsy that samples only <1% of the kidney is the gold standard for detecting kidney allograft fibrosis. We report the use of magnetic resonance elastography (MRE) to quantify tissue stiffness as a noninvasive and whole-kidney measurement tool of allograft fibrosis in a kidney transplant patient at 2 time points. The MRE whole-kidney stiffness values reflected the changes in fibrosis of the kidney allograft as assessed by histologic examination. To our knowledge, this technique is the first observation of change over time in MRE-derived whole-kidney stiffness in an allograft that is consistent with changes in histology-derived fibrosis scores in a single patient.

Gastrointestinal-specific patient-reported outcome instruments differentiate between renal transplant patients with or without GI complications.

BACKGROUND: Gastrointestinal (GI) complications are frequently reported postrenal transplant and are often associated with immunosuppressant regimens including mycophenolate mofetil (MMF). This study evaluated the ability of two GI-specific patient-reported outcome (PRO) instruments to differentiate between patients with and without GI complaints. METHODS: Discriminant validity of the Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI), as well as two generic instruments (Psychological General Well-Being Index (PGWB) and EQ-5D, was assessed in a multinational study of renal transplant recipients. Patients received therapy that included a calcineurin inhibitor and MMF. Both t-tests and ANOVAs were used to examine differences between patients with and without GI complaints, among levels of severity, and between patients reporting presence/absence of specific GI side effects. RESULTS: Of 96 patients recruited (56% male), 43% had none, 39% mild, 13% moderate, and 6% severe GI symptoms. All GSRS subscales and the GIQLI total and four of the five subscale scores significantly differentiated between patients with/without GI complications (P < .05). The PGWB total score and three subscales, the EQ-5D significantly differentiated between the two groups (P < .05). Only GI-specific instruments discriminated between some severity levels; for example, the GSRS abdominal pain subscale discriminated between patients at all levels of severity (P < .05). The GIQLI total score and symptoms subscale differentiated between patients with no symptoms and those with mild or moderate or severe symptoms (P < .05). CONCLUSIONS: The GSRS and GIQLI differentiated between patients with/without GI side effects and by symptom severity better than did generic instruments, demonstrating excellent discriminant ability in this population.

The 2015 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.

The Canadian Hypertension Education Program reviews the hypertension literature annually and provides detailed recommendations regarding hypertension diagnosis, assessment, prevention, and treatment. This report provides the updated evidence-based recommendations for 2015. This year, 4 new recommendations were added and 2 existing recommendations were modified. A revised algorithm for the diagnosis of hypertension is presented. Two major changes are proposed: (1) measurement using validated electronic (oscillometric) upper arm devices is preferred over auscultation for accurate office blood pressure measurement; (2) if the visit 1 mean blood pressure is increased but < 180/110 mm Hg, out-of-office blood pressure measurements using ambulatory blood pressure monitoring (preferably) or home blood pressure monitoring should be performed before visit 2 to rule out white coat hypertension, for which pharmacologic treatment is not recommended. A standardized ambulatory blood pressure monitoring protocol and an update on automated office blood pressure are also presented. Several other recommendations on accurate measurement of blood pressure and criteria for diagnosis of hypertension have been reorganized. Two other new recommendations refer to smoking cessation: (1) tobacco use status should be updated regularly and advice to quit smoking should be provided; and (2) advice in combination with pharmacotherapy for smoking cessation should be offered to all smokers. The following recommendations were modified: (1) renal artery stenosis should be primarily managed medically; and (2) renal artery angioplasty and stenting could be considered for patients with renal artery stenosis and complicated, uncontrolled hypertension. The rationale for these recommendation changes is discussed.

Diabetic nephropathy with concurrent hepatitis C virus infection related membranoproliferative glomerulonephritis.

Diabetes mellitus is often complicated by nephropathy with progression to renal failure. Various forms of glomerulonephritis have been associated with diabetes, sometimes resulting in more rapid deterioration in renal function and occasionally dictating alternative management of these patients in attempts to reverse or contain nephrosis or renal failure. We report the occurrence of Type I membranoproliferative glomerulonephritis (MPGN) with hepatitis C virus (HCV) infection in two patients, in association with diabetic nephropathy. One patient had cryoglobulinemia and cryoglobulin deposits in the kidney. A brief review of the literature on glomerulonephritides occurring in patients with diabetes mellitus is also presented. Clinicians should be aware of the possible occurrence of Type I MPGN and cryoglobulinemia in patients with diabetes mellitus and HCV infection with the appropriate history and physical findings. The therapeutic approach to managing patients with two distinct concurrent lesions remains unresolved.

Type I membranoproliferative glomerulonephritis in an HIV-infected individual without hepatitis C co-infection.

Type I membranoproliferative glomerulonephritis (MPGN) is an uncommon manifestation of human immunodeficiency virus (HIV)-associated renal disease in patients co-infected with hepatitis C virus (HCV). We describe a case of Type I MPGN in an HIV-positive diabetic man with nephrotic-range proteinuria and renal insufficiency who was not co-infected with HCV. Tubuloreticular inclusions were present but there was no evidence for either cryoglobulinemia or cryoglobulin deposits in the kidney. This finding suggests that Type I MPGN may represent a reaction of the kidney to HIV independent of the effects of HCV co-infection. Clinical suspicion must be maintained for Type I MPGN in all HIV infected patients presenting with significant proteinuria regardless of HCV infection status.

Factors affecting system clotting in continuous renal replacement therapy: results of a randomized, controlled trial.

BACKGROUND: System clotting and the anticoagulation techniques employed to prevent it are important causes of morbidity in continuous renal replacement therapy (CRRT). Different means have been employed in attempts to prolong system lifespan while minimizing complications. SUBJECTS, MATERIALS AND METHODS: To determine whether augmenting blood flow and flush frequency could reduce clotting frequency, we compared system lifespan in a standard blood flow and saline flush group (125 ml/min and 100 ml once hourly, respectively) to an augmented blood flow and saline flush group (200-250 ml/min and 100 ml twice hourly). A total of 34 patients treated with continuous venovenous hemodialysis were randomized to receive either the standard or augmented regimens in a prospective trial conducted between August 1995 and March 1997. A total of 130 systems were studied. RESULTS: Based on intention-to-treat analysis, there was no difference in time to clot between the two groups. In a multivariate analysis of the outcome, red blood cell and platelet transfusion during CRRT were significantly associated with decreased clotting, and systemic heparin infusion significantly prolonged lifespan of CRRT systems. CONCLUSION: Increasing blood flow and flush frequency does not prevent clotting in CRRT. Since this intervention is more costly than standard treatment, its use cannot be justified.

Death with graft function in elderly patients after cadaveric renal transplantation: effect of waiting time.

Survival after kidney transplantation is better than on the waiting list, even in the elderly. However, the effects of a prolonged waiting time for an organ on death with graft function have not been critically examined in this patient group. We conducted a single-center retrospective analysis of our cadaveric renal transplant experience in patients older than 60 years who received a kidney between January 1, 1990 and December 31, 2003. Besides waiting time, the effects of recipient age, gender, and diabetes were also examined. Cox proportional hazards analysis using patient death as a time-dependent outcome was used to estimate the hazard ratio of death posttransplantation. Using Kaplan-Meier survival methodology, patients with waiting times < or =5 years had significantly better survival times posttransplantation compared with those with waiting times >5 years (6.2 vs 2.8 years; P <.001). Each year of waiting was associated with hazard ratio 1.16 (95% confidence interval [CI], 1.06-1.27) for death. Prolonged waiting time on dialysis is deleterious to patient survival in recipients older than 60 years at transplantation. Early transplantation thus should be strongly encouraged in this group of patients.

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

BACKGROUND: 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. METHODS: After counseling based on Dietary Approaches to Stop Hypertension (DASH) guidelines, we measured timed 24-h urine excretion rates of sodium, potassium, calcium, and magnesium as a surrogate for their dietary intake, in 244 stable adult single-organ renal transplant recipients, correlating these with averaged blinded clinic-measured BP values. Multiple linear regression analysis adjusting for factors affecting BP in transplant recipients was performed. RESULTS: There was no correlation between systolic (SBP) or diastolic pressure (DBP) and 24-h urine excretion rates of each cation. There was no BP difference between patients receiving cyclosporine and tacrolimus (127/77 vs. 129/78 mmHg, p = 0.38), or in cation excretion except for calcium (2.85 +/- 2.0 vs. 2.90 +/- 2.8, p = 0.002). Protein excretion (p < 0.0001), age (p = 0.002), and weight (p = 0.04) were positively associated with SBP, while only weight (p = 0.01) was associated with DBP by multivariate analysis. CONCLUSION: Dietary cation intake is not significantly associated with BP in renal transplant recipients. These data do not support recommendations to alter dietary cation intake as part of the management of post-transplantation hypertension.

Psychosocial health of living kidney donors: a systematic review.

Knowledge of the psychosocial benefits and harms faced by living kidney donors is necessary for informed consent and follow-up. We reviewed any English language study where psychosocial function was assessed using questionnaires in 10 or more donors after nephrectomy. We searched MEDLINE, EMBASE, Web of Science, Psych INFO, Sociological Abstracts and CINAHL databases and reviewed reference lists from 1969 through July 2006. Independently, two reviewers abstracted data on study, donor and control group characteristics, psychosocial measurements and their outcomes. Fifty-one studies examined 5139 donors who were assessed an average of 4 years after nephrectomy. The majority experienced no depression (77-95%) or anxiety (86-94%), with questionnaire scores similar to controls. The majority reported no change or an improved relationship with their recipient (86-100%), spouse (82-98%), family members (83-100%) and nonrecipient children (95-100%). Some experienced an increase in self-esteem. A majority (83-93%) expressed no change in their attractiveness. Although many scored high on quality of life measures, some prospective studies described a decrease after donation. A small proportion of donors had adverse psychosocial outcomes. Most kidney donors experience no change or an improvement in their psychosocial health after donation. Harms may be minimized through careful selection and follow-up.