Rahul Mainra

Daily hemodialysis: a systematic review.

Several studies have reported improved outcomes with daily hemodialysis (DHD), but the strength of this evidence has not been evaluated. The published evidence on DHD was synthesized and its quality rated to inform need and sample size calculations for a randomized trial. Citations were identified in MEDLINE and EMBASE using validated search strategies. Dialysis journals that were not indexed and bibliographies of relevant articles were hand-searched. Two authors reviewed all citations. Articles that reported original data on five or more adults who were receiving DHD (1.5 to 3 h, 5 to 7 d/wk) for > or = 3 mo were included. Twenty-five articles reporting 14 unique populations with 268 patients (five to 72 per study) met inclusion criteria. Of the 14 cohorts, 13 were studied with an observational design, 10 were studied prospectively, and four had parallel control groups. Mean age ranged form 41 to 64 yr, mean time on dialysis was 2 to 11 yr, 0 to 28% of patients had diabetes, > 90% had arteriovenous fistulae, and > 50% were dialyzed at home. Most data were described at < or = 12 mo of follow-up. Outcomes included quality of life, cardiovascular disease, erythropoiesis, nutritional status, hospitalizations, and vascular access failures. Reporting was too heterogeneous to allow pooling of data. Ten of 11 studies suggested improvements in blood pressure; findings for other outcomes varied. Discontinuation of DHD occurred in 0 to 57% in-center and 0 to 15% home patients. Studies of DHD are limited by small sample size, nonideal control groups, selection and dropout biases, and paucity of data on potential risks. Randomized trials with adequate statistical power are required to establish the efficacy and the safety of DHD.

Canadian Society of Transplantation and Canadian Society of Nephrology Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

KDIGO (Kidney Disease: Improving Global utcomes) is an international initiative to deelop and implement clinical practice guideines. In November 2009, KDIGO published ts guideline for the management of kidney ransplant recipients. This guideline was exremely comprehensive and spanned more than 50 pages. The Canadian Society of Transplanation (CST) and the Canadian Society of Nehrology (CSN) congratulate KDIGO, memers of the guideline work group, and the vidence review team for producing such a horough and exhaustive document. This guideine will be of great value to health professionls involved in the management of kidney ransplant recipients. KDIGO is an international organization and hus its guidelines have international scope. To ave practical applicability, the various recomendations and suggestions will need adaptation o suit individual countries or jurisdictions. As uch, the CST and CSN formed a joint work roup to review the KDIGO guideline and make uggestions about its applicability and relevance n a Canadian context. This commentary was ritten acknowledging the unique nature of our ransplant population with its ethnic diversity, ur health care system that has variable funding nd access to different medications and services, nd our geography, which has transplant care ocused in larger urban areas, requiring many atients to travel considerable distances. Our ommentary provides supplementary informaion regarding the care of kidney transplant recipints in a Canadian context and should be viewed n conjunction with the full KDIGO document hen making clinical decisions.

Individualized Therapy to Prevent Bone Mineral Density Loss after Kidney and Kidney-Pancreas Transplantation

BACKGROUND AND OBJECTIVES Most patients who undergo kidney or kidney-pancreas transplantation have renal osteodystrophy, and immediately after transplantation bone mineral density (BMD) commonly falls. Together, these abnormalities predispose to an increased fracture incidence. Bisphosphonate or calcitriol therapy can preserve BMD after transplantation, but although bisphosphonates may be more effective, they pose potential risks for adynamic bone. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 153 kidney (61%) and kidney-pancreas (39%) transplant recipients were allocated to bisphosphonate (62%) or calcitriol (38%) therapy using an algorithm that incorporated BMD, prevalent vertebral fracture, biomarkers of bone turnover, and risk factor assessment. Patients received cholecalciferol and calcium as appropriate and were followed for 12 mo. RESULTS Patients who were treated with bisphosphonates had lower BMD at the lumbar spine and femoral neck and longer time on dialysis. Age and gender were similar between the groups. At 12 mo, bisphosphonate-treated patients had significant BMD increases at the lumber spine and femoral neck and a negative trend at the wrist. Patients who were allocated to calcitriol, who were assessed to have lower baseline fracture risk, had no significant change in BMD at any site. At 1 yr, mean levels of bone turnover marker and intact parathyroid hormone normalized in both groups. Incident fracture rates did not differ significantly. CONCLUSIONS With targeted treatment, BMD levels were stable or improved and bone turnover markers normalized. This algorithm provides a guide to targeting therapy after transplantation that avoids BMD loss and may reduce suppression of bone turnover.

Effect of N-Acetylcysteine on Serum Creatinine and Kidney Function: Results of a Randomized Controlled Trial

BACKGROUND Evidence for a protective effect of N-acetylcysteine (NAC) on acute and chronic kidney disease is equivocal, and controversy persists about whether NAC affects creatinine level independently of actual kidney function. Study objectives are to investigate whether NAC affects serum creatinine level independently of alterations in other measures of kidney function. STUDY DESIGN Double-blind randomized controlled trial. SETTING & PARTICIPANTS Patients with stage 3 chronic kidney disease (n = 60), Canada, 2007-2008. INTERVENTION Participants were randomly allocated to receive 4 doses of oral NAC (each 1,200 mg) or placebo, administered at 12-hour intervals. OUTCOME The primary outcome was change in serum creatinine level between baseline and 4 hours after the last treatment dose. In addition, changes in other parameters of kidney function were measured between baseline and 4, 24, or 48 hours after the last treatment dose. MEASUREMENTS Serum creatinine, cystatin C, 24-hour urine protein and creatinine excretion, and creatinine clearance. RESULTS 60 patients, mean age of 70 years, 75% men, 50% had diabetes, with mean creatinine clearance of 43.7 ± 18.8 (SD) mL/min were enrolled. Between baseline and 4 hours posttreatment, serum creatinine level decreased by 0.044 ± 0.15 mg/dL in the NAC group and 0.040 ± 0.18 mg/dL in the placebo group (95% CI for difference, -0.09 to 0.08; P = 0.9). No significant differences between groups were observed for change in serum creatinine, cystatin C, urine protein, urine creatinine, or creatinine clearance values at any time. LIMITATIONS Blinding patients to orally administered liquid NAC is difficult and it is possible that patients receiving NAC were not sufficiently blinded. Effects of NAC beyond 48 hours of treatment were not evaluated. CONCLUSIONS In this randomized controlled trial, NAC had no short-term effect on creatinine level and did not decrease urine protein excretion within 48 hours of treatment.

Effect of N-acetylcysteine on renal function in patients with chronic kidney disease.

Background:  N‐acetylcysteine (NAC) is commonly administered to high‐risk individuals to attenuate the risk of contrast‐induced nephropathy in spite of the debate regarding its efficacy. In several studies serum creatinine decreased after exposure to NAC and contrast dye. The mechanism by which NAC attenuates the decline in renal function is not known. Studies in subjects with normal renal function suggest NAC may have an effect on tubular secretion.

Therapeutic role of sirolimus in non-transplant kidney disease

Sirolimus is a member of a novel class of immunosuppressant drug that potently suppresses T cell proliferation and expansion by inhibition of the Target of Rapamycin Complex 1 (TORC1) protein kinase. Sirolimus also has anti-proliferative effects on intrinsic cells of the kidney, and increasing evidence suggests that it may have a therapeutic role in non-transplant renal diseases. In the normal kidney, sirolimus is considered to be non-nephrotoxic. In the diseased kidney, sirolimus may be beneficial or detrimental, depending on the type of renal injury. In polycystic kidney disease, TORC1 activation mediates renal tubular epithelial cell (TEC) proliferation and cyst growth in animals, and Phase III clinical trials are underway to determine the effect of sirolimus in attenuating disease progression in humans. In contrast, in acute kidney injury, sirolimus transiently impairs proximal TEC regeneration and delays renal recovery. In animal models of lupus nephritis and diabetic kidney disease, sirolimus prevents disease progression. However, the efficacy of sirolimus in human glomerulonephritis as well as in diabetic chronic kidney disease remains unclear, as it paradoxically exacerbates renal dysfunction when the baseline glomerular filtration rate is low (< 40 ml/min/1.73 m(2)) and there is heavy proteinuria (> 300 mg/day). This may, in part, be due to inhibition of compensatory glomerular capillary repair through the suppression of endothelial cell proliferation and angiogenic growth factor production by podocytes. Therefore, at present, polycystic kidney disease is the most promising therapeutic application for sirolimus in non-transplant renal diseases, and further studies are needed to clarify its role in other situations.

Review article: Managing bone complications after kidney transplantation

Chronic kidney disease mineral and bone disorder (CKD‐MBD) describes the laboratory, bone and vascular abnormalities that exist in patients with CKD stages 3–5D and that may persist after transplantation. Persisting abnormalities of bone turnover and abnormal mineralization, together with bone mineral density (BMD) loss from glucocorticoids, may all predispose to a loss of structural integrity and increased fracture risk in kidney and kidney pancreas recipients. Vitamin D, calcitriol, calcitonin and bisphosphonates have all been used to preserve BMD following transplantation, despite a lack of safety data and the potential for some of these drugs to cause harm. A limited number of post‐transplant studies utilizing these drugs have not yet documented improved fracture prevention or fracture‐related mortality and have not considered allocation based on risk factors for fracture or markers of bone turnover. Targeted allocation of the available therapies based on a stratification of risk appears warranted. This might be achieved using an algorithm incorporating BMD, X‐ray evaluation, laboratory investigations including bone turnover markers and the assessment of standard fracture risk factors at the time of and soon after transplantation. This approach, which is similar to protocols used in the general population, may result in more effective management of patients and fewer adverse effects such as adynamic bone disease. Although BMD is a surrogate for fracture risk in the general population it is not validated in this transplant population. Consequently, such an approach should be confirmed by studies that include bone biopsy data and an evaluation of patient level outcomes.

Differential nature of cross-talk among three G-coupled receptors regulating adenylyl cyclase in rat cardiomyocytes chronically exposed to receptor agonists

Chronic exposure of cells to cognate agonists has been established to cause homologous desensitization of G protein-coupled receptors. In this work, we show that exposure of adult rat eardiomyoeytes to isoproterenol (ISO) for 24 h led to the desensitization of β-adrenoceptor (β-AR) coupled adenylyl cyclase (AC) activity, which was associated with an increased inhibition of AC by M2-muscarinic receptor (MR) agonist, carbachol (Cch), and a decreased inhibition of AC by A1-adenosine receptor (AdR) agonist, N6-phenylisopropyladenosine (R-PIA). Chronic exposure of eells to Cch caused the desensitization of M2-MR-coupled AC, decreased the inhibitory action of R-PIA on AC and increased ISO-stimulated AC, while chronic exposure to R-PIA caused the desensitization of A1-AdR-coupled AC and modestly increased ISO-stimulated AC without any significant effect on Cch inhibition of the enzyme. Thus, chronic exposure ol cardiomyocytes revealed for the first time a more complex and differential nature of cross-talk among the three major G-coupled receptors in modulating AC.

Severe antibody-mediated rejection following IVIG infusion in a kidney transplant recipient with BK-virus nephropathy☆

Intravenous immune-globulin (IVIG) use in renal transplantation has increased, with common uses including desensitization, treatment of antibody mediated rejection and adjunctive therapy for BK virus nephropathy. Although considered generally safe, potential side effects can occur in up to 23% of patients including acute kidney injury. We present a case of an unexpected cause of acute kidney injury in a renal transplant recipient following IVIG infusion. A 48-year-old nonsensitized female with end stage renal disease secondary to polycystic kidney disease received a deceased donor kidney transplant. The initial post-transplant period was unremarkable however at three years post-transplant the patient develops BK virus nephropathy. Despite a reduction in immunosuppression, graft function worsened and IVIG infusion was commenced. Immediately following the IVIG infusion, the patient develops anuric acute kidney injury necessitating hemodialysis. Renal transplant biopsy performed before and after the IVIG infusion revealed the de novo development of acute antibody mediated rejection and donor specific antibodies in the serum. Anti-HLA and donor-specific antibodies were also confirmed in a diluted sample of the IVIG preparation. We argue that the anti-HLA antibodies present in the IVIG caused an acute antibody mediated rejection in this previously nonsensitized female.

Mesna for Treatment of Hyperhomocysteinemia in Hemodialysis Patients: A Placebo-Controlled, Double-Blind, Randomized Trial

BACKGROUND AND OBJECTIVES Increased plasma total homocysteine is a graded, independent risk factor for the development of atherosclerosis and thrombosis. More than 90% of patients with end-stage renal disease have hyperhomocysteinemia despite vitamin supplementation. It was shown in previous studies that a single intravenous dose of mesna 5 mg/kg caused a drop in plasma total homocysteine that was significantly lower than predialysis levels 2 d after dosing. It was hypothesized 5 mg/kg intravenous mesna administered thrice weekly, before dialysis, for 8 wk would cause a significant decrease in plasma total homocysteine compared with placebo. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients with end-stage renal disease were randomly assigned to receive either intravenous mesna 5 mg/kg or placebo thrice weekly before dialysis. Predialysis plasma total homocysteine concentrations at weeks 4 and 8 were compared between groups by paired t test. RESULTS Mean total homocysteine at 8 wk in the placebo group was 24.9 micromol/L compared with 24.3 micromol/L in the mesna group (n = 22 [11 pairs]; mean difference 0.63). Interim analysis at 4 wk also showed no significant difference between mesna and placebo (n = 32 [16 pairs]; placebo 26.3 micromol/L, mesna 24.5 micromol/L; mean difference 1.88). Multivariable adjustments for baseline characteristics did not alter the analysis. Plasma mesna seemed to reach steady-state concentrations by 4 wk. CONCLUSIONS It is concluded that 5 mg/kg mesna does not lower plasma total homocysteine in hemodialysis patients and that larger dosages may be required.