Renal physiology and kidney injury during intense (CrossFit®) exercise.

BACKGROUND: High-intensity training (HIT) programmes are popularly associated with improvements in exercise efficiency and body composition, although, at extremes, have been accompanied by concerns of secondary rhabdomyolysis and severe acute kidney injury (AKI). Beyond the anecdotal, robust literature on the physiological impact of HIT on renal function is currently limited. AIMS: To investigate the acute impact of high-intensity (CrossFit®) training on renal function, and to evaluate the incidence of AKI by Risk, Injury, Failure, Loss, End-stage renal disease (RIFLE) criteria following CrossFit® training. METHODS: Clinical and biochemical parameters were measured in 22 healthy adults before and after two CrossFit® workouts: 'Fran' (12 men, 10 women) and 'Macho Man' (9 men, 4 women). RESULTS: Serum creatinine increased by 16 ± 10 µmol/L following Fran and 18 ± 12 µmol/L following Macho Man (P < 0.05). Cystatin C did not change significantly following Fran and increased by 0.06 ± 0.06 mg/L (P < 0.05) following Macho Man. AKI, as defined by RIFLE 'Risk' criteria, was observed in 5/22 (23%) participants following Fran and 5/13 (38%) participants following Macho Man. Urinary albumin/creatinine ratio rose by 18.7 ± 18.3 and 5.2 ± 6.0 mg/mmol following Fran and Macho Man respectively off non-albuminuric baselines (P < 0.05). CONCLUSIONS: Intense (CrossFit®) exercise is associated with significant metabolic demands and alterations in parameters of renal physiology and function. The observed rise in both conventional and novel biomarkers of renal function following the workout Macho Man specifically might indicate a degree of transient subclinical functional impairment with CrossFit®-type training.

Patient reported barriers are associated with low physical and mental well-being in patients with co-morbid diabetes and chronic kidney disease.

BACKGROUND: Little is known about how patient reported barriers to health care impact the quality of life (HRQoL) of patients with comorbid disease. We investigated patient reported barriers to health care and low physical and mental well-being among people with diabetes and chronic kidney disease (CKD). METHODS: Adults with diabetes and CKD (estimated Glomerular Filtration Rate < 60 ml/min/1.73m2) were recruited and completed a questionnaire on barriers to health care, the 12-Item HRQoL Short Form Survey and clinical assessment. Low physical and mental health status were defined as mean scores < 50. Logistic regression models were used. RESULTS: Three hundred eight participants (mean age 66.9 ± 11 years) were studied. Patient reported 'impact of the disease on family and friends' (OR 2.07; 95% CI 1.14 to 3.78), 'feeling unwell' (OR 4.23; 95% CI 1.45 to 12.3) and 'having other life stressors that make self-care a low priority' (OR 2.59; 95% CI 1.20 to 5.61), were all associated with higher odds of low physical health status. Patient reported 'feeling unwell' (OR 2.92; 95% CI 1.07 to 8.01), 'low mood' (OR 2.82; 95% CI 1.64 to 4.87) and 'unavailability of home help' (OR 1.91; 95% CI 1.57 to 2.33) were all associated with higher odds of low mental health status. The greater the number of patient reported barriers the higher the odds of low mental health but not physical health status. CONCLUSIONS: Patient reported barriers to health care were associated with lower physical and mental well-being. Interventions addressing these barriers may improve HRQoL among people with comorbid diabetes and CKD.

De novo or early conversion to everolimus and long-term cancer outcomes in kidney transplant recipients: A trial-based linkage study.

Choice of immunosuppression may modify the risk of cancer after kidney transplantation, however, long-term data are lacking. Using the Australian and New Zealand Dialysis and Transplant Registry, we compared the 9-year risk of incident cancer, non-melanoma skin cancer (NMSC), and death attributed to cancer among participants from Australia and New Zealand in four randomized-controlled trials which compared de novo or early switch to an everolimus-containing regimen with calcineurin-inhibitor-based triple therapy. An adjusted Cox-model with random effects was used to determine such risks. Two hundred seventy-nine patients (192 everolimus, 87 control) were followed for a median of 9 years (IQR 6.7, 11.2). Compared with control, everolimus use was not associated with a reduction in the risk of incident cancer, NMSC, or cancer-related death (unadjusted HR [95% CI] 0.86 [0.49-1.48], 0.58 [0.30-1.12], and 1.18 [0.32-4.38], respectively). Subgroup analyses showed a 56% reduction for NMSC in patients randomized to everolimus + reduced-dose calcineurin-inhibitor versus control (unadjusted HR 0.44 [0.21-0.92]), which remained significant after adjusting for age, gender and smoking (adjusted HR 0.45 [0.21-0.96]). Although de novo or early switch to everolimus did not alter the 9-year risk of incident cancer or cancer-related death, everolimus with reduced-dose calcineurin-inhibitor strategy may reduce the long-term risk of NMSC.

Known unknowns: Examining the burden of neurocognitive impairment in the end-stage renal failure population.

The burden of neurocognitive impairment (NCI) in patients receiving maintenance dialysis represents a spectrum of deficits across multiple cognitive domains that are associated with hospitalization, reduced quality-of-life, mortality and forced decision-making around dialysis withdrawal. Point prevalence data suggest that dialysis patients manifest NCI at rates 3- to 5-fold higher than the general population, with executive function the most commonly affected cognitive domain. The unique physiology of the renal failure state and maintenance dialysis appears to drive an excess of vascular dementia subtype compared to the general population where classical Alzheimer's disease predominates. Despite the absence of evidence-based cost-effective therapies for NCI, detecting it in this population creates opportunity to proactively personalize care through education, supported decision making and targeted communication strategies to cover specific areas of deficit and help define goals of care. This review discusses NCI in the dialysis setting, including developments in the definition of neurocognitive impairment, dialysis-specific epidemiology across modalities, screening strategies and opportunities for dialysis providers in this space.

Incidence of renal Fanconi syndrome in patients taking antiretroviral therapy including tenofovir disoproxil fumarate.

The objective of this study was to determine the incidence and predictors of Fanconi Syndrome (FS) in a cohort of patients taking tenofovir disoproxil fumarate (TDF). Clinical records and laboratory investigations from patients receiving TDF between 2002 and 2016 were extracted. FS was defined as normoglycaemic glycosuria and proteinuria and at least one other marker of renal dysfunction. Regression analysis was performed with time to development of FS and the following covariates: ritonavir co-administration, age, gender, co-morbidities (hypertension, hyperlipidaemia, diabetes, viral hepatitis), CD4 cell count nadir and baseline eGFR. One thousand and forty-four patients received TDF without ritonavir and 398 patients with ritonavir. Thirteen cases of FS were identified with a mean duration of exposure of 55 months. The incidence of FS was 1.09/1000PY (0.54-1.63) of TDF exposure (without ritonavir) and 5.50/1000PY (3.66-7.33) of TDF-ritonavir co-administration (p=0.0057). The adjusted hazards ratio for ritonavir co-administration was 4.71 (1.37-16.14, p=0.014). Known risk factors for chronic kidney disease were not associated with development of FS. Ritonavir co-administration, but not other factors, is associated with a greater risk of FS. FS developed late. Known risk factors for chronic kidney disease and length of treatment are not useful for identifying patients most at risk of developing FS in patients taking TDF.

The longitudinal effects of peritonitis on peritoneal membrane function
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BACKGROUND: The longitudinal effects of peritoneal dialysis (PD) peritonitis on small solute clearance and ultrafiltration are controversial. MATERIALS AND METHODS: We identified 27 patients with PD peritonitis over a 4-year period at a tertiary hospital. Adequacy tests at an "early" (1 - 3 months), "intermediate" (6 ± 2 months), and a "late" (12 ± 2 months) time period after the episode were compared with a pre-peritonitis baseline. The effect of time on serum albumin, weekly creatinine clearance, Kt/V, and net fluid volume removal was assessed. RESULTS: At 12 months, 16/27 (59.3%) patients were no longer on PD. Ten were transferred to hemodialysis, predominantly due to peritonitis (60%). Five patients died, and 1 received a renal allograft. Total daily fluid volume removal significantly decreased over time with an aggregated mean reduction of 523 mL/day between the baseline and 12-month test (1,624 ± 139 mL vs. 1,101 ± 160 mL; p = 0.02). This was due to an equivalent loss of both ultrafiltration and residual urine output, although the separate decline in these individual parameters was not statistically significant. There was no significant change in Kt/V, creatinine clearance, or serum albumin indicating preserved solute transport in those patients with sustained technique survival post peritonitis. CONCLUSION: Peritonitis is a common cause for transfer to hemodialysis. Fluid volume removal is the most significantly affected parameter at 12 months post peritonitis, driven by the combination of both ultrafiltration reduction and loss of residual diuresis. Clinicians should be aware that peritonitis identifies patients at high risk for technique failure. These findings should prompt clinicians to closely surveil volume status and consider backup dialytic strategies as early as 12 months post peritonitis.
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Predictive performance of different kidney function estimation equations in lung transplant patients.

BACKGROUND: There has been limited examination of the performance of glomerular filtration rate estimation (eGFR) equations in lung transplant populations. This study aimed to compare the performance of serum creatinine and cystatin C based eGFR equations with Tc-99m diethylenetriaminepentaacetic acid (DTPA) GFR measurements in individuals with end-stage lung disease, either prior to, or following, lung transplantation. METHODS: In this prospective observational study, participants underwent GFR measurements with Tc-99m Pentetate. Measured results were compared with GFR estimates derived from estimation equations [4-variable Modification of Diet in Renal Disease, Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine, cystatin C and creatinine-cystatin C combined equations]. RESULTS: Ninety-seven individuals were studied (77 post- and 20 wait-listed for transplantation). Median (range) radionucleotide GFR was 56.7ml/min/1.73m2 (22.8-109.2ml/min/1.73m2). In the study cohort as a whole, the CKD-EPI creatinine-cystatin C combined equation showed the highest performance, but was only slightly superior to the CKD-EPI creatinine equation. However, in individuals with cystic fibrosis, low arm muscle mass and/or low body mass index, all of the creatinine-based equations showed unacceptable performance. In these subgroups, improved GFR estimation was seen with the CKD-EPI cystatin C equation, and predictions were better still using the CKD-EPI creatinine-cystatin C combined equation. CONCLUSIONS: This study shows adequate predictive ability of CKD-EPI creatinine in the cohort as a whole, but unacceptable performance in patients with cystic fibrosis, low arm muscle mass and/or low body mass index. Our findings demonstrate that cystatin C may be a preferable filtration marker in these subgroups.

Association between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial.

BACKGROUND: Pentoxifylline has been shown to increase haemoglobin levels in patients with chronic kidney disease (CKD) and erythropoietin-stimulating agent (ESA)-hyporesponsive anaemia in the Handling Erythropoietin Resistance with Oxpentifylline multicentre double-blind, randomized controlled trial. The present sub-study evaluated the effects of pentoxifylline on the iron-regulatory hormone hepcidin in patients with ESA-hyporesponsive CKD. METHODS: This sub-study included 13 patients in the pentoxifylline arm (400 mg daily) and 13 in the matched placebo arm. Hepcidin-25 was measured by ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry following isolation from patient serum. Serum hepcidin-25, serum iron biomarkers, haemoglobin and ESA dosage were compared within and between the two groups. RESULTS: Hepcidin-25 concentration at 4 months adjusted for baseline did not differ significantly in pentoxifylline versus placebo treated patients (adjusted mean difference (MD) -7.9 nmol, P = 0.114), although the difference between the groups mean translated into a >25% reduction of circulating hepcidin-25 due to pentoxifylline compared with the placebo baseline. In paired analysis, serum hepcidin-25 levels were significantly decreased at 4 months compared with baseline in the pentoxifylline group (-5.47 ± 2.27 nmol/l, P < 0.05) but not in the placebo group (2.82 ± 4.29 nmol/l, P = 0.24). Pentoxifylline did not significantly alter serum ferritin (MD 55.4 mcg/l), transferrin saturation (MD 4.04%), the dosage of ESA (MD -9.93 U/kg per week) or haemoglobin concentration (MD 5.75 g/l). CONCLUSION: The reduction of circulating hepcidin-25 due to pentoxifylline did not reach statistical significance; however, the magnitude of the difference suggests that pentoxifylline may be a clinically and biologically meaningful modulator of hepcidin-25 in dialysis of patients with ESA-hyporesponsive anaemia.

Predictors of Health-Related Quality of Life in Patients with Co-Morbid Diabetes and Chronic Kidney Disease.

BACKGROUND: People living with diabetes and chronic kidney disease (CKD) experience compromised quality of life. Consequently, it is critical to identify and understand factors influencing their health-related quality of life (HRQoL). This study examined factors associated with HRQoL among patients with diabetes and CKD. METHODS: A cross sectional study among adults with comorbid diabetes and CKD (eGFR <60 mL/min/1.73m2) recruited from renal and diabetes clinics of four large tertiary referral hospitals in Australia was performed. Each participant completed the Kidney Disease Quality of Life (KDQoL ™ -36) questionnaire, which is comprised of two composite measures of physical and mental health and 3 kidney disease specific subscales with possible scores ranging from 0 to 100 with higher values indicating better HRQoL. Demographic and clinical data were also collected. Regression analyses were performed to determine the relationship between HRQoL and potential predictor factors. RESULTS: A total of 308 patients were studied with a mean age of 66.9 (SD = 11.0) years and 70% were males. Mean scores for the physical composite summary, mental composite summary, symptom/problem list, effects of kidney disease and burden of kidney disease scales were 35.2, 47.0, 73.8, 72.5 and 59.8 respectively. Younger age was associated with lower scores in all subscales except for the physical composite summary. Female gender, obese or normal weight rather than overweight, and smoking were all associated with lower scores in one or more subscales. Scores were progressively lower with more advanced stage of CKD (p<0.05) in all subscales except for the mental composite summary. CONCLUSION: In patients with diabetes and CKD, younger age was associated with lower scores in all HRQoL subscales except the physical composite summary and female gender, obese or normal weight and more advanced stages of CKD were associated with lower scores in one or more subscales. Identifying these factors will inform the timely implementation of interventions to improve the quality of life of these patients.

Percutaneous insertion of peritoneal dialysis catheters using ultrasound and fluoroscopic guidance: A single centre experience and review of literature.

Various methods of peritoneal dialysis (PD) catheter insertion are available. The purpose of this study was to evaluate a percutaneous insertion technique using ultrasound (US) and fluoroscopy performed under conscious sedation and as day case procedure. Data of 87 percutaneous inserted dialysis catheters were prospectively collected, including patients' age, gender, body mass index, history of previous abdominal surgery and cause of end stage renal failure. Length of hospital stay, early complications and time to first use were also recorded. Institutional review board approval was obtained. A 100% technical success rate was observed. Early complications included bleeding (n = 3), catheter dysfunction (n = 6), exit site infection (n = 1) and exit site leakage (n = 1). All cases of catheter dysfunction and one case of bleeding required surgical revision. Median time of follow-up was 18 months (range 3-35), and median time from insertion to first use was days 14 (1-47). Of the 82 patients who started dialysis, 20 (23%) ceased PD at some stage during follow-up. Most frequently encountered reasons include deteriorating patient cognitive or functional status (n = 5), successful transplant kidney (n = 4) and pleuro-peritoneal fistula (n = 4). Sixty-two (71%) PD catheter insertions were performed as day case. The remaining insertions were performed on patients already admitted to the hospital. Percutaneous insertion of dialysis catheter using US and fluoroscopy is not only safe but can be performed as day case procedure in most patients, even with a medical history of abdominal surgery and/or obesity.

Morphology of the humeral insertion of the supraspinatus and infraspinatus tendons: Application to rotator cuff repair.

In shoulder surgery, a precise understanding of anatomical relationships is required for accurate reconstruction. Reports in recent literature have challenged the traditional definitions of the humeral footprints of the supraspinatus and infraspinatus tendons. This study aims to precisely delineate these footprints. The rotator cuffs of 54 shoulders from 27 Australian Caucasoid donor cadavers were examined. The tendinous portions were dissected down to their region/footprint of attachment upon the humerus. Measurements of those footprints, upon the greater and lesser tuberosities, were made. Those measurements were statistically analyzed for any association with age, sex, height, or side. Twenty-seven cadavers had an average age at death of 74.9 (± 12.8), 56% were male, average height was 168 (± 8.6) cm. Due to premorbid fracture, or degeneration, 11 shoulders were excluded. The footprint of the supraspinatus was triangular, with a medial, anteroposterior length of 20.4 ± 4.2 mm. Its lateral anteroposterior length was 6.3 ± 1.6 mm and its maximal mediolateral width was 6.6 ± 2.7 mm. Its calculated area was 122.0 ± 66.6 mm(2). The footprint of the infraspinatus was trapezoidal, with a medial anteroposterior length 22.6 ± 3.0 mm. Its lateral anteroposterior length was 25.4 ± 3.3mm and its maximal mediolateral width was 12.0 ± 2.7 mm. Its calculated area was 294.9 ± 74.1 mm(2). There was no statistical correlation between size of the footprint and age, sex, side, or height. The humeral footprints of the supraspinatus and infraspinatus tendons upon the greater tuberosity were distinct. The lateral border of the infraspinatus' humeral attachment extended much farther anteriorly upon the highest facet of the greater tuberosity than in traditional descriptions.

Long-term successful outcomes from kidney transplantation after lung and heart-lung transplantation.

BACKGROUND: Renal dysfunction is common after lung and heart-lung transplantation (Tx), and it limits the recipient's survival and quality of life. This study analyzed the outcomes of simultaneous and late kidney Tx following lung and heart-lung Tx. METHODS: From a single-center retrospective chart review of 1031 lung and heart-lung Tx recipients, we identified 13 simultaneous or late kidney Tx cases in 12 patients. RESULTS: Three patients underwent simultaneous deceased donor lung and kidney Tx. Eight patients underwent lung and heart-lung Tx, followed by nine living donor kidney Tx (including one ABO-incompatible Tx). One additional patient underwent a late deceased donor kidney Tx following heart-lung Tx. The median time from lung and heart-lung Tx to later kidney Tx was 127 (interquartile range [IQR], 23 to 263) months. Three patients died, 1 of sepsis, 1 of multiple organ failure, and 1 of transplant coronary disease. At a median follow-up of 33 (IQR, 10 to 51) months, 9 patients are alive and well. Eight patients required dialysis before kidney Tx for a median time of 14 months (IQR, 5 to 49). Kidney graft loss occurred in 1 patient at 51 months. After kidney Tx, dialysis was necessary in association with acute allograft dysfunction in 2 patients. No acute kidney rejection has been detected in any patient. Treatable acute lung rejection was seen in 1 patient. Well-preserved pulmonary function was noted in recipients of late kidney Tx. CONCLUSIONS: Simultaneous kidney Tx and late deceased donor kidney Tx have challenges in the setting of lung Tx. By contrast, late living related kidney Tx after lung Tx is associated with excellent long-term survival and acceptable kidney and lung allograft function.

Radiological insertion of Tenckhoff catheters for peritoneal dialysis: a 1-year single-centre experience.

BACKGROUND: Peritoneal dialysis (PD) is an important home-based dialysis modality for patients with end-stage kidney disease (ESKD). The initiation of PD requires timely and skilled insertion of a Tenckhoff catheter (TC). At most centres, TCs are inserted laparoscopically by surgeons under general anaesthetic. This requires access to increasingly scarce surgical, anaesthetic and hospital inpatient resources. Radiological insertion of TCs performed as a day procedure under local anaesthetic allows for easier access to the TC insertion with reduced resource requirements. We report our 1-year experience following the introduction of this technique to our PD programme. METHODS: This is a retrospective review of the outcomes for all patients who had TCs inserted radiologically (percutaneously with the assistance of ultrasound and fluoroscopy) over the 12-month period from December 2011 to December 2012. Relevant patient demographics collected included age, gender, body mass index (BMI), previous abdominal surgery and cause of ESKD. Extended details of the insertion procedure were also obtained including length of stay, early complications and time to first use of the catheter for PD. RESULTS: Thirty Argyle(™) Swan Neck TCs were inserted under radiological guidance during the study period. The mean age of patients was 56 (SD ± 14). The male-to-female ratio was 2:1. The mean BMI was 25.7 (SD ± 4.8). PD was the initial dialysis modality in 22 (73%) patients. Of the 30 patients, 14 (46.7%) had previously undergone extraperitoneal abdominal surgery. All catheters were inserted successfully as day cases except four patients (13.3%) who had catheters inserted during an inpatient hospital admission. Most catheters were not accessed for a minimum of 10 days to reduce the chance of exit site leakage, in two cases the catheters were used within 5 days without complication. There were no cases of peritonitis or exit site infection during the observation period. Catheter migration occurred in four patients (13.3%) but only one required surgical intervention. Minor pain issues were noted in six patients (20%) and bleeding around the exit site requiring suturing in two patients (6.7%). The introduction of this technique at our institution saw a 67% increase in the number of patients performing PD. CONCLUSIONS: Radiological insertion of TCs for PD provided improved access to catheter insertion in a timely manner with reduced resource requirements. Over the 12-month observation period we noted a high technical success rate with very few complications. Our study supports radiological insertion of TCs under local anaesthetic as a viable alternative to catheter insertion in theatre under general anaesthetic. The relative ease of radiological TC insertion has resulted in a significant increase in patient uptake of PD at our centre.

Incidence of acute kidney injury following total joint arthroplasty: a retrospective review by RIFLE criteria.

BACKGROUND: Total joint arthroplasty (TJA) is a common procedure with demand for arthroplasties expected to increase exponentially. Incidence of acute kidney injury (AKI) following TJA is reportedly low, with most studies finding an incidence of <2%, increasing to 9% when emergency orthopaedic patients are included. METHODS: Retrospective medical record review of consecutive primary, elective TJA procedures was undertaken at a large tertiary hospital (Alfred). Demographic, peri-operative and post-operative data were recorded. Factors associated with AKI (based on RIFLE criteria) were determined using multiple logistic regression. RESULTS: Between January 2011 and June 2013, 425 patients underwent TJA; 252 total knee replacements (TKR) and 173 total hip replacements (THR). Sixty-seven patients (14.8%) developed AKI, including 51 TKR. Factors associated with AKI (adjusting for known confounders) include increasing body mass index [adjusted odds ratio (AOR) 1.14; 95% CI: 1.07, 1.21], older age (AOR 1.07; 95% CI 1.02, 1.13) and lower pre-operative glomerular filtration rate (AOR 0.97; 95% CI 0.96, 0.99) and taking angiotensin-converting enzyme inhibitors (AOR 2.70; 95% CI 1.12, 6.48) and angiotensin-II receptor blockers (AOR 2.64; 95% CI 1.18, 5.93). In most patients, AKI resolved by discharge, however, only 62% of patients had renal function tests after discharge. CONCLUSIONS: This study showed a rate of AKI of nearly 15% in our TJA population, substantially higher than previously reported. Given that AKI and long-term complications are associated, prospective research is needed to further understand the associated factors and predict those at risk of AKI. There may be opportunities to maximize the pre-operative medical management and mitigate risk.

The influence of clinical donor factors on acute rejection among lung and kidney recipients from the same multi-organ donor.

BACKGROUND: Acute (AR) and Chronic (CR) rejection cause considerable morbidity and mortality following transplantation. This study explores the associations of biopsy proven AR in lung (LTx) and kidney (KTx) transplants recipients from the one donor. MATERIAL AND METHODS: Between 2001 and 2006, 136 multiorgan donors contributed 144 LTx and 261 matching KTx. Utilizing LTx records and the Australian and New Zealand Dialysis and Transplant Registry, this study analyses the incidence and associations of LTx and KTx AR. RESULTS: AR was noted in 49% of LTx [median of 17 (11-347) days] and 29% of KTx [median of 22 (1-1044) days]. Following univariate and multivariate analyses: 1) LTx AR was not associated with PGD in either LTx or KTX, nor with AR in KTx recipients, but was associated with donor PaO2/FiO2 ratio, type of LTx, CMV bronchoalveolar lavage load and extent of HLA mismatching; 2) KTx AR was not associated with PGD, but was associated with AR in the paired kidney, HLA DR mismatching and HLA A matching. CONCLUSIONS: AR in LTx and KTx recipients from the same donor are not associated. AR and PGD do not appear linked in either organ. KTx (and not LTx) AR was associated with CR-related graft loss.

Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation.

BACKGROUND: Strategies allowing calcineurin inhibitor minimization while maintaining efficacy may improve renal transplant outcomes. METHODS: A2309 was a 24-month, phase IIIb, open-label trial of 833 de novo renal transplant recipients randomized to everolimus, targeting trough concentrations of 3-8 or 6-12 ng/mL plus reduced-exposure cyclosporine A (CsA) or to mycophenolic acid (MPA) 1.44 g per day plus standard-exposure CsA. All patients received basiliximab ± corticosteroids. The incidence of the primary composite efficacy endpoint and its components (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up), renal function (serum creatinine and estimated glomerular filtration rate), and adverse events (AEs) were compared at 24 months; as per the protocol, these analyses were not noninferiority. RESULTS: Composite efficacy failure rates (95% confidence interval for difference vs. MPA) were 32.9% (-2.2%, 13.0%), 26.9% (-7.9%, 6.8%), and 27.4% at month 24 in the everolimus 3-8 and 6-12 ng/mL and MPA groups, respectively. Mean estimated glomerular filtration rate (Modification of Diet in Renal Disease) at month 24 was 52.2 (-2.1, 5.5 mL/min/1.73 m(2)), 49.4 (-4.8, 2.7 mL/min/1.73 m(2)), and 50.5 mL/min/1.73 m(2), respectively. AEs were generally mild to moderate in severity and comparable between the groups. AEs leading to discontinuation were reported in 28.5% (P = 0.03 vs. MPA), 30.6% (P = 0.007 vs. MPA), and 20.5% of patients receiving everolimus 3-8 and 6-12 ng/mL and MPA, respectively. CONCLUSIONS: Everolimus trough concentrations targeted to 3-8 ng/mL, along with a greater than 60% reduction in CsA exposure, was associated with comparable efficacy and renal function versus MPA plus standard-exposure CsA over the 2-year period. A significantly higher incidence of AEs led to discontinuation in the everolimus groups compared with the MPA group.

Enteric-coated mycophenolate sodium in combination with full dose or reduced dose cyclosporine, basiliximab and corticosteroids in Australian de novo kidney transplant patients.

AIM: Cyclosporine (CsA), dosed to achieve C2 targets, has been shown to provide safe and efficacious immunosuppression when used with a mycophenolate and steroids for de novo kidney transplant recipients. This study examined whether use of enteric-coated mycophenolate sodium (EC-MPS) together with basiliximab and steroids would enable use of CsA dosed to reduced C2 targets in order to achieve improved graft function. METHODS: Twelve-month, prospective, randomized, open-label trial in de novo kidney transplant recipients in Australia. Seventy-five patients were randomized to receive either usual exposure (n = 33) or reduced exposure (n = 42) CsA, EC-MPS 720 mg twice daily, basiliximab and corticosteroids. RESULTS: There was no significant difference in mean Cockcroft-Gault CrCl (creatinine clearance) (60.2 ± 17.6 mL/min per 1.73 m(2) vs 63.2 ± 24.3, P = 0.64 for usual versus reduced exposure respectively) at 6 months. There was no significant difference between treatment groups in the incidence of treatment failure defined as biopsy proven acute rejection, graft loss or death (secondary endpoint: 30.3% full exposure vs 35.7% reduced exposure). At 12 months the incidence of overall adverse events was the same in both groups. CONCLUSION: This exploratory study suggests de novo renal transplant patients can safely receive a treatment regimen of either full or reduced exposure CsA in combination with EC-MPS, corticosteroids and basiliximab, with no apparent difference in efficacy or graft function during the first year after transplant.