Safety and Efficacy of Short Daily Hemodialysis with Physidia S3 System: Clinical Performance Assessment during the Training Period.

BACKGROUND: A growing body of scientific evidence indicates that clinical outcomes of hemodialysis patients can be improved with short daily dialysis treatment. Current in-center hemodialysis machines do not fulfill the requirements needed for self-care home hemodialysis (HHD) treatment. In line with the reviviscence of home therapy, several hemodialysis devices have been developed and deployed for treatment. Physidia S3 is one of these new dialysis delivery systems featuring an appealing design and functionalities intended for daily HHD treatment. METHODS: In this French multicenter proof-of-concept study enrolling 13 training centers, we report our preliminary experience with a special focus on quantifying clinical performances in short daily HHD treatment performed during the training period of the patients. RESULTS: Among the 80 patients included in this study, a total of 249 sessions could be analyzed. Dialysis dose, estimated from weekly standardized Kt/V, was maintained at 2.22 [1.95-2.61] with a normalized protein catabolic rate of 0.93 [0.73-1.18] g/kg/24 h. Furthermore, anemia and nutritional status were adequately controlled as indicated by 11.6 ± 1.4 g/dL of hemoglobin level and 39.4 ± 5.7 g/L of serum albumin as well as electrolyte disorders. CONCLUSIONS: The safety and efficacy of the S3 therapy concept relying on a short daily hemodialysis treatment using a bagged delivery system are in total agreement with daily HHD recommendations. Clinical performances are aligned to the metabolic needs of the vast majority of HHD patients. Currently ongoing studies at home will provide further evidence and value of this therapeutic approach.

Natriuretic Peptides as Predictors of Protein-Energy Wasting in Hemodialysis Population.

OBJECTIVE: Imbalance between anabolism and catabolism is linked to cachexia and protein-energy wasting (PEW), especially in frail populations such as patients with chronic kidney disease. PEW is responsible of poor outcomes with increased morbidity and mortality. Several causes are involved in PEW such as insulin resistance, acidosis, or hyperparathyroidism. Natriuretic peptides (NPs) have recently been described as activators of resting energy expenditure through the induction of browning of white adipose tissue in rodents with chronic kidney disease. The present study was therefore implemented to investigate whether NPs could be associated with PEW criteria and predict clinical outcomes. METHODS: We quantified serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a prospective cohort of 231 patients undergoing maintenance hemodialysis and atrial natriuretic peptide in a subgroup of 35 patients. Body composition parameters were measured with bioimpedance spectroscopy. RESULTS: NT-proBNP was inversely associated with serum albumin, prealbumin, and body mass index and, conversely, positively associated with age and C-reactive protein. NT-proBNP as well as atrial natriuretic peptide were significantly higher in patients with PEW criteria. NT-proBNP was negatively associated with body fat mass. In multiple linear regression, NT-proBNP remained associated with body mass index. Kaplan-Meier analysis revealed a significant correlation between serum NT-proBNP concentrations and all-cause mortality and cardiovascular events. This association remained significant after multivariable Cox regression models adjusted for demographic factors and cardiovascular risk factors. CONCLUSION: Accumulation of NPs seems to be associated with poor nutritional status and reduced survival among hemodialysis patients. Further studies are needed to confirm this association using resting energy expenditure measurement and adipose tissue biopsy.

Accumulation of natriuretic peptides is associated with protein energy wasting and activation of browning in white adipose tissue in chronic kidney disease.

Protein energy wasting is a common feature of patients with chronic kidney disease (CKD) and is associated with poor outcomes. Protein energy wasting and cachexia, a severe form of protein energy wasting, are characterized by increased resting energy expenditure but the underlying mechanisms are unclear. Browning corresponds to the activation of inducible brown adipocytes in white adipose tissue and occurs in states of cachexia associated with hypermetabolic disease such as cancer. Here we tested the hypothesis that CKD-associated protein energy wasting could result from browning activation as a direct effect of the uremic environment on adipocytes. In a murine model of CKD (5/6 nephrectomy), there was increased resting energy expenditure, expression of uncoupling protein 1 (a thermogenic protein uncoupling oxidative phosphorylation in mitochondria) and citrate synthase activity (a proxy of mitochondrial density in white adipose tissue). Mice with CKD also exhibited increased levels of atrial natriuretic peptide, a well known activator of browning. The incubation of primary adipose cells with plasma from patients receiving dialysis treatment and having signs of protein energy wasting led to an increased synthesis of uncoupling protein 1. Similarly, primary adipose cells exposed to atrial natriuretic peptide at concentrations relevant of CKD led to a significant increase of uncoupling protein 1 content. Thus, accumulation of cardiac natriuretic peptides during CKD could contribute to the browning of white adipose tissue and protein energy wasting.

Is 3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) a Clinically Relevant Uremic Toxin in Haemodialysis Patients?

3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) is a metabolite of furan fatty acid and a marker of fish oil intake. CMPF is described as a protein-bound uremic toxin and interacts with free oxygen radicals, which can induce cell damages. However, the clinical consequences of CMPF accumulation in haemodialysis patients remain poorly documented. The aims of this study are to investigate potential association between CMPF levels and (i) biochemical and nutritional parameters; (ii) cardiovascular events and (iii) mortality. Two hundred and fifty-two patients undergoing maintenance haemodialysis were included. Routine clinical biochemistry tests and assay for CMPF by HPLC technique were performed at the inclusion. Body composition parameters were measured using a bioimpedance spectroscopy method. The enrolled patients were prospectively monitored for cardiovascular events and mortality. CMPF level was positively correlated with nutritional parameters and lean mass and is significantly higher in patients without protein-energy wasting. However, the multivariate linear regression analysis indicated that CMPF level was not independently associated with albumin, prealbumin, creatinemia and body mass index. Elevated serum CMPF was not associated with mortality and cardiovascular morbidity. Our results indicate that CMPF is not a relevant uremic toxin in haemodialysis and in contrast could be a marker of healthy diet and omega 3 intakes.

PAI-1 donor polymorphism influences long-term kidney graft survival.

BACKGROUND: The type 1 plasminogen activator inhibitor (PAI-1) is involved in the development of fibrosis, and its intrarenal expression is increased in interstitial fibrosis and tubular atrophy (IFTA). Moreover, a 4G/5G polymorphism of the PAI-1 gene has been described associating 4G haplotype with higher PAI-1 plasma activity. We investigated the relationship between the donor and recipient PAI-1 polymorphism and kidney graft survival. METHODS: The PAI-1 genotype was determined for both the 304 donors and the 337 corresponding recipients. In recipients, PAI-1 antigen levels were also determined. We compared 4G/4G donors versus donors with other genotypes. RESULTS: Donor or recipient genotype did not influence the PAI-1 plasma level in recipients. Actuarial kidney graft survival was significantly reduced in the 4G/4G donor group (107 months versus 147.5 months, P = 0.013), while recipient PAI-1 genotype did not show any influence on graft survival. Moreover, graft loss due to IFTA proved significantly higher in the 4G/4G donor group (13% versus 6%, P = 0.03). Multivariate analysis showed that the significant independent variables associated with graft loss were the donor 4G/4G genotype, acute clinical rejection and donor age. CONCLUSION: Our study suggests that donor PAI-1 polymorphism influences kidney graft survival and that the donor 4G/4G genotype is an independent risk factor for graft loss. Prospective studies are needed to confirm these results.

[Renal transplantation in the elderly: a survey]. / Transplantation rénale du sujet âgé.

For ten years, an increase in the number of elderly patients on renal transplant waiting lists has occured. In an attempt to close the widening gap between supply and demand and because the demand for kidneys for younger patients already surpasses the supply, transplant physicians nowadays accept organs from older donors that might have been deemed inappropriate in the past. Programs of age matching between donors and recipients and of dual-kidneys transplantation have emerged. The initial results of these programs are encouraging with excellent patient and graft survival at one and three years.

CYP3A5*3 influences sirolimus oral clearance in de novo and stable renal transplant recipients.

BACKGROUND: The low and highly variable oral bioavailability of the immunosuppressant sirolimus is thought to result partly from genetic polymorphism of the CYP3A5 gene. METHODS: This study aimed to evaluate the contribution of the CYP3A5 single-nucleotide polymorphism A6986G to the interindividual variability of sirolimus pharmacokinetics in 47 renal transplant patients at steady state, 21 of whom were also followed up for the first 3 months after transplantation. The patients were administered sirolimus, mycophenolate mofetil, and corticosteroids but no calcineurin inhibitor. They were genotyped for CYP3A5*3 by use of real-time quantitative polymerase chain reaction based on the 5'-nuclease allelic discrimination assay. Full sirolimus blood concentration profiles were measured at steady state (3 months after transplantation or more) in all patients, as well as at weeks 1 and 2 and month 1 in 21 of these patients, by use of liquid chromatography-tandem mass spectrometry. The sirolimus area under the concentration-time curve (AUC) was calculated via the standard noncompartmental approach. Maximal concentration (C(max)) and trough level (C(0)) values were measured. RESULTS: Significantly lower AUC/dose, C(max)/dose, and C(0)/dose values were found at steady state (n = 47) in individuals carrying at least 1 CYP3A5*1 allele (n = 6) than in *3/*3 patients (26.6 +/- 15.7 versus 51.1 +/- 21.1 [P = .008], 4.8 +/- 3.3 versus 7.7 +/- 3.3 [P = .02], and 1.5 +/- 0.8 versus 3.0 +/- 1.5 [P = .01], respectively), as well as during all posttransplant periods in the subgroup of 21 patients who were followed up for the first 3 months after transplantation (n = 21) (P < .05 always). Patients with the CYP3A5*1/*1 and *1/*3 genotypes required a significantly higher sirolimus daily dose to achieve the same blood concentration at steady state as *3/*3 patients. In patients followed up for the first 3 months after transplantation, C(0) levels within the target range were only achieved after 1 to 3 months of repeated dosing and dose adjustment in both genotypic groups. CONCLUSION: These results confirm that sirolimus metabolic activity and oral clearance are significantly decreased in patients who are homozygous for the CYP3A5*3 single-nucleotide polymorphism and suggest that the determination of this polymorphism could be useful for a priori dose adjustment of sirolimus, given the long half-life of this drug.

A reverse transcription-nested PCR assay for HHV-6 mRNA early transcript detection after transplantation.

Monitoring of human herpesvirus-6 (HHV-6) reactivation is important, especially in immunocompromised patients such as transplant recipients. Reverse transcription PCR (RT-PCR) is a useful method to distinguish between latent and active infection. Here, a RT-nested PCR coupled with a colorimetric plate hybridization assay was established to detect HHV-6 types A and B U79/80 mRNAs. After confirming the reliability of the assay on HHV-6 cultures, it was applied to the detection of HHV-6 reactivation after renal (27 patients), bone marrow (14 patients) or heart (7 patients) transplantation. A total of 206 blood samples were tested from renal (137), bone marrow (58) and heart (11) transplant recipients. U79/80 mRNAs were found in 32 samples that were considered as indicative of HHV-6 reactivation: 15, 13 and 5 from kidney, bone marrow and heart transplant recipients, respectively. Finally, U79/80 mRNA detection was correlated with clinical manifestations including leucopenia, skin rash, graft rejection or dysfunction and diarrhoea.

Multiplex real-time PCR assay for simultaneous quantitation of human cytomegalovirus and herpesvirus-6 in polymorphonuclear and mononuclear cells of transplant recipients.

Human cytomegalovirus (HCMV) and human herpesvirus-6 (HHV-6) are two closely related viruses, which belong to the Herpesviridae family. Following primary infection, they are thought to persist for life as latent forms in mononuclear cells. HCMV and HHV-6 can cause considerable morbidity in immunocompromised individuals, such as transplant patients. A sensitive and specific LightCycler multiplex real-time PCR assay based on fluorescence energy transfer (known as FRET) was developed. This assay, by using two sets of hybridization probes specific for HHV-6 (A and B) and HCMV, can differentiate reliably and quantify simultaneously both viruses in order to diagnose reactivation processes. The assay was optimized and the lower limit of detection for both viruses was determined to be 10 viral genome copies per reaction. Both viruses were quantified in 83 peripheral blood mononuclear cells (PBMCs) and 87 polymorphonuclear leukocytes (PMNLs) collected from 32 transplant recipients. This multiplex real-time quantitative PCR was finally compared with two other quantitation and detection assays used daily in laboratory (PCR DIG detection and antigenemia for HCMV, TaqMan Assay for HHV-6). This technique can be useful for the differentiation and quantitation of HCMV and HHV-6 for monitoring transplant patients.

Intracranial granuloma and skull osteolysis: complication of a primary cutaneous cryptococcosis in a kidney transplant recipient.

Cryptococcosis is the third most common invasive fungal infection in organ transplant recipients after candidiasis and aspergillosis. It occurs almost exclusively in the late posttransplantation period (>6 months after the initiation of immunosuppression). Subclinical onset of meningitis is the usual clinical presentation. Despite initiation of therapy, the mortality rate associated with this infection in this patient population remains high. To the best of our knowledge, this report describes one of the first cases of a rare entity: a primary cutaneous cryptococcosis in a renal transplant recipient disclosed by skull osteomyelitis and pseudotumoral intracranial extension. Surgical debridement and azole antifungal therapy were performed. Ten months after the onset of treatment, the patient feels good, clinical examination findings are normal, and no sign of evolutive cryptococcosis is noted.

Maximum a posteriori bayesian estimation of mycophenolic acid pharmacokinetics in renal transplant recipients at different postgrafting periods.

The aim of this study was to develop maximum a posteriori probability (MAP) Bayesian estimators of mycophenolic acid (MPA) pharmacokinetics (PK) capable of accurately estimating the MPA interdose AUC in renal transplant patients using a limited number of blood samples. The individual MPA plasma concentration-time profiles of 44 adult kidney transplant recipients were retrospectively studied: in 24 de novo transplant patients, 2 profiles were obtained on day 7 and day 30 after transplantation, and in 20 stable transplant patients, 1 profile was obtained in the stable period (>3 months). MPA was assayed by liquid chromatography-mass spectrometry. Concentration data were fitted using previously designed PK models, including 1 or 2Gamma-distribution to describe the absorption rate. MAP-Bayesian estimations were performed using an in-house program. For each posttransplantation period, the limited sampling strategies (LSS) providing either the best determination coefficient or the lowest bias for AUC estimates with respect to trapezoidal AUCs were selected and compared with respect to the percentage of "clinically acceptable" AUC estimates (ie, within -20% to +20% of the true value) they yielded. A common LSS (blood samples collected at T20 min, T1 h, and T3 h postdosing), convenient for all 3 periods, was also selected and validated: bias (RMSE%) values were -5.7% (20.5%), -8.2% (14.4%), and +0.4% (12.0%) on D7, D30, and for >M3 with respect to the reference values obtained using the trapezoidal rule, respectively. For the first time, MAP-Bayesian estimators of MPA systemic exposure at different posttransplantation periods (early as well as later periods) could be designed. They have since been used for MPA dose adaptation in concentration-controlled studies as well as for MPA therapeutic drug monitoring in clinical practice.