ABSTRACT
BACKGROUND: There is concern about the impact of immunosuppressive agents taken by male kidney transplant (KT) recipients on the risk of foetal malformations. The aim of our survey was to estimate the paternity rate and the outcomes of pregnancies fathered by kidney transplanted males. METHODS: This survey analysed 1332 male KT recipients older than 18 years, followed in 13 centres in France. A self-reported questionnaire was used to collect data on the patients, treatments at the time of conception and the pregnancy outcomes. RESULTS: The study included data on 349 children from 404 pregnancies fathered by 232 male KT recipients. The paternity rate was 17% (95% CI [15-20]). There were 37 (9%, 95% CI [7-12]) spontaneous abortions, 12 (3%, 95% CI [2-5]) therapeutic abortions, 2 (0.5%, 95% CI [0.1-1]) still births, and 13 (4%, 95% CI [2-6]) malformations reported. Compared to the general population, there was no difference in the proportion of congenital malformations nor unwanted outcomes whether the father was exposed or not to immunosuppressive agents. CONCLUSIONS: This survey does not provide any warning signal that pregnancies fathered by male patients exposed to immunosuppressive agents, notably the debated MMF/MPA, have more complications than pregnancies in the general population.
Subject(s)
Fathers , Immunosuppressive Agents/adverse effects , Paternal Exposure/adverse effects , Pregnancy Complications/etiology , Transplant Recipients , Congenital Abnormalities/epidemiology , Congenital Abnormalities/etiology , Female , France , Humans , Infertility, Male , Kidney Transplantation , Male , Pregnancy , Pregnancy Complications/epidemiology , Pregnancy Outcome , Self ReportABSTRACT
Human leukocyte antigen (HLA) mismatching and minimization of immunosuppression are two major risk factors for the development of de novo donor-specific antibodies, which are associated with reduced kidney graft survival. Antibodies do not recognize whole HLA antigens but rather individual epitopes, which are short sequences of amino acids in accessible positions. However, compatibility is still assessed by the simple count of mismatched HLA antigens. We hypothesized that the number of mismatched epitopes, or ("epitope load") would identify patients at the highest risk of developing donor specific antibodies following minimization of immunosuppression. We determined epitope load in 89 clinical trial participants who converted from cyclosporine to everolimus 3 months after kidney transplantation. Twenty-nine participants (32.6%) developed de novo donor specific antibodies. Compared to the number of HLA mismatches, epitope load was more strongly associated with the development of donor specific antibodies. Participants with an epitope load greater than 27 had a 12-fold relative risk of developing donor-specific antibodies compared to those with an epitope load below that threshold. Using that threshold, epitope load would have missed only one participant who subsequently developed donor specific antibodies, compared to 8 missed cases based on a 6-antigen mismatch. DQ7 was the most frequent antigenic target of donor specific antibodies in our population, and some DQ7 epitopes appeared to be more frequently involved than others. Assessing epitope load before minimizing immunosuppression may be a more efficient tool to identify patients at the highest risk of allosensitization.
Subject(s)
Graft Rejection/prevention & control , HLA-DQ Antigens/blood , Immunosuppressive Agents/administration & dosage , Isoantigens/blood , Kidney Transplantation/adverse effects , Patient Selection , Adult , Cyclosporine/administration & dosage , Cyclosporine/adverse effects , Drug Substitution , Epitopes/immunology , Everolimus/administration & dosage , Everolimus/adverse effects , Female , Follow-Up Studies , Graft Rejection/blood , Graft Rejection/immunology , Graft Survival/immunology , HLA-DQ Antigens/immunology , Histocompatibility Testing , Humans , Immunosuppressive Agents/adverse effects , Isoantigens/immunology , Male , Middle Aged , Transplantation, Homologous/adverse effectsABSTRACT
BACKGROUND: BK polyomavirus associated nephropathy (BKPyVAN) is a significant clinical issue in kidney transplant (KT) recipients. No specific therapy is currently available, although treatment with leflunomide may be part of the therapeutic strategy. Here, we sought to examine the impact of leflunomide on the evolution of BKPyVAN. METHODS: This was an observational retrospective study conducted in 3 French transplant centers. KT recipients who developed BKPyVAN and received leflunomide after failure of other treatment approaches were deemed eligible. Graft function, viral clearance, patient survival, rejection rates, treatment tolerability, and immunosuppression levels served as the main outcome measures. RESULTS: A total of 55 patients were included. Treatment with leflunomide was started after a mean of 1.4 ± 4.1months after BKPyVAN diagnosis. Between the introduction of leflunomide and the end of follow-up, creatinine levels increased by 31 ± 118% (P = 0.04), whereas viremia decreased by 79 ± 37% (P < 0.001). Blood viral clearance was observed in 76% of the study patients. Rejection episodes occurred in 33% of the participants. Eleven patients lost their graft (9 of which because of BKPyVAN). Ten patients developed adverse effects and 3 discontinued leflunomide. CONCLUSION: We cannot conclude about the exact place of leflunomide in the therapeutic strategy of BKPyVAN. It may be a part of the therapy to promote BK polyomavirus clearance in cases of BKPyVAN who fail to improve after immunosuppression lowering alone. Unfortunately, a significant decline in renal function and high rejection rates remain major clinical challenges.
Subject(s)
Kidney Diseases/drug therapy , Kidney Diseases/virology , Kidney Transplantation/adverse effects , Leflunomide/therapeutic use , Polyomavirus Infections/drug therapy , Tumor Virus Infections/drug therapy , Adult , Aged , Female , Graft Rejection , Humans , Immunosuppressive Agents/administration & dosage , Kidney/drug effects , Kidney/pathology , Kidney/virology , Kidney Diseases/etiology , Male , Middle Aged , Polyomavirus Infections/complications , Retrospective Studies , Transplant Recipients , Tumor Virus Infections/complications , Viral Load , ViremiaABSTRACT
Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.
Subject(s)
Intellectual Disability/genetics , Kidney Diseases, Cystic/genetics , Microtubule-Associated Proteins/genetics , Mutation , Alleles , Central Nervous System/abnormalities , Centrioles/genetics , Centrioles/metabolism , Child, Preschool , Cilia/metabolism , Exons , Female , Humans , Infant , Male , Microtubule-Associated Proteins/metabolism , Orofaciodigital Syndromes/geneticsABSTRACT
BACKGROUND: POR*28 is a recently newly described allelic variant of the cytochrome P450 oxidoreductase (POR), which might be associated with an increased metabolic activity of P450 cytochromes (CYP) 3A5 and 3A4. Consequently, carriers of at least 1 allele of this polymorphism could require increased calcineurin inhibitors doses to reach the target residual concentrations (C0). The objective of this study was to test whether the allelic variant of POR, which is associated with an increased metabolic activity of CYP3A, impacts tacrolimus (Tac) pharmacokinetics. METHODS: We tested this hypothesis in a population of 229 kidney transplant recipients (KTR) from a large, multicenter, prospective and randomized study. We have analyzed the association between POR*28 genotype and the proportion of individuals reaching the target Tac residual concentration (Tac C0) 10 days after transplantation. We have also measured the association between POR*28 and the Tac C0, and adjusted Tac C0 (Tac C0/Tac dose) over time using generalized mixed linear models. RESULTS: Ten days after transplantation, there was no difference of frequencies of KTR within the target range of Tac C0 (C0 10-15 ng/mL) according to the POR*28 genotype (P = 0.8). The mean Tac C0 at day 10 in the POR*1/*1 group was 15.3 ± 9.7 ng/mL compared with 15.7 ± 7.8 ng/mL in the POR*1/*28 group and 14.2 ± 6.8 ng/mL, in the POR*28/*28 group, P = 0.8. The adjusted Tac C0 was not associated with POR*28 genotype over time (random effects model, P = 0.9). When restricted to KTR expressing CYP3A5, POR*28 genotype did not impact the proportion of individuals within the Tac C0 target range neither the adjusted Tac C0 (random effects model, P = 0.1). CONCLUSIONS: POR*28 does not significantly influence Tac pharmacokinetic parameters in a large cohort of KTR. This study does not confirm recent findings indicating that POR*28 carriers require more Tac to reach target C0.
Subject(s)
Cytochrome P-450 Enzyme System/genetics , Genetic Variation/genetics , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/therapeutic use , Tacrolimus/pharmacokinetics , Tacrolimus/therapeutic use , Adult , Alleles , Cytochrome P-450 CYP3A/genetics , Female , Genotype , Graft Rejection/genetics , Graft Rejection/metabolism , Graft Rejection/prevention & control , Humans , Kidney Transplantation/methods , Male , Middle Aged , Prospective Studies , Transplant RecipientsABSTRACT
We present the results at 8 years of the Spiesser study, a randomized trial comparing de novo sirolimus and cyclosporine in kidney transplant recipients at low immunologic risk. We assessed estimated glomerular filtration (eGFR), graft, patient, and death-censored graft survival (log-rank compared), de novo DSA appearance, risk of malignancy, post-transplant diabetes mellitus (PTDM), and anemia. Intent-to-treat and on-treatment analyses were performed. Graft survival was similar in both groups (sirolimus: 73.3%, cyclosporine: 77.7, P = 0.574). No difference was observed between treatment groups concerning patient survival (P = 0.508) and death-censored graft survival (P = 0.858). In conditional intent-to-treat analysis, mean eGFR was greater in sirolimus than in cyclosporine group (62.5 ± 27.3 ml/min vs. 47.8 ± 17.1 ml/min, P = 0.004), in particular because graft function was excellent in patients maintained under sirolimus (eGFR = 74.0 ml/min). Importantly, no detrimental impact was observed in patients in whom sirolimus has been withdrawn (eGFR = 49.5 ml/min). Overall, 17 patients showed de novo DSAs, with no difference between the two groups (P = 0.520). Malignancy did not differ by treatment. An initial maintenance regimen based on sirolimus provides a long-term improvement in renal function for kidney transplant patients, especially for those maintained on sirolimus.
Subject(s)
Cause of Death , Cyclosporine/administration & dosage , Immunosuppressive Agents/administration & dosage , Kidney Transplantation/mortality , Sirolimus/administration & dosage , Adult , Analysis of Variance , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Graft Rejection , Graft Survival , Humans , Immunosuppression Therapy/methods , Kaplan-Meier Estimate , Kidney Transplantation/adverse effects , Kidney Transplantation/methods , Male , Middle Aged , Prospective Studies , Risk Assessment , Statistics, Nonparametric , Survival Rate , Time Factors , Treatment OutcomeABSTRACT
Long-term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post-transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients' survival was 100%, 94.2%, and 95.8% (P = 0.25), and death-censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m(2), respectively (P = 0.16). The incidence of biopsy-proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus-associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody-mediated rejection (n = 6). De novo donor-specific antibodies were detected in 13% of AZA-, 21% of MMF-, and 14% of CsA-treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well-selected renal transplant recipient (ClinicalTrials.gov number: 980654).
Subject(s)
Azathioprine/administration & dosage , Cyclosporins/administration & dosage , Immunosuppressive Agents/administration & dosage , Kidney Transplantation/mortality , Maintenance Chemotherapy/methods , Mycophenolic Acid/analogs & derivatives , Adult , Azathioprine/adverse effects , Cyclosporins/adverse effects , Drug Therapy, Combination , Female , Follow-Up Studies , Graft Rejection , Graft Survival , Humans , Immunosuppression Therapy/methods , Immunosuppressive Agents/adverse effects , Kidney Transplantation/adverse effects , Kidney Transplantation/methods , Male , Middle Aged , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/adverse effects , Prospective Studies , Risk Assessment , Statistics, Nonparametric , Survival Analysis , Time Factors , Treatment OutcomeABSTRACT
We report the case of a human immunodeficiency virus-seropositive patient whose initial kidney transplant failed because of BK polyomavirus-induced nephropathy, and who underwent a second transplantation 3 years later. BK viruria was detected 1 day after transplantation. After 1 month, BK viremia developed along with a donor-specific antibody. After decreasing tacrolimus and mycophenolic acid and 2 courses of intravenous immunoglobulins, BK viremia and donor-specific antibody permanently disappeared, with stable renal function.
Subject(s)
BK Virus/isolation & purification , Graft Rejection/surgery , HIV Seropositivity/drug therapy , Kidney Transplantation/adverse effects , Polyomavirus Infections/complications , Reoperation , Tumor Virus Infections/complications , Allografts/immunology , Allografts/pathology , Anti-Retroviral Agents/administration & dosage , Anti-Retroviral Agents/therapeutic use , Biopsy , Graft Rejection/etiology , Graft Rejection/immunology , Graft Rejection/pathology , Humans , Immunoglobulins, Intravenous/administration & dosage , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/administration & dosage , Immunologic Factors/therapeutic use , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Polyomavirus Infections/blood , Polyomavirus Infections/virology , Renal Insufficiency/surgery , Tumor Virus Infections/blood , Tumor Virus Infections/virology , Viremia/blood , Viremia/drug therapy , Viremia/virologyABSTRACT
Preemptive kidney transplantation is associated with both longer patient and graft survival. This study was carried out to estimate the association between the renal units and preemptive registration on the waiting list for first deceased donor renal transplantation in a French network of care. From 2008 to 2012, 1529 adult patients followed in 48 units of the French North-West network and registered on the waiting list for a first deceased donor renal allograft were included. We used a mixed logistic regression with renal units as random-effects term for statistical analysis. Of the 1529 patients included, 407 were placed on the waiting list preemptively. There was a significant variability across renal units (variance 0.452). In multivariate analysis, factors independently associated with preemptive registration were cardiovascular disease (odds ratio (OR) 0.57, [95% CI: 0.42-0.79]), social deprivation (OR 0.73, [95% CI 0.57-0.94]), and renal units' characteristics (ownership of the facility: academic hospital, reference-community hospital, OR 0.44, [95% CI 0.24-0.80]-private hospital, OR 0.35, [95% CI 0.18-0.69] and transplant center; P < 0.10]. Variability between renal units was reduced after taking into account their characteristics but was not influenced by patient characteristics. Preemptive registration is associated with renal units, transplant centers, and social deprivation and can be partly explained by disparities in practices.
Subject(s)
Kidney Failure, Chronic/surgery , Kidney Transplantation/methods , Waiting Lists , Adolescent , Adult , Body Mass Index , Cardiovascular Diseases/complications , Female , France , Graft Survival , Health Services Accessibility , Healthcare Disparities , Hospitals , Humans , Male , Middle Aged , Models, Statistical , Multivariate Analysis , Odds Ratio , Regression Analysis , Retrospective Studies , Social Class , Treatment Outcome , Young AdultABSTRACT
In this ancillary study of the CONCEPT trial, we studied the role of CsA withdrawal at 3 months (3M) post-transplant on the intensity of epithelial phenotypic changes (EPC, an early marker for kidney fibrogenesis) on the 12 M surveillance biopsy. Although conversion from CsA to sirolimus (SRL) at 3M was reported to have improved mean graft function at 12 M, it did not reduce the score of EPC (1.73 ± 1.15 in the SRL group vs. 1.87 ± 1 in the CsA group, P = 0.61). Acute rejection, which had occurred twice more frequently in SRL-converted patients included here, was associated with 12 M EPC. Interestingly, we observed that the patients durably exposed to CsA and who developed 12 M EPC had a significant progression of blood pulse pressure (pp) from 1 to 6M post-transplantation (Δpp = +12.3 mmHg, P = 0.0035). Pulse pressure at 4, 6, and 9 M and pp progression from 1 to 6M were significantly associated with the development of EPC at 12 M in renal grafts. Logistic regression analysis revealed that a high 6M pp (≥ 60 mmHg) was an independent risk factor for 12 M EPC with an odds ratio of 2.25 per additional 10 mmHg pp (95%CI: 1.14-4.4, P = 0.02) after adjustment with recipient's and donor's age, acute rejection incidence and immunosuppressive regimen. A post hoc analysis of the data collected in the whole population CONCEPT study revealed that pp was significantly higher at 6 months in patients maintained on CsA and that at this time point pp correlated negatively with GFR at 1 year.
Subject(s)
Blood Pressure/drug effects , Cyclosporine/adverse effects , Immunosuppressive Agents/adverse effects , Kidney Transplantation/adverse effects , Adult , Calcineurin Inhibitors , Cyclosporine/administration & dosage , Epithelium/drug effects , Epithelium/pathology , Female , Fibrosis , Glomerular Filtration Rate/drug effects , Graft Rejection , Humans , Immunosuppressive Agents/administration & dosage , Kidney/drug effects , Kidney/pathology , Kidney/physiopathology , Male , Middle Aged , Phenotype , Risk Factors , Sirolimus/administration & dosage , Time FactorsABSTRACT
BACKGROUND: Kidney graft survival in simultaneous pancreas-kidney (SPK) recipients is known to decrease after pancreas graft failure. METHODS: Sixty-three consecutive SPK recipients were retrospectively reviewed. Kidney graft function and proteinuria were evaluated at three months after the transplantation and at last follow-up. Histopathologic findings of protocol biopsies performed three months and one yr after transplantation were analyzed. RESULTS: Twelve patients lost the pancreas graft. Donors' characteristics were similar in patients with or without pancreas failure. After a median follow-up of 36 months, mean eGFR with a functional pancreas was 69.5 mL/min/1.73 m² vs. 56.3 mL/min/1.73 m² (p = 0.01) after pancreas loss. Patients who lost pancreas had a median proteinuria of 0.28 g vs. 0.13 g per 24 h (p = 0.02). Analysis of three-month protocol biopsies revealed more frequent isolated glomerulitis after pancreas failure (p = 0.0001), without peritubular capillaritis or C4d deposition. No donor-specific anti-HLA antibodies were detectable in these patients. Chronic tubulointerstitial changes were more frequent in patients with pancreas loss. There was no evidence of diabetic nephropathy recurrence. CONCLUSION: SPK recipients develop an early kidney graft dysfunction after pancreas failure. Histopathologic findings revealed frequent glomerulitis without antibody-mediated rejection and early chronic changes.
Subject(s)
Diabetes Complications/etiology , Diabetes Mellitus, Type 1/complications , Graft Rejection/etiology , Kidney Diseases/etiology , Kidney Transplantation/adverse effects , Pancreas Transplantation/adverse effects , Pancreatic Diseases/etiology , Adult , Diabetes Complications/pathology , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/surgery , Female , Follow-Up Studies , Glomerular Filtration Rate , Graft Rejection/pathology , Humans , Kidney Diseases/pathology , Male , Middle Aged , Pancreatic Diseases/pathology , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: This study was carried out to estimate the modification of hydration status within the first three months of renal transplantation. SUBJECTS AND METHODS: Fifty patients who underwent a first kidney allograft were prospectively followed for three months after renal transplantation to assess hydration status by bioimpedance spectroscopy. RESULTS: Two hours before the transplant procedure, 10/42 (23.8%) patients were overhydrated. Two days after surgery, 32/40 (80.0%) patients were overhydrated and at three months, 14/27 (51.9%) patients remained fluid-overloaded. Peritoneal dialysis (PD) patients had a lower hydration status (-0.60 L) than hemodialysis (HD) patients (0.70 L; p < 0.05) and better residual diuresis (41.7 vs. 8.3 mL/h for HD patients, p < 0.01). Compared with patients who had a delayed graft function (DGF) or a slow graft function (SGF), the immediate graft function (IGF) group had a better hydration status before transplantation (p = 0.031). At three months, 12/14 of the overhydrated patients had a creatinine clearance between 30 and 60 mL/min/1.73 m(2) . CONCLUSION: Patients receiving a first kidney transplant frequently have a hydration disorder. Transplantation is associated with increased hydration status, which seems to persist if DGF or SGF occurs.
Subject(s)
Body Water/physiology , Delayed Graft Function , Graft Rejection , Kidney Failure, Chronic/physiopathology , Kidney Failure, Chronic/therapy , Kidney Transplantation , Adult , Creatinine/metabolism , Female , Follow-Up Studies , Glomerular Filtration Rate , Graft Survival/physiology , Humans , Kidney Function Tests , Male , Middle Aged , Prognosis , Prospective Studies , Renal Dialysis , Risk FactorsABSTRACT
Post-transplant diabetes mellitus (PTDM) is a well-known complication in renal transplant recipients (RTRs). While a number of risk factors for PTDM have been identified, the potential impact of pre-transplant dialysis modality on subsequent development of PTDM has not yet been explored. We performed a multicenter retrospective study on 2010 consecutive RTRs who did not have a history of diabetes prior to renal transplantation. PTDM was defined as a need for anti-diabetic therapy in an RTR without a history of diabetes prior to transplantation. Analysis of the risk factors for development of PTDM was performed with respect to pre-transplant dialysis modality. A total of 137 (6.8%) patients developed PTDM; 7% in the hemodialysis group and 6.5% in the peritoneal dialysis (PD) group (p = 0.85). In the multivariate analysis, age (p < 0.001), body mass index (BMI) (p < 0.001), use of tacrolimus (p = 0.002), and rejection episodes (p < 0.001) were identified as independent risk factors for development of PTDM. Patients in the PD group were younger (p = 0.004), had lower BMI (p = 0.07), and were less likely to have a history of hepatitis C (p = 0.007) and autosomal dominant polycystic kidney disease (p = 0.07). Adjustment for these variables did not modify the results. The results of this study suggest that pre-transplant dialysis modality does not have an impact on the subsequent development of PTDM in RTRs.
Subject(s)
Diabetes Complications/etiology , Diabetes Mellitus/physiopathology , Kidney Failure, Chronic/complications , Kidney Transplantation/adverse effects , Postoperative Complications , Renal Dialysis/mortality , Diabetes Complications/mortality , Female , Graft Rejection/drug therapy , Graft Rejection/etiology , Graft Rejection/mortality , Humans , Immunosuppressive Agents/therapeutic use , Kidney Failure, Chronic/surgery , Kidney Transplantation/mortality , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , Survival RateABSTRACT
Long-term function of kidney allografts depends on multiple variables, one of which may be the compatibility in size between the graft and the recipient. Here, we assessed the long-term consequences of the ratio of the weight of the kidney to the weight of the recipient (KwRw ratio) in a multicenter cohort of 1189 patients who received a transplant between 1995 and 2006. The graft filtration rate increased by a mean of 5.74 ml/min between the third and sixth posttransplantation months among patients with a low KwRw ratio (<2.3 g/kg; P<0.0001). In this low KwRw ratio group, the graft filtration rate remained stable between 6 months and 7 years but then decreased at a mean rate of 3.17 ml/min per yr (P<0.0001). In addition, low KwRw ratios conferred greater risk for proteinuria, more antihypertensive drugs, and segmental or global glomerulosclerosis. Moreover, a KwRw ratio<2.3 g/kg associated with a 55% increased risk for transplant failure by 2 years of follow-up. In conclusion, incompatibility between graft and recipient weight is an independent predictor of long-term graft survival, suggesting that avoiding kidney and recipient weight incompatibility may improve late clinical outcome after kidney transplantation.
Subject(s)
Graft Survival/physiology , Kidney Transplantation/physiology , Kidney/anatomy & histology , Transplantation/physiology , Adult , Body Weight/physiology , Cohort Studies , Female , Follow-Up Studies , Humans , Hypertension/epidemiology , Male , Middle Aged , Organ Size/physiology , Proteinuria/epidemiology , Retrospective Studies , Risk Factors , Transplantation, Homologous , Treatment OutcomeABSTRACT
Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.
Subject(s)
Complement C3/genetics , Hemolytic-Uremic Syndrome/genetics , Mutation , Adolescent , Adult , Child , Child, Preschool , Codon, Nonsense , Complement C3/analysis , DNA Mutational Analysis , Genetic Predisposition to Disease , Hemolytic-Uremic Syndrome/etiology , Hemolytic-Uremic Syndrome/immunology , Heterozygote , Humans , Infant , Mutation, Missense , Young AdultABSTRACT
BACKGROUND: Although cyclosporine maintenance therapy reduces the risk of acute rejection and increases short-term graft survival in renal transplant recipients, its associated nephrotoxicity increases the risk of chronic graft dysfunction. The dose that allows an optimal risk-to-benefit ratio has not been established. METHODS: This multicentre study enrolled stable renal allograft recipients receiving cyclosporine and mycophenolate mofetil without corticosteroids in their second year post-transplant. Patients were randomized to a cyclosporine dose targeted to a standard area under the concentration-time curve (AUC)(0-12 h) (usual exposure, n = 104) or 50% of the study standard AUC(0-12 h) (low exposure, n = 108) using a three-point pharmacokinetic sampling. The primary endpoint was the percentage of patients with treatment failure at 24 months (graft loss/acute rejection/nephrotoxicity/>15% serum creatinine level increase). RESULTS: Treatment failure was reported in 37 out of 101 (37%) patients in the usual-exposure and 19 out of 106 (18%) patients in the low-exposure groups (P = 0.003). Mean estimated glomerular filtration rate decreased from baseline to 2 years with usual exposure and increased with low exposure (P < 0.001). Mean systolic and diastolic blood pressures were lower with low exposure (P = 0.03 and P = 0.008, respectively). CONCLUSION: In renal transplant recipients receiving maintenance therapy without corticosteroids, a minimization strategy using three-point pharmacokinetic sampling to reduce and maintain cyclosporine exposure to 50% of the usual levels is safe and reduces the risk of graft dysfunction.
Subject(s)
Cyclosporine/administration & dosage , Graft Rejection/prevention & control , Graft Survival , Immunosuppressive Agents/administration & dosage , Kidney Failure, Chronic/therapy , Kidney Transplantation/mortality , Adolescent , Adult , Aged , Area Under Curve , Cadaver , Creatinine/metabolism , Cyclosporine/pharmacokinetics , Female , Follow-Up Studies , Glomerular Filtration Rate , Humans , Immunosuppressive Agents/pharmacokinetics , Kidney Function Tests , Male , Middle Aged , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/pharmacokinetics , Prospective Studies , Survival Rate , Tissue Distribution , Tissue Donors , Treatment Outcome , Young AdultABSTRACT
This study attempted to establish whether a calcineurin inhibitor (CNI)-free immunosuppressant regimen based on sirolimus (SRL) is associated with a preservation of conduit arteries endothelial function in kidney recipients or not. Twenty-nine kidney recipients were randomized to receive since transplantation SRL (n=15) or cyclosporin A (CsA, n=14) associated with mycophenolate mofetil (MMF) and steroids (6months) in a parallel prospective study. Systolic, diastolic blood pressures, glomerular filtration rate (GFR) and radial artery flow-mediated dilatation (FMD) induced by postischaemic hyperaemia were assessed in a blind manner at one (M1) and 7months (M7) after transplantation. Endothelium-independent dilatation was assessed by glyceryl trinitrate spray. There was no difference between the groups for all vascular parameters at M1. At M7, systolic blood pressure was lower (SRL: 119±3 vs. CsA: 138±4mmHg, P<0.05) and FMD was higher in SRL compared with CsA (SRL: 13.1±0.9 vs. CsA: 9.9±0.9%, P<0.05) without any difference for hyperaemia, endothelium-independent dilatation and GFR (SRL: 66.7±1.05 vs. CsA: 67.5±1.22ml/min). Our results demonstrate that a CNI-free regimen based on SRL and MMF prevents conduit artery endothelial dysfunction compared with CsA and MMF in kidney recipients suggesting a beneficial arterial wall effect that may also contribute to the decrease in systolic blood pressure.
Subject(s)
Cyclosporine/therapeutic use , Endothelium, Vascular/drug effects , Sirolimus/therapeutic use , Adult , Arteries/drug effects , Blood Pressure , Female , Glomerular Filtration Rate , Humans , Immunosuppressive Agents/therapeutic use , Ischemia/pathology , Kidney/drug effects , Kidney Transplantation/adverse effects , Kidney Transplantation/methods , Male , Middle Aged , Prospective Studies , Time FactorsABSTRACT
Hypocomplementemic urticarial vasculitis is a rare systemic vasculitis, affecting small vessels, characterised by chronicle urticaria, hypocomplementemia, and systemic manifestations. Renal involvement, whose prevalence varies between 9% and 60%, is mainly glomerular. We here report the case of a 59 years old woman presenting kidney failure, associated with chronicle urticaria and arthralgias. Laboratory investigation showed haematuria, proteinuria, hypocomplementemia and anti-SSa antibody positivity. A percutaneous kidney biopsy revealed focal and segmental glomerulonephritis associated with an acute interstitial nephritis. Hypocomplementemic urticarial vasculitis diagnosis was established after identifying anti-C1q antibodies. The lack of a dry syndrome, the negativity of a Schirmer test and the lack of sialadenitis on a salivary gland biopsy excluded an associated Gougerot-Sjögren Syndrome. The patient was treated with hydroxychloroquine and low-dose steroids, enabling a clinical and biological recovery. Of the 82 cases in the literature describing hypocomplementemic urticarial vasculitis associated nephropathies, 72 (88%) were a glomerular impairment, most frequently secondary to membranoproliferative glomerulonephritis. Only 6 (7%) tubulo-interstitial nephritis have been reported, 4 of them being associated with a glomerulonephritis. Patients were more likely to be women, aged in their third decade. The most frequent renal manifestations were haematuria (60%), and proteinuria (52%). Kidney failure was rarely observed (22%), with a fairly good renal prognosis. Hypocomplementemic urticarial vasculitis was associated with a systemic disease in 11 (13%) patients. In the absence of recommendations, the treatment strategy remains to be defined.
Subject(s)
Complement C1/deficiency , Glomerulonephritis, Membranoproliferative/complications , Nephritis, Interstitial/complications , Urticaria/complications , Vasculitis/complications , Female , Humans , Middle AgedABSTRACT
UNLABELLED: This study was carried out to evaluate dialysis initiation of failed transplant patient and the short-term outcome of these patients on dialysis. PATIENTS AND METHOD: We conducted a retrospective study of transplanted patients from one centre returning in dialysis after allograft failure. Those patients were transplanted between 31st October 1986 and 3rd March 2004. Patients who experienced allograft failure after 6 months on transplantation were included in the study. RESULTS: Among 600 transplanted patients, 92 patients restarted dialysis after allograft failure. Of the 92 failed transplant patients, 69 had a graft survival of more than 6 months. The mean glomerular filtration rate at dialysis initiation was 13+/-5mL per minute. At time of dialysis initiation, patients had mean haemoglobin level at 80.7+/-10.7g/L, and mean serum albumin level at 34+/-6g/L. Urgent dialysis was needed for 39 over 57 patients. Fourteen over 58 patients had no vascular access or peritoneal catheter at dialysis initiation. Fifty-six over 69 patients were treated by haemodialysis. Of the 13 patients treated by peritoneal dialysis 7 were on PD before transplantation whereas 49 over 57 haemodialysis patients were treated by haemodialysis before transplant failure (p<0.05). Immunosuppressive therapy was stopped during the first year following transplantation failure in 52 over 69 patients and 36 over 69 patients underwent transplantectomy. Thirteen over 56 patients presented a least one cardiovascular events after transplantation failure. CONCLUSION: Unplanned dialysis initiation is frequent in failed transplant patients, in whom an early dialysis start is probably mandatory.
Subject(s)
Kidney Transplantation , Renal Dialysis , Adult , Aged , Female , Humans , Male , Middle Aged , Retrospective Studies , Time Factors , Treatment Failure , Treatment Outcome , Young AdultABSTRACT
INTRODUCTION: Although kidney transplantation carries a survival benefit compared with dialysis, mortality, especially the first year after transplantation, is high in recipients older than 70. The aim of this study was to evaluate early death and graft failure, and to determine the risk factors associated with these events in this specific population. METHODS: All patients older than 70 years who received a kidney transplant between January 2000 and December 2014 in the North-West of France were included (n = 171). Baseline characteristics and outcomes after transplantation were studied. Kaplan-Meier analysis was performed to assess patient and graft survival, and Cox regression analysis to evaluate risk factors for graft failure and patient death. RESULTS: The mean recipient age was 73.3 ± 2.5 years. Death-censored graft survival at 1, 3, and 5 years were 82.6%, 78.7%, and 75.4%, respectively. Patient survival at 1, 3, and 5 years was 90.1%, 82.5%, and 68.1%, respectively. One year after transplantation, 17 patients (9.9%) were dead, mainly from infectious (58.5%) or cardiovascular disease (29.4%). According to the Cox multivariate analysis, the independent risk factors for death or graft failure during the first year were arrhythmia (odds ratio [OR] 2.26; 95% confidence interval [CI] 1.08-4.8), left-ventricular ejection fraction (LVEF) under 56% (OR 2.38; 95% CI 1.18-4.83), human leucocyte antigen (HLA) antibodies (OR 2.1; 95% CI 1.04-4.2), deceased donor from cardiovascular cause (OR 5.18; 95% CI 1.22-6.3), and acute rejection (OR 2.77; 95% CI 1.2-6.3). CONCLUSION: In kidney transplant recipients older than 70 years, cardiac evaluation and immunosuppression optimization seem to be crucial to improve short-term patient and graft survival.