Abstract
As the use of elderly kidney donors for transplantation is increasing with time, there is a need to understand which factors impact on their prognosis. No data exist on the impact of an ...impaired renal function (IRF) in such population. 116 kidney recipients from deceased kidney donors over 70 years were included from 2005 to 2015 in a single-center retrospective study. IRF before organ procurement was defined as a serum creatinine above 1.0 mg/dl or a transient episode of oligo-anuria. Mean ages for donors and recipients were respectively 74.8 ± 3.5 and 66.7 ± 8.0. Graft survival censored for death at 5 years was of 77%. Using a multivariate analysis by Cox model, the only predictor of graft loss present in the donor was IRF before organ procurement (HR 4.2 CI951.8–9.7). IRF was also associated with significant lower estimated glomerular filtration rates up to 1 year post-transplantation. By contrast, KDPI score (median of 98 96–100), was not associated with the risk of graft failure. Then, IRF before kidney procurement may define a risk subgroup among very-old deceased kidney donors, in whom pre-implantatory biopsies, dual kidney transplantation or calcineurin inhibitor-free immunosuppressive regimen could help to improve outcomes.
C3 glomerulopathy (C3G) is a prototypic complement-mediated kidney disease. Rapidly progressive forms of C3G usually respond poorly to conventional treatments. We report on the efficacy of the ...terminal complement inhibitor eculizumab in 3 adult patients with rapidly progressive C3G. In all 3 patients, serum creatinine levels had increased by >50% in the 2 months preceding initiation of eculizumab treatment despite the use of conventional immunosuppressive drugs and/or plasma exchanges in 2 of these individuals. Of note, 2 patients had long-standing nephrotic syndrome. Kidney biopsy performed prior to eculizumab treatment disclosed marked glomerular inflammatory changes and increased C5b-9 deposition in all patients. Eculizumab use was associated with significant improvement in kidney function, with estimated glomerular filtration rates of patients increasing 22 to 38 mL/min/1.73 m2 . Eculizumab use also was associated with remission of nephrotic syndrome in the 2 affected patients, an effect observed as early as one week after treatment initiation. Repeat kidney biopsy disclosed regression of glomerular inflammatory changes and decreases in glomerular staining for C5b-9 in all patients. These results warrant further assessment of eculizumab for treatment of rapidly progressive forms of C3G with markedly increased glomerular C5b-9 deposits.
Atypical hemolytic uremic syndrome (aHUS) is a rare renal thrombotic microangiopathy commonly associated with rare genetic variants in complement system genes, unique to each patient/family. Here, we ...report 14 sporadic aHUS patients carrying the same mutation, R139W, in the complement C3 gene. The clinical presentation was with a rapid progression to end-stage renal disease (6 of 14) and an unusually high frequency of cardiac (8 of 14) and/or neurologic (5 of 14) events. Although resting glomerular endothelial cells (GEnCs) remained unaffected by R139W-C3 sera, the incubation of those sera with GEnC preactivated with pro-inflammatory stimuli led to increased C3 deposition, C5a release, and procoagulant tissue-factor expression. This functional consequence of R139W-C3 resulted from the formation of a hyperactive C3 convertase. Mutant C3 showed an increased affinity for factor B and a reduced binding to membrane cofactor protein (MCP; CD46), but a normal regulation by factor H (FH). In addition, the frequency of at-risk FH and MCP haplotypes was significantly higher in the R139W-aHUS patients, compared with normal donors or to healthy carriers. These genetic background differences could explain the R139W-aHUS incomplete penetrance. These results demonstrate that this C3 mutation, especially when associated with an at-risk FH and/or MCP haplotypes, becomes pathogenic following an inflammatory endothelium-damaging event.
TAFRO syndrome is a clinical subtype of idiopathic multicentric Castleman disease (iMCD) that is characterized by thrombocytopenia, anasarca, fever and/or elevated serum C-reactive protein, renal ...dysfunction, and organomegaly.
A 28-year-old woman with fever, weight gain of 13 kgs, lower extremity edema, hepatosplenomegaly, and multicentric peripheral lymphadenopathy was referred to our center. Laboratory investigations revealed anemia, thrombocytopenia, creatinine at 1.19 mg/dL and hypoalbuminemia at 33 g/L. Proteinuria was measured at 2 g/day including albuminuria at 1.5 g/day. Urinary sediment examination found leukocyturia at 44,000/mL and hematuria at 645,000/mL. Vascular endothelial growth factor (VEGF) level was elevated. A cervical lymph node biopsy found features consistent with the mixed histopathological subtype of iMCD. A renal biopsy revealed a membranoproliferative glomerulonephritis (MPGN) pattern. We initiated 3 days of methylprednisolone pulse-therapy at 1,000 mg per day, followed by prednisone 1 mg/kg/day and evolution was favorable.
19 iMCD patients with TAFRO syndrome had undergone a renal biopsy: 8 cases with author's diagnosis consistent with MPGN-like and 11 cases of thrombotic microangiopathy (TMA)-like glomerulopathy without fibrin thrombi in glomerular capillaries or arterioles and without typical biological signs. Clinical, biological, and outcome characteristics were similar between the cases described as having MPGN and TMA-like presentation. After a thorough review of histopathological descriptions for each case, MPGN lesions seems to be the consequences of chronic glomerular endothelial injury in persistent TMA. We suspect that VEGF and IL-6 play a key role in the physiopathology of the spectrum of renal involvement from TMA-like to MPGN observed in TAFRO syndrome.
We present a Caucasian iMCD patient with TAFRO syndrome with renal insufficiency secondary to MPGN, which might be secondary to a chronic TMA-like disease. We suspect that there is a continuum between TMA and MPGN lesions in TAFRO syndrome favored by VEGF and IL-6.
Background. The effect of potentially relevant genetic polymorphisms, CYP3A5 6986A>G and ABCB1 3435C>T, on Tacrolimus pharmacokinetics and graft clinical outcome was investigated in donor and ...recipient DNA samples from 209 kidney transplant patients.
Methodology/principal findings. The mean follow-up was 21.8 ± 9 months. The Tacrolimus dose, trough blood concentrations (C0) and C0/dose ratio were only statistically correlated with the recipient CYP3A5 genotype. CYP3A5 and ABCB1 genotypes appeared to have no influence on the incidence of Biopsy Proven Acute Rejection and Delayed Graft Function. Renal function was not affected by CYP3A5 and ABCB1 genotypes. Histological evaluation of biopsies revealed also no significant association between Tacrolimus toxicity features and donor or recipient CYP3A5 and ABCB1 polymorphisms. Tacrolimus sparing appeared to be independent of CYP3A5 and ABCB1 genotypes.
Conclusions/significance. Recipient CYP3A5 6986A>G polymorphism explains part of the interindividual variability of the pharmacokinetics of Tacrolimus. The clinical outcome at 2-year follow-up does not appear to be related to the donor or recipient CYP3A5 6986A>G and/or ABCB1 3435C>T polymorphisms.
MicroRNAs (miRNAs) are small, non-coding RNA species that control gene expression and confer robustness to biological processes. Over the last two decades, their important roles during kidney ...development, homeostasis and the treatment of diseases have been established, in particular during the onset and progression of various forms of acute and chronic renal disorders. In recent years, miR-21, one of the best-characterized miRNAs to date, has received much attention in renal physiology in particular given its high degree of conservation and expression in kidneys, as well as its potent pathogenic role in various debilitating renal diseases. This review summarizes the current knowledge on miR-21's involvement in both renal homeostasis and diseases, in particular its double-edged-sword role in acute versus chronic kidney injuries. Finally, we also discuss the potential of miR-21 as a biomarker and therapeutic target in renal diseases.
The benefit of extracorporeal photopheresis on the course of kidney transplant rejection is unknown. The aim of our study was to investigate the variations in transcriptomics on graft biopsies when ...extracorporeal photopheresis was used to treat chronic humoral rejection after kidney transplantation.
We retrospectively analyzed the mRNA expression of 770 genes of interest in graft biopsies performed before and after treatment. Eight patients received an average of 23 extracorporeal photopheresis sessions over 4 mo between the 2 biopsies.
Transcriptomic analysis of the graft biopsies identified a significant (adjusted
< 0.05) increase in
mRNA in all patients and a significant decrease in
,
,
, and
FTPA2 mRNAs in 7 of 8 patients.
In patients treated with extracorporeal photopheresis for chronic humoral rejection after renal transplantation, omic analysis of repeated biopsies shows a reduction in fibrotic and inflammatory transcriptomic biologicals markers.
Tacrolimus is metabolized by cytochrome P450 (CYP) 3A5. The objective of this study was to investigate the influence of the genetic polymorphism of CYP3A5 on the pharmacokinetics of a new ...modified-release, once-daily formulation of tacrolimus (Advagraf®) after a switch from the immediate-release formulation (Prograf®).
This was a prospective, single-centre, open-label study in stable kidney transplant recipients. Seventeen 'expressor' patients (CYP3A5*1/*3 or *1/*1) were matched to 15 'non-expressor' patients (CYP3A5*3/*3). Exposure variables (concentrations and area under the blood concentration-time curve from 0 to 24 hours AUC(24)) were obtained before and 15 days after the switch. Delay since grafting was similar for both groups of patients (expressors: 49 ± 24 months; non-expressors: 45 ± 22 months).
During administration of tacrolimus as Prograf® or Advagraf®, the mean tacrolimus daily dose was significantly higher and the dose-adjusted AUC(24) was significantly lower in the expressor group. Following the switch to Advagraf®, there was a significant decrease in the dose-adjusted AUC(24) for both non-expressor (5910 ± 3019 vs 5334 ± 2668 ng·h/mL per mg/kg/day; p = 0.041) and expressor patients (3701 ± 1409 vs 3273 ± 1372 ng·h/mL per mg/kg/day; p = 0.03). In the non-expressor group, mean blood trough concentration (C(0)) was comparable for both formulations while it decreased significantly in the expressor group after the switch (8.2 ± 2.2 vs 6.3 ± 2.5 ng/mL; p = 0.02). However, a good correlation between AUC(24) and C(0) was observed for both Advagraf® and Prograf® regardless of CYP3A5 genotype.
Tacrolimus exposure significantly decreases after a switch from Prograf® to Advagraf®, on a milligram-for-milligram basis, in CYP3A5 expressor recipients. Consequently, these patients should be carefully monitored.
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