Impaired renal function before kidney procurement has a deleterious impact on allograft survival in very old deceased kidney donors

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 CI95[1.8–9.7]). 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

Increased circulating miR-21 levels are associated with kidney fibrosis.

MicroRNAs (miRNAs) are a class of noncoding RNA acting at a post-transcriptional level to control the expression of large sets of target mRNAs. While there is evidence that miRNAs deregulation plays a causative role in various complex disorders, their role in fibrotic kidney diseases is largely unexplored. Here, we found a strong up-regulation of miR-21 in the kidneys of mice with unilateral ureteral obstruction and also in the kidneys of patients with severe kidney fibrosis. In addition, mouse primary fibroblasts derived from fibrotic kidneys exhibited higher miR-21 expression level compared to those derived from normal kidneys. Expression of miR-21 in normal primary kidney fibroblasts was induced upon TGFβ exposure, a key growth factor involved in fibrogenesis. Finally, ectopic expression of miR-21 in primary kidney fibroblasts was sufficient to promote myofibroblast differentiation. As circulating miRNAs have been suggested as promising non-invasive biomarkers, we further assess whether circulating miR-21 levels are associated with renal fibrosis using sera from 42 renal transplant recipients, categorized according to their renal fibrosis severity, evaluated on allograft biopsies (Interstitial Fibrosis/Tubular Atrophy (IF/TA). Circulating miR-21 levels are significantly increased in patients with severe IF/TA grade (IF/TA grade 3: 3.0±1.0 vs lower grade of fibrosis: 1.5±1.2; p = 0.001). By contrast, circulating miR-21 levels were not correlated with other renal histological lesions. In a multivariate linear regression model including IF/TA grade and estimated GFR, independent associations were found between circulating miR-21 levels and IF/TA score (ß = 0.307, p = 0.03), and between miR-21 levels and aMDRD (ß = -0.398, p = 0.006). Altogether, these data suggest miR-21 has a key pathogenic role in kidney fibrosis and may represent a novel, predictive and reliable blood marker of kidney fibrosis

Successful Reuse of Kidney Graft After Early Recurrence of Primary Focal and Segmental Glomerulosclerosis

International audiencePrimary focal and segmental glomerulosclerosis (FSGS) frequently recurs after transplantation and is associated with a poor prognosis. We describe here the successful kidney graft reuse in an adult recipient, 8 months after early primary FSGS recurrence resistant to all available therapeutics. Patient 1, a 23-year-old man, followed for kidney failure secondary to primary FSGS, was first transplanted in 2018 with a deceased donor graft. Unfortunately, we observed an immediate recurrence of biopsy-proven primary FSGS. After 4 lines of treatment (intravenous cyclosporine + corticosteroids, plasma exchanges, immunoadsorption, and rituximab), the patient was still highly nephrotic and kidney function was slowly deteriorating. After approval from both the patient and the health authority (Biomedicine Agency), the graft was detransplanted 8 months after transplantation and reimplanted in patient 2, a 78-year-old nonimmunized and anephric recipient (bi-nephrectomy 2 years previously for bilateral renal carcinoma). We observed immediate kidney function and progressive resolution of proteinuria (serum creatinine of 1.2 mg/dL and proteinuria of 0.1 g/d 1 year later). Biopsies performed after surgery showed persistent FSGS lesions with a decrease in overall foot-process effacement. To our knowledge, this is the first reported case showing that kidney graft transfer may still be a viable option for refractory primary FSGS several months after transplantation

miR-21 is up-regulated in kidneys from Unilateral Ureteral Obstruction (UUO) mice.

<p>(A) miR-21 expression in kidneys from C57BL/6 mice after UUO at the indicated time points. SNO-251 was used as normalizer, n = 5 to 9 mice in each group. (B) <i>In situ</i> hybridization assay was performed to determine the stromal localization of miR-21 and its colocalization with α-SMA in kidneys of C57BL/6 mice harvested 28 days after UUO. (C) COL1A1, (D) fibronectin, (E) ACTA2 and (F) TGFβ expression in kidney from C57BL/6 mice after UUO at the indicated time points. PPIA was used as normalizer, n = 5 to 9 mice in each group. Data are expressed as mean ± SEM. * p<0.05 and ** p<0.01.</p

Circulating miR-21 is a potential biomarker of kidney fibrosis.

<p>(A, B) Circulating miR-21 levels are not affected by patient gender or age. (C, D) miR-21 circulating levels are increased in patients with high grade of Interstitial Fibrosis/Tubular Atrophy grade 3 (IF/TA grade 3). MiR-16 was used as normalizer. (E) Receiver operating characteristic curve analysis displaying the diagnostic power in predicting severe kidney fibrosis (IF/TA grade 3) of circulating miR-21 levels (area under the curve (AUC): 0.891). (F) Significant correlation (p<0.003, R = −0.451) between circulating miR-21 and glomerular filtration rate (based on MDRD formula) in patients with various grade of kidney fibrosis is shown. Data are expressed as mean ± SEM. ** p<0.01.</p

Association between acute graft pyelonephritis and kidney graft survival: A single-center observational study

International audienceThe association between acute graft pyelonephritis (AGPN) and graft failure in kidney transplant recipients (KTR) remains controversial. In this single-center observational study, we aimed to assess the incidence of AGPN as a time-dependent posttransplantation event. We also examined the association between the diagnosis of AGPN and graft outcomes. In total, we evaluated 1480 patients who underwent kidney transplantation between January 2007 and December 2017. During a median follow-up of 5.04 years, we observed 297 AGPN episodes that occurred in 158 KTR. To evaluate the association between AGPN and clinical outcomes, we performed Cox proportional hazards regression analyses in which AGPN was entered as a time-dependent covariate. AGPN was independently associated with an increased risk of graft loss (hazard ratio = 1.66; 95% confidence interval [CI]: 1.05−2.64, p &lt;.03) and a persistently decreased eGFR (fixed effect on intercept: −2.29 ml/min/1.73 m2; 95% CI: from −3.23 to −1.35, p &lt;.01). However, neither mortality nor biopsy-proven acute rejection was found to correlate with AGPN. Moreover, recurrent AGPN episodes did not appear to have an additive detrimental impact on graft loss. These data represent a promising step in understanding whether AGPN prevention may decrease the risk of graft loss in KTR

miR-21 is up-regulated in kidneys from patients with severe kidney fibrosis.

<p>(A) miR-21 expression obtained by real time PCR in kidneys from patients with severe kidney fibrosis (cases n = 11) versus normal human kidneys (controls n = 12). RNU6B was used as normalizer. Data are expressed as mean ± SEM. * p<0.05. (B) <i>In situ</i> hybridization assay was performed to determine to determine the stromal localization of miR-21 and its colocalization with α-SMA in the kidney from detransplanted patients. Results represent one out of three independent experiments.</p

Circulating miR-21 levels are not associated with Banff criteria related to acute lesions or chronic vascular or glomerular lesions.

<p>i: Mononuclear Cell Interstitial Inflammation, t: Tubulitis, g: Glomerulitis, v: Intimal Arteritis, ptc: Peritubular Capillaritis, cg: Allograft Glomerulopathy, mm: Mesangial Matrix Increase, cv: Fibrous Intimal Thickening, ah: Arteriolar Hyaline Thickening. NS: not significant.</p

miR-21 is expressed in activated renal fibroblasts and upregulated in response to TGFβ stimulation

<p>. miR-21 and ACTA2 expression levels obtained by real time PCR in (A–B) control primary kidney fibroblasts exposed or not to TGF-β1 (10 ng/mL), and in (C–D) primary fibroblasts derived from fibrotic kidneys (UUO mice) and primary fibroblasts derived from normal kidneys (sham mice). (E–F) ACTA2 and COL1A1 expression levels obtained by real time PCR in control primary kidney fibroblasts transfected with either scrambled miRNA (neg) or premiR-21 (10 nM). Data are expressed as mean ± SEM. * p<0.05.</p