Search

Objectives Severity of chronic kidney disease is defined by glomerular filtration rate (GFR) and albuminuria (ACR) by the KDIGO and are related to cardiovascular outcomes and end-stage-kidney-failure. However, proteinuria (PCR) is more often available than ACR in records. Recently, equations were developed to estimate ACR from PCR. We investigated their performances in our population. Methods In the academic medical hospital of Liège, we retrospectively analysed same day measurement of ACR and PCR and staged them according to the KDIGO A1-A2-A3 categories. Analyser Roche Cobas (R) gathered 2,633 urinalysis (May 2018-May 2019) and analyser Abbott Alinity (A) 2,386 urinalysis (May 2019-March 2020). We compared the KDIGO staging of mACR and eACR obtained from Weaver’s and Sumida’s equations. Results Median age was 63 [52;71]/64 [53;72] years old, 43/42% were female; 78/74% had diabetes; proportion of mACR-A1 was 65.6%/64.2%, A2 was 25.5%/25.5% and A3 was 8.8%/10.3% (Method R/A, respectively). Both equations gave similar distribution of KDIGO staging of eACR. Overall agreements were higher than 88% regardless of the analyser or of the equation. Performances in between equations were equivalent according to the multi-level AUC (multinomial logistic regression model). Conclusions Good concordance was observed between mACR and eACR regardless of the equation or of the analyser. No patient with an A3-measured ACR was estimated within the KDIGO A1 category. Though ACR should be measured when clinically needed, it may be reasonably estimated from the PCR through these equations, for epidemiologic retrospective studies or research purposes.

The nondipping blood pressure (BP) pattern corresponds to a disruption in the circadian BP rhythm with an insufficient decrease in BP levels during nighttime sleep as observed using 24-hour ambulatory BP monitoring. Patients with nondipping BP pattern have poorer renal and cardiovascular outcomes, independent of their average 24-hour BP levels. The pathophysiology of nondipping BP is complex and involves numerous mechanisms: perturbations of (1) the circadian rhythm, (2) the autonomic nervous system, and (3) water and sodium regulation. This review provides an outline of the pathways potentially involved in the nondipping BP profile in different conditions. A recent hypothesis is also discussed involving the role of gut microbiota in the dipping/nondipping patterns, via the fecal diet-derived short chain fatty acids.

Contains fulltext : 244896.pdf (Publisher’s version ) (Closed access) BACKGROUND: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis. METHODS: We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). RESULTS: In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. CONCLUSIONS: Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function. 01 november 2021

Purpose. [18F]FDG-PET/CT may predict the absence of acute allograft rejection (AR) in kidney transplant recipients (KTRs) with acute kidney injury (AKI). Still, the proposed threshold of 1.6 of the mean of mean standardized uptake values (mSUVmean) in the renal parenchyma needs validation. Methods. We prospectively performed 86 [18F]FDG-PET/CT in 79 adult KTRs who underwent per cause transplant biopsy for suspected AR. Biopsy-proven polyoma-BK nephropathies (n=7) were excluded. PET/CT was performed 192 ± 18 minutes after administration of 254.4 ± 30.4 MBq of [18F]FDG. The SUVmean was measured in both upper and lower poles of the renal allograft. One-way analysis of variance (ANOVA) and Tukey’s studentized range test were sequentially performed. The receiver operating characteristic (ROC) curve was drawn to discriminate “AR” from non-pathological (“normal” + “borderline”) conditions. Results. The median age of the cohort was 55 [43; 63] years, with M/F gender ratio of 47/39. The mean eGFR was 31.9 ± 14.6 ml/min/1.73m². Biopsies were categorized in 4 groups: “normal” (n=54), “borderline” (n=9), “AR” (n=14) or “others” (n=2). The median [min; max] mSUVmean reached 1.72 [1.02; 2.07], 1.97 [1.55; 2.11], 2.13 [1.65, 3.12] and 1.84 [1.57; 2.12] in “normal”, “borderline”, “AR” and “others” groups, respectively. ANOVA demonstrated a significant difference of mSUVmean among groups (F=13.25, p). The ROC area under the curve was 0.86. Test sensitivity and specificity corresponding to the threshold value of 1.6 were 100% and 30%, respectively.Conclusion. [18F]FDG-PET/CT may help noninvasively prevent inessential transplant biopsies in KTR with AKI.

Renal ischemia-reperfusion (I/R) causes acute kidney injury (AKI). Ischemic preconditioning (IPC) attenuates I/R-associated AKI. Whole body irradiation induces renal IPC in mice. Still, the mechanisms remain largely unknown. Furthermore, the impact of kidney-centered irradiation on renal resistance against I/R has not been studied. Renal irradiation (8.5 Gy) was done in male 8- to 12-wk-old C57bl/6 mice using a small animal radiation therapy device. Left renal I/R was performed by clamping the renal pedicles for 30 min, with simultaneous right nephrectomy, at 7, 14, and 28 days postirradiation. The renal reperfusion lasted 48 h. Following I/R, blood urea nitrogen (BUN) and serum creatinine (SCr) levels were lower in preirradiated mice compared with controls; so was the histological Jablonski score of AKI. The metabolomics signature of renal I/R was attenuated in preirradiated mice. The numbers of proliferating cell nuclear antigen (PCNA)-, cluster of differentiation molecule 11b (CD11b)-, and cell surface glycoprotein F4/80-positive cells in the renal parenchyma post-I/R were reduced in preirradiated versus control groups. Such IPC was significantly observed as early as

Gut microbiota (GM) has been involved in the pathophysiology of hypertension (HT), notablyMale volunteers (Higher amounts of acetate, butyrate and propionate were found in the stools of non-dippers (Our pilot study highlights a putative link between GM-derived SCFAs and the BP dipping status, independently of the BP status itself or the anti-hypertensive medications.

BACKGROUND AND AIMS Autosomal dominant polycystic kidney disease (ADPKD) is prone to multiple complications, including cyst infection (CyI). 18F-FDG PET/CT imaging proved useful in the diagnosis of renal and hepatic CyI. A 4-point scale comparing the uptake of 18F-FDG in the suspected infected cyst versus the hepatic physiological background has been proposed. We performed an independent validation of this semi-quantitative score system. METHOD All ADPDK patients hospitalized between January 2007 and March 2019 who underwent an 18F-FDG PET/CT for suspected CyI were retrospectively identified using computer-based databases. Medical files were systematically reviewed. CyI was conventionally defined by: fever (>38°C), abdominal pain, increased plasma CRP levels (≥70 mg/dL), absence of any other cause of inflammation and favorable outcomes after ≥21 days of antibiotics. The 18F-FDG uptake around the suspected CyI was evaluated using the 4-point scale. Stats were performed using SAS version 9.4. RESULTS Our cohort included 51 18F-FDG PET/CT in 51 patients, including 11 cases of CyI according to the above-detailed definition. The agreement between the 4-point scale and the gold-standard criteria of CyI was significant, with an odds ratio of 6.03 for CyI in case of a score ≥3 (P, 0.014). The corresponding sensitivity and specificity of PET/CT using the 4-point scale were 63.3% and 77.5%, respectively. CONCLUSION Our independent validation cohort confirms that the use of a semi-quantitative 4-point scoring system helps in the diagnosis of CyI by 18F-FDG PET/CT imaging in patients with ADPKD.

BACKGROUND AND AIMS Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disorder. Defective glucose metabolism was identified as a key feature in ADPKD, and several ‘metabolic’ approaches are currently under evaluation in adults with ADPKD. Whether this defective glucose metabolism could be an early primary event and a potential therapeutic option in the early disease stages is still unknown. In this study, we evaluated the insulin sensitivity profile in genotyped children with ADPKD. METHOD We performed a cross-sectional study to evaluate the insulin sensitivity profile in a genotyped cohort of ADPKD children ( 30 kg/m2. The Homeostasis Model Assessment Index (HOMA-IR) was calculated: fasting insulin (μIU mL− 1) x fasting glucose (mmol L − 1)/22.5. The Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated: 1/[log (fasting insulin μU/mL) + log (fasting glucose mg/dL)]. RESULTS A total of 37 ADPKD patients (22 boys) were included with a mean ($ \pm $ SD) age at diagnosis was 10.3 $ \pm $ 4.2 years. A total of 36 patients had PKD1 mutation (one GANAB mutation). Median BMI was 16.8 ± 4.3 kg/m2. Median serum fasting glucose: 86.0 ± 9.3 mg/dL, median fasting insulin: 6.1 ± 7.2 μU/mL and median serum C-peptide: 0.4 ± 0.3 nmol/L. Median HOMA-IR was 1.4 ± 1.7 and median QUICKI was 0.4 ± 0.1. A total of 16 patients presented a HOMA-IR > 1.6 and 6 normal-weight children had a HOMA-IR > 2.3. No patient displayed glucosuria. An oral glucose tolerance test was performed on five overweight patients, four of them showed insulin resistance and were treated with metformin. CONCLUSION Even with normal BMI, ADPKD children displayed a high index of insulin resistance. Further clinical studies are needed to determine whether ADPKD could be an additional risk factor for insulin resistance.

BACKGROUND AND AIMS Bone loss and mineral abnormalities are frequent in kidney transplant recipients (KTRs) and associated with a high risk of fracture, cardiovascular mortality and an increase in health care costs. In daily clinics, the detection of bone abnormalities after transplantation includes bone biomarkers and imaging technique [Dual Energy X-ray (DEXA)] to assess respectively the bone turnover and the bone mineral density (BMD), but with limitations. The high-resolution peripheral quantitative computed tomography (HR-pQCT) provides additional noninvasive information on bone microarchitecture and BMD with a better distinction between cortical and trabecular areas. The goal of our study is to evaluate the evolution of bone structure using HR-pQCT compared to standard technique (DXA) in a prospective cohort of KTRs. METHOD All patients referred for a single kidney transplant at the university hospital of Liège with no history of exposure to antiresorptive agents were eligible for inclusion (NCT04713774). Participants underwent baseline and 3-month biomarkers analysis, BMD measurements by DEXA. HR-pQCT images were obtained of the distal radius and distal tibia (non-dominant, non-fractured limb) using the XtremeCT device with standard protocols. HR-pQCT assessed quantitative measurement of the volumetric density of trabecular and cortical bone as well as bone structure (trabecular number or thickness or cortical porosity for instance). RESULTS A total of 26 patients were prospectively included. The mean age was 57.3 ± 12.1 years. The mean dialysis vintage was 27.5 ± 16.4 months before transplantation. Bone biomarkers showed a significant decrease at 3 months after transplantation. PTH decreased from 221.72 ng/L to 59.6 ng/L (P CONCLUSION HR-pQCT is sensitive enough to show a significant decrease of BMD at the trabecular site, as soon as 3 months after transplantation compared to DEXA at the lumbar spine. However, no change in bone structure nor cortical bone volume has been observed. The sensibility of this technique might be higher than DEXA. The rapid assessment of bone structure (3 months post-transplantation) might be too soon to evaluate such abnormalities. Detecting properly rapid changes in bone density, as soon as 3 months after renal transplantation seems feasible. The impact on bone health management needs to be further studied.

Purpose [18F]FDG PET/CT (PET/CT) proved useful in the diagnosis of renal and hepatic cyst infection (CyI) in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the definition of CyI by PET/CT is unclear. Here, we characterize the [18F]FDG uptake in CyI in order to infer a visual 4-point diagnostic scale. Methods All ADPKD patients hospitalized between 2007 and 2019 for suspected CyI and who underwent an [18F]FDG PET/CT scan were listed. CyI was defined by 5 concomitant criteria: fever ≥ 38 °C; abdominal pain; peak plasma CRP ≥ 70 mg/L; no other cause of inflammation; and favorable outcomes after antibiotics for ≥ 21 days. First, all PET/CT images were visually interpreted. Next, the [18F]FDG uptake around the suspected CyI was scored using a semiquantitative 4-point scale in comparison to blood and liver activities. Results Sixty [18F]FDG PET/CT scans were performed for suspected CyI in 38 ADPKD patients. Twenty-nine episodes met the gold-standard criteria for CyI. The visual assessment of PET/CT images reached a sensitivity of 73.1% and a specificity of 70.6%. Using the 4-point scale, an [18F]FDG score ≥ 3 (i.e., cyst uptake > liver) improved the specificity to 85.3%. Conclusion [18F]FDG PET-CT is helpful in CyI diagnosis in ADPKD, and the use of a 4-point scoring of [18F]FDG uptake improves its diagnostic yield, with positive and negative predictive values of 78.3 and 78.4%, respectively. External validation is required.

Subclinical kidney allograft acute rejection (SCR) corresponds to "the unexpected histological evidence of acute rejection in a stable patient." SCR detection relies on surveillance biopsy. Noninvasive approaches may help avoid biopsy-associated complications. From November 2015 to January 2018, we prospectively performed positron emission tomography/computed tomography (PET/CT) after injection of F18 -fluorodeoxyglucose (18 F-FDG) in adult kidney transplant recipients with surveillance biopsy at ~3 months posttransplantation. The Banff-2017 classification was used. The ratio of the mean standard uptake value (mSUVR) between kidney cortex and psoas muscle was measured. Urinary levels of CXCL-9 were concomitantly quantified. Our 92-patient cohort was categorized upon histology: normal (n = 70), borderline (n = 16), and SCR (n = 6). No clinical or biological difference was observed between groups. The mSUVR reached 1.87 ± 0.55, 1.94 ± 0.35, and 2.41 ± 0.54 in normal, borderline, and SCR groups, respectively. A significant difference in mSUVR was found among groups. Furthermore, mSUVR was significantly higher in the SCR vs normal group. The area under the receiver operating characteristic curve (AUC) was 0.79, with 83% sensitivity using an mSUVR threshold of 2.4. The AUC of urinary CXCL-9/creatinine ratios comparatively reached 0.79. The mSUVR positively correlated with ti and acute composite Banff scores. 18 F-FDG-PET/CT helps noninvasively exclude SCR, with a negative predictive value of 98%. External validations are required.

AMP-activated protein kinase (AMPK) activation promotes early stages of epithelial junction assembly. AMPK activation in MDCK renal epithelial cells facilitates localization of the junction-associated proteins aPKCζ and Par3 to the plasma membrane and promotes conversion of Cdc42, a key regulator of epithelial polarization and junction assembly, to its active GTP bound state. Furthermore, Par3 is an important regulator of AMPK-mediated aPKCζ localization. Both aPKCζ and Par3 serve as intermediates in AMPK-mediated junction assembly, with inhibition of aPKCζ activity or Par3 knockdown disrupting AMPK’s ability to facilitate zonula occludens (ZO-1) localization. AMPK phosphorylates the adherens junction protein afadin and regulates its interaction with the tight-junction protein zonula occludens-1. Afadin is phosphorylated at two critical sites, S228 (residing within an aPKCζ consensus site) and S1102 (residing within an AMPK consensus site), that are differentially regulated during junction assembly and that exert different effects on the process. Expression of phospho-defective mutants (S228A and S1102A) perturbed ZO-1 localization to the plasma membrane during AMPK-induced junction assembly. Expression of S228A increased the ZO-1/afadin interaction, while S1102A reduced this interaction during extracellular calcium-induced junction assembly. Inhibition of aPKCζ activity also increased the ZO-1/afadin interaction. Taken together, these data suggest that aPKCζ phosphorylation of afadin terminates the ZO-1/afadin interaction and thus permits the later stages of junction assembly.

Aim Dual Specificity Phosphatase 3 (DUSP3) regulates the innate immune response, with a putative role in angiogenesis. Modulating inflammation and perfusion contributes to renal conditioning against ischemia/reperfusion (I/R). We postulate that the functional loss of DUSP3 is associated with kidney resistance to I/R. Methods Ten C57BL/6 male WT and Dusp3-/- mice underwent right nephrectomy and left renal I/R (30min/48h). Renal injury was assessed based on serum levels of urea (BUN) and Jablonski score. The expression of CD31 and VEGF vascular markers was quantified by RT-qPCR and immuno-staining. Renal resistivity index (RRI) was measured in vivo by Doppler ultrasound. Comparative phosphoproteomics was conducted using IMAC enrichment of phosphopeptides. Inflammatory markers were quantified at both mRNA and protein levels in ischemic vs. non-ischemic kidneys in WT versus Dusp3-/- . Results At baseline, we located DUSP3 in renal glomeruli and endothelial cells. CD31-positive vascular network was significantly larger in Dusp3-/- kidneys compared to WT, with a lower RRI in Dusp3-/- mice. Following I/R, BUN and Jablonski score were significantly lower in Dusp3-/- vs. WT mice. Phosphoproteomics highlighted a down-regulation of inflammatory pathways and up-regulation of phospho-sites involved in cell metabolism and VEGF-related angiogenesis in Dusp3-/- vs. WT ischemic kidneys. Dusp3-/- ischemic kidneys showed decreased mRNA levels of CD11b, TNF-α, KIM-1, IL-6, IL-1β and caspase-3 compared to controls. The numbers of PCNA-, F4-80- and CD11b-positive cells were reduced in Dusp3-/- vs. WT kidneys post I/R. Conclusion Genetic inactivation of Dusp3 is associated with kidney conditioning against I/R, possibly due to attenuated inflammation and improved perfusion.

Background Various properties of mesenchymal stromal cells (MSCs) might be particularly of interest after liver transplantation (LT). In this paper, we report the long-term results of their prospective, controlled and first-in-human phase-1 study evaluating the safety of a single MSC infusion after LT. Methods Ten LT recipients under standard immunosuppression received 1.5-3x106 /kg third-party unrelated MSCs on post-operative day 3±2 and were prospectively compared to a control group of 10 LT recipients. Primary endpoints were set to prospectively detect potential delayed side effects of MSC infusion, and particularly occurrence of infections and cancers. Secondary endpoints of liver graft and patient survival, graft rejection and function, occurrence of bile duct complications, and development of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) against liver or MSC donors, were studied. Median follow-up was 85 months. Results There was no difference in overall rates of infection or cancer at 5 years of follow-up between the two groups. There was also no difference in secondary endpoints. The prevalence of de novo liver DSAs related to HLA-mismatches was twice as high in the MSC group compared to the control group. All the de novo class II HLA antibodies against MSCs were linked to a shared HLA mismatch between the liver and MSCs. Conclusions This study confirms the safety of a single MSC infusion after LT. The potential benefits of MSC injections in the context of organ transplantation have still to be demonstrated by larger prospective studies. The development of anti-HLA antibodies against MSC donor should be further evaluated especially in cases of shared HLA mismatches between graft and MSC donors, despite the fact that no deleterious effect has been detected.

The clinical course of autosomal dominant polycystic kidney disease (ADPKD) starts in childhood. Evidence of the beneficial impact of early nephron-protective strategies and lifestyle modifications on ADPKD prognosis is accumulating. Recent studies have described the association of overweight and obesity with rapid disease progression in adults with ADPKD. Moreover, defective glucose metabolism and metabolic reprogramming have been reported in distinct ADPKD models highlighting these pathways as potential therapeutic targets in ADPKD. Several "metabolic" approaches are currently under evaluation in adults, including ketogenic diet, food restriction, and metformin therapy. No data are available on the impact of these approaches in childhood thus far. Yet, according to World Health Organization (WHO), we are currently facing a childhood obesity crisis with an increased prevalence of overweight/obesity in the pediatric population associated with a cardio-metabolic risk profile. The present review summarizes the knowledge about the role of glucose metabolism in the pathophysiology of ADPKD and underscores the possible harm of overweight and obesity in ADPKD especially in terms of long-term cardiovascular outcomes and renal prognosis.

Contains fulltext : 251702.pdf (Publisher’s version ) (Closed access)

ispartof: JOURNAL OF NEPHROLOGY vol:34 issue:4 pages:967-969 ispartof: location:Italy status: published

Positron emission tomography combined with computed tomography (PET/CT) is a nuclear imaging technique which provides anatomical and functional information. PET/CT is increasingly used in non-oncological nephrology since conventional radiological approaches after injection of contrast agents are relatively contra-indicated in patients with chronic kidney disease (CKD). PET/CT after i.v. injection of 18F-fluoro-deoxy-glucose (FDG) is not toxic and is characterized by a high sensitivity. The level of irradiation (∼5mSv) is acceptable. CKD does not significantly influence tissue uptake of 18F-FDG. The purpose of the present review aims at detailing the non-oncological indications of 18F-FDG PET/CT in general nephrology and after kidney transplantation. Particularly, 18F-FDG PET/CT appears useful in the diagnosis of cyst infection in patients with autosomal dominant polycystic kidney disease, as well as in the characterization of retroperitoneal fibrosis. In kidney transplant recipients, 18F-FDG PET/CT may help in the diagnostic work-up of suspected acute rejection, thereby eventually avoiding unnecessary kidney transplant biopsy. Perspectives in 18F-FDG PET/CT imaging are discussed, including innovative approaches of image analysis.

Gut microbiota may influence blood pressure (BP), namely via end products of carbohydrate fermentation. After informed consent, male volunteers were prospectively categorized into 3 groups upon European Society of Hypertension criteria based on 24-hour ambulatory BP measurements: (1) hypertension, (2) borderline hypertension, and (3) normotension. Stool, urine and serum samples were collected in fasting conditions. Gut microbiota was characterized by 16S amplicon sequencing. Metabolomics, including quantification of short-chain fatty acids, was conducted using nuclear magnetic resonance. Two-way ANOVA combined with Tukey post hoc test, as well as multiple permutation test and Benjamini-Hochberg-Yekutieli false discovery rate procedure, was used. The cohort included 54 males: 38 hypertensive (including 21 under treatment), 7 borderline, and 9 normotensive. No significant difference was observed between groups concerning age, body mass index, smoking habits, and weekly alcohol consumption. The genus Clostridium sensu stricto 1 positively correlated with BP levels in nontreated patients (n=33). This correlation was significant after multiple permutation tests but was not substantiated following false discovery rate adjustment. Short-chain fatty acid levels were significantly different among groups, with higher stool levels of acetate, butyrate, and propionate in hypertensive versus normotensive individuals. No difference was observed in serum and urine metabolomes. Correlation between stool metabolome and 24-hour BP levels was evidenced, with R 2 reaching 0.9. Our pilot study based on 24-hour ambulatory BP measurements, 16S amplicon sequencing, and metabolomics supports an association between gut microbiota and BP homeostasis, with changes in stool abundance of short-chain fatty acids.

Mesenchymal stromal cells (MSCs) exhibit anti-inflammatory and immune-regulatory properties, and preclinical studies suggest a potential benefit in solid organ transplantation. We report on the 1-year follow-up of an open-label phase I-II trial of a single infusion of third-party MSC post-kidney transplantation, in addition to standard immunosuppression. Ten kidney transplant recipients from deceased donors received third-party bone marrow MSCs (∼2 × 106/kg) on day 3 ± 2 post-transplant and were compared to 10 concurrent controls. No adverse effects were noted at MSC injection. One participant with a history of cardiac disease had a non-ST-elevation myocardial infarction approximately 3 hours after MSC infusion. Incidences of opportunistic infections and acute rejection were similar. At day 7 post-transplant, estimated glomerular filtration rate (eGFR) in MSC-treated recipients reached 48.6 ml/min/1.73m2, compared to 32.5 ml/min/1.73m2 in controls and 29.3 ml/min/1.73m2 in our overall cohort of kidney transplant recipients. No difference in eGFR was found at 1 year. MSC-treated recipients showed increased frequencies of regulatory T cells at day 30, with no significant change in B cell frequencies compared to concurrent controls. Four MSC-treated participants developed antibodies against MSC or shared kidney-MSC HLA, with only 1 with MFI >1500. A single infusion of third-party MSC following kidney transplantation appears to be safe, with one cardiac event of unclear relationship to the intervention. MSC therapy is associated with increased regulatory T cell proportion and with improved early allograft function. Long-term effects, including potential immunization against MSC, remain to be studied.

Renal segmental metabolism is reflected by the complex distribution of the main energy pathways along the nephron, with fatty acid oxidation preferentially used in the cortex area. Ischemia/reperfusion injury (IRI) is due to the restriction of renal blood flow, rapidly leading to a metabolic switch toward anaerobic conditions. Subsequent unbalance between energy demand and oxygen/nutrient delivery compromises kidney cell functions, resulting in a complex inflammatory cascade including the production of reactive oxygen species (ROS). Renal IRI especially involves lipid accumulation. Lipid peroxidation is one of the major events of ROS-associated tissue injury. Here, we briefly review the current knowledge of renal cell lipid metabolism in normal and ischemic conditions. Next, we focus on renal lipid-associated injury, with emphasis on its mechanisms and consequences during the course of IRI. Finally, we discuss preclinical observations aiming at preventing and/or attenuating lipid-associated IRI.

Background and Aims Dysbiosis of gut microbiota (GM) has been involved in the pathophysiology of arterial hypertension (HT), via a putative role of food-derived short chain fatty acids (SCFAs). Among the clinical manifestations of HT, the absence of a significant drop in blood pressure (BP) overnight (i.e. non-dipping BP profile) has been associated with poor cardiovascular outcomes. The link between GM and non-dipping BP profile is unknown. Method After informed consent, 16 male patients and their female partners (n=10) were subjected to 24-hours ambulatory BP monitoring and were categorized in 2 groups: HT (n=7; 6 men) and normotension (NT) (n=19). According to the conventional night–day systolic BP ratio >0.9, 15 individuals (8 men and 7 women) were categorized as non-dippers. Metabolomics using Nuclear Magnetic Resonance was performed on stool samples, including the quantification of the 3 main SCFAs (i.e. acetate, propionate and butyrate). Results Multivariate analysis (principal component analyses (PCA) and partial least squares (PLS-DA)) of stool metabolomics were not able to statistically separate HT versus NT groups. However, this approach discriminated dippers versus non-dippers groups in both male and female cohorts (Q²=0.87 and 0.98, respectively), as well as in the entire cohort (Q²=0.68). As previously described, fecal amounts of acetate, propionate and butyrate were higher in HT patients than in NT patients in the entire cohort (p=0.027; p=0.015 and p=0.015, respectively). Fecal amounts of acetate, propionate and butyrate were also significantly higher in non-dippers versus dippers in the entire cohort (p=0.027; p=0.038 and p=0.036, respectively). Significant correlations between stool metabolomes and the 24h-mean BP levels were found in male and female cohorts (R²=0.63 and 0.79 respectively) as well as in the entire cohort (R²=0.54). Conclusion In conclusion, this 26-patient cohort highlights significant correlations between stool metabolome and (i) BP levels and (ii) non-dipping BP profile in both men and women.

Background and Aims Whole-body irradiation has been suggested to induce renal ischemic preconditioning (RIP) in rodent models, possibly via neo-angiogenesis. First, we comprehensively investigate the pathways involved in kidney-centered irradiation. Next, we assess the functional and structural impact of kidney-centered irradiation applied before ischemia/reperfusion (I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the neo-angiogenesis prevents irradiation-associated RIP. Method Experiment 1: Unilateral irradiation of the left kidney (8.56 Gy) was performed in male 10-week-old wild-type C57bl/6 mice (n=10). One month later, total kidney RNA was extracted from irradiated and control (n=5) mice for comparative high-throughput RNA-Seq (using BaseSpace Sequence Hub Illumina). Functional enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). Experiment 2: Two x-ray beams (225Kv, 13mA) specifically targeted both kidneys for a total dose of 8.56Gy. The right kidneys were removed and harvested, and the left kidneys undergo 30-minute ischemia followed by 48-hour reperfusion (n=8) at Days 7-14-21-28 post irradiation. Experiment 3: Following the same protocol of renal I/R at Day14, 3 groups of male 10-week-old wild-type C57bl/6 mice were compared (n=8 per group): 1/ bilateral pre-irradiation; 2/ bilateral pre-irradiation and gavage with Sunitinib from Day2 to Day13; 3/ control group without irradiation or gavage. Results Experiment 1: Comparative transcriptomics showed a significant up-regulation of various signaling pathways, including angiogenesis (HMOX1) and stress response (HSPA1A, HSPA1B). Expressions of angiogenesis markers (CD31, TGFb1, HMOX1) showed an increase at both mRNA (real-time qPCR) and protein (immuno-staining) levels in irradiated kidneys compared to controls (p Experiment 2: Following I/R, the blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly lower in the irradiated animals compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p Experiment 3: One-way analysis of variance followed by Tukey’s test showed that, following I/R, the serum levels of BUN and SCr were lower in irradiated group compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and in irradiated group compared to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p Conclusion Renal irradiation induces the activation of signaling pathways involved in angiogenesis in mice. Renal pre-irradiation leads to RIP, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced RIP.

Background and Aims Gut microbiota (GM) has been involved in the pathophysiology of hypertension (HT), possibly via its role in the production of short chain fatty acids (SCFAs) from diet carbohydrate fermentation. The absence of a significant drop in night-time BP (also known as the non-dipping BP profile) measured by 24-hour ambulatory BP monitoring (24h-ABPM) has been associated with poor renal and cardiovascular outcomes, independently of HT. The putative link between GM-derived metabolites and BP dipping status is still unknown. Method We investigated a cohort of male volunteers who were prospectively recruited and subjected to 24h-ABPM, stool sample collection and a medical questionnaire. A patient was categorized as non-dipper if the ratio between night and day systolic BP was >0.9. The patients were categorized in two groups, i.e. NT or HT, on the basis of the European Society of Hypertension criteria. Metabolomics analyses were conducted using Nuclear Magnetic Resonance. Fecal concentrations of acetate, butyrate and propionate were obtained by integrating the signals at 1.93 ppm, 1.56 ppm and 1.05 ppm, respectively. Mann-Whitney test and Chi-square test were used to compare continuous and categorical variables, respectively. Results Our 44-case cohort included 13 non-dippers (29.6%) and 31 dippers, with 35 HT (79.4%) and 9 NT patients. Ten non-dippers (28.6%) and 25 dippers were HT. Nineteen HT patients were under anti-hypertensive medications (43.1%), including 7 non-dippers and 12 dippers. The mean age and body mass index (BMI) of the cohort were 50.8±9.5 years and 26.3±3.5 kg/m², respectively. No significant difference in age, BMI, smoking habits, alcohol consumption, familial HT, personal history of diabetes, cardiovascular or gastro-intestinal disorders was observed between dippers and non-dippers. The relative quantification of fecal SCFAs showed higher amounts of acetate, butyrate and propionate in the stools of non-dippers versus dippers (p=0.0252, p=0.0468, and p=0.0496, respectively; n=44 in toto) (Figure 1A). Similarly, the fecal amounts of acetate, butyrate and propionate were higher in non-dippers versus dippers in patients without anti-hypertensive medications (p=0.0414, p=0.0108, and p=0.0602, respectively; n=25 in toto) (Figure 1B). When focusing only on HT patients without any anti-hypertensive medications, a not significant trend for higher amounts of the 3 main SCFAs was still found in the stools of non-dippers versus dippers (p=0.0556; n=16 in toto). Conclusion Our pilot study highlights a putative link between GM-derived SCFAs and the BP dipping status, despite the BP status itself or the anti-hypertensive medications. No significant confounding factors were found between dippers and non-dippers in our cohort. The non-dipping BP profile is thought to reflect the disruption of the circadian BP rhythm. A circadian misalignment between peripheral and central clocks has also been described in the GM of jetlagged animals and patients, which may in turn perturb the rhythmic secretion of metabolites. One may thus speculate that the non-dipping BP profile may be linked to an altered homeostasis of GM-derived SCFAs. Although confirmatory data in larger cohorts are required, our original observations unravel innovative pathophysiological pathways in the field of the circadian regulation of BP levels.

Background and Aims Acute T-cell mediated rejection (TCMR) is associated with the recruitment of mononuclear leukocytes into the renal transplant, which corresponds to the core of the conventional Banff classification. The boosted metabolism of these inflammatory cells can be assessed by positron emission tomography (PET) quantifying the renal uptake of 18F-fluorodeoxyglucose (18FDG). The correlation of biopsy-based Banff versus PET-based scores of acute inflammation in the renal transplant is unknown. Method From January 2013 to December 2019, we prospectively performed 114 18FDG-PET/CT in 105 adult KTR who underwent per cause transplant biopsy for suspected TCMR. Biopsy-proven polyoma-BK nephropathies (n=7) and uninterpretable PET images (n=2) were excluded. PET/CT was performed 194±19 minutes after administration of 243±35 MBq of 18FDG, before any immunosuppression change. The mSUVs were measured in both upper and lower poles of the renal allograft. The acute Banff score was conventionally defined as the sum (from 0 to 15) of g (glomerulitis), ptc (peritubular capillaritis), t (tubulitis), i (inflammation in non-scarred cortex) and v (endarteritis). The Banff “total i” score (from 0 to 3) corresponds to the total cortical inflammation, including scarred and non-scarred cortex. Regression of mSUV against the acute Banff score was performed, and Pearson correlation coefficients were calculated. The distribution of mSUV between “total i” groups was assessed by the non-parametric Kruskal-Wallis test followed by Dunn’s post hoc test. Results The mean age of the cohort was 51.5±14.3 years, with M/F ratio of 67/38. The prevalence of biopsy-proven TCMR and borderline was 20.9% and 16.2%, respectively. The mean mSUV of the 105-case cohort was 1.82±0.45. The highest value of acute Banff score was 12, while 55.2% of biopsies were scored as 0. The distribution of “Total i” score was: 0 (58.8%); 1 (20.6%); 2 (8.8%); 3 (11.8%). Regression showed a significant correlation between mSUV and acute Banff score (p Conclusion 18FDG-PET/CT may help noninvasively assess the degree of allograft inflammation in KTR with suspected TCMR.

Background and Aims Proteinuria, hematuria and acute kidney injury (AKI) are frequently observed in hospitalized patients with COVID-19. However, few data are available on these parameters after hospital discharge. Method This retrospective, observational and monocentric study included 153 hospitalized patients, in whom urine total proteinuria and α1-microglobulin (a marker of tubular injury) were measured. Thirty patients died. Among the 123 survivors, follow-up urine and creatinine analyses were available for 72 patients (after a median of 51 [19;93] days following hospital discharge). Results The median proteinuria at hospitalization and follow-up (n=72) was 419 [239; 748] and 79 [47; 129] mg/g, respectively (p15 mg/g (%) 88 29 Urine β2-microglobulin (n=60) (mg/L) 0.92 [0.41;4.52] 0.00 [0.00;0.00] 0.19 mg/L (%) 82 13 Hematuria (>10 per field) (%) (n=51) 19 12 ns

Background and Aims Dual Specificity Phosphatase 3 (DUSP3) is a positive regulator of the innate immune response in case of sepsis, but its role in the ischemic damage is unknown. Here, we study (i) whether and where DUSP3 is expressed in the renal parenchyma, and (ii) whether its genetic deletion in Dusp3 systemic knock-out (Dusp3-/-) mice attenuates the I/R-associated inflammation and injury. Method Experiment 1: Ten C57BL/6 male WT and Dusp3-/- mice underwent right nephrectomy and left renal ischemia for 30 minutes followed by a reperfusion of 48 hours. Blood and kidneys were collected. Renal function was assessed upon I/R biomarkers, i.e. blood urea nitrogen (BUN) and creatinine (SCr). Expressions of inflammatory and immune markers were comparatively quantified at both mRNA (real-time qPCR) and protein (immuno-blotting and –staining) levels in ischemic vs. non-ischemic kidneys in Dusp3 WT vs. KO mice. Experiment 2: Ten C57BL/6 male WT and Dusp3-/- mice were anesthetized. Renal Doppler ultrasound was performed to assess the renal resistivity index (RRI). The expression of CD31 and VEGF vascular markers was quantified by the means of real-time qPCR and and immuno-staining (FiJi software). Results Experiment 1: An immuno-reactive signal for DUSP3 was detected in the glomeruli (in co-localization with nephrin) and in Meca-32-positive endothelial cells of both outer and inner medulla of mouse non-ischemic WT kidneys. No significant immunoreactivity for DUSP3 was detected in Dusp3-/- kidneys. Following renal I/R, the mRNA level of Dusp3 was increased 1.8-fold compared to baseline (p Experiment 2: The RRI non-invasively measured by ultrasound was lower in Dusp3-/- group compared to controls (0.56± 0.03 vs. 0.66±0.02; p Conclusion The genetic deletion of DUSP3 is associated with (i) increased renal vascular density, (ii) decreased RRI and (iii) nephroprotection against renal I/R injury.

BackgroundOver the last decaces, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, ±20% of all tubulopathy patients remain without genetic diagnosis. Here, we explore a large multicentric patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia and dilated cardiomyopathy (DCM).MethodsWhole exome and genome sequencings were performed with various subsequent functional analyses of identified RRAGD variants in vitro.ResultsIn 8 children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt-wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients additionally suffered from DCM requiring heart transplantation in 3 of them. An additional dominant variant in RRAGD was simultaneously identified in eight members of a large family with a similar renal phenotype. RRAGD encodes GTPase RagD mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron include the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro,ConclusionsOur findings establish a novel disease phenotype combining kidney tubulopathy and cardiomyopathy (KICA) caused by an activation of mTOR signaling suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.SIGNIFICANCE STATEMENTHere, we report on heterozygous variants in RRAGD in patients with profound hypomagnesemia, renal salt wasting, nephrocalcinosis, and dilated cardiomyopathy. The identified RagD variants induce a constitutive activation of mTOR signaling in vitro. These findings not only establish a novel monogenic disorder of the kidney tubule, but demonstrate the essential role of mTOR signaling for distal tubular electrolyte handling and cardiac function.

Grupper et al. have reported on a positive humoral response post full vaccination with mRNA SARS-CoV2 BNT162b2 in only 51/136 (37.5%) kidney transplant recipients (KTRs) without prior exposure to the virus1 . We have conducted an IRB-approved (B707201215598-2021/80) prospective small sample-size study comparing the humoral response to BNT162b2 in 40 consecutive individuals early exposed to the Belgian vaccination program, including 20 KTRs with (n=10, COVID-19(+)) versus without (n=10, COVID-19(-)) history of exposure to SARS-CoV-2 and 20 controls including 10 COVID-19(+) versus 10 COVID-19(-).