Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Effect of Hypoxia Preconditioning on the Regenerative Capacity of Adipose Tissue Derived Mesenchymal Stem Cells in a Model of Renal Artery Stenosis.

Atherosclerotic renal artery stenosis (ARAS) is associated with irreversible parenchymal renal disease and regenerative stem cell therapies may improve renal outcomes. Hypoxia preconditioning (HPC) may improve the regenerative functions of adipose tissue-derived mesenchymal stem cells (AMSC) by affecting DNA 5-hydroxymethylcytosine (5hmC) marks in angiogenic genes. Here, we investigated using a porcine ARAS model, whether growth of ARAS AMSCs in hypoxia (Hx) versus normoxia (Nx) would enhance renal tissue repair, and comprehensively analyze how HPC modifies DNA hydroxymethylation compared to untreated ARAS and healthy/normal pigs (n=5 each). ARAS pigs exhibited elevated serum cholesterol, serum creatinine and renal artery stenosis, with a concomitant decrease in renal blood flow (RBF) and increased blood pressure (BP) compared to healthy pigs. Renal artery injection of either autologous Nx or Hx AMSCs improved diastolic BP, reduced kidney tissue fibrosis, and inflammation (CD3+ T-cells) in ARAS pigs. In addition, renal medullary hypoxia significantly lowered with Nx but not Hx AMSC treatment. Mechanistically, levels of epigenetic 5hmC marks (which reflect gene activation) estimated using DNA immunoprecipitation technique were elevated in profibrotic and inflammatory genes in ARAS compared with normal AMSCs. HPC significantly reduced 5hmC levels in cholesterol biosynthesis and oxidative stress response pathways in ARAS AMSCs. Thus, autologous AMSCs improve key renovascular parameters and inflammation in ARAS pigs, with HPC mitigating pathological molecular effects on inflammatory and profibrotic genes which may play a role in augmenting regenerative capacity of AMSCs.

Association of Proton Pump Inhibitor Use and Immune Checkpoint Inhibitor Mediated Acute Kidney Injury: A Meta-Analysis and a Review of Related Outcomes.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, they pose the risk of immune-related adverse events, including ICI-mediated acute kidney injury (ICI-AKI). Recent studies have implicated proton pump inhibitors (PPIs) as potential contributors to ICI-AKI development. This meta-analysis examines the association between PPI use and ICI-AKI, exploring a potential modifiable risk factor in ICI therapy, while also reviewing the possible outcomes of ICI-AKI. METHODS: We conducted a comprehensive systematic review and meta-analysis of observational studies, assessing the risk of ICI-AKI in cancer patients concurrently using PPIs and potential outcomes. Odds ratios (ORs) were pooled using random-effects models. Subgroup analyses and sensitivity analyses were performed to evaluate heterogeneity and potential biases. RESULTS: A total of 14 studies involving 12,694 patients were included. In total, we analyzed 639 patients with all-cause AKI and 779 patients with ICI-AKI. The pooled OR for the overall incidence of AKI from all-cause was 1.57 (95% Confidence Interval (CI), 1.02 to 2.40) among patients on PPIs. Specifically, the risk of ICI-AKI associated with PPI use was significantly higher, with a pooled OR of 1.84 (95% CI 1.16 to 2.90). This indicates approximately 84% higher likelihood of developing ICI-AKI with concurrent use of PPIs. Additionally, among patients with ICI-AKI, 67% had complete or partial recovery of renal function, 32% progressed to chronic kidney disease (CKD) and about 36% died during a follow-up period of at least 3 months. CONCLUSION: This meta-analysis highlights the importance of cautious PPI prescription in cancer patients undergoing ICI therapy. Clinicians are advised to evaluate the risks and benefits of PPI use and consider alternative therapies when feasible.

Renal ischemia alters the transcriptomic and epigenetic profile of inflammatory genes in swine scattered tubular-like cells.

BACKGROUND: Scattered tubular-like cells (STCs) are differentiated renal tubular cells that during recovery from ischemic injury dedifferentiate to repair other injured renal cells. Renal artery stenosis (RAS), often associated with chronic inflammatory injury, compromises the integrity and function of STCs, but the underlying mechanisms remain unknown. We hypothesized that RAS alters the transcriptomic and epigenetic profile of inflammatory genes in swine STCs. METHODS: STCs were harvested from pig kidneys after 10 weeks of RAS or sham (n=6 each). STC mRNA profiles of inflammatory genes were analyzed using high-throughput mRNA-sequencing (seq) and their DNA methylation (5mC) and hydroxymethylation (5hmC) profiles by DNA immunoprecipitation and next-generation sequencing (MeDIP-seq) (n=3 each), followed by an integrated (mRNA-seq/MeDIP-seq) analysis. STC protein expression of candidate differentially expressed (DE) genes and common proinflammatory proteins were subsequently assessed in vitro before and after epigenetic (Bobcat339) modulation. RESULTS: mRNA-seq identified 57 inflammatory genes up-regulated in RAS-STCs versus Normal-STCs (>1.4 or <0.7-fold, P<0.05), of which 14% exhibited lower 5mC and 5% higher 5hmC levels in RAS-STCs versus Normal-STCs, respectively. Inflammatory gene and protein expression was higher in RAS-STCs compared with Normal-STCs but normalized after epigenetic modulation. CONCLUSIONS: These observations highlight a novel modulatory mechanism of this renal endogenous repair system and support development of epigenetic or anti-inflammatory therapies to preserve the reparative capacity of STCs in individuals with RAS.

Hypertension and Prohypertensive Antineoplastic Therapies in Cancer Patients.

The development of a wide range of novel antineoplastic therapies has improved the prognosis for patients with a wide range of malignancies, which has increased the number of cancer survivors substantially. Despite the oncological benefit, cancer survivors are exposed to short- and long-term adverse cardiovascular toxicities associated with anticancer therapies. Systemic hypertension, the most common comorbidity among cancer patients, is a major contributor to the increased risk for developing these adverse cardiovascular events. Cancer and hypertension have common risk factors, have overlapping pathophysiological mechanisms and hypertension may also be a risk factor for some tumor types. Many cancer therapies have prohypertensive effects. Although some of the mechanisms by which these antineoplastic agents lead to hypertension have been characterized, further preclinical and clinical studies are required to investigate the exact pathophysiology and the optimal management of hypertension associated with anticancer therapy. In this way, monitoring and management of hypertension before, during, and after cancer treatment can be improved to minimize cardiovascular risks. This is vital to optimize cardiovascular health in patients with cancer and survivors, and to ensure that advances in terms of cancer survivorship do not come at the expense of increased cardiovascular toxicities.

The 'other' big complication: how chronic kidney disease impacts on cancer risks and outcomes.

Cancer is the second leading cause of death in people with chronic kidney disease (CKD) after cardiovascular disease. The incidence of CKD in patients with cancer is higher than in the non-cancer population. Across various populations, CKD is associated with an elevated risk of cancer incidence and cancer death compared with people without CKD, although the risks are cancer site-specific. Higher risk of cancer is detectable in mild CKD [estimated glomerular filtration rate (eGFR) 60-89 mL/min/1.73 m2], although this risk is more obvious if sensitive markers of kidney disease are used, such as cystatin C. Independent of eGFR, albuminuria is associated with increased risk of site-specific cancer incidence and death. Here, we explore the potential mechanisms for the increased risk of cancer observed in CKD, including patient factors (shared risks such as cardiometabolic disease, obesity, smoking, diet, lifestyle and environment), disease (genetic, inflammatory and infective) and treatment factors. In particular, we discuss the ways in which renal adverse events associated with conventional chemotherapies and newer systemic anti-cancer therapies (including targeted and immunotherapies) may contribute to worse cancer outcomes in people with CKD. Finally, we review the potential benefits of acknowledging increased risk of cancer in risk prediction tools used for the management of CKD.

Capmatinib-Induced Pseudo-Acute Kidney Injury: A Case Report.

We present a case of pseudo-acute kidney injury (AKI) following capmatinib therapy in an 84-year-old man with combined non-small cell (adenocarcinoma) and small cell lung cancer with MET exon 14-skipping mutation. His past medical history was significant for chronic kidney disease stage 3 with a baseline serum creatinine (Scr) of 1.6mg/dL rising to 2.44mg/dL (estimated glomerular filtration rate [GFR] 24mL/min/1.73m2) while on capmatinib. Scr improved to 1.84mg/dL with the cessation of capmatinib but rose again to 2.22mg/dL upon resumption of therapy. Further investigation with cystatin C and renal iothalamate clearance showed that despite fluctuation in Scr levels, there was not much variation in GFR calculated using these methods. Urinalysis and urinary protein-creatinine ratio were unremarkable. Treatment with capmatinib was continued at reduced dose and a third instance of rise in Scr was observed, followed by a spontaneous return to baseline. Thus, MET inhibitor therapy can result in an asymptomatic rise in Scr, and it must be distinguished from AKI with more accurate non-creatinine-based methods to evaluate GFR. This could spare such patients from invasive diagnostic tests, such as a kidney biopsy, and premature cessation of prognostically important cancer therapies.

Frequency of family meals and food consumption in families at high risk of type 2 diabetes: the Feel4Diabetes-study.

A family meal is defined as a meal consumed together by the members of a family or by having ≥ 1 parent present during a meal. The frequency of family meals has been associated with healthier food intake patterns in both children and parents. This study aimed to investigate in families at high risk for developing type 2 diabetes across Europe the association (i) between family meals' frequency and food consumption and diet quality among parents and (ii) between family meals' frequency and children's food consumption. Moreover, the study aimed to elucidate the mediating effect of parental diet quality on the association between family meals' frequency and children's food consumption. Food consumption frequency and anthropometric were collected cross-sectionally from a representative sample of 1964 families from the European Feel4Diabetes-study. Regression and mediation analyses were applied by gender of children. Positive and significant associations were found between the frequency of family meals and parental food consumption (ß = 0.84; 95% CI 0.57, 1.45) and diet quality (ß = 0.30; 95% CI 0.19, 0.42). For children, more frequent family meals were significantly associated with healthier food consumption (boys, ß = 0.172, p < 0.05; girls, ß = 0.114, p < 0.01). A partial mediation effect of the parental diet quality was shown on the association between the frequency of family meals and the consumption of some selected food items (i.e., milk products and salty snacks) among boys and girls. The strongest mediation effect of parental diet quality was found on the association between the frequency of family breakfast and the consumption of salty snacks and milk and milk products (62.5% and 37.5%, respectively) among girls. CONCLUSIONS: The frequency of family meals is positively associated with improved food consumption patterns (i.e., higher intake of fruits and vegetables and reduced consumption of sweets) in both parents and children. However, the association in children is partially mediated by parents' diet quality. The promotion of consuming meals together in the family could be a potentially effective strategy for interventions aiming to establish and maintain healthy food consumption patterns among children. TRIAL REGISTRATION: The Feel4Diabetes-study is registered with the clinical trials registry (NCT02393872), http://clinicaltrials.gov , March 20, 2015. WHAT IS KNOWN: • Parents' eating habits and diet quality play an important role in shaping dietary patterns in children • Family meals frequency is associated with improved diet quality of children in healthy population What is New: • Frequency of family meals was significantly associated with healthier food consumption among parents and children in families at high risk of type 2 diabetes in six European countries. • Parental diet quality mediates the association between family meals frequency and the consumption of some selected food items among children.

Quantification of morning stiffness to assess disease activity and treatment effects in rheumatoid arthritis.

OBJECTIVES: The clinical parameter of morning stiffness is widely used to assess the status of RA, but its accurate quantitative assessment in a clinical setting has not yet been successful. This lack of individual quantification limits both personalized medication and efficacy evaluation in the treatment of RA. METHODS: We developed a novel technology to assess passive resistance of the MCP III joint (stiffness) and its passive range of motion (PRoM). Within this pilot study, 19 female postmenopausal RA patients and 9 healthy controls were examined in the evening as well as the morning of the following day. To verify the specificity of the biomechanical quantification, 11 patients with RA were assessed both prior to and ∼3 h after glucocorticoid therapy. RESULTS: While the healthy controls showed only minor changes between afternoon and morning, in RA patients the mean PRoM decreased significantly by 18% (s.d. 22) and stiffness increased significantly by 20% (s.d. 18) in the morning compared with the previous afternoon. We found a significant positive correlation between RA activity and biomechanical measures. Glucocorticoids significantly increased the mean PRoM by 16% (s.d. 11) and reduced the mean stiffness by 23% (s.d. 22). CONCLUSION: This technology allowed mechanical stiffness to be quantified in MCP joints and demonstrated high sensitivity with respect to disease status as well as medication effect in RA patients. Such non-invasive, low-risk and rapid assessment of biomechanical joint stiffness opens a novel avenue for judging therapy efficacy in patients with RA and potentially also in other non-RA inflammatory joint diseases.

Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study.

BACKGROUND: Despite increasing recognition of the importance of immune checkpoint inhibitor-associated AKI, data on this complication of immunotherapy are sparse. METHODS: We conducted a multicenter study of 138 patients with immune checkpoint inhibitor-associated AKI, defined as a ≥2-fold increase in serum creatinine or new dialysis requirement directly attributed to an immune checkpoint inhibitor. We also collected data on 276 control patients who received these drugs but did not develop AKI. RESULTS: Lower baseline eGFR, proton pump inhibitor use, and combination immune checkpoint inhibitor therapy were each independently associated with an increased risk of immune checkpoint inhibitor-associated AKI. Median (interquartile range) time from immune checkpoint inhibitor initiation to AKI was 14 (6-37) weeks. Most patients had subnephrotic proteinuria, and approximately half had pyuria. Extrarenal immune-related adverse events occurred in 43% of patients; 69% were concurrently receiving a potential tubulointerstitial nephritis-causing medication. Tubulointerstitial nephritis was the dominant lesion in 93% of the 60 patients biopsied. Most patients (86%) were treated with steroids. Complete, partial, or no kidney recovery occurred in 40%, 45%, and 15% of patients, respectively. Concomitant extrarenal immune-related adverse events were associated with worse renal prognosis, whereas concomitant tubulointerstitial nephritis-causing medications and treatment with steroids were each associated with improved renal prognosis. Failure to achieve kidney recovery after immune checkpoint inhibitor-associated AKI was independently associated with higher mortality. Immune checkpoint inhibitor rechallenge occurred in 22% of patients, of whom 23% developed recurrent associated AKI. CONCLUSIONS: This multicenter study identifies insights into the risk factors, clinical features, histopathologic findings, and renal and overall outcomes in patients with immune checkpoint inhibitor-associated AKI.

In a Phase 1a escalating clinical trial, autologous mesenchymal stem cell infusion for renovascular disease increases blood flow and the glomerular filtration rate while reducing inflammatory biomarkers and blood pressure.

Atherosclerotic renovascular disease (ARVD) reduces tissue perfusion and eventually leads to loss of kidney function with limited therapeutic options. Here we describe results of Phase 1a escalating dose clinical trial of autologous mesenchymal stem cell infusion for ARVD. Thirty-nine patients with ARVD were studied on two occasions separated by three months. Autologous adipose-derived mesenchymal stem cells were infused through the renal artery in 21 patients at three different dose levels (1, 2.5 and 5.0 × 105 cells/kg) in seven patients each. We measured renal blood flow, glomerular filtration rate (GFR) (iothalamate and estimated GFR), renal vein cytokine levels, blood pressure, and tissue oxygenation before and three months after stem cell delivery. These indices were compared to those of 18 patients with ARVD matched for age, kidney function and blood pressure receiving medical therapy alone that underwent an identical study protocol. Cultured mesenchymal stem cells were also studied in vitro. For the entire stem cell treated-cohort, mean renal blood flow in the treated stenotic kidney significantly increased after stem cell infusion from (164 to 190 ml/min). Hypoxia, renal vein inflammatory cytokines, and angiogenic biomarkers significantly decreased following stem cell infusion. Mean systolic blood pressure significantly fell (144 to 136 mmHg) and the mean two-kidney GFR (Iothalamate) modestly but significantly increased from (53 to 56 ml/min). Changes in GFR and blood pressure were largest in the high dose stem cell treated individuals. No such changes were observed in the cohort receiving medical treatment alone. Thus, our data demonstrate the potential for autologous mesenchymal stem cell to increase blood flow, GFR and attenuate inflammatory injury in post-stenotic kidneys. The observation that some effects are dose-dependent and related to in-vitro properties of mesenchymal stem cell may direct efforts to maximize potential therapeutic efficacy.

Clinical outcomes of solid organ transplant recipients with metastatic cancers who are treated with immune checkpoint inhibitors: A single-center analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but to the authors' knowledge, limited data exist regarding the safety and efficacy of these agents in transplant recipients. Herein, the authors have reported their experience with 17 patients who were treated with ICIs for metastatic malignancies after undergoing solid organ transplantation. METHODS: Data were abstracted for solid organ transplant recipients who received ICIs for the treatment of malignancy between January 1, 2016, and September 30, 2019. The authors identified 7 kidney, 8 liver, and 2 heart transplant recipients. Outcomes of interest were adverse drug reactions, cancer progression, and patient survival. RESULTS: The most common malignancies treated with ICIs were metastatic squamous cell carcinoma (5 patients; 29%) and hepatocellular carcinoma (5 patients; 29%), which were noted exclusively among liver transplant recipients. The median duration on ICIs was 1.7 months (interquartile range, 0.4-7.6 months). Five patients (29%) developed adverse reactions, including 4 patients (24%) with immune-related adverse events(irAEs), 3 patients (18%) with acute allograft rejections, 1 patient (6%) with autoimmune colitis, and 1 patient (6%) with ICI-induced cardiotoxicity (the patient was a heart transplant recipient). The cumulative incidence of cancer progression was 50% and 69%, respectively, at 6 months and 12 months. Eleven patients (65%) died over the median follow-up period of 4.6 months (interquartile range, 1.5-13.2 months) from the time of ICI initiation, with cancer progression being the most common cause of death. CONCLUSIONS: ICIs can be used as individualized therapy in selected patients who have undergone solid organ transplantation but more studies are needed to determine how best to use these agents to improve outcomes further.

Nail-patella-like renal disease masquerading as Fabry disease on kidney biopsy: a case report.

BACKGROUND: Genetic changes in the LIM homeobox transcription factor 1 beta (LMX1B) have been associated with focal segmental glomerulosclerosis (FSGS) without the extra-renal or ultrastructural manifestations of Nail-patella syndrome (NPS) known as Nail-patella-like renal disease (NPLRD). Fabry disease (FD) is an X-linked lysosomal disease caused by the deficiency of alpha-galactosidase A. The classic form of the disease is characterized by acroparesthesia, angiokeratomas, cornea verticillata, hypertrophic cardiomyopathy, strokes, and chronic kidney disease. Podocyte myelin bodies on ultrastructural examination of kidney tissue are very characteristic of FD; however some medications and other conditions may mimic this finding. CASE PRESENTATION: Here, we report on a female patient with chronic kidney disease (CKD), positive family history for kidney disease and kidney biopsy showing a FSGS lesion and presence of focal myelin figures within podocytes concerning for FD. However, genetic testing for FD was negative. After comprehensive clinical, biochemical, and genetic evaluation, including whole exome and RNA sequencing, she was ultimately diagnosed with NPLRD. CONCLUSIONS: This case illustrates the difficulties of diagnosing atypical forms of rare Mendelian kidney diseases and the role of a multidisciplinary team in an individualized medicine clinic setting in combination with state-of-the-art sequencing technologies to reach a definitive diagnosis.

Tissue hypoxia, inflammation, and loss of glomerular filtration rate in human atherosclerotic renovascular disease.

The relationships between renal blood flow (RBF), tissue oxygenation, and inflammatory injury in atherosclerotic renovascular disease (ARVD) are poorly understood. We sought to correlate RBF and tissue hypoxia with glomerular filtration rate (GFR) in 48 kidneys from patients with ARVD stratified by single kidney iothalamate GFR (sGFR). Oxygenation was assessed by blood oxygenation level dependent magnetic resonance imaging (BOLD MRI), which provides an index for the levels of deoxyhemoglobin within a defined volume of tissue (R2*). sGFR correlated with RBF and with the severity of vascular stenosis as estimated by duplex velocities. Higher cortical R2* and fractional hypoxia and higher levels of renal vein neutrophil-gelatinase-associated-lipocalin (NGAL) and monocyte-chemoattractant protein-1 (MCP-1) were observed at lower GFR, with an abrupt inflection below 20 ml/min. Renal vein MCP-1 levels correlated with cortical R2* and with fractional hypoxia. Correlations between cortical R2* and RBF in the highest sGFR stratum (mean sGFR 51 ± 12 ml/min; R = -0.8) were degraded in the lowest sGFR stratum (mean sGFR 8 ± 3 ml/min; R = -0.1). Changes in fractional hypoxia after furosemide were also absent in the lowest sGFR stratum. These data demonstrate relative stability of renal oxygenation with moderate reductions in RBF and GFR but identify a transition to overt hypoxia and inflammatory cytokine release with severely reduced GFR. Tissue oxygenation and RBF were less correlated in the setting of reduced sGFR, consistent with variable oxygen consumption or a shift to alternative mechanisms of tissue injury. Identifying transitions in tissue oxygenation may facilitate targeted therapy in ARVD.

Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis.

Background: The aim of this meta-analysis was to assess the risks and incidence of nephrotoxicity and electrolyte abnormalities in patients receiving programmed cell death protein 1 (PD-1) inhibitors. Methods: We conducted a meta-analysis of clinical trials that monitored electrolyte levels and kidney functions during treatment with nivolumab or pembrolizumab by searching MEDLINE, EMBASE and the Cochrane Database from inception through April 2017. Our protocol is registered with International Prospective Register of Systematic Reviews; no.CRD42017060579. Results: A total of 48 clinical trials with a total of 11 482 patients were included. The overall pooled risk ratios (RR) of all acute kidney injury (AKI) and all electrolyte abnormalities in patients treated with PD-1 inhibitors were 1.86 [95% confidence interval (CI) 0.95-3.64] and 1.67 (95% CI 0.89-3.12), respectively. Compared with non-nephrotoxic controls, the pooled RR of AKI in patients treated with PD-1 inhibitors was 4.19 (95% CI 1.57-11.18). Prespecified subgroup analyses demonstrated a significant association between PD-1 inhibitors and hypocalcemia with a pooled RR of 10.87 (95% CI 1.40-84.16). The pooled estimated incidence rates of AKI and hypocalcemia in patients treated with PD-1 inhibitors were 2.2% (95% CI 1.5-3.0%) and 1.0% (95% CI 0.6-1.8%), respectively. Among patients who developed AKI with PD-1 inhibitors, the pooled estimated rate of interstitial nephritis was 16.6% (95% CI 10.2-26.0%). Conclusions: Treatment with PD-1 inhibitors is associated with a higher risk of AKI compared with non-nephrotoxic agents. It will be important to characterize the AKI patients to better understand the etiology behind the event. In addition, treatment with PD-1 inhibitors is associated with an increased risk of hypocalcemia. This study highlights a rare but serious adverse event of anti-PD-1 antibodies and we recommend, in addition to electrolytes panel, routine calcium monitoring.

Association between urologic malignancies and end-stage renal disease: A meta-analysis.

AIM: Previous studies have suggested a higher incidence of urologic malignancies in end-stage renal disease (ESRD) patients. However, incidence trends of urologic malignancies in ESRD patients remain unclear. The aims of the present study were: (i) to investigate the pooled incidence/incidence trends; and (ii) to assess the risk of urologic malignancies in ESRD patients. METHODS: A literature search was conducted using MEDLINE, EMBASE and Cochrane Database from inception through April 2017. Studies that reported incidence or odds ratios of urologic malignancies among ESRD patients were included. Pooled odds ratios (OR) and 95%CI were calculated using a random-effect model. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017067687). RESULTS: Nineteen observational studies with 1 931 073 ESRD patients were enrolled. The pooled estimated incidence of kidney cancer and urothelial cancers (carcinomas of the bladder, ureters, and renal pelvis) in ESRD patients were 0.3% (95%CI: 0.2-0.5%) and 0.5% (95%CI: 0.3-0.8%), respectively. Meta-regression showed significant positive correlation between incidence of urologic malignancies in ESRD patients and year of study (slopes = +0.05 and +0.07, P < 0.001 for kidney cancer and urothelial cancers, respectively). Compared to non-ESRD status, ESRD was significantly associated with both kidney cancer (pooled OR 6.04; 95% CI 4.70-7.77) and urothelial cancers (pooled OR 4.37; 95% CI 2.40-7.96). CONCLUSION: Our study demonstrates a significant association between ESRD and urologic malignancies. The overall estimated incidence rates of kidney cancer and urothelial cancers are 0.4% and 0.5%, respectively. There is a significant positive correlation between the incidence of urologic malignancies and year of study.

Total Renal Artery Occlusion: Recovery of Function After Revascularization.

Current trends in managing atherosclerotic renal artery stenosis favor medical therapy, on account of negative results from prospective trials of revascularization, such as CORAL and ASTRAL. One result of this trend has been encountering occasional patients with progressive disease, sometimes leading to total arterial occlusion. We illustrate a case of accelerated hypertension with complete renal artery occlusion in which the patient recovered function after surgical bypass and we review the clinical approach used and the advanced imaging modalities available to us. A high index of suspicion and careful radiologic imaging play important roles in selecting patients who may have residual function and may benefit from revascularization. This case illustrates an example whereby restoring renal artery perfusion for carefully selected patients can be life changing, with recovery of kidney function and improved blood pressure, pill burden, and overall quality of life.

Preserved endothelial progenitor cell angiogenic activity in African American essential hypertensive patients.

Background: African American (AA) subjects with essential hypertension (EH) have greater inflammation and cardiovascular complications than Caucasian EH. An impaired endogenous cellular repair system may exacerbate vascular injury in hypertension, yet whether these differ between AA EH and Caucasian EH remains unknown. Vascular repair by circulating endothelial progenitor cells (EPCs) is controlled by regulators of EPC mobilization, homing, adhesion and new vessel formation, but can be hindered by various cytokines. We hypothesized that EPC levels and function would be impaired in AA EH compared with Caucasian EH, in association with increased levels of inflammatory mediators and EPC regulators. Methods: CD34+/KDR+ EPCs were isolated from inferior vena cava and renal vein blood samples of AA EH and Caucasian EH patients (n = 18 each) and from peripheral veins of 17 healthy volunteers (HVs) and enumerated using fluorescence-activated cell sorting. Angiogenic function of late-outgrowth endothelial cells expanded from these samples for 3 weeks was tested in vitro. Levels of inflammatory mediators, angiogenic factors and EPC regulators were measured by Luminex. Results: EPC levels were decreased in both AA and Caucasian EH compared with HVs, whereas their late-outgrowth endothelial cell angiogenic function was comparable. Levels of several inflammatory mediators were elevated in AA EH compared with Caucasian EH and HVs. Contrarily, vascular endothelial growth factor and its receptor-2 were lower. EPC levels inversely correlated with blood pressure in all hypertensive patients and estimated glomerular filtration rate with inflammatory mediators only in AA EH. Conclusions: Despite lower EPC numbers, decreased vascular endothelial growth factor signaling and inflammation, EPC function is preserved in AA EH compared with Caucasian EH and HVs, suggesting compensatory mechanisms for vascular repair.

Autologous Mesenchymal Stem Cells Increase Cortical Perfusion in Renovascular Disease.

Atherosclerotic renovascular disease (RVD) reduces renal blood flow (RBF) and GFR and accelerates poststenotic kidney (STK) tissue injury. Preclinical studies indicate that mesenchymal stem cells (MSCs) can stimulate angiogenesis and modify immune function in experimental RVD. We assessed the safety and efficacy of adding intra-arterial autologous adipose-derived MSCs into STK to standardized medical treatment in human subjects without revascularization. The intervention group (n=14) received a single infusion of MSC (1.0 × 105 or 2.5 × 105 cells/kg; n=7 each) plus standardized medical treatment; the medical treatment only group (n=14) included subjects matched for age, kidney function, and stenosis severity. We measured cortical and medullary volumes, perfusion, and RBF using multidetector computed tomography. We assessed tissue oxygenation by blood oxygen level-dependent MRI and GFR by iothalamate clearance. MSC infusions were well tolerated. Three months after infusion, cortical perfusion and RBF rose in the STK (151.8-185.5 ml/min, P=0.01); contralateral kidney RBF increased (212.7-271.8 ml/min, P=0.01); and STK renal hypoxia (percentage of the whole kidney with R2*>30/s) decreased (12.1% [interquartile range, 3.3%-17.8%] to 6.8% [interquartile range, 1.8%-12.9%], P=0.04). No changes in RBF occurred in medical treatment only subjects. Single-kidney GFR remained stable after MSC but fell in the medical treatment only group (-3% versus -24%, P=0.04). This first-in-man dose-escalation study provides evidence of safety of intra-arterial infusion of autologous MSCs in patients with RVD. MSC infusion without main renal artery revascularization associated with increased renal tissue oxygenation and cortical blood flow.