The latest medical research on Transplant Nephrology
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Request AccessOral dysbiosis initiates periodontal disease in experimental kidney disease.
Nephrol Dial TransplantIt is presently unclear why there is a high prevalence of periodontal disease in individuals living with chronic kidney disease (CKD). Whilst some have argued that periodontal disease causes CKD, we hypothesised that alterations in saliva and the oral microenvironment in organisms with kidney disease may initiate periodontal disease by causing dysbiosis of the oral microbiota.
Experimental kidney disease was created using adenine feeding and subtotal nephrectomy in rats, and by adenine feeding in mice. Loss of periodontal bone height was assessed using a dissecting microscope supported by micro-CT, light, confocal and electron microscopy, and immunohistochemistry. Salivary biochemistry was assessed using NMR spectroscopy. The oral microbiome was evaluated using culture-based and molecular methods, and the transmissibility of dysbiosis was assessed using co-caging and microbial transfer experiments into previously germ-free recipient mice.
We demonstrate that experimental kidney disease causes a reproducible reduction of alveolar bone height, without gingival inflammation or overt hyperparathyroidism but with evidence of failure of bone formation at the periodontal crest. We show that kidney disease alters the biochemical composition of saliva and induces progressive dysbiosis of the oral microbiota, with microbial samples from animals with kidney disease displaying reduced overall bacterial growth, increased alpha diversity, reduced abundance of key components of the healthy oral microbiota such as Streptococcus and Rothia, and an increase in minor taxa including those from gram-negative phyla Proteobacteria and Bacteroidetes. Co-housing diseased rats with healthy ones ameliorates the periodontal disease phenotype, whilst transfer of oral microbiota from mice with kidney disease causes periodontal disease in germ-free animals with normal kidney function.
We advocate that periodontal disease should be regarded as a complication of kidney disease, initiated by oral dysbiosis through mechanisms independent of overt inflammation or hyperparathyroidism.
CD38 ligation in sepsis promotes nicotinamide phosphoribosyltransferase-mediated IL-6 production in kidney stromal cells.
Nephrol Dial TransplantActivated macrophages, pivotal for driving the immune response in sepsis, express high levels of CD38. Although the circulating levels of its ligand, CD31, increase in sepsis, the functions of CD38 and its ligation remain elusive. This study aimed to elucidate the impact of CD38 ligation on sepsis using single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq, respectively) to identify a novel therapeutic target for severe sepsis.
We performed scRNA-seq analysis of mouse peritoneal immune cells to precisely identify cell types exhibiting increased CD38 expression upon exposure to lipopolysaccharide (LPS). Subsequently, we induced CD38 ligation using a well-established agonistic anti-CD38 antibody in a mouse model of LPS-induced sepsis. We analyzed its pathophysiological effects using kidney snRNA-seq. Finally, we performed histological analysis of septic tissues collected from patients to ensure consistency of our findings between mice and humans.
LPS stimulation upregulated CD38 expression in peritoneal macrophages. CD38 ligation significantly exacerbated LPS-induced inflammation in vivo, particularly in the kidneys. Kidney snRNA-seq analysis revealed that CD38 ligation induced interleukin (IL)-6 production in renal stromal cells via nicotinamide phosphoribosyltransferase (NAMPT) signaling originating from CD38-positive macrophages. NAMPT inhibition significantly ameliorated LPS-induced IL-6 production and kidney injury. Histological analysis of human septic tissues demonstrated upregulation of IL6 mRNA and NAMPT in renal stromal cells and CD38-positive macrophages, respectively.
Our findings elucidate the implications of CD38 ligation in an LPS-induced sepsis model and uncover shared signaling pathways between mice and human sepsis. NAMPT signaling identified in this study may be a novel therapeutic target for mitigating systemic inflammation and kidney injury associated with severe sepsis.
Prophylactic 2-week Glecaprevir/Pibrentasvir in Hepatitis C positive to negative kidney transplantation.
Nephrol Dial TransplantHepatitis C virus (HCV) positive-to-negative kidney transplants (KT) require direct acting antiviral therapy, but the optimal timing and duration remain unclear. We hypothesized that 14-day prophylactic course of glecaprevir/pibrentasvir 300/120 mg (GLE/PIB) would be safe and effective at treating donor-derived HCV viremia.
This was a prospective, single-center, single-arm, open-label pilot study. 20 adult HCV negative recipients of HCV nucleic acid amplification test positive deceased-donor kidneys (HCV positive-to-negative) received a 14-day course of GLE/PIB, with the first dose pre-transplant. HCV RNA viral loads (VL) were monitored on post-operative days (POD) 1, 3, 7, and 13. If VL was undetectable on POD 13, GLE/PIB was stopped, and if detectable, GLE/PIB was continued to complete an 8-week course. Surveillance monitoring continued after treatment to ensure sustained viral response (SVR). The primary outcome was efficacy of 14-day prophylactic GLE/PIB. Secondary outcomes included patient and allograft survival, the incidence, timing, and clearance of HCV viremia, and safety events.
7/20 subjects (35%) never developed detectable HCV viremia. Only one subject had a detectable, but nonquantifiable, VL on POD 13 and completed an 8-week course. All subjects achieved SVR 12 weeks post-treatment with no relapses through 1-year follow-up. Mean time to undetectable HCV RNA VL was 10.5 (±4.7) days and mean peak VL was 371 (±715) copies/mL. 6-month and 1-year patient and allograft survival were 100% and 95%.
A 14-day course of prophylactic GLE/PIB is safe and effective for HCV positive-to-negative KT and may prevent HCV transmission or significantly reduce the VL for those with detectable transmission allowing for rapid clearance within 2 weeks.
The uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) may enhance eryptosis and increase erythrocyte osmotic fragility through potential activation of Piezo1.
Nephrol Dial TransplantIn patients with advanced chronic kidney disease (CKD), the lifespan of red blood cells (RBC) is often shortened, a condition attributed to the "uremic milieu." We reported recently that the uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) shares structural similarities with Jedi1, a chemical activator of the mechanosensitive cation channel Piezo1, whose activation increases calcium influx into cells. Against this backdrop, we hypothesized that CMPF may induce premature RBC death (eryptosis) through prolonged CMPF-induced activation of Piezo1 located on RBC. To test this hypothesis, we explored if CMPF, at concentrations found in uremia, interacts with Piezo1 located on RBC, increases intracellular calcium (icCa2+), and induces eryptosis.
RBC from healthy individuals were incubated with CMPF or Jedi1 (both at a concentration of 87 µM), in the presence or absence of the Piezo1 inhibitor GsMTx-4 (2 µM). We challenged RBC osmotically through incubation in solutions of NaCl at concentrations between 3.0 and 9.0 g/L and determined their osmotic fragility. Using flow cytometry, we quantified in incubated RBC icCa2+ levels and phosphatidylserine exposure, a cellular marker of eryptosis.
Incubation of RBC with CMPF and Jedi1 significantly increased RBC osmotic fragility, an effect prevented by GsMTx-4. At 6.0 g/L NaCl, incubation with CMPF and Jedi1 increased exposure of phosphatidylserine and elevated icCa2+ levels of RBC, indicating increased eryptosis. Notably, at an isotonic NaCl concentration of 9.0 g/L, CMPF - but not Jedi1 - significantly increased RBC phosphatidylserine exposure and icCa2+ levels; both effects were diminished by GsMTx-4.
Our findings support the hypothesis that CMPF may function as an endogenous activator of Piezo1, increase icCa2+ levels, trigger eryptosis, and, through this pathway, possibly shorten the RBC life span. To what extent these in vitro findings are operative in advanced CKD warrants clinical studies.
Genetic testing in a national cohort of adults with chronic kidney disease of unknown origin.
Nephrol Dial TransplantChronic kidney disease (CKD) remains unexplained in at least 20% of patients. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, but prospective data from routine clinical practice are limited. We aimed to determine the diagnostic yield and relevance of MPS-based gene panel testing in patients with unexplained CKD in a real-world context. We additionally examined barriers to implementation of genetic testing.
In this prospective cohort study, we recruited patients with unexplained CKD (eGFR <60mL/min/1.73 m2 without underlying clinical diagnosis) with onset <50 years who underwent MPS-based multi-gene panel testing from 11 academic and non-academic hospitals across the Netherlands. In patients with a (likely) pathogenic variant, we verified that the variant likely explained the clinical phenotype. A nationwide online survey was sent out to all Dutch nephrologists and residents to investigate potential barriers for gene panel testing.
A diagnostic variant was identified in 59/340 participants (17%). Most common diagnostic variants were in NPHP1 (13 patients), COL4A3 (12 patients), COL4A4 (5 patients), COL4A5 (6 patients), and PAX2 (5 patients). A genetic diagnosis led to at least one clinical consequence in 73% of patients. Main barriers reported by Dutch nephrologists (N=71) included genetic illiteracy (53%), difficulties with test selection (51%), and lack of time (43%).
MPS-based multi-gene panel testing yielded a genetic diagnosis in 17% of patients with unexplained CKD. Our findings support the relevance of MPS in the diagnostic workup of adults with unexplained CKD with onset <50 years. Additionally, our results underline the need to improve genetic education among nephrologists to better the implementation of MPS-based diagnostic testing in clinical practice.
Long-term outcomes of IgA nephropathy in China.
Nephrol Dial TransplantThe long-term prognosis of IgA nephropathy (IgAN) and the optimal target for proteinuria treatment remain controversial. This study, utilizing a large prospective cohort from China, aims to assess the long-term outcomes of IgAN and to explore the definition of proteinuria remission.
We enrolled 2 141 patients with biopsy-proven IgAN, all with at least 12 months of follow-up, from a prospective IgAN cohort at Peking University First Hospital. We utilized Kaplan-Meier analysis, Cox regression, and an eGFR slope calculated via a linear mixed model to investigate kidney outcomes.
The median (Q1, Q3) baseline proteinuria was 1.26 (0.65, 2.40) g/d, and the estimated GFR was 80 (52, 103) mL/min/1.73m2. After a mean follow-up of 5.8 (±4.4) years, 509 (24%) patients progressed to end-stage kidney disease (ESKD). The median kidney survival time was 12.4 years, the annual event rate of ESKD was 41.1 per 1000 person-years, and the 15-year kidney survival rate was 40%. Time-averaged proteinuria level was strongly associated with kidney failure (adjusted HR: 1.76, 95%CI: 1.65 to 1.88). Restriction cubic spline analysis indicated that the risk of ESKD increases rapidly when time-average proteinuria exceeded 0.5 g/d. There was no significant difference in long-term kidney survival between patients with proteinuria < 0.3 g/d and those with 0.3-0.5 g/d, with both groups demonstrating a better prognosis.
The long-term outcomes for patients with IgAN under current treatment strategies remain poor, with most progressing to ESKD within 15 years. Patients with time-averaged proteinuria ≥ 0.5 g/d experience worse kidney outcomes, challenging the previous view that proteinuria < 1.0 g/d was associated with a low risk of kidney failure.
Smoking cessation and atherosclerotic cardiovascular events and mortality in chronic kidney disease.
Nephrol Dial TransplantSmoking cessation is recommended to reduce excess atherosclerotic cardiovascular disease (ASCVD) and mortality in patients with chronic kidney disease (CKD). However, this recommendation is largely based on observational studies on the general population Therefore, we aimed to evaluate the association of smoking dose and smoking cessation duration with ASCVD and mortality in patients with CKD.
We compiled a comprehensive pooled dataset comprising 66 245 participants with CKD from the KNOW-CKD and the UK Biobank cohort. Additionally, we included 307 353 participants without CKD from the UK Biobank cohort. Participants were categorized according to smoking dose and duration of smoking cessation base on a questionnaire. The primary outcome was a composite of ASCVD events or all-cause mortality.
Over a median follow-up period of 13.2 years, 14 671 (22.1%) participants reached the primary outcome. In the pooled CKD cohort, compared to never smokers, former and current smokers exhibited a 1.30- and 2.14-fold higher risk of the primary outcome, respectively. Among former smokers, the hazard ratios (HRs) (95% confidence intervals [CIs]) for smoking loads < 20 and ≥ 20 pack-years were 1.05 (1.00-1.10) and 2.14 (2.05-2.25), respectively. The increased risk of the primary outcome was attenuated by longer smoking cessation. The HRs (95% CIs) for smoking cessation of < 10 years, 10-20 years, and ≥ 20 years were 1.75 (1.65-1.86), 1.43 (1.34-1.52), and 1.11 (1.06-1.16), respectively, compared with never smokers. This association was also observed in individuals without CKD, but the risk was comparable between former smokers with smoking cessation ≥ 20 years and non-smokers, suggesting that a longer cessation is required in patients with CKD to offset the smoking-related adverse effects.
Among former smokers with CKD, the risk of ASCVD or mortality was substantially attenuated with less smoking load and a longer duration of smoking cessation.
Acquired and genetic determinants of disease phenotype and therapeutic strategies in C3 glomerulopathy and immunoglobulin-associated MPGN.
Nephrol Dial TransplantC3 glomerulopathy (C3G), a prototype of complement mediated disease, is characterized by significant heterogeneity, not only in terms of clinical, ...
Acquired and genetic drivers of C3 and C5 convertase dysregulation in C3 glomerulopathy and immunoglobulin-associated MPGN.
Nephrol Dial TransplantDysregulation of the alternative pathway of complement plays a central role in the pathophysiology of C3 Glomerulopathy (C3G). Various autoimmune a...
Physical activity and cardiorenal health - from associations to interventional studies.
Nephrol Dial TransplantClustering of traditional and kidney-specific risk factors leads to elevated cardiovascular disease (CVD) risk across the trajectory of chronic kid...
Inherited kidney disease and CAKUT are common causes of kidney failure requiring kidney replacement therapy: an ERA Registry study.
Nephrol Dial TransplantInherited kidney diseases (IKD) and congenital anomalies of the kidney and urinary tract (CAKUT) are causes of kidney failure requiring kidney replacement therapy (KRT) that major renal registries usually amalgamate into the primary renal disease (PRD) category 'miscellaneous' or in the glomerulonephritis or pyelonephritis categories. This makes IKDs invisible (except for polycystic kidney disease) and may negatively influence the use of genetic testing, which may identify a cause for IKDs and some CAKUT.
We have re-examined the etiology of KRT by composing a separate IKD and CAKUT PRD group using data from the European Renal Association (ERA) Registry.
In 2019, IKD-CAKUT was the fourth most common cause of kidney failure among incident KRT patients, accounting for 8.9% of cases (IKD 7.4% [including 5.0% ADPKD], CAKUT 1.5%), behind diabetes (23.0%), hypertension (14.4%) and glomerulonephritis (10.6%). IKD-CAKUT was the most common cause of kidney failure among patients younger than 20 years (41.0% of cases), but their incidence rate was highest among those aged 45-74 years (22.5 per million age-related population). Among prevalent KRT patients, IKD-CAKUT (18.5%) and glomerulonephritis (18.7%) were the two most common causes of kidney failure overall, while IKD-CAKUT was the most common cause in women (21.6%) and in patients younger than 45 years (29.1%).
IKD and CAKUT are common causes of kidney failure among KRT patients. Distinct categorization of IKD and CAKUT better characterizes the epidemiology of the causes of chronic kidney disease, and highlights the importance of genetic testing in the diagnostic workup of CKD.
Mineralocorticoid receptor antagonism attenuates arteriovenous fistula stenosis by modulating the phenotype of vascular smooth muscle cells.
Nephrol Dial TransplantFistula stenosis is a primary contributor to arteriovenous fistula (AVF) failure in maintenance hemodialysis patients. Emerging data indicated excessive fibrotic remodeling was the primarily contributor to fistula stenosis during AVF remodeling. The mineralocorticoid receptor (MR) has been implicated in vascular remodeling across various cardiovascular pathologies. However, its role in AVF remodeling, particularly concerning fibrotic remodeling, remains elusive.
MR expression and the phenotypes of vascular smooth muscle cells (VSMCs) were assessed in dysfunctional AVF. The effects of MR on VSMC phenotypic switching were examined in vitro, and the protective effects of MR antagonists on AVF outcome were evaluated in a rat AVF model.
Dysfunctional fistula exhibited significant medial fibrosis and extracellular matrix deposition, alongside markedly increased MR activity. In the dysfunctional fistula vessels, VSMC displayed reduced expression of the contractile marker SMMHC and featured characteristic of a synthetic phenotype, including increased osteopontin expression and heightened proliferation. In vitro studies with cultured VSMC revealed that MR overactivity induced by aldosterone led to phenotypic switching from contractile to synthetic state, concomitant with EGFR-ERK1/2 pathway overactivation. These effects were largely abolished by the MR antagonist fineronone. Knockdown of EGFR expression abrogated ERK1/2 phosphorylation and inhibited the VSMC phenotypic switching. Conversely, ectopic overexpression of EGFR in VSMC diminished the protective effect of finerenone. In rat AVF models, pharmacologic targeting of MR with finerenone significantly improved AVF outcomes, characterized by increased luminal diameters and flow volume, reduced medial fibrosis, and inhibited VSMC phenotypic switching. These beneficial outcomes were likely attributable to a restrained activity of EGFR-ERK1/2 pathway in VSMC and elevated NO production in endothelial cells.
Our study demonstrated that therapeutic targeting of MR may improve AVF outcome by modulating VSMC phenotypic switching. These findings offer promising avenues for further clinical investigations aimed at optimizing AVF outcomes in the hemodialysis population.
