Mechanisms Of Chronic Kidney Disease Research Articles

#2985 Gut microbiome-dependent systemic alterations in experimental chronic kidney disease

Abstract Background and Aims Patients diagnosed with Chronic Kidney Disease (CKD) undergo a notable decline in both quality of life and life expectancy, primarily attributable to the heightened prevalence of cardiovascular diseases (CVD). These conditions not only contribute to the initiation of CKD but are also a consequence of inflammation associated with CKD. Despite optimal kidney replacement therapies, irreversible alterations of the CV system may persist. The responsible mechanisms in CKD leading to CVD are incompletely understood. CKD is characterized by gut microbial dysbiosis, with a significant proportion of uremic toxins suspected to have microbial origin. We hypothesize that the gut microbiota promotes inflammation and CV risk in states of impaired kidney function. Method Experimental CKD was induced in 129sv mice by 5/6 nephrectomy. Prior to nephrectomy, mice were assigned to receive either glucose (Ctrl) or a non-absorptive antibiotic cocktail (comprising Ampicillin, Metronidazole, Neomycin, and Vancomycin, Abx) via the drinking water to deplete their microbiomes throughout the 13-week study period. Ctrl and Abx-treated Sham-operated mice served as controls. Plasma, feces, and urine specimens were systematically collected at diverse time intervals, facilitating the longitudinal exploration of metabolite dynamics and CKD progression through an untargeted Nuclear Magnetic Resonance (NMR) approach. Simultaneously, echocardiography assessments were conducted at identical time points to assess cardiac function. Results Abx-treated CKD mice displayed improved kidney function, demonstrated by significantly reduced levels of plasma Cystatin C (0.2913 ± 0.1850 mg/L) compared to Ctrl (0.9133 ± 0.6616 mg/L)(p = 0.0256). Hearts from Abx-treated CKD mice exhibited significantly less remodeling, independent of their blood pressure (radiotelemetry measurements). The ratio of left ventricular (LV) mass to tibia length was 4.858 ± 0.3453 in the Abx-treated group compared to Ctrl (8.198 ± 0.3542) (p < 0.0001). Sirius red stained hearts revealed significantly less fibrosis in Abx-treated CKD mice (5.784 ± 5.465%) compared to Ctrl (11.98 ± 3.741%) (p = 0.0218). The cardiac expression of several damage-associated genes (Npbb, Ctgf, and Ngal) portrayed the same trend. To elucidate the interplay between the microbiome and the immune system underlying these observed effects, we provide a comprehensive atlas of the immune landscape in different organs (blood, spleen, heart, intestine), along with a catalogue of gut-derived metabolites, shedding light on the systemic alterations induced by microbiome-dependent mechanisms in CKD. Conclusion Our findings suggest that microbiome-dependent mechanisms drive kidney function decline and cardiac remodeling in experimental CKD. These results underscore the interplay between microbial alterations, metabolite dynamics, immune response, and cardiovascular complications in the context of CKD.

Effect of Executive Function on Health-Related Quality of Life in Children with Chronic Kidney Disease.

As the highest function in the brain that regulates our daily activity, executive dysfunction might affect someone's health-related quality of life (HRQoL), especially in those with chronic diseases, including chronic kidney disease (CKD). Neurocognitive functions, including intelligence quotient (IQ) and executive function can be affected through various mechanisms in CKD. However, there was still no specific study regarding how IQ and executive function might affect HRQoL in children with CKD. To assess Executive Function's impact on HRQoL and to find association between treatment modalities and CKD stages with HRQoL in children with CKD. A cross sectional study was conducted at Pediatric Nephrology Clinic at Hasan Sadikin General Hospital, Bandung, Indonesia from September 2022 to April 2023. We included 38 children whose age range were 6-16 years 11 months old with CKD stage III - V. Assessment tools used were: BRIEF questionnaire for executive function; WISC III tool for IQ; PedsQLTM questionnaire generic module for HRQoL. Data was analyzed using SPSS ver. 26.0. Total number of samples was 38. Complete examinations were done on 30 patients. Eight other patients did not undergo the IQ test. There was a negative correlation between executive function components scores (GEC, BRI, MI) with HRQoL scores on parents' proxy in all domains. We found no correlation between HRQoL and IQ scores, but we found a correlation between IQ and CKD stage. There was a significant difference in HRQoL from the children's perspective among the three modalities; children who underwent conservative treatment were having the best HRQoL scores. Interventions to improve executive function of children with CKD should be done to improve their HRQoL in the future. Early diagnosis and treatment of CKD should be done at the earliest to improve neurocognitive function and HRQoL.

Emerging Preventive Strategies in Chronic Kidney Disease: Recent Evidence and Gaps in Knowledge.

Chronic kidney disease (CKD) is increasingly prevalent worldwide and is associated with increased cardiovascular risk. New therapeutic options to slow CKD progression and reduce cardiovascular morbidity and mortality have recently emerged. This review highlights recent evidence and gaps in knowledge in emerging CKD preventive strategies. EMPA-Kidney trial found that empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i) led to 28% lower risk of progression of kidney disease or death from cardiovascular causes, compared to placebo. This reinforced the previous findings from DAPA-CKD and CREDENCE trials and led to inclusion of SGLT2i as the cornerstone of CKD preventive therapy in both diabetic and non-diabetic CKD. Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, slowed diabetic kidney disease progression by 23% compared to placebo in a pool analysis of FIDELIO-DKD and FIGARO-DKD trials. Non-pharmacological interventions, including low protein diet, and early CKD detection and risk stratification strategies based on novel biomarkers have also gained momentum. Ongoing efforts to explore the wealth of molecular mechanisms in CKD, added to integrative omics modeling are well posed to lead to novel therapeutic targets in kidney care. While breakthrough pharmacological interventions continue to improve outcomes in CKD, the heterogeneity of kidney diseases warrants additional investigation. Further research into specific kidney disease mechanisms will facilitate the identification of patient populations most likely to benefit from targeted interventions.

The efficacy and safety of sacubitril/valsartan in chronic kidney disease: a systematic review and meta-analysis.

Sacubitril/valsartan, a new pharmacological class of angiotensin receptor neprilysin inhibitor, is beneficial to heart failure through blocking the degradation of natriuretic peptides and inhibiting renin-angiotensin-aldosterone system (RAAS) activation which also relate to the pathophysiologic mechanisms of chronic kidney disease (CKD). However, its effects on CKD remain unclear. To assess the efficacy and safety of sacubitril/valsartan for patients with CKD, we performed this meta-analysis. The Embase, PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sacubitril/valsartan with ACEI/ARBs in patients with CKD whose estimated glomerular filtration rate (eGFR) was below 60mL/min/1.73m2. We adopted the Cochrane Collaboration tool for assessing the risk of bias. The effect size was estimated using the odds ratio (OR) with 95% confidence interval (CI). Six trials with a total of 6217 patients with CKD were included. In terms of cardiovascular events, sacubitril/valsartan attenuated the risk of cardiovascular death or heart failure hospitalization (OR: 0.68, 95% CI 0.61-0.76, P < 0.00001, I2 = 43%). With respect to renal function, sacubitril/valsartan prevented the incidence of serum creatinine (Scr) elevation among patients with CKD (OR: 0.79, 95% CI 0.67-0.95, P = 0.01, I2 = 0%). Subgroup analysis about eGFR demonstrated that with long follow-up, sacubitril/valsartan significantly decreased the number of patients with more than 50% reduction in eGFR compared with ACEI/ARBs (OR: 0.52, 95% CI 0.32-0.84, P = 0.008, I2 = 9%). In patients with CKD, the incidence of end-stage renal disease (ESRD) was reduced with sacubitril/valsartan treatment, despite no statistically significant difference between the two groups (OR: 0.59, 95% CI 0.29-1.20, P = 0.14, I2 = 0%). As for the safety, we found that sacubitril/valsartan was associated with the occurrence of hypotension (OR: 1.71, 95% CI 1.15-2.56, P = 0.008, I2 = 51%). However, there was no trend towards increasing the risk of hyperkalemia in patients who received sacubitril/valsartan (OR: 1.09, 95% CI 0.75-1.60, P = 0.64, I2 = 64%). This meta-analysis indicated that sacubitril/valsartan improved renal function and conferred effective cardiovascular benefits in patients with CKD, without serious safety issues being observed. Thus, sacubitril/valsartan may be a promising option for patients with CKD. Certainly, further large-scale randomized controlled trials are needed to confirm these conclusions. [ https://inplasy.com/inplasy-2022-4-0045/ ], identifier [INPLASY202240045].

Induction of macrophages matriptase and activation of macrophage stimulating protein 1 in sickle cell anemia - related chronic kidney disease

BACKGROUND: More than 50% of sickle cell anemia (SCA) patients develop chronic kidney disease (CKD). The mechanism of CKD is multifactorial and is not yet fully understood. SCA is a vasculopathy associated with multiple mechanisms driven by cell-free mutated hemoglobin (HbS). We have demonstrated that activation of recepteur d'origine nantais (RON) kinase contributes to the renal endothelial injury in SCA mouse model. Inhibition of RON reduces endothelial injury and ameliorates renal disease. Macrophage-stimulating protein 1 (MSP1) is the only known ligand for RON. MSP1 is synthesized by the liver and released in the circulation as biologically inactive pro-MSP1 protein that is activated by proteolytic cleavage. Macrophage membrane matriptase (MT-SP1) cleaves MSP1, making it able to bind RON receptor. The levels of plasma MSP1 and macrophage MT-SP1 in SCA have not been investigated. OBJECTIVES: To evaluate MT-SP1 expression and serum MSP1 levels in SCA patients and mouse model. HYPOTHESIS: The level of circulating MSP1 is reduced in SCA patients and mice due to its accumulation in organs. METHODS: The study was approved by Howard University IRB.All subjects provided written informed consent. Whole blood samples were obtained from 44 SCA patients enrolled at HU CSCD Registry study and 6 healthy control individuals. SCA mice (Townes) were housed in Howard University; the animal protocol was approved by the IACUC. ELISA kits were used to test human and mouse MSP1. Human THP-1 promonocytic cells were differentiated into macrophages with 25 nM PMA for 72 hrs and treated with either purified HbS or HbA (5 μM). Total RNA was used for RNA Seq. Comparisons were conducted using Dragen differential expression software v. 3.6.3 (Illumina), and gene counts were normalized using DESeq2 package from Bioconductor. RESULTS: RNA Seq results demonstrated increased levels of MT-SP1 in THP-1-derived macrophages after treatment with HbS compared to treatment with normal hemoglobin (HbA) (p=0.036). The results were further confirmed by real-time RT-PCR. The levels of plasma MSP1 were about 7-fold lower in SCD patients compared to non-SCD controls (146.8±111.7 ng/ml, N=6 in control vs. 20.6 ng/ml, N=44 in SCD, p=3.97x10-10). Log2 (MSP1) slightly correlated with albuminuria log2 (ALB/CRE) (r=0.1243, R2=0.0154, p=0.4216, N=44). This correlation was more profound in females (r=0.3158, R2=0.0997, p=0.1632, N=21). No correlation was found in males. We found moderate inverted correlation between eGFR and log2 (MSP1) (r=-0.3313, R2=0.1094, p=0.0280, N=44). In SCA patients with renal disease, MSP1 levels positively correlated with stages of CKD (r=0.3990, R2=0.1592, p=0.0320, N=29). In mouse, serum MSP1 levels were about 2.3-fold reduced in SCA compared to control mice (441.0±97.98 ng/ml, N=5 in control vs. 192.2 ±27.02, N=7 in SCD, p=0.0173). Immunostaining demonstrated the high levels of MSP1 accumulation on the surface of endothelial cells in the ki This work was supported by NIH Research Grants SC1HL150685, P50HL118006, R01HL125005, and G12MD007597. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sarcopenia in chronic kidney disease: from bench to bedside.

Sarcopenia is a condition characterized by a loss of muscle mass and function. In chronic kidney disease (CKD), where a chronic catabolic state exists, sarcopenia commonly occurs through various mechanisms, resulting in muscle wasting and decreased muscle endurance. Sarcopenic patients with CKD have high morbidity and mortality rates. Indeed, the prevention and treatment of sarcopenia are mandatory. An imbalance between protein synthesis and degradation in muscle and increased oxidative stress and inflammation persist in CKD and induce muscle wasting. In addition, uremic toxins negatively affect muscle maintenance. A variety of potential therapeutic drugs targeting these muscle-wasting mechanisms in CKD have been investigated, but most of the trials focused on aged patients without CKD, and none of these drugs have been approved for the treatment of sarcopenia so far. Further studies on the molecular mechanisms of sarcopenia in CKD and targets for potential therapeutics are needed to improve the outcomes of sarcopenic patients with CKD.

Exercise and chronic kidney disease: potential mechanisms underlying the physiological benefits.

Increasing evidence indicates that exercise has beneficial effects on chronic inflammation, cardiorespiratory function, muscle and bone strength and metabolic markers in adults with chronic kidney disease (CKD), kidney failure or kidney transplants. However, the mechanisms that underlie these benefits have received little attention, and the available clinical evidence is mainly from small, short-duration (<12 weeks) exercise intervention studies. The available data, mainly from patients with CKD or on dialysis, suggest that exercise-mediated shifts towards a less inflammatory immune cell profile, enhanced activity of the NRF2 pathway and reduced monocyte infiltration into adipose tissue may underlie improvements in inflammatory biomarkers. Exercise-mediated increases in nitric oxide release and bioavailability, reduced angiotensin II accumulation in the heart, left ventricular remodelling and reductions in myocardial fibrosis may contribute to improvements in left ventricular hypertrophy. Exercise stimulates an anabolic response in skeletal muscle in CKD, but increases in mitochondrial mass and satellite cell activation seem to be impaired in this population. Exercise-mediated activation of the canonical wnt pathway may lead to bone formation and improvements in the levels of the bone-derived hormones klotho and fibroblast growth factor 23 (FGF23). Longer duration studies with larger sample sizes are needed to confirm these mechanisms in CKD, kidney failure and kidney transplant populations and provide evidence for targeted exercise interventions.

Differences in susceptibility to ADR nephropathy among C57BL/6 substrains.

Adriamycin (ADR) nephropathy is the most widely used nephropathy model to study the pathophysiological mechanisms of chronic kidney disease (CKD) in mice. However, its application is limited to a few mouse strains such as the BALB/c strain; the standard strain, C57BL/6J (B6J), does not develop ADR nephropathy. Nevertheless, Arif et al. reported that C57BL/6N (B6N), another standard strain, is ADR-susceptible. Since then, no follow-up reports or other studies have been published on ADR nephropathy in B6N mice. Therefore, the goal of this study was to determine whether B6N mice are indeed susceptible to ADR nephropathy and whether there are differences in ADR susceptibility among the substrains of C57BL/6NCrl (NCrl) and C57BL/6NJcl (NJcl). NCrl mice showed marked albuminuria and mesangial cell proliferation, which are associated with mild ADR nephropathy, confirming that NCrl mice were susceptible to ADR nephropathy. On the other hand, NJcl mice did not exhibit these symptoms. ADR nephropathy models are usually generated by administering ADR through the tail vein, but Arif et al. administered ADR through the orbital vein. Therefore, we investigated the effect of the route of administration on ADR nephropathy. The degree of ADR nephropathy was found to vary based on the route of administration: more severe nephropathy was observed upon administration through the tail vein than through the orbital vein. Therefore, we conclude that NCrl mice are susceptible to ADR nephropathy, and the severity of ADR-induced nephropathy through orbital vein administration is relatively lower than that through the tail vein.

TGF-β Inhibitors for Therapeutic Management of Kidney Fibrosis.

Kidney fibrosis is a common pathophysiological mechanism of chronic kidney disease (CKD) progression caused by several underlying kidney diseases. Among various contributors to kidney fibrosis, transforming growth factor-β1 (TGF-β1) is the major factor driving fibrosis. TGF-β1 exerts its profibrotic attributes via the activation of canonical and non-canonical signaling pathways, which induce proliferation and activation of myofibroblasts and subsequent accumulation of extracellular matrix. Over the past few decades, studies have determined the TGF-β1 signaling pathway inhibitors and evaluated whether they could ameliorate the progression of CKD by hindering kidney fibrosis. However, therapeutic strategies that block TGF-β1 signaling have usually demonstrated unsatisfactory results. Herein, we discuss the therapeutic concepts of the TGF-β1 signaling pathway and its inhibitors and review the current state of the art regarding regarding TGF-β1 inhibitors in CKD management.

The potential mechanisms of cardiovascular calcification in patients with chronic kidney disease

Based on current literature data, the important potential role of calciprotein particles, matrix vesicles, and extracellular matrix degradation in cardiovascular calcification mechanisms in chronic kidney disease (CKD) can be confirmed. The involvement of advanced glycation end products, insulin resistance, microRNAs, iron metabolism disorders, fluid overload, and hemodialysis treatment in these processes is discussed. It was concluded that the above potential mechanisms of ectopic calcification, which are being actively explored, are directly or indirectly related to endothelial damage/dysfunction and metabolic disturbances in the nitric oxide system. It was concluded that further thorough scientific investigations and close collaboration between clinical and experimental nephrologists are useful to optimize programs for the early detection of cardiovascular calcification, develop new effective therapeutic strategies, and improve the prognosis of CKD patients.

New Insights into Molecular Mechanisms of Chronic Kidney Disease.

Chronic kidney disease (CKD) is a major public health problem with a developing incidence and prevalence. As a consequence of the growing number of patients diagnosed with renal dysfunction leading to the development of CKD, it is particularly important to explain the mechanisms of its underlying causes. In our paper, we discuss the molecular mechanisms of the development and progression of CKD, focusing on oxidative stress, the role of the immune system, neutrophil gelatinase-associated lipocalin, and matrix metalloproteinases. Moreover, growing evidence shows the importance of the role of the gut-kidney axis in the maintenance of normal homeostasis and of the dysregulation of this axis in CKD. Further, we discuss the therapeutic potential and highlight the future research directions for the therapeutic targeting of CKD. However, additional investigation is crucial to improve our knowledge of CKD progression and, more importantly, accelerate basic research to improve our understanding of the mechanism of pathophysiology.

Mechanisms in Chronic Kidney Disease and Associated Cardiovascular Remodeling Contributes to the Progression of Cognitive Impairment in Women

IntroductionIn end‐stage chronic kidney disease (CKD) (stages 4‐5) the prevalence of cognitive impairment (CI) has been estimated at 30‐60%, twice the values observed in age‐ and sex‐matched controls. CKD is greater in females vs. males due to a higher risk of renal infections, especially during the pregnancy, which may result in the renal complications later in life, when the level of protective estrogen declines. Cardiovascular diseases (CVD) including hypertension and increased central arterial stiffness (CAS) accompany CKD development across all stages of this disease. CAS drives pulse pressure (PP) and pulsatile component index (PCI) increases and cerebral microvascular damage resulting in a reduction of blood supply to the brain hereby contributing to CI. Elevated PP and PCI are associated with higher mortality in CVD and CKD independently of BP. Moreover, PP is a cardiovascular risk factor independent on PCI in women &gt;55 years.HypothesisThe aim of the study was to determine whether CKD potentiates development of CI due to cardiovascular remodeling and whether CI in CKD is more pronounced in women. Furthermore, this study also aimed to determine whether reduced estrogen levels in older women with CKD contribute to the progression of CI.MethodsAll research was performed in accordance with the guidelines and regulations set forth by the Declaration of Helsinki regarding the use and enrollment of human subjects in research. A total of 26 female CKD patients (age 45‐50 years and older, CKD stage 4, GFR 15‐29, and Creatinine &gt; 1mg/dL) and 30 age and sex‐ matched healthy control patients were enrolled with exclusion criteria (history of HIV, hepatitis, malignancies, admission and/or surgery for trauma, head injury and pregnancy at time of enrollment). Blood pressure (systolic and diastolic blood pressure (SBP, DBP) was measured, clinical blood work, echocardiography (ECHO) and mini‐mental state examination (MMSE) was performed as well as levels of amyloid beta‐40 (Aβ‐40) measured. PCI was calculated as difference between peak systolic and end diastolic flow velocity, divided by the flow velocity. Estrogen levels were measured in the plasma samples. The data were analyzed by unpaired two‐tailed t‐test and Pearson correlation with P values adjusted for false discovery rate.ResultsCKD patients had higher SBP, PP, PCI, LV systolic and diastolic volume (estimated by ECHO), lower LV ejection fraction, higher plasma NT‐proBNP and AST (CVD markers), glucose, triglycerides, plasma Aβ‐40 (Alzheimer’s disease marker), BUN and creatinine (CKD markers) and lower score in MMSE vs. healthy control (p&lt;0.05). Plasma estrogen levels were significantly lower in CKD patients which correlated with the cognitive test scores and the renal function. Cognitive test results positively correlated with LV stroke volume, negatively correlated with PCI, a measurement of pulsatility of blood pressure, and negatively correlated with plasma ASP, a marker of CVD.ConclusionHigher PP, PCI, plasma Aβ‐40 and lower levels of estrogen and lower score in MMSE in female CKD patients supports our hypothesis that cardiovascular remodeling in women with CKD contributes to the development and progression of CI.

Relaxin inhibits renal fibrosis and the epithelial-to-mesenchymal transition via the Wnt/β-catenin signaling pathway

Renal fibrosis is a common characteristic and the final pathological mechanism of chronic kidney disease (CKD). Although CKD remains incurable, inhibition of renal fibrosis is beneficial to inhibit the CKD process. Relaxin alleviates renal fibrosis in some experimental models, but its mechanism remains unclear. In the following, we studied the regulatory effect of relaxin on epithelial-mesenchymal transition (EMT) after unilateral ureteral obstruction (UUO). Our results demonstrate that relaxin could downregulate Wnt/β-catenin signaling and decrease EMT, thus protecting against loss of transporters in tubular epithelial cells (TECs) and abrogate renal interstitial fibrosis following UUO. We confirmed that relaxin can downregulate Wnt/β-catenin signaling and decrease EMT in NRK52E, thus abrogating G2 cell cycle arrest in vitro experiments. Therefore, a novel mechanism by which relaxin is antifibrotic is that relaxin regulates the EMT program of TECs via Wnt/β-catenin signaling pathway. The inhibition of EMT contributes to protecting the functional capabilities of TECs and promoting the regeneration of TECs.

Olfactory receptors contribute to progression of kidney fibrosis

Olfactory receptors (ORs) which are mainly known as odor-sensors in the olfactory epithelium are shown to be expressed in several non-sensory tissues. Despite the specified role of some of these receptors in normal physiology of the kidney, little is known about their potential effect in renal disorders. In this study, using the holistic view of systems biology, it was determined that ORs are significantly changed during the progression of kidney fibrosis. For further validation, common differentially expressed ORs resulted from reanalysis of two time-course microarray datasets were selected for experimental evaluation in a validated murine model of unilateral ureteral obstruction (UUO). Transcriptional analysis by real-time quantitative polymerase chain reaction demonstrated considerable changes in the expression pattern of Olfr433, Olfr129, Olfr1393, Olfr161, and Olfr622 during the progression of kidney fibrosis. For localization of these ORs, single-cell RNA-sequencing datasets of normal and UUO mice were reanalyzed. Results showed that Olfr433 is highly expressed in macrophages in day-2 and 7 post-injury in UUO mice and not in normal subgroups. Besides, like previous findings, Olfr1393 was shown to be expressed prominently in the proximal tubular cells of the kidney. In conclusion, our combinatorial temporal approach to the underlying mechanisms of chronic kidney disease highlighted the potential role of ORs in progression of fibrosis. The expression of Olfr433 in the macrophages provides some clue about its relation to molecular mechanisms promoted in the fibrotic kidney. The proposed ORs in this study could be the subject of further functional assessments in the future.

Collecting Duct-Specific CR6-Interacting Factor-1-Deletion Aggravates Renal Inflammation and Fibrosis Induced by Unilateral Ureteral Obstruction.

Although inflammation and fibrosis, which are key mechanisms of chronic kidney disease, are associated with mitochondrial damage, little is known about the effects of mitochondrial damage on the collecting duct in renal inflammation and fibrosis. To generate collecting duct-specific mitochondrial injury mouse models, CR6-interacting factor-1 (CRIF1) flox/flox mice were bred with Hoxb7-Cre mice. We evaluated the phenotype of these mice. To evaluate the effects on unilateral ureteral obstruction (UUO)-induced renal injury, we divided the mice into the following four groups: a CRIF1flox/flox (wild-type (WT)) group, a CRIF1flox/flox-Hob7 Cre (CRIF1-KO) group, a WT-UUO group, and a CRIF1-KO UUO group. We evaluated the blood and urine chemistries, inflammatory and fibrosis markers, light microscopy, and electron microscopy of the kidneys. The inhibition of Crif1 mRNA in mIMCD cells reduced oxygen consumption and membrane potential. No significant differences in blood and urine chemistries were observed between WT and CRIF1-KO mice. In UUO mice, monocyte chemoattractant protein-1 and osteopontin expression, number of F4/80 positive cells, transforming growth factor-β and α-smooth muscle actin staining, and Masson’s trichrome staining were significantly higher in the kidneys of CRIF1-KO mice compared with the kidneys of WT mice. In sham mice, urinary 8-hydroxydeoxyguanosine (8-OHDG) was higher in CRIF1-KO mice than in WT mice. Moreover, CRIF1-KO sham mice had increased 8-OHDG-positive cell recruitment compared with WT-sham mice. CRIF1-KO-UUO kidneys had increased recruitment of 8-OHDG-positive cells compared with WT-UUO kidneys. In conclusion, collecting duct-specific mitochondrial injury increased oxidative stress. Oxidative stress associated with mitochondrial damage may aggravate UUO-induced renal injury.

Hepatocellular carcinoma in patients with renal dysfunction: Pathophysiology, prognosis, and treatment challenges.

The population of patients with hepatocellular carcinoma (HCC) overlaps to a high degree with those for chronic kidney disease (CKD) and end-stage renal disease (ESRD). The degrees of renal dysfunction vary, from the various stages of CKD to dialysis-dependent ESRD, which often affects the prognosis and treatment choice of patients with HCC. In addition, renal dysfunction makes treatment more difficult and may negatively affect treatment outcomes. This study summarized the possible causes of the high comorbidity of HCC and renal dysfunction. The possible mechanisms of CKD causing HCC involve uremia itself, long-term dialysis status, immunosuppressive agents for postrenal transplant status, and miscellaneous factors such as hormone alterations and dysbiosis. The possible mechanisms of HCC affecting renal function include direct tumor invasion and hepatorenal syndrome. Finally, we categorized the risk factors that could lead to both HCC and CKD into four categories: Environmental toxins, viral hepatitis, metabolic syndrome, and vasoactive factors. Both CKD and ESRD have been reported to negatively affect HCC prognosis, but more research is warranted to confirm this. Furthermore, ESRD status itself ought not to prevent patients receiving aggressive treatments. This study then adopted the well-known Barcelona Clinic Liver Cancer guidelines as a framework to discuss the indicators for each stage of HCC treatment, treatment-related adverse renal effects, and concerns that are specific to patients with pre-existing renal dysfunction when undergoing aggressive treatments against CKD and ESRD. Such aggressive treatments include liver resection, simultaneous liver kidney transplantation, radiofrequency ablation, and transarterial chemoembolization. Finally, focusing on patients unable to receive active treatment, this study compiled information on the latest systemic pharmacological therapies, including targeted and immunotherapeutic drugs. Based on available clinical studies and Food and Drug Administration labels, this study details the drug indications, side effects, and dose adjustments for patients with renal dysfunction. It also provides a comprehensive review of information on HCC patients with renal dysfunction from disease onset to treatment.

Renin‐Angiotensin System Blockade is Associated with Exercise Capacity, Sympathetic Activity and Endothelial Function in Patients with Chronic Kidney Disease

Chronic kidney disease (CKD) patients have exercise intolerance that is associated with cardiovascular mortality. CKD patients have exaggerated increases in blood pressure (BP) reactivity and impaired ability to maintain skeletal muscle perfusion during exercise mediated by sympathetic nervous system (SNS) overactivation and decreased nitric oxide (NO) bioavailability. Activation of the renin-angiotensin system (RAS) increases central SNS activation and reduces NO synthesis, and prior studies have suggested that RAS blockade may modulate physical function declines. The aim of this study was to investigate whether use of RAS inhibitors (RASi) is associated with greater exercise capacity in CKD, and whether greater exercise capacity with RASi is linked to lower SNS activity and increased NO-dependent endothelial function. 35 hypertensive CKD patients (56.7 ± 7.0 yr) and 20 age-matched controls without CKD (CON, 52.5 ± 8.2 yr) were recruited. Exercise capacity was measured via VO2 peak from a maximal treadmill test, muscle sympathetic nervous activity (MSNA) was measured via microneurography, and vascular endothelial function was measured by flow-mediated dilation (FMD). Participants with CKD were further grouped by current usage of RASi including angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) for group difference analyses. There were no baseline differences in demographics or hemodynamics between CKD patients with and without RASi. VO2 peak was greater in CKD patients with RASi compared to CKD patients not on RASi and lower compared to CON (23.3 ± 5.8 vs.16.4 ± 2.9, p=0.007; vs.30.0 ± 7.7, p=0.005 ml/min/kg respectively). MSNA in CKD patients with RASi was lower compared to CKD patients not on RASi but similar with CON (43.9 ± 7.1 vs. 53.8 ± 8.2; p=0.009, vs.38.0 ± 20.3; p=0.103 bursts/min respectively). FMD in CKD patients with RASi was greater compared to CKD patients not on RASi and lower compared to CON (3.2 ± 2.6 vs. 1.3 ± 1.6; p=0.007, vs. 5.0 ± 3.0; p=0.045 % respectively). VO2 peak was positively associated with FMD (r=0.417, p=0.038) and was predicted by the combination of FMD and RASi status (r2 =0.344, p=0.01) and MSNA and RASi status (r2 =0.575, p=0.040) in CKD patients. In summary, hypertensive CKD patients on RASi have better exercise capacity compared to those not on RASi. Furthermore, greater exercise capacity in RASi-treated group was associated with lower resting SNS activity and better NO-dependent vascular endothelial function. Long-term randomized trials examining the effects of RASi on physical function and underlying autonomic and vascular mechanisms are needed to determine its causal effect and its responsible mechanisms in CKD.

Serum Adropin Levels in Patients on Hemodialysis.

Adropin is a novel pleotropic peptide involved in energy homeostasis, with possible contribution to cardiovascular protection through production of nitric oxide and subsequent blood pressure regulation. Given that patients undergoing hemodialysis (HD) are related with high cardiovascular risk, hyperlipidemia, chronic low-grade inflammation, and malnutrition the aim of our study was to investigate serum adropin levels in HD patients to evaluate possible associations with nutritional status and other relevant clinical and laboratory parameters. The study included 70 patients on HD and 60 healthy controls. Serum adropin levels were determined by an enzyme-linked immunosorbent assay in a commercially available diagnostic kit. Serum adropin levels were significantly lower in the HD group compared to the control group (2.20 ± 0.72 vs. 4.05 ± 0.93 ng/mL, p < 0.001). Moreover, there was a significant negative correlation with malnutrition-inflammation score (r = −0.476, p < 0.001), dialysis malnutrition score (r = −0.350, p = 0.003), HD duration (r = −0.305, p = 0.010), and high sensitivity C-reactive protein (hsCRP) (r = −0.646, p < 0.001). Additionally, there was a significant negative correlation between adropin levels and pre-dialysis systolic (r = −0.301, p = 0.011) and diastolic blood pressure (r = −0.299, p = 0.011). These results are implying that adropin is potentially involved in the pathophysiological mechanisms of chronic kidney disease (CKD)/HD and its complications. However, future larger scale longitudinal studies need to further address it.

Impact of gender, C-reactive protein and body mass index on erythropoietin resistance index in maintenance hemodialysis patients

Introduction: Anemia is caused by a variety of mechanisms in chronic kidney disease (CKD), including erythropoietin (EPO) deficiency, resistance to erythropoiesis-stimulating agents (ESAs), impaired iron metabolism and its clinical management remains challenging. Objectives: The aim of the current study was to evaluate the impact of CRP, BMI, gender and duration of hemodialysis. Patients and Methods: A total of 94 maintenance HD patients participated in this study. Laboratory investigation included CBC, renal function test and qualitatively C-reactive protein was performed. Erythropoietin resistance index (ERI) was calculated as weekly EPO dose/ body weight in kg/hemoglobin level. Results: Female gender had significantly higher ERI (11.36 ± 1.52) compared to male HD patients (10.68 ± 1.56) (P ˃ 0.05). Patients with low BMI had significant higher ERI (12.08 ± 1.09) compared to HD patients with overweight (10.62 ± 0.79) and obese (9.62 ± 1.68) (P ˃ 0.05). The highest ERI were found in the positive CPR group (P ˃ 0.05) compared to negative CRP group. There is no significant difference between duration of hemodialysis. Conclusion: Our data exposed that female gender; low BMI and inflammation (positive CRP) contributed to EPO hyporesponsiveness. In addition, there is no significant difference between lengths on hemodialysis.

RIPK3 blockade attenuates kidney fibrosis in a folic acid model of renal injury.

Renal fibrosis is common to all forms of progressive kidney disease. However, current therapies to limit renal fibrosis are largely ineffective. Phosphorylation of receptor-interacting serine/threonine-protein kinase (RIPK) 3 has been recently suggested to be a key regulator of the pyrin domain containing 3 (NLRP3) inflammasome, which provides new insights into mechanisms of chronic kidney disease (CKD). However, the specific effect of RIPK3 on renal cortical fibrosis has not been fully understood. To study the function of RIPK3, both genetic ablation and pharmacological inhibition of RIPK3 (dabrafenib) were used in the study. Our studies identify that RIPK3 promotes renal fibrosis via the activation of the NLRP3 inflammasome in a mouse model of folic acid-induced nephropathy. Both interventional strategies decreased the renal fibrotic response, and beneficial effects converged on the NLRP3 inflammasome. This study demonstrates a role for RIPK3 as the mediator of renal fibrosis via the upregulation of inflammasome activation. Dabrafenib, as an inhibitor of RIPK3, may be an effective treatment to limit the progression of the tubulointerstitial fibrosis.