Progressive Loss Of Renal Function Research Articles

Propionate and butyrate counteract renal damage and progression to chronic kidney disease.

Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies. SCFA levels were measured in chronic kidney disease (CKD) patients (n=54) at different stages of the disease and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD. Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by TNF-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term. Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, demonstrating their therapeutic potential independently of the gut microbiota.

Zinc oxide nanoparticles prevent the onset of diabetic nephropathy by inhibiting multiple pathways associated with oxidative stress

BackgroundZinc deficiency is strongly correlated with prolonged diabetes mellitus and diabetic nephropathy (DN). Previously, glucose-lowering, insulinomimetic, and β-cell proliferative activities of zinc oxide nanoparticles (ZON) have been reported. Considering these pleiotropic effects, we hypothesized that ZON modulates multiple cellular pathways associated with necroptosis, inflammation, and renal fibrosis, which are involved in progressive loss of renal function. AimThis study evaluated the effect of ZON on renal function, leading to the alleviation of DN in streptozotocin (STZ)-induced type 1 diabetic Wistar rats and proposed a probable mechanism for its activity. MethodsWistar rats (n = 6/group) were used as healthy controls, diabetic controls, diabetic rats treated with ZON (1, 3, and 10 mg/kg), and insulin controls. Urine and serum biochemical parameters, glomerular filtration rate (GFR), and renal histology were also evaluated. Cultured E11 podocytes were evaluated in vitro for markers of oxidative stress, proteins associated with the loss of renal function, and genes associated with renal damage. Key findingsSTZ-treated rats receiving oral doses of ZON showed enhanced renal function, with no histological alterations in the kidney tissue. ZON inhibited the TGF-β/Samd3 pathway in renal fibrosis; blocked Ripk1/Ripk3/Mlkl mediated necroptosis and protected against hyperglycemia-induced pyroptosis. In E11 podocytes, ZON reduced oxidative stress under high glucose conditions and retained podocyte-specific proteins. SignificanceA probable mechanism by which ZON prevents DN has been proposed, suggesting its use as a complementary therapeutic agent for the treatment of diabetic complications. To the best of our knowledge, this is the first study to demonstrate the in vitro effects of ZON in cultured podocytes.

Changes in the Progression of Chronic Kidney Disease in Patients Undergoing Fecal Microbiota Transplantation.

Chronic kidney disease (CKD) is a progressive loss of renal function in which gut dysbiosis is involved. Fecal microbiota transplantation (FMT) may be a promising alternative for restoring gut microbiota and treating CKD. This study evaluated the changes in CKD progression in patients treated with FMT. Patients with diabetes and/or hypertension with CKD clinical stages 2, 3, and 4 in this single-center, double-blind, randomized, placebo-controlled clinical trial (NCT04361097) were randomly assigned to receive either FMT or placebo capsules for 6 months. Laboratory and stool metagenomic analyses were performed. A total of 28 patients were included (15 FMT and 13 placebo). Regardless of CKD stages, patients responded similarly to FMT treatment. More patients (53.8%) from the placebo group progressed to CKD than the FMT group (13.3%). The FMT group maintained stable renal function parameters (serum creatinine and urea nitrogen) compared to the placebo group. Adverse events after FMT treatment were mild or moderate gastrointestinal symptoms. The abundance of Firmicutes and Actinobacteria decreased whereas Bacteroidetes, Proteobacteria and Roseburia spp. increased in the FMT group. CKD patients showed less disease progression after FMT administration. The administration of oral FMT in patients with CKD is a safe strategy, does not represent a risk, and has potential benefits.

Deep venous thrombosis in autosomal dominant polycystic kidney

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic cystic condition that results in progressive loss of renal function. The disease is associated with various complications, including compression of adjacent structures like the inferior vena cava (IVC), which can lead to deep vein thrombosis (DVT) and ultimately, pulmonary embolism. This report details a case of a 41-year-old patient with ADPKD who presented with left leg DVT. Imaging revealed IVC compression due to enlarged kidneys, and blood tests indicated low levels of coagulation proteins C and S. The patient is hypertensive and has advanced renal failure (glomerular filtration rate [GFR] 12.6 mL/min) but has not yet initiated dialysis. The patient was initiated on treatment with the novel oral anticoagulant, apixaban, and exhibited favorable outcomes. His DVT is believed to be the result of multiple factors acting in concert. IVC compression, a significant precipitant doctor of DVT, is frequently observed in ADPKD patients, with rates as high as 15% in severe cases and 15% in mild cases, according to a study by Yin et al. The incidence of venous thromboembolism (VTE) in patients with chronic kidney disease increases as GFR decreases, with rates 2.5–5.5-fold higher in moderate-to-severe end-stage renal disease than in the general population. VTE is a multifactorial disease with both acquired and inherited thrombophilia factors. This particular case presents a unique event within our medical practice, as it is relatively uncommon to witness such a correlation between DVT and polycystic kidney disease. It serves as an exemplification of a case that necessitates diligent monitoring due to the heightened risk of recurrent DVT.

Calculation of Kidney Volumes with Magnetic Resonance in Patients with Autosomal Dominant Polycystic Kidney Disease: Comparison between Methods

Autosomal dominant polycystic renal disease (ADPKD) is the most frequent kidney inheritable disease, characterized by the presence of numerous bilateral renal cysts, causing a progressive increase in total kidney volume (TKV) and a progressive loss of renal function. Several methods can be used to measure TKV by using MRI, and they differ in complexity, accuracy and time consumption. This study was performed to assess the performance of the ellipsoid method and the semi-automatic segmentation method, both for TKV and SKV (single kidney volume) computation. In total, 40 patients were enrolled, and 78 polycystic kidneys analyzed. Two independent operators with different levels of experience evaluated renal volumetry using both methods. Mean error for ellipsoid method for SKV computation was −2.74 ± 11.79% and 3.25 ± 10.02% for the expert and the beginner operator, respectively (p = 0.0008). A Wilcoxon test showed a statistically significant difference between the two operators for both methods (SKV p = 0.0371 and 0.0034; TKV p = 0.0416 and 0.0171 for the expert and the beginner operator, respectively). No inter-operator significant difference was found for the semi-automatic method, in contrast to the ellipsoid method. Both with a Wilcoxon test and Bland–Altman plot, statistically significant differences were found when comparing SKV and TKV measurements obtained with the two methods for both operators, even if the differences are stronger for the beginner operator than for the expert one. The semi-automatic segmentation method showed more inter-observer reproducibility. The ellipsoid method, in contrast, appears to be affected by greater inter-observer variability, especially when performed by operators with limited experience.

The crucial role of the nephrologist in the management of pregnancy in women with adult autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic kidney disease characterized by gradual kidney enlargement and progressive renal function loss. Pregnancy is a significant risk factor for adverse maternal and fetal outcomes in chronic kidney disease (CKD), regardless of the nephropathy. Women with ADPKD often face concerns about worsening their renal condition and passing the disease on to their offspring. Recent studies show better outcomes due to improved pregnancy surveillance and prior counseling. Risk factors for poor fetal and maternal outcomes include advanced maternal age, pre-existing hypertension, urinary infections, proteinuria, and renal failure. Collaboration between nephrologists and gynecologists is essential for addressing clinically significant concerns in pregnant women with ADPKD. Nephrologists should play an active role in assisting and supporting pregnant ADPKD patients as part of a multidisciplinary team.

Noscapine alleviates unilateral ureteral obstruction-induced inflammation and fibrosis by regulating the TGFβ1/Smads signaling pathways

Renal fibrosis is a common pathway leading to progressive renal function loss in various forms of chronic kidney disease. Many fibrogenic factors regulate renal fibrosis; two key players are post-injury inflammation and transforming growth factor-β1 (TGF-β1)-induced myofibroblast differentiation. Myofibroblast differentiation is tightly regulated by the microtubule polymerization. Noscapine, an antitussive plant alkaloid, is a potent microtubule-interfering agent previously identified as a potential anticancer compound. Here, we examined how noscapine affects renal fibrogenesis in an in vitro renal fibroblast model and an in vivo unilateral ureteral obstruction (UUO) model. UUO mice were intraperitoneally treated with noscapine at 1 day before UUO surgery and daily thereafter. At 7 days post-surgery, kidneys were collected for further analysis. To analyze whether noscapine inhibits downstream TGF-β1-related signaling, we pre-incubated NRK-49F fibroblasts with noscapine and then performed TGF-β1 stimulation. In UUO mice, noscapine attenuated extracellular matrix protein deposition and the expression levels of type I collagen, type IV collagen, α-smooth muscle actin, and fibronectin. In addition, noscapine decreased tubulointerstitial inflammation in UUO kidneys by reducing TLR2 expression, modulating NLRP3 inflammasome activation, reducing macrophage infiltration, and antagonizing the M2 macrophage phenotype. Furthermore, noscapine pre-incubation suppressed the TGF-β1-induced fibroblast-myofibroblast transformation by downregulating the TGF-β/Smads signaling pathways in NRK-49F cells. These results suggest that noscapine reduces tubulointerstitial inflammation and fibrosis in the kidneys of UUO mice and inhibits the fibroblast-myofibroblast transformation induced by TGF-β1. Noscapine is an over-the-counter antitussive that has been used safely for several decades. Therefore, noscapine is an attractive therapeutic agent for inhibiting renal tubulointerstitial fibrosis.

Renal biopsy pattern in diabetes mellitus patients and their correlation with clinical parameters

Background. Diabetic nephropathy is a condition marked by persistent proteinuria, hypertension, and a progressive loss of renal function. End-stage kidney disease needing continuous renal replacement treatment is now primarily caused by diabetes. According to Kimmelstiel and Wilson, the hallmark lesion of diabetic nephropathy is nodular glomerulosclerosis. Diabetic nephropathy or Nondiabetic renal disease, or the coexistence of both can be seen in renal histopathology and in differentiating between these diagnostic groups can have an impact on patient care and prognosis.Patients and Methods. Total of 21 cases of Diabetic nephropathy were included in the study. Clinical details and laboratory parameters like diastolic blood pressure, creatinine level, 24 hrs urinary protein level and HbA1C% were recorded in pretested performa in all cases. The biopsy specimens were stained with hematoxylin & eosin and special stains.Results. Among the total DM cases only 21 patients have done renal biopsy, 11 cases (52.3 %) showed KW lesion (Class III) while 06 cases (28.5 %) showed diffuse diabetic glomerulosclerosis (Class IV). The remaining 04 cases (19 %) showed a mild increase in mesangial matrix and slight thickening of glomerular basement membrane (Class II). When compared with clinical parameters, they were more raised in Nodular diabetic glomerulosclerosis type (Class III) lesion as compared to diffuse diabetic glomerulosclerosis.Conclusion. Nodular diabetic glomerulosclerosis was the most common lesion in renal biopsy of type II diabetes mellitus patients. This KW lesion is responsible for more severe clinical and biochemical renal abnormality in most patients with type II diabetes mellitus.

Alpha-cyano-4-hydroxycinnamic acid alleviates renal fibrosis and inflammation in chronic kidney disease

Renal fibrosis is a crucial pathological phenomenon of chronic kidney disease (CKD) that contributes to the progressive loss of renal function. Monocarboxylate transporter 1 (MCT1) plays an important role in clear cell renal cell carcinoma; however, the role of the MCT1 inhibitor alpha-cyano-4-hydroxycinnamic acid (α-CHCA) in renal fibrosis remains unclear. In this study, we evaluated the role of α-CHCA, an MCT1 inhibitor, in treating renal fibrosis associated with CKD. We used α-CHCA in a CKD mouse model of unilateral ureteral obstruction (UUO), and mouse proximal tubular epithelial cells (mPTCs) stimulated by transforming growth factor-β1 (TGF-β1). In vivo, administration of α-CHCA improved tubulointerstitial fibrosis, which was consistent with the reduced expression of collagen I/III, fibronectin (FN1), and α-smooth muscle actin (α-SMA) in the kidneys of UUO mice. Similarly, the overexpression of inflammatory factors in UUO kidneys decreased in response to α-CHCA treatment. In vitro, α-CHCA pretreatment inhibited the induction of collagen I/III, FN1, and α-SMA production in mPTCs treated with TGF-β1. Collectively, these findings indicate that α-CHCA may play a therapeutic role in renal fibrosis associated with CKD by inhibiting collagen deposition and subsequent fibrosis and inflammation. Highlights Chronic kidney disease (CKD) mice have increased MCT1 expression. α-CHCA, a MCT1 inhibitor, alleviates renal fibrosis in CKD mice. α-CHCA improves the inflammation in CKD mice. α-CHCA inhibits TGF-β1-induced extracellular matrix secretion of proximal tubular epithelial cells.

#6428 PERCUTANEOUS RENAL BIOPSY (PRB) IN METASTATIC RENAL CELL CARCINOMA (MRCC) PATIENTS WITH ACUTE KIDNEY INJURY (AKI) ON SYSTEMIC ANTICANCER THERAPY

Abstract Background and Aims PRB is relatively contraindicated in patients with solitary kidney (SK) due to the perception that PRB is a risky procedure in this patient population. There are however situations in which a renal biopsy is essential to assess renal toxicity of systemic therapy and/or to identify the underlying kidney disease in the remaining kidney. Data on pathological findings of the kidney disease in mRCC patients receiving systemic anticancer therapy is scarce and it may influence the cancer treatment plan. The main aim of this study was to characterize the pathological findings of PRB in patients with SK undergoing systemic therapy. Method We retrospectively analyzed the pathological findings of mRCC patients with AKI who underwent PRB during systemic treatment with antiangiogenic tyrosine kinase inhibitors (TKIs) and/or immune check point inhibitors (ICIs) at the Institute of Oncology Ljubljana between 2018 and 2022. All biopsies were performed under ultrasound guidance by the treating nephrologist in patients with clinical evidence of AKI and no other formal contraindications for PRB. Results A total of 11 PRBs were performed in 10 patients, eight of whom had SK (Table 1). Six patients were treated with TKIs and ICIs, three with ICIs and one with a TKI alone. None of the patients had major bleeding or required any additional intervention as a consequence of the PRB. Histology revealed thrombotic microangiopathy (TMA) in three, diabetic nephropathy in three, acute interstitial nephritis in two and focal segmental glomerulosclerosis in three patients. Based on pathological findings, the therapy was discontinued after seven PRBs. One patient with TMA showed progressive loss of renal function (RF) after discontinuation of antiangiogenic therapy while the other two had either stable or improved RF. Conclusion Our results indicate that PRB is a safe procedure in patients with SK undergoing systemic treatment for mRCC. The pathological findings in our patients guided the decision either to continue or to discontinue the treatment, which resulted in improvement or stabilization of RF in the vast majority of patients. This study suggests that in patients with SK, PRB can provide important information, which may have a significant impact on the oncological and the nephrological therapeutic approaches.

#5399 VONAFEXOR AS A NOVEL THERAPY FOR CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney diseases (CKD) are characterized by the progressive loss of renal function. The molecular mechanisms underlying this progression are still poorly characterized and probably multifactorial. Therefore, there is a real need to expand the very limited number of therapies able to slow down the rate of CKD progression. Recent findings indicate that NR1H4, a druggable nuclear receptor, might play an important role in CKD. The aim of this study was to investigate the benefit of Vonafexor, a novel small molecule and specific NR1H4 agonist in acquired and genetic models of CKD. Method Two complementary experimental models of CKD (the 75% excision of total renal mass (Subtotal Nephrectomy; Nx) and the Col4a3−/− mice, a model of Alport disease) were studied. NR1H4 and the expression of some of its downstream targets were evaluated by quantitative RT-PCR, western blot and immunohistochemistry. In the Nx model, mice were treated with Vonafexor by daily oral gavage from 5 to 8 weeks after the surgery. The possible beneficial effect was compared to that of Losartan and other NR1H4 agonists. In the Alport model, mice were treated by Vonafexor from 5 to 8 weeks after birth. In both models, group of mice were sacrificed at 5 weeks to evaluate the extent of renal lesions at baseline. Renal lesions were quantified using image J. Renal inflammation, myofibroblast activation and podocyte number were quantified after specific staining. Human biopsies were also studied. RNAseq was performed using Illumina NovaSeq6000. Results We observed that NR1H4 expression and OSTA and OSTB, two downstream targets of NR1H4, were significantly reduced in remnant kidneys of Nx FVB/N mice compared to sham-operated animals 8 weeks after surgery. Co-localization staining revealed that NR1H4 is mainly expressed in proximal tubules and, to a minor extent, in Henle loops. Renal lesions were already present at 5 weeks in both experimental models. Remarkably, Vonafexor stopped the progression of renal lesions, in terms of glomerulosclerosis and tubular dilatations and, more importantly, induced a regression of interstitial fibrosis 8 weeks after nephrectomy as compared to the 5-week baseline. Lymphocytes and macrophage infiltration, as well as activated myofibroblasts, were also significantly reduced. Similarly, podocyte loss was stopped by Vonafexor treatment. Of note, the beneficial effect of Vonafexor was unique compared to other classes of NR1H4 agonists and also higher than that of Losartan. The same beneficial curative effect was found in Col4a3−/− mice. RT-PCR confirmed the activation of several NR1H4 downstream targets in mice treated with Vonafexor, while RNAseq analysis revealed that Vonafexor impacted the pathological activation of pathways involved in cell cycle, cell signaling and metabolism. These results may be relevant to humans, since NR1H4 expression was significantly reduced in biopsies from patients with CKD of different etiologies as compared to control kidneys. Conclusion Altogether our results identified in Vonafexor a novel key drug to control CKD. This is consistent with recent results obtained in LIVIFY phase 2 clinical trial in which Vonafexor has already demonstrated beneficial effects on eGFR in NASH patients with mild to moderate CKD.

#4485 CLINICAL CASE OF MOSAICISM IN ADPKD PATIENT

Abstract Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) it's mainly characterized by renal involvement with progressive bilateral development of renal cysts and volumetric increase of the kidneys, responsible for the progressive loss of renal function that leads to chronic kidney disease (CKD) and the need of renal replacement therapy. There are some cases (doubtful, uncertain) in which it is necessary to perform genetic testing to achieve a definitive diagnosis. It looks like in ADPKD patients, mosaicism could modulate the clinical course of the disease. Mosaicism is characterized by few cell populations with different genomes. In these special cases the diagnosis is very difficult and the genetic analysis could be an important and helpful tool. With this report, we want to highlight the importance of the use of several diagnostic methods in those ‘atypical’ cases where otherwise the analysis would have been negative from a first molecular approach. Method A 47 years old woman came to our attention with typical picture of ADPKD, arterial hypertension and chronic kidney disease CKD (3b). She had no ADPKD family history, but since she had a son, genetic testing was performed. According to our workflow, first level analysis includes Next Generation Sequencing (NGS). Second level analysis, performed to investigate other genes and large rearrangement, was based on Multiplex Ligation-dependent Probe Amplification (MLPA) analysis of PKD1 and PKD2 genes, using Salsa MLPA ProbeMix P352 PKD1PKD2 kit and ProbeMix P351 PKD1 kit ©MRC Holland. Results NGS did not detect the presence of any genomic variants. Therefore, second-level genetic analysis (several approaches), showed a large deletion in heterozygosis of the portion comprising the 3-33 exons of PKD1 gene in mosaic in percentage close to the resolution limits of the used technique (25-30%). The same analysis was confirmed in another laboratory. Conclusion We concluded that the identified large deletion, without establishing the real borders due to MLPA technical restrictions, was present as mosaicism. The variant is not reported, but due to the type of mutation and the clinical picture of the patient, it is to be considered as likely pathogenic. A stepwise genetic approach might be useful in those cases where standard methods do not allow to reach a definitive diagnosis.

Another piece in the puzzle of kidney fibrosis

Kidney fibrosis is a chronic physiomorphologic transformation of the renal parenchyma. Despite the known characteristics of the related structural and cellular changes, the mechanisms responsible for the initiation and progression of renal fibrosis are not completely understood. Development of efficient therapeutic drugs aimed at preventing the progressive loss of renal function requires an in-depth understanding of the complex phenomena associated with the pathophysiology of human diseases. The investigation of Li etal. provides novel evidence in this direction.

Mechanisms Limiting Renal Tissue Protection and Repair in Glomerulonephritis.

Glomerulonephritis are renal disorders resulting from different pathogenic mechanisms (i.e., autoimmunity, complement, inflammatory activation, etc.). Clarifying details of the pathogenic cascade is basic to limit the progression from starting inflammation to degenerative stages. The balance between tissue injury, activation of protective systems and renal tissue repair determines the final outcome. Induction of an oxidative stress is part of glomerular inflammation and activation of protective antioxidant systems has a crucial role in reducing tissue effects. The generation of highly reactive oxygen species can be evaluated in vivo by tracing the inner-layer content of phosphatidyl ethanolamine and phosphatidyl serine in cell membranes. Albumin is the major antioxidant in serum and the level of oxidized albumin is another indirect sign of oxidative stress. Studies performed in Gn, specifically in FSGS, showed a high degree of oxidation in most contexts. High levels of circulating anti-SOD2 antibodies, limiting the detoxyfing activity of SOD2, have been detected in autoimmune Gn(lupus nephritis and membranous nephropathy) in association with persistence of proteinuria and worsening of renal function. In renal transplant, high levels of circulating anti-Glutathione S-transferase antibodies have been correlated with chronic antibody rejection and progressive loss of renal function. Annexins, mainly ANXA1 and ANXA2, play a general anti-inflammatory effect by inhibiting neutrophil functions. Cytosolic ANXA1 is decreased in apoptotic neutrophils of patients with glomerular polyangitis in association with delayed apoptosis that is considered the mechanism for polyangitis. High circulating levels of anti-ANXA1 and anti-ANXA2 antibodies characterize lupus nephritis implying a reduced anti-inflammatory effect. High circulating levels of antibodies targeting Macrophages (anti-FMNL1) have been detected in Gn in association with proteinuria. They potentially modify the intra-glomerular presence of protective macrophages (M2a, M2c) thus acting on the composition of renal infiltrate and on tissue repair.

Evaluating the drug repurposing benefits of clopidogrel against adenine induced chronic renal failure in experimental animals

Introduction: Chronic renal failure (CRF) is a life-threatening condition which can be defined as a progressive and irreversible loss of renal function associated with inflammation and oxidative stress having limited treatment options. The anti-platelet drug, clopidogrel showed nephroprotective action in 5/6 nephrectomy model, lithium induced nephrogenic diabetes insipidus and diabetes-induced renal fibrosis. Objectives: In this study we evaluated the effect of clopidogrel on various serum, urine parameters linked with CRF, vascular calcification, electrolyte abnormalities, inflammatory markers and renal histology. Materials and Methods: Seven groups of male Wistar rats were treated with saline normal control), adenine (50 mg/kg, disease control), clopidogrel (15, 30, 60 mg/kg) concomitantly with adenine (preventive regimen), clopidogrel 60 mg/kg from day 15th curative regimen) and acetylcysteine (50 mg/kg) in combination with taurine as standard drug (50 mg/kg) from day 15th in a 4-week model. Following the completion of the treatments, urine, blood, and kidneys were collected from all rats, and then various biochemical, oxidative, and histological parameters were estimated. Results: Adenine administration decreased body weight and kidney function due to injury as indicated by increased markers like serum urea, uric acid, creatinine and potassium in all animals except normal control group. There was a significant difference between disease and test drug groups especially for 60 mg/kg of preventive and curative regimen for all the estimated parameters. Adenine administration caused histopathological alterations, significant reduction in antioxidant indices and initiated a fibrotic response in kidney by increasing the profibrotic protein like transforming growth factor-beta (TGF-β1). Conclusion: The results suggest that clopidogrel treatment improves majority of the parameters in a dose-dependent manner and the renoprotective effect might be associated with its antioxidant and anti- fibrosis activity.

Stem Cells in Kidney Ischemia: From Inflammation and Fibrosis to Renal Tissue Regeneration

Ischemic nephropathy consists of progressive renal function loss due to renal hypoxia, inflammation, microvascular rarefaction, and fibrosis. We provide a literature review focused on kidney hypoperfusion-dependent inflammation and its influence on renal tissue's ability to self-regenerate. Moreover, an overview of the advances in regenerative therapy with mesenchymal stem cell (MSC) infusion is provided. Based on our search, we can point out the following conclusions: 1. endovascular reperfusion is the gold-standard therapy for RAS, but its success mostly depends on treatment timeliness and a preserved downstream vascular bed; 2. anti-RAAS drugs, SGLT2 inhibitors, and/or anti-endothelin agents are especially recommended for patients with renal ischemia who are not eligible for endovascular reperfusion for slowing renal damage progression; 3. TGF-β, MCP-1, VEGF, and NGAL assays, along with BOLD MRI, should be extended in clinical practice and applied to a pre- and post-revascularization protocols; 4. MSC infusion appears effective in renal regeneration and could represent a revolutionary treatment for patients with fibrotic evolution of renal ischemia.

The prevalence and risk factors of chronic kidney disease among type 2 diabetes mellitus follow-up patients at Debre Berhan Referral Hospital, Central Ethiopia

Background: Chronic kidney disease is a progressive loss in renal function that is more accepted as global public health importance and its magnitude is overgrowing in the least developed countries like Ethiopia. No data was found in Debre Birhan Central Ethiopia on the magnitude of chronic kidney disease among type 2 diabetes patients. Methods: Institution-based cross-sectional study was conducted among 327 at Debre Berhan Referral Hospital from March to June 2019 in Adult (≥ 18 years) type 2 diabetes follow-up patients who volunteered to give informed written consent were included in the study. Systematic random sampling was used. Data were collected by interviews using structured and pre-tested questionnaires. Descriptive statistics of the continuous and categorical variables were done. The bi-variable and multivariable logistic regression was done to show the net effect of explanatory variables on chronic renal disease. Results: A total of 327 study participants were involved in the final analysis. The Prevalence of CKD among type 2 diabetic patients was 15.9%. A significant association was found with age > 60 years [AOR 3.5 (95% CI 1.8-6.8)], alcoholic patients [AOR 2.4 (95% CI 1.2-5.1)], glycated hemoglobin levels above 7% [AOR 2.5 (95 CI 1.5-4.1)], higher level of LDL greater than 100 g/dl [AOR 2.7 (95% CI 1.9-4)] and lower level of HDL [AOR 2.9 (95% CI 1.4-6)]. Conclusion: The magnitude of chronic kidney disease among type 2 diabetic follow-up patients was 15.9%. Estimated GFR should be determined for diabetic patients at regular intervals of time for earlier diagnosis of chronic kidney disease.

Estimations of Serum Creatinine, Urea, and Some Urine Parameters among Patients with Type 2 Diabetes Mellitus after More than Ten Years Disease Onset

Background: Assessment of a patient’s renal function may be used for two different purposes. One is to diagnose impaired renal function, and the other is to detect the presence of a progressive loss of renal function over time 1. In Sudan according to our knowledge there is lack of information regarding the impact of prolong type 2 diabetes mellitus on the renal function.
 Objective: This study aims to assess renal function described as serum creatinine, urea and some urine parameters in type 2 diabetics after more than ten years onset. To detect impact of patient age and the duration on renal function.
 Materials and methods: This study was designed as case control study, carried out in Northern State, Al Dabbah, during the period from Februarys to June 2014. Include 100 samples (57 males and 43 females), 50 samples collected from patient with more than ten years type 2 diabetic (27 males and 23 females) and 50 samples collected from healthy volunteers as pre described by physical examination and medical history (30 males and 20 females). 
 Results: The results showed statistically significant increase in the serum levels of creatinine and urea in diabetic compared to their copartner with p.value 0.000 and mean ± SD (3.29±2.25, 1.28±0.35) mg/dl and (63.88±3.38, 21.28±5.48) mg/dl for diabetic and non-diabetic respectively. urine parameters showed elevation and presence of albumin 35% in diabetic and 1% in non-diabetic, sugar 99% for diabetic and 0% in non-diabetic, acetone 60% for diabetic and 0% for non-diabetic, pus 55% for diabetic and 5% for non-diabetic, calcium oxalate 66% for diabetic and 1% for non-diabetic, RBCs 5% for diabetic and 2% for non-diabetic, yeast cells 2% for diabetic and 1% for non-diabetic, epithelial cells 11% for diabetic and 1% for non-diabetic. 
 Conclusion: There were significant increase in serum levels of creatinine and urea. And urine albumin, sugar, acetone, pus and calcium oxalate. Positive correlation between duration and urea and no correlation between duration and creatinine in case group. There were no significant changes in RBCs, yeast cells and epithelial cells. Patients should have regular screening renal function tests.

Potential Efficacy of Proteasome Inhibitor, Delanzomib, for the Treatment of Renal Fibrosis.

Renal fibrosis is scarring and tissue hardening caused by the excess deposition of extracellular matrix proteins in response to chronic inflammation. Renal fibrosis is the primary cause of a progressive loss of renal function, and is an important therapeutic target because it ultimately leads to end-stage renal failure, which can be treated only by either dialysis or kidney transplantation. There is no effective treatment that specifically targets renal fibrosis. Myofibroblasts are known to evade apoptosis by activating molecular mechanisms in response to pro-survival biomechanical and growth factor signals from the fibrotic microenvironment. In this study, we screened and selected compounds that selectively cause cell death in myofibroblasts in vitro and studied their possible potency against renal fibrosis in a mouse model. Several proteasome inhibitors induced selective cell death in myofibroblasts differentiated from the human fibroblast cell line (MRC5). The in vivo antifibrotic effect of Delanzomib (Dz), one of the proteasome inhibitors most sensitive to myofibroblasts in vitro, was investigated in a Unilateral Ureteric Obstruction (UUO) mouse model. Treatment with Dz decreased the expression levels of the actin-alpha-2 (ACTA2) and collagen-type-1-alpha-1 (COL1A1) genes in the kidney, which are common fibrosis markers. These results suggest that Dz might be a compound that suppresses renal fibrosis by inducing selective cell death of myofibroblasts, although further investigation is required.

Potential Neuromodulation of the Cardio-Renal Syndrome.

The cardio-renal syndrome (CRS) type 2 is defined as a progressive loss of renal function following a primary insult to the myocardium that may be either acute or chronic but is accompanied by a decline in myocardial pump performance. The treatment of patients with CRS is difficult, and the disease often progresses to end-stage renal disease that is refractory to conventional therapy. While a good deal of information is known concerning renal injury in the CRS, less is understood about how reflex control of renal sympathetic nerve activity affects this syndrome. In this review, we provide insight into the role of the renal nerves, both from the afferent or sensory side and from the efferent side, in mediating renal dysfunction in CRS. We discuss how interventions such as renal denervation and abrogation of systemic reflexes may be used to alleviate renal dysfunction in the setting of chronic heart failure. We specifically focus on a novel cardiac sensory reflex that is sensitized in heart failure and activates the sympathetic nervous system, especially outflow to the kidney. This so-called Cardiac Sympathetic Afferent Reflex (CSAR) can be ablated using the potent neurotoxin resinferitoxin due to the high expression of Transient Receptor Potential Vanilloid 1 (TRPV1) receptors. Following ablation of the CSAR, several markers of renal dysfunction are reversed in the post-myocardial infarction heart failure state. This review puts forth the novel idea of neuromodulation at the cardiac level in the treatment of CRS Type 2.