Role of vitamin D in diabetes mellitus and chronic kidney disease

Approximately 30%-50% of people are recognized to have low levels of vitamin D,and insufficiency and deficiency of vitamin D are recognized as global health problems worldwide.Although the presence of hypovitamin D increases the risk of rickets and fractures,low vitamin D levels are also associated with hypertension,cancer,and cardiovascular disease.In addition,diabetes mellitus(DM) and chronic kidney disease(CKD) are also related to vitamin D levels.Vitamin D deficiency has been linked to onset and progression of DM.Although in patients with DM the relationship between vitamin D and insulin secretion,insulin resistance,and β-cell dysfunction are pointed out,evidence regarding vitamin D levels and DM is contradictory,and well controlled studies are needed.In addition,vitamin D influences the renin-angiotensin system,inflammation,and mineral bone disease,which may be associated with the cause and progression CKD.There is increasing evidence that vitamin D deficiency may be a risk factor for DM and CKD;however,it remains uncertain whether vitamin D deficiency also predisposes to death from DM and CKD.Although at this time,supplementation with vitamin D has not been shown to improve glycemic control or prevent incident DM,clinical trials with sufficient sample size,study periods,and optimal doses of vitamin D supplementation are still needed.This review focuses on the mechanism of vitamin D insufficiency and deficiency in DM or CKD,and discusses the current evidence regarding supplementation with vitamin D in patients with these diseases.

Research progress between gut microbiota, diabetes mellitus and chronic kidney disease

In recent years, gut microbiota has become one of the hot spots of research. A large number of studies have shown that gutmicrobiota are closely related to a variety of diseases. Diabetes and chronic kidney disease as a multifactorial cause are also affected by the gutmicrobiota. Inthefuture, gut microbiota may become a new therapeutic strategy. This article focuses on the relationship between gutmicrobiota and diabetes and chronic kidney disease, and reviews its research progress in the pathogenesis and treatment of diabetes and chronic kidney disease.

Prevalence, Risk Factors, and Awareness of Chronic Kidney Disease among Diabetes Mellitus and Hypertensive Individuals at the Buea Regional Hospital, Cameroon

Background: Kidney failure, cardiovascular disease, and early mortality are just a few of the major negative effects of chronic renal disease, a serious global health issue. The considerable financial and public health burden associated with chronic kidney disease can be lessened by raising awareness and adopting better practices for its impact, prevention, and early identification. Objective: In this study, individuals with hypertension and diabetes were evaluated for their knowledge of chronic kidney disease, its prevalence, and its risk factors. Method: It was a hospital-based cross-sectional study conducted on adult (>18 years) patients with diabetes mellitus and hypertension. Each participant provided written informed consent before having their data collected through interviews, medical information, and blood samples for CKD screening. The CKD epidemiology collaboration (CKD-EPI) equation was used to calculate the glomerular filtration rate (GFR) from serum creatinine, and CKD was determined using the estimated GFR (e-GFR). To find independent CKD factors, multivariate logistic regression was employed, with a p-value of 0.05 being regarded as statistically significant. This was accomplished using SPSS (Statistical Program for Social Sciences) version 22.0, IBM Corp., Armonk, NY. Result: A total of 156 participants took part in the study among which 95 (60.9%) were male, most of the participants 82 (52.6%) were aged between 51 - 70 years (mean 59.42 ± 11.007), 76 (48.7%) were unemployed and 97 (62.2%) were single. Overall, the knowledge score of participants on CKD was 65.4% for good knowledge and 34.6% for poor or inadequate knowledge of CKD. More than half of the participants (60%) had chronic kidney disease. Among these, the greatest proportion of CKD patients were those who were hypertensive (88.2%) followed by those who were both hypertensive and diabetic (70.7%). Conclusion: There is poor management of CKD in the South West Region of Cameroon which has contributed greatly to the progression of CKD and increases in the mortality rate.

Outpatient insulin use in type 2 diabetes mellitus and acute respiratory distress syndrome outcomes:A retrospective cohort study

BACKGROUND The impact of type 2 diabetes mellitus(T2DM)on acute respiratory distress syndrome(ARDS)is debatable.T2DM was suspected to reduce the risk and complications of ARDS.However,during coronavirus disease 2019(COVID-19),T2DM predisposed patients to ARDS,especially those who were on insulin at home.AIMTo evaluate the impact of outpatient insulin use in T2DM patients on non-COVID-19 ARDS outcomes.METHODS We conducted a retrospective cohort analysis using the Nationwide Inpatient Sample database.Adult patients diagnosed with ARDS were stratified into insulin-dependent diabetes mellitus(DM)(IDDM)and non-insulindependent DM(NIDDM)groups.After applying exclusion criteria and matching over 20 variables,we compared cohorts for mortality,duration of mechanical ventilation,incidence of acute kidney injury(AKI),length of stay(LOS),hospitalization costs,and other clinical outcomes.RESULTS Following 1:1 propensity score matching,the analysis included 274 patients in each group.Notably,no statistically significant differences emerged between the IDDM and NIDDM groups in terms of mortality rates(32.8%vs 31.0%,P=0.520),median hospital LOS(10 d,P=0.537),requirement for mechanical ventilation,incidence rates of sepsis,pneumonia or AKI,median total hospitalization costs,or patient disposition upon discharge.CONCLUSION Compared to alternative anti-diabetic medications,outpatient insulin treatment does not appear to exert an independent influence on in-hospital morbidity or mortality in diabetic patients with non-COVID-19 ARDS.

Diabetes mellitus increases the prevalence of anemia in patients with chronic kidney disease:A nested case-control study

AIM: To compare anemia prevalence between matched chronic kidney disease(CKD) patients with and without diabetes mellitus(DM) and to assess factors associated with anemia development.METHODS: This is a nested case-control study of 184 type-2 diabetic and 184 non-diabetic CKD patients from a prospectively assembled database of a Nephrology outpatient clinic, matched for gender, age and estimated glomerular filtration rate(eG FR). Prevalence of anemia(hemoglobin: Men: < 13 g/dL, women: < 12 g/dL and/or use of recombinant erythropoietin) was examined in comparison, in the total population and by CKD Stage. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with anemia.RESULTS: The total prevalence of anemia was higher in diabetics(47.8% vs 33.2%, P = 0.004). Accordingly, prevalence was higher in diabetics in CKD Stage 3(53.5% vs 33.1%, P < 0.001) and particularly in Stage 3a(60.4% vs 26.4%, P < 0.001), whereas it was nonsignificantly higher in Stage 4(61.3% vs 48.4%; P = 0.307). Serum ferritin was higher in diabetics in total and in CKD stages, while serum iron was similar between groups. In multivariate analyses, DM(OR = 2.206, 95%CI: 1.196-4.069), CKD Stages 3a, 3b, 4(Stage 4: OR = 12.169, 95%CI: 3.783-39.147) and serum iron(OR = 0.976, 95%CI: 0.968-0.985 per mg/d L increase) were independently associated with anemia.CONCLUSION: Prevalence of anemia progressively increases with advancing stages of CKD and is higher in diabetic than matched non-diabetic CKD patients and diabetes is independently associated with anemia occurrence. Detection and treatment of anemia in diabetic CKD patients should be performed earlier than non-diabetic counterparts.

Risk factors and urinary biomarkers of non-albuminuric and albuminuric chronic kidney disease in patients with type 2 diabetes

BACKGROUND A number of recent studies indicate a transformation in the natural course of chronic kidney disease(CKD)in type 2 diabetes(T2D)patients:an increasing prevalence of declined renal function without proceeding to the accompanying elevation of albuminuria.It has been suggested that albuminuric and nonalbuminuric CKD patterns could be different in their phenotypes and pathogenic mechanisms.AIM To identify the risk factors and biomarkers of albuminuric and non-albuminuric patterns of CKD in patients with T2D.METHODS Three hundred sixty patients with T2D duration≥10 years were included in this observational cross-sectional study.The associations of a panel of demographic and clinical characteristics,complications,comorbidities,and metabolic and hematology parameters with albuminuric and non-albuminuric CKD patterns were analyzed.The urinary excretion of nephrin and podocin,two podocytespecific markers,and WAP-four-disulfide core domain protein 2(WFDC-2),a marker of tubulointerstitial fibrosis,was determined by ELISA in comparison with healthy controls.RESULTS Non-albuminuric CKD was associated with age≥65 years(P=0.0001),female sex(P=0.04),diabetes duration≥15 years(P=0.0009),and the use of diuretics(P=0.0005).Male sex(P=0.01),smoking(P=0.01),waist-to-hip ratio>1.0(P=0.01)and hemoglobin A1c(HbA1c)>8.0%(P=0.005)were risk factors for elevated albuminuria not accompanied by a decrease in estimated glomerular filtration rate(eGFR).Duration of diabetes≥15 years and the use of calcium channel blockers were risk factors for albuminuria with decreased eGFR(both P=0.01).In multivariate logistic regression analysis,age,HbA1c,female sex and diuretics were significant predictors for reduced eGFR,while waist-to-hip ratio,HbA1c and male sex were associated with elevated urinary albumin-to-creatinine ratio(UACR).Excretion of nephrin and podocin was increased in patients with albuminuria,regardless of decline in renal function(P<0.001),correlating positively with UACR.The urinary excretion of WFDC-2 was markedly higher in men than in women(P<0.000001).Men with T2D demonstrated increased WFDC-2 levels independently of the CKD pattern(all P<0.05).In T2D women,WFDC-2 excretion was increased in those with reduced renal function(P≤0.01),correlating negatively with eGFR.CONCLUSION The data provide further evidence that albuminuric and non-albuminuric CKD phenotypes correspond to different pathways of diabetic kidney disease progression.

Performance of Dexcom G5 and FreeStyle Libre sensors tested simultaneously in people with type 1 or 2 diabetes and advanced chronic kidney disease

BACKGROUND Advanced chronic kidney disease(CKD) is a common complication for people with type 1 and 2 diabetes and can often lead to glucose instability. Continuous glucose monitoring(CGM) helps users monitor and stabilize their glucose levels. To date, CGM and intermittent scanning CGM are only approved for people with diabetes but not for those with advanced CKD.AIM To compare the performance of Dexcom G5 and FreeStyle Libre sensors in adults with type 1 or 2 diabetes and advanced CKD.METHODS This was a non-randomized clinical trial that took place in two outpatient clinics in western Sweden. All patients with type 1 or 2 diabetes and an estimated glomerular filtration rate(eGFR) of < 30 mL/min per 1.73 m^(2) were invited to participate. Forty patients(full analysis set = 33) carried the Dexcom G5 sensor for 7 d and FreeStyle Libre sensor for 14 d simultaneously. For referencing capillary blood glucose(SMBG) was measured with a high accuracy glucose meter(HemoCue®) during the study period. At the end of the study, all patients were asked to answer a questionnaire on their experience using the sensors.RESULTS The mean age was 64.1(range 41-77) years, hemoglobin A1 c was 7.0% [standard deviation(SD) 3.2], and diabetes duration was 28.5(SD 14.7) years. A total of 27.5% of the study population was on hemodialysis and 22.5% on peritoneal dialysis. The mean absolute relative difference for Dexcom G5 vs SMBG was significantly lower than that for FreeStyle Libre vs SMBG [15.2%(SD 12.2) vs 20.9%(SD 8.6)], with a mean difference of 5.72 [95% confidence interval(CI): 2.11-9.32;P = 0.0036]. The mean absolute difference was also significantly lower for Dexcom G5 than for FreeStyle Libre, 1.21 mmol/L(SD 0.78) and 1.76 mmol/L(SD 0.78), with a mean diffrenec of 0.55(95%CI: 0.27-0.83;P = 0.0004).The mean difference(MD) was-0.107 mmol/L and-1.10 mmol/L(P = 0.0002), respectively. In all, 66% of FreeStyle Libre values were in the no risk zone on the surveillance error grid compared to 82% of Dexcom G5 values.CONCLUSION Dexcom G5 produces more accurate sensor values than FreeStyle Libre in people with diabetes and advanced CKD and is likely safe to be used by those with advanced CKD.

Utilising continuous glucose monitoring for glycemic control in diabetic kidney disease

In this editorial,we comment on the article by Zhang et al.Chronic kidney disease(CKD)presents a significant challenge in managing glycemic control,especially in diabetic patients with diabetic kidney disease undergoing dialysis or kidney transplantation.Conventional markers like glycated haemoglobin(HbA1c)may not accurately reflect glycemic fluctuations in these populations due to factors such as anaemia and kidney dysfunction.This comprehensive review discusses the limitations of HbA1c and explores alternative methods,such as continuous glucose monitoring(CGM)in CKD patients.CGM emerges as a promising technology offering real-time or retrospective glucose concentration measure-ments and overcoming the limitations of HbA1c.Key studies demonstrate the utility of CGM in different CKD settings,including hemodialysis and peritoneal dialysis patients,as well as kidney transplant recipients.Despite challenges like sensor accuracy fluctuation,CGM proves valuable in monitoring glycemic trends and mitigating the risk of hypo-and hyperglycemia,to which CKD patients are prone.The review also addresses the limitations of CGM in CKD patients,emphasizing the need for further research to optimize its utilization in clinical practice.Altogether,this review advocates for integrating CGM into managing glycemia in CKD patients,highlighting its superiority over traditional markers and urging clinicians to consider CGM a valuable tool in their armamentarium.

Reference gene panel for urinary exosome-based molecular diagnostics in patients with kidney disease

BACKGROUND Kidney disease is a severe complication of diabetes that often leads to end-stage renal disease.Early diagnosis is crucial for prevention or delay.However,the current diagnostic methods,with their limitations in detecting the disease in its early stages,underscore the urgency and importance of finding new solutions.miRNAs encapsulated inside urinary exosomes(UEs)have potential as early biomarkers for kidney diseases.The need for reference miRNAs for accurate interpretation currently limits their translational potential.AIM To identify consistently expressing reference miRNAs from UEs of controls and patients with type 2 diabetesmellitus(T2DM)and biopsy-confirmed kidney diseases.METHODS miRNA profiling was performed on UEs from 31 human urine samples using a rigorous and unbiased method.The UEs were isolated from urine samples collected from healthy individuals(n=6),patients with T2DM(n=13),and T2DM patients who also had kidney diseases(including diabetic nephropathy,n=5;membranous nephropathy,n=5;and IgA nephropathy,n=2)through differential ultracentrifugation.After characterizing the UEs,miRNA expression profiling using microarray technology was conducted.RESULTS Microarray data analysis identified 14 miRNAs that were consistently expressed in UEs from 31 human samples,representing various kidney conditions:diabetic controls,diabetic nephropathy,membrane nephropathy,IgA nephropathy,and healthy controls.Through in silico analysis,we determined that 10 of these miRNAs had significant potential to serve as reference genes in UEs.CONCLUSION We identified uniformly expressing UE miRNAs that could serve as reference genes kidney disease biomarkers.

Simultaneous pancreas-kidney transplantation for end-stage renal failure in type 1 diabetes mellitus: Current perspectives

Type 1 diabetes mellitus(T1DM)is one of the important causes of chronic kidney disease(CKD)and end-stage renal failure(ESRF).Even with the best available treatment options,management of T1DM poses significant challenges for clinicians across the world,especially when associated with CKD and ESRF.Substantial increases in morbidity and mortality along with marked rise in treatment costs and marked reduction of quality of life are the usual consequences of onset of CKD and progression to ESRF in patients with T1DM.Simultaneous pancreas-kidney transplant(SPK)is an attractive and promising treatment option for patients with advanced CKD/ESRF and T1DM for potential cure of these diseases and possibly several complications.However,limited availability of the organs for transplantation,the need for long-term immunosuppression to prevent rejection,peri-and post-operative complications of SPK,lack of resources and the expertise for the procedure in many centers,and the cost implications related to the surgery and postoperative care of these patients are major issues faced by clinicians across the globe.This clinical update review compiles the latest evidence and current recommendations of SPK for patients with T1DM and advanced CKD/ESRF to enable clinicians to care for these diseases.

Patient selection and preparation strategies for the use of contrast material in patients with chronic kidney disease

The prevalence of chronic kidney disease and peripheral arterial disease is increasing.Thus,it is increasingly problematic to image these patients as the number of patients needing a vascular examination is increasing accordingly.In high-risk patients with impaired kidney function,intravascular administration of iodinated contrast media can result in contrast-induced acute kidney injury and Gadolinium can induce nephrogenic systemic fibrosis(NSF).It is important to identify these highrisk patients by means of se-creatinine/e glomerular filtration rate.The indication for contrast examination should counterbalance the increased risk.One or more alternative examination methods without contrast media,such as CO 2 angiography,Ultrasound/Doppler examination or magnetic resonance angiography without contrast should be considered,but at the same time,allow for a meaningful outcome of the examination.If contrast is deemed essential,the patient should be well hydrated,the amount of contrast should be restricted,the examination should be focused,metformin and diuretics stopped,and renal function monitored.Sodium bicarbonate and N-acetylcysteine are popular but their efficiency is not evidence-based.There is no evidence that dialysis protects patients with impaired renal function from contrast-induced nephropathy or NSF.

Uric acid and chronic kidney disease: A time to act?

A role for uric acid in the pathogenesis and progression of renal disease had been proposed almost a century ago, but, too hastily dismissed in the early eighties. A body of evidence, mostly accumulated during the last decade, has led to a reappraisal of the infuence of uric acid on hypertension, cardiovascular, and renal disease. The focus of this review will be solely on the relationship between serum uric acid and renal function and disease. We will review experimental evidence derived from ani-mal and human studies, evidence gathered from a num-ber of epidemiological studies, and from the few （up to now） studies of uric-acid-lowering therapy. Some space will be also devoted to the effects of uric acid in special populations, such as diabetics and recipients of kidney allografts. Finally we will briefy discuss the challenges of a trial of uric-acid-lowering treatment, and the recent suggestions on how to conduct such a trial.

Interplay between metabolic dysfunction-associated fatty liver disease and chronic kidney disease:Epidemiology,pathophysiologic mechanisms,and treatment considerations

The recently proposed nomenclature change from non-alcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease(MAFLD)has resulted in the reappraisal of epidemiological trends and associations with other chronic diseases.In this context,MAFLD appears to be tightly linked to incident chronic kidney disease(CKD).This association may be attributed to multiple shared risk factors including type 2 diabetes mellitus,arterial hypertension,obesity,dyslipidemia,and insulin resistance.Moreover,similarities in their molecular pathophysiologic mechanisms can be detected,since inflammation,oxidative stress,fibrosis,and gut dysbiosis are highly prevalent in these pathologic states.At the same time,lines of evidence suggest a genetic predisposition to MAFLD due to gene polymorphisms,such as the PNPLA3 rs738409 G allele polymorphism,which may also propagate renal dysfunction.Concerning their management,available treatment considerations for obesity(bariatric surgery)and novel antidiabetic agents(glucagon-like peptide 1 receptor agonists,sodiumglucose co-transporter 2 inhibitors)appear beneficial in preclinical and clinical studies of MAFLD and CKD modeling.Moreover,alternative approaches such as melatonin supplementation,farnesoid X receptor agonists,and gut microbiota modulation may represent attractive options in the future.With a look to the future,additional adequately sized studies are required,focusing on preventing renal complications in patients with MAFLD and the appropriate management of individuals with concomitant MAFLD and CKD.

Vitamin D levels in subjects with or without chronic kidney disease among Veterans with diabetes in North East United States

AIM To evaluate the prevalence of vitamin D deficiency and its relation to diabetes and kidney disease in Veterans residing in the North East United States(VISN 2). METHODS In this retrospective study, we used data from the computerized patient record system at Stratton Veterans Administration Medical Center at Albany, NY(VHA) for those patients who had 25-hydroxyvitamin D levels and 1,25(OH) vitamin D levels measured between 2007 and 2010. We collected demographic information including age, sex, body mass index and race; clinical data including diabetes, hypertension and CAD; and laboratory data including calcium, creatinine and parathyroid hormone(PTH)(intact). Vitamin D deficiency is defined as a serum 25-hydroxyvitamin D level of less than 20 ng/mL(50 nmol/L), and insufficiency is defined as a serum 25-hydroxyvitamin D level of 20 to 30 ng/mL(50 to 75 nmol/L). RESULTS Data was available for approximately 68000 subjects. We identified 64144 subjects for analysis after exclusion of duplicates. Among them, 27098 had diabetes. Themean age of subjects with diabetes was 68 ± 11 with a mean body mass index(BMI) of 32 ± 7 and duration of diabetes of 5.6 ± 3.2 years. The mean 25(OH) vitamin D level among subjects with diabetes was 27 ± 11.6. There was no significant difference in 25(OH) vitamin D levels between subjects with diabetes and glomerular filtration rate(e-GFR) < 60 compared to those with e-GFR ≥ 60. As expected, subjects with e-GFR < 60 had significantly lower 1,25(OH) vitamin D levels and significantly elevated PTH-intact. Of the 64144 subjects, 580 had end-stage renal disease. Of those, 407 had diabetes and 173 did not. Vitamin D levels in both groups were in the insufficiency range and there was no significant difference irrespective of presence or absence of diabetes. Subjects with vitamin D levels less than 20 ng/mL had a higher BMI and elevated PTH, and higher HbA 1C levels compared to those with vitamin D levels more than 20 ng/mL. CONCLUSION We conclude that we need to keep a close eye on vitamin D levels in subjects with mild chronic kidney disease as well as those with moderate control of diabetes.

Study of Angiotensin Converting Enzyme Gene Polymorphism in Egyptian Type 2 Diabetes Mellitus with Diabetic Kidney Disease

Objective: Diabetic kidney disease DKD (Diabetic nephropathy DN) is considered one of the chronic micro vascular complications of diabetes mellitus and considered the commonest cause leading to chronic renal failure and chronic renal dialysis. Genetic susceptibility has been implicated in DKD. The angiotensin converting enzyme (ACE) is one of the key roles in the renin angiotensin system cascade by converting angiotensin I to angiotensin II which plays a key role in regulation of blood pressure as well as electrolytes and fluid balance. This study addressed the association of (ACE) gene polymorphisms with DN in Egyptian (T2DM) patients. Methods: Our research comprised of 75 cases of T2DM with diabetic kidney disease, 100 cases of T2DM without DKD and 94 healthy volunteers. Different genotypes of ACE gene were determined by SSP-PCR analysis. Results: Gene polymorphism of ACE (DD, ID, II) in diabetic patient with DKD is 44%, 52%, 4% respectively and for T2DM individuals without DKD is 23%, 72%, 5% respectively. (DD) had significant higher frequencies in T2DM patients with DKD compared to those without DKD (p < 0.005) and (ID) had significant higher frequencies in T2DM without DKD (p < 0.0001). These results indicated that there is an association between ACE gene polymorphisms and susceptibility of diabetic patients to be affected by diabetic kidney disease. Conclusion: From our results, we can conclude that genotype of ACE in Egypt DD is the genotype of cases diabetic kidney disease. So the presence of D allele has a significant relation with diabetic kidney disease. Our data confirm the role of ACE in its relationship with diabetic kidney disease in Egyptian type 2 diabetic patients.

Percutaneous Angioplasty in Diabetic Patients with Critical Limb Ischemia and Chronic Kidney Disease

Introduction: Diabetes and Chronic Kidney Disease (CKD) are two strong risk factors for peripheral arterial disease (PAD) and Critical Limb Ischemia (CLI). Further renal insufficiency increases the risk of non healing wounds and major amputation. Primary amputation rates of 22% to 44% have been reported for ischaemic foot lesion in End-Stage Renal Disease (ESRD) patients. In our study we evaluated the outcomes after Percutaneus Transluminal Angioplasty (PTA) in diabetic patient in relation to different CKD classes. Materials and Methods: We studied a group of 456 diabetic patients with PAD complicated by foot lesion who underwent PTA because of a CLI. According to the estimated Glomerular Filtration Rate (eGFR mL/min/1.73 m2) we divided the patients into five CKD groups: group 1 eGFR > 90, group 2 eGFR 90 - 60 (n = 160), group 3 eGFR 60 - 30 (n = 152), group 4 eGFR 30 -15 (n = 34) and group 5 < 15 or in ESRD) (n = 60). The following outcomes were recorded: alive without major amputation, alive with major amputation and death. The follow-up was 16.7 ± 14.3 months. Results: Alive without major amputation, alive with major amputation and death were respectively: for group 1 (77.8%, 11.1%, 11.1%), for group 2 (74.4%, 12.5%, 13.1%), for group 3 (80.3%, 11.2%, 8.5%), for group 4 (82.3%, 8.8%, 8.8%). They were 60%, 18.3%, 21.7% for group 5 significantly different from the other CKD groups (χ2 = 0.0175). Our analysis did not highlight any relationship between eGFR and outcomes and eGFR did not show any significant difference according to the different outcomes, and were respectively 60.2 ± 1.3, 61.8 ± 3.4, 63.8 ± 3.5 (P = ns). Conclusion: The outcomes were similar for groups 1-4 and therefore, according to our data, they seemed not to be influenced by the decline of GFR. Outcomes worse significantly in group 5, but this group included only patients with ESRD in dialysis treatment. Although the outcomes after PTA in group 5 was significantly worse than the other groups, still a 60% limb salvage rate was obtained with PTA also in these very fragile patients. PTA was much less aggressive than by-pass and PTA was the only method used to treat CLI in our patients. This could explain why we recorded similar outcomes in all groups despite the decline of GFR that, generally speaking, mirrors a worsening of the general clinical conditions. Worse outcomes were recorded only in group 5 and in this group dialysis by itself might be responsible of the different outcomes.

Hepatogenous diabetes: Is it a neglected condition in chronic liver disease?

Diabetes mellitus(DM) that occurs because of chronic liver disease(CLD) is known as hepatogenous diabetes(HD). Although the association of diabetes and liver cirrhosis was described forty years ago, it was scarcely studied for long time. Patients suffering from this condition have low frequency of risk factors of type 2 DM. Its incidence is higher in CLD of viral, alcoholic and cryptogenic etiology. Its pathophysiology relates to liver damage, pancreatic dysfunction, interactions between hepatitis C virus(HCV) and glucose metabolism mechanisms and genetic susceptibility. It associates with increased rate of liver complications and hepatocellular carcinoma, and decreased 5-year survival rate. It reduces sustained virological response in HCV infected patients. In spite of these evidences, the American Diabetes Association does not recognize HD. In addition, the impact of glucose control on clinical outcomes of patients has not been evaluated. Treatment of diabetes may be difficult due to liver insufficiency and hepatotoxicity of antidiabetic drugs. Notwithstanding, no therapeutic guidelines have been implemented up to date. In this editorial, authors discuss the reasons why they think that HD may be a neglected pathological condition and call attention to the necessity for more clinical research on different fields of this disease.

Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/NF-κB/miR-155-5p inflammatory loop

BACKGROUND Type 2 diabetes mellitus(T2DM)is significantly increasing worldwide,and the incidence of its complications is also on the rise.One of the main complications of T2DM is diabetic kidney disease(DKD).The glomerular filtration rate(GFR)and urinary albumin creatinine ratio(UACR)increase in the early stage.As the disease progresses,UACR continue to rise and GFR begins to decline until endstage renal disease appears.At the same time,DKD will also increase the incidence and mortality of cardiovascular and cerebrovascular diseases.At present,the pathogenesis of DKD is not very clear.Therefore,exploration of the pathogenesis of DKD to find a treatment approach,so as to delay the development of DKD,is essential to improve the prognosis of DKD.AIM To detect the expression of tenascin-C(TNC)in the serum of T2DM patients,observe the content of TNC in the glomerulus of DKD rats,and detect the expression of TNC on inflammatory and fibrotic factors in rat mesangial cells(RMCs)cultured under high glucose condition,in order to explore the specific molecular mechanism of TNC in DKD and bring a new direction for the treatment of DKD.METHODS The expression level of TNC in the serum of diabetic patients was detected by enzyme-linked immunosorbent assay(ELISA),the protein expression level of TNC in the glomerular area of DKD rats was detected by immunohistochemistry,and the expression level of TNC in the rat serum was detected by ELISA.Rat glomerular mesangial cells were cultured.Following high glucose stimulation,the expression levels of related proteins and mRNA were detected by Western blot and polymerase chain reaction,respectively.RESULTS ELISA results revealed an increase in the serum TNC level in patients with T2DM.Increasing UACR and hypertension significantly increased the expression of TNC(P<0.05).TNC expression was positively correlated with glycosylated haemoglobin(HbA1c)level,body mass index,systolic blood pressure,and UACR(P<0.05).Immunohistochemical staining showed that TNC expression in the glomeruli of rats with streptozotocin-induced diabetes was significantly increased compared with normal controls(P<0.05).Compared with normal rats,serum level of TNC in diabetic rats was significantly increased(P<0.05),which was positively correlated with urea nitrogen and urinary creatinine(P<0.05).The levels of TNC,Toll-like receptor-4(TLR4),phosphorylated nuclear factor-κB p65 protein(Ser536)(p-NF-κB p65),and miR-155-5p were increased in RMCs treated with high glucose(P<0.05).The level of TNC protein peaked 24 h after high glucose stimulation(P<0.05).After TNC knockdown,the levels of TLR4,p-NF-κB p65,miR-155-5p,connective tissue growth factor(CTGF),and fibronectin(FN)were decreased,revealing that TNC regulated miR-155-5p expression through the TLR4/NF-κB p65 pathway,thereby regulating inflammation(NF-κB p65)and fibrosis(CTGF and FN)in individuals with DKD.In addition,metformin treatment may relive the processes of inflammation and fibrosis in individuals with DKD by reducing the levels of the TNC,p-NF-κB p65,CTGF,and FN proteins.CONCLUSION TNC can promote the occurrence and development of DKD.Interfering with the TNC/TLR4/NF-κB p65/miR-155-5p pathway may become a new target for DKD treatment.

Diabetes treatment in patients with renal disease: Is the landscape clear enough?

Diabetes is the most important risk factors for chronic kidney disease(CKD). The risk of CKD attributable to diabetes continues to rise worldwide. Diabetic patients with CKD need complicated treatment for their metabolic disorders as well as for related comorbidities. They have to treat, often intensively, hypertension, dyslipidaemia, bone disease, anaemia, and frequently established cardiovascular disease. The treatment of hypoglycaemia in diabetic persons with CKD must tie their individual goals of glycaemia(usually less tight glycaemic control) and knowledge on the pharmacokinetics and pharmacodynamics of drugs available to a person with kidney disease. The problem is complicated from the fact that in many efficacy studies patients with CKD are excluded so data of safety and efficacy for these patients are missing. This results in fear of use by lack of evidence. Metformin is globally accepted as the first choice in practically all therapeutic algorithms for diabetic subjects. The advantages of metformin are low risk of hypoglycaemia, modest weight loss, effectiveness and low cost. Data of UKPDS indicate that treatment based on metformin results in less total as well cardiovascular mortality. Metformin remains the drug of choice for patients with diabetes and CKD provided that their estimate Glomerular Filtration Rate(eGFR) remains above 30 mL/min per square meter. For diabetic patients with eGFR between 30-60 mL/min per square meter more frequent monitoring of renal function and dose reduction of metformin is needed. The use of sulfonylureas, glinides and insulin carry a higher risk of hypoglycemia in these patients and must be very careful. Lower doses and slower titration of the dose is needed. Is better to avoid sulfonylureas with active hepatic metabolites, which are renally excreted. Very useful drugs for this group of patients emerge dipeptidyl peptidase 4 inhibitors. These drugs do not cause hypoglycemia and most of them(linagliptin is an exception) require dose reduction in various stages of renal disease.

Stop chronic kidney disease progression: Time is approaching

Progression of chronic kidney disease （CKD） is inevitable. However, the last decade has witnessed tremendous achievements in this field. Today we are optimistic; the dream of withholding this progression is about to be realistic. The recent discoveries in the field of CKD management involved most of the individual diseases leading the patients to end-stage renal disease. Most of these advances involved patients suffering diabetic kidney disease, chronic glomerulonephritis, polycystic kidney disease, renal amyloidosis and chronic tubulointer-stitial disease. The chronic systemic inflammatory status and increased oxidative stress were also inve-stigated. This inflammatory status influences the anti-senescence Klotho gene expression. The role of Klotho in CKD progression together with its therapeutic value are explored. The role of gut as a major source of infam-mation, the pathogenesis of intestinal mucosal barrier damage, the role of intestinal alkaline phosphatase and the dietary and therapeutic implications add a novel therapeutic tool to delay CKD progression.