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Incidence and predictors of chronic kidney disease in type-II diabetes mellitus patients attending at the Amhara region referral hospitals, Ethiopia: A follow-up study.
Ahmed, MA, Ferede, YM, Takele, WW
PloS one. 2022;(1):e0263138
Abstract
BACKGROUND Chronic kidney disease (CKD) is the severest form of kidney disease characterized by poor filtration. The magnitude of chronic kidney disease is trending upward in the last few years linked with the rapidly escalating cases of non-communicable chronic diseases, particularly diabetes mellitus. However, little is known about when this problem may occur, the incidence as well as predictors of chronic kidney disease among type-II diabetes mellitus patients. Thus, this study was conducted to determine the incidence, time to the occurrence, and predictors of chronic kidney disease in type-II diabetic patients attending the Amhara region referral hospitals, Ethiopia. METHODS A retrospective follow-up study was conducted involving 415 participants with type-II diabetes mellitus that enrolled in the chronic follow-up from 2012 to 2017. Multivariable shared Frailty Weibull (Gamma) survival model was employed considering the hospitals as a clustering variable. Model fitness was checked by both the Akaike information criteria (AIC) and log-likelihood. Factors having a p-value of ≤0.2 in the bi-variable analysis were considered to enter the multivariable model. Variables that had a p-value of <0.05 with its corresponding 95% confidence level were deemed to be significant predictors of chronic kidney disease. RESULTS The overall cumulative incidence of chronic kidney disease was 10.8% [95%; CI: 7.7-14.0%] with a median occurrence time of 5 years. The annual incidence rate was 193/10,000 [95%; CI: 144.28-258.78]. Having cardiovascular disease/s [AHR = 3.82; 95%CI: 1.4470-10.1023] and hypercholesterolemia [AHR = 3.31; 95% CI: 1.3323-8.2703] were predictors of chronic kidney disease. CONCLUSION One out of every ten diabetic patients experienced chronic kidney disease. The median time to develop chronic kidney disease was five years. Hypercholesterolemia and cardiovascular diseases have escalated the hazard of developing CKD. Thus, health promotion and education of diabetic patients to optimize cholesterol levels and prevent cardiovascular disease is recommended to limit the occurrence of this life-threatening disease.
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A physician-initiated double-blind, randomised, placebo-controlled, phase 2 study evaluating the efficacy and safety of inhibition of NADPH oxidase with the first-in-class Nox-1/4 inhibitor, GKT137831, in adults with type 1 diabetes and persistently elevated urinary albumin excretion: Protocol and statistical considerations.
Reutens, AT, Jandeleit-Dahm, K, Thomas, M, Salim, A, De Livera, AM, Bach, LA, Colman, PG, Davis, TME, Ekinci, EI, Fulcher, G, et al
Contemporary clinical trials. 2020;:105892
Abstract
PURPOSE Kidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox - 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. DESIGN This is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m2. PRIMARY OUTCOME MEASURES Difference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. CONCLUSION This study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment.
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Association of non-alcoholic fatty liver disease with microvascular complications of type 2 diabetes.
Afarideh, M, Aryan, Z, Ghajar, A, Ganji, M, Ghaemi, F, Saadat, M, Heidari, B, Mechanick, JI, Esteghamati, A
Primary care diabetes. 2019;(6):505-514
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) affects risks of type 2 diabetes (T2D), diabetes-related complications, and cardiovascular disease in a complex manner. This study is designed to clarify associations of sonographically-detected NAFLD and serum liver enzymes with diabetes-related microvascular complications. METHODS A matched case-contorl study was designed for 440 patients with T2D and at least one of the chronic diabetes-related microvascular complications and 495 age- and gender-matched control patients with T2D. RESULTS Considering pre-existing and newly developed chronic microvascular complications, diabetic peripheral neuropathy was found in 347 out of 935 (37.1%) study patients, diabetic retinopathy in 141/935 (15.1%), and diabetic nephropathy in 103/935 (11.0%). Diagnosis of diabetic retinopathy and diabetic nephropathy were inversely associated with the presence of NAFLD in the crude logistic regressions (OR [95% CI] = 0.18 [0.05-0.63], p value = 0.007; OR [95% CI] = 0.17 [0.04-0.59], p value = 0.011, respectively). The subgroup of NAFLD with elevated liver enzymes had lower odds of having diabetic peripheral neuropathy in the fully adjusted model (OR [95% CI] = 0.34 [0.12-0.98], p value = 0.048). CONCLUSION Diagnosis of NAFLD with or without elevated serum liver enzymes was inversely correlated with certain chronic diabetes microvascular complications. Possible explanations for this counter-intuitive and unexpected finding are discussed and center on reverse-causality, wherein sicker patients may develop beneficial compensatory physiological and behavioral adaptations. Diversity of studied patients, in particular with regards to the ethnic and racial differences among the Western and Asian populations may also partly account for contrasting findings of the relationship between NAFLD and microvascular complications of diabetes.
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Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.
Gerstein, HC, Colhoun, HM, Dagenais, GR, Diaz, R, Lakshmanan, M, Pais, P, Probstfield, J, Botros, FT, Riddle, MC, Rydén, L, et al
Lancet (London, England). 2019;(10193):131-138
Abstract
BACKGROUND Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING Eli Lilly and Company.
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Impact of Moderate Sodium Restriction and Hydrochlorothiazide on Iodine Excretion in Diabetic Kidney Disease: Data from a Randomized Cross-Over Trial.
Binnenmars, SH, Corpeleijn, E, Kwakernaak, AJ, Touw, DJ, Kema, IP, Laverman, GD, Bakker, SJL, Navis, G
Nutrients. 2019;(9)
Abstract
Sodium restriction may potentially reduce iodine intake. This study aimed to determine the effect of sodium restriction (dietary counseling) on 24-h urinary iodine excretion. Diuretics provide an alternative to sodium restriction and are frequently added to sodium restriction, so the effects of hydrochlorothiazide (50 mg daily) and combined therapy were also studied. We performed a post-hoc analysis of a Dutch multi-center, randomized cross-over trial in 45 patients with diabetic kidney disease with a mean age of 65 ± 9 years, mean eGFR of 65 ± 27 mL/min/1.73 m2, median albuminuria of 648 [230-2008] mg/24 h and 84% were male. During regular sodium intake with placebo, mean 24 h urinary sodium and iodine excretion were 224 ± 76 mmol/24 h and 252 ± 94 ug/24 h, respectively (r = 0.52, p < 0.001). Mean iodine excretion did not change significantly if sodium restriction and hydrochlorothiazide were applied separately; mean difference -8 ug/day (95% CI -38, 22; p = 0.6) and 14 ug/day (95% CI -24, 52; p = 0.5), respectively. Combined therapy induced a significant decrease in mean iodine excretion (-37 ug/day; 95% CI -67, -7; p = 0.02), yet this was not seen to a clinically meaningful level. The number of patients with an estimated intake below recommended daily allowances did not differ significantly between the four treatment periods (p = 0.3). These findings show that sodium restriction is not a risk factor for iodine deficiency.
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Longitudinal Assessment of the Effect of Atrasentan on Thoracic Bioimpedance in Diabetic Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial.
Webb, DJ, Coll, B, Heerspink, HJL, Andress, D, Pritchett, Y, Brennan, JJ, Houser, M, Correa-Rotter, R, Kohan, D, Makino, H, et al
Drugs in R&D. 2017;(3):441-448
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Abstract
BACKGROUND Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, atrasentan. OBJECTIVE We performed longitudinal assessments of thoracic bioimpedance in patients with type 2 diabetes mellitus and nephropathy to determine whether a decrease in bioimpedance accurately reflected fluid retention during treatment with atrasentan. STUDY DESIGN We conducted a randomized, double-blind, placebo-controlled study in 48 patients with type 2 diabetes mellitus and nephropathy who were receiving stable doses of renin angiotensin system inhibitors and diuretics. METHODS Patients were randomized 1:1:1 to placebo, atrasentan 0.5 mg, or atrasentan 1.25 mg once daily for 8 weeks. Thoracic bioimpedance, vital signs, clinical exams, and serologies were taken at weeks 1, 2, 4, 6, and 8, with the exception of serum hemoglobin, which was not taken at week 1, and serum brain natriuretic peptide, which was only taken at baseline, week 4, and week 8. RESULTS Alterations in bioimpedance were more often present in those who received atrasentan than in those who received placebo, though overall differences were not statistically significant. Transient declines in thoracic bioimpedance during the first 2 weeks of atrasentan exposure occurred before or during peak increases in body weight and hemodilution (decreased serum hemoglobin). CONCLUSIONS We conclude that thoracic bioimpedance did not reflect changes in weight gain or edema with atrasentan treatment in this study. However, the sample size was small, and it may be of interest to explore the use of thoracic bioimpedance in a larger population to understand its potential clinical use in monitoring fluid retention in patients with chronic kidney disease who receive ET receptor antagonists.
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Methylglyoxal is associated with changes in kidney function among individuals with screen-detected Type 2 diabetes mellitus.
Jensen, TM, Vistisen, D, Fleming, T, Nawroth, PP, Rossing, P, Jørgensen, ME, Lauritzen, T, Sandbaek, A, Witte, DR
Diabetic medicine : a journal of the British Diabetic Association. 2016;(12):1625-1631
Abstract
AIMS: The glycolysis-derived metabolite methylglyoxal has been linked to clinical microvascular complications, including diabetic nephropathy. We aimed to further investigate the hypothesis that methylglyoxal is involved in decline in renal function by assessing the associations between measures of renal function during a 6-year follow-up in 1481 people with screen-detected Type 2 diabetes, as part of the Danish arm of the ADDITION-Europe trial (ADDITION-DK). METHODS Biobank serum samples collected at ADDITION-DK baseline (2001-2006) and follow-up (2009-2010) were used in the current analysis of methylglyoxal. We assessed cross-sectional baseline and longitudinal associations between methylglyoxal and urinary albumin-to-creatinine ratio (ACR) or estimated GFR (eGFR), and between methylglyoxal and categories of albuminuria or reduced eGFR. RESULTS Baseline methylglyoxal was positively associated with ACR at baseline (12% higher ACR per doubling in methylglyoxal levels), and change in methylglyoxal during 6 years of follow-up was inversely associated with change in eGFR (-1.6 ml/min/1.73 m2 per doubling in methylglyoxal change), in models adjusted for age, sex, HbA1c , systolic blood pressure, anti-hypertensive treatment, LDL-cholesterol, lipid-lowering treatment, C-reactive protein and smoking. CONCLUSIONS In a population of people with screen-detected Type 2 diabetes, we observed associations between methylglyoxal and markers of renal function: 6-year change in methylglyoxal was inversely associated with 6-year change in eGFR. Also, methylglyoxal at baseline was positively associated with ACR at baseline. Our study lends further support to a role for methylglyoxal in the pathogenesis of diabetic nephropathy.
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Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes.
Wanner, C, Inzucchi, SE, Lachin, JM, Fitchett, D, von Eynatten, M, Mattheus, M, Johansen, OE, Woerle, HJ, Broedl, UC, Zinman, B, et al
The New England journal of medicine. 2016;(4):323-34
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BACKGROUND Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial. METHODS We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m(2) of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria. RESULTS Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P<0.001). Doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group, a significant relative risk reduction of 44%. Renal-replacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no significant between-group difference in the rate of incident albuminuria. The adverse-event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population. CONCLUSIONS In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care. (Funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).
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Hypertriglyceridemia Is Independently Associated with Renal, but Not Retinal Complications in Subjects with Type 2 Diabetes: A Cross-Sectional Analysis of the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study.
Penno, G, Solini, A, Zoppini, G, Fondelli, C, Trevisan, R, Vedovato, M, Gruden, G, Lamacchia, O, Pontiroli, AE, Arosio, M, et al
PloS one. 2015;(5):e0125512
Abstract
OBJECTIVE Atherogenic dyslipidemia seems to play a major role in microvascular complications and in residual microvascular risk after statin therapy, which reduces triglycerides up to 40%. We assessed whether raised TG levels are associated with an increased burden from microvascular complications in patients with type 2 diabetes. METHODS Subjects from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study (n=15,773) were divided in 4 groups depending on whether they had plasma triglycerides below (NTG, 67.8%) or above (HTG, 32.2%) 1.7 mmol/L and were (42.4%) or not on (57.6%) statin therapy. Estimated GFR (eGFR) was calculated from serum creatinine, albuminuria was measured by immunonephelometry or immunoturbidimetry, and retinopathy was evaluated by fundus examination. RESULTS HTG subjects, either with or without statin, had higher prevalence of albuminuria, reduced eGFR and chronic kidney disease (CKD), especially the albuminuric forms, but not of retinopathy, than NTG subjects. In contrast, cardiovascular disease and advanced DR were more prevalent in subjects on statin than in those not, independently of triglyceride levels. Logistic regression analysis confirmed that HTG, without or with statin, was independently associated with micro and macroalbuminuria, mildly to severely reduced eGFR, and all CKD phenotypes, but not with retinopathy. The adjusted odd ratios for CKD increased linearly for every 0.26 mmol/L increase (approximately one decile) in triglyceride levels. The increase was higher with increasing severity of albuminuria, eGFR loss and CKD phenotype as well as in subjects receiving than in those not receiving statin treatment. CONCLUSIONS Triglycerides are associated with CKD, but not retinopathy in subjects with type 2 diabetes, independently of statin treatment. These data point to a possible role of hypertriglyceridemia in the development of CKD, though it remains to be demonstrated that diabetic individuals might benefit from triglyceride reduction with statins and eventually with combination therapy with fibrates. TRIAL REGISTRATION www.ClinicalTrials.gov NCT00715481.
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Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial.
de Zeeuw, D, Anzalone, DA, Cain, VA, Cressman, MD, Heerspink, HJ, Molitoris, BA, Monyak, JT, Parving, HH, Remuzzi, G, Sowers, JR, et al
The lancet. Diabetes & endocrinology. 2015;(3):181-90
Abstract
BACKGROUND The role of lipid-lowering treatments in renoprotection for patients with diabetes is debated. We studied the renal effects of two statins in patients with diabetes who had proteinuria. METHODS PLANET I was a randomised, double-blind, parallel-group trial done in 147 research centres in Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, and the USA. We enrolled patients with type 1 or type 2 diabetes aged 18 years or older with proteinuria (urine protein:creatinine ratio [UPCR] 500-5000 mg/g) and taking stable angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both. We randomly assigned participants to atorvastatin 80 mg, rosuvastatin 10 mg, or rosuvastatin 40 mg for 52 weeks. The primary endpoint was change from baseline to week 52 of mean UPCR in each treatment group. The study is registered with ClinicalTrials.gov, number NCT00296374. FINDINGS We enrolled 353 patients: 118 were assigned to rosuvastatin 10 mg, 124 to rosuvastatin 40 mg, and 111 to atorvastatin 80 mg; of these, 325 were included in the intention-to-treat population. UPCR baseline:week 52 ratio was 0·87 (95% CI 0·77-0·99; p=0·033) with atorvastatin 80 mg, 1·02 (0·88-1·18; p=0·83) with rosuvastatin 10 mg, and 0·96 (0·83-1·11; p=0·53) with rosuvastatin 40 mg. In a post-hoc analysis to compare statins, we combined data from PLANET I with those from PLANET II (a similar randomised parallel study of 237 patients with proteinuria but without diabetes; registered with ClinicalTrials.gov, NCT00296400). In this analysis, atorvastatin 80 mg lowered UPCR significantly more than did rosuvastatin 10 mg (-15·6%, 95% CI -28·3 to -0·5; p=0·043) and rosuvastatin 40 mg (-18·2%, -30·2 to -4·2; p=0·013). Adverse events occurred in 69 (60%) of 116 patients in the rosuvastatin 10 mg group versus 79 (64%) of 123 patients in the rosuvastatin 40 mg group versus 63 (57%) of 110 patients in the atorvastatin 80 mg group; renal events occurred in nine (7·8%) versus 12 (9·8%) versus five (4·5%). INTERPRETATION Despite high-dose rosuvastatin lowering plasma lipid concentrations to a greater extent than did high-dose atorvastatin, atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population. FUNDING AstraZeneca.