Persistent Macroalbuminuria Research Articles

The Impact of Glucagon-Like Peptide-1 Receptor Agonists on Kidney Outcomes: A Meta-Analysis of Randomized Placebo-Controlled Trials.

Key Points This is an updated meta-analysis about glucagon-like peptide-1 receptor agonists (GLP-1 RAs) incorporating findings from the recently published FLOW and SELECT studies.Our findings show that GLP-1 RAs reduce kidney disease progression in patients with type 2 diabetes or overweight/obesity status, with or without CKD.Our meta-analysis supports the use of GLP-1 RAs for reducing the risk of adverse kidney outcomes across different populations. Background Recent data indicate a potential benefit of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on the progression of kidney disease among patients with CKD. Our aim was to evaluate the effect of GLP-1 RAs on the risk of worsening kidney function across different populations. Methods We conducted a meta-analysis of randomized controlled trials that tested GLP-1 RA treatment versus placebo in individuals with type 2 diabetes or with overweight/obesity status, with or without CKD, with kidney events reported as primary or secondary end points. The primary outcome was the occurrence of worsening kidney function, defined as either a doubling of serum creatinine or a ≥40% or ≥50% decline in eGFR, according to each study report. Secondary outcomes included development of persistent macroalbuminuria and a composite of worsening kidney function or the development of persistent macroalbuminuria. Subgroup analyses were performed by eGFR and albuminuria categories. The results are presented as risk ratios with 95% confidence intervals. Results Eight trials were eligible, including a total of 68,572 patients, of whom 34,042 (49.6%) received GLP-1 RA treatment. During follow-up, 1028 participants receiving GLP-1 RA (3.0%) and 1150 participants receiving placebo (3.5%) experienced worsening kidney function. Treatment with GLP-1 RAs (versus placebo) resulted in a reduction in the risk of worsening kidney function (risk ratios, 0.84; 95% confidence interval, 0.77 to 0.91; P < 0.001). In addition, treatment with GLP-1 RAs significantly reduced the risk of developing persistent macroalbuminuria and the risk of the composite outcome of worsening kidney function or development of persistent macroalbuminuria. The results were consistent in patients with and without CKD. Conclusions In conclusion, our meta-analysis suggests that GLP-1 RA reduce kidney disease progression in type 2 diabetes or overweight/obesity regardless of CKD status.

Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial

The SELECT trial previously reported a 20% reduction in major adverse cardiovascular events with semaglutide (n = 8,803) versus placebo (n = 8,801) in patients with overweight/obesity and established cardiovascular disease, without diabetes. In the present study, we examined the effect of once-weekly semaglutide 2.4 mg on kidney outcomes in the SELECT trial. The incidence of the pre-specified main composite kidney endpoint (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent estimated glomerular filtration rate (eGFR) < 15 ml min−1 1.73 m−2, persistent ≥50% reduction in eGFR or onset of persistent macroalbuminuria) was lower with semaglutide (1.8%) versus placebo (2.2%): hazard ratio (HR) = 0.78; 95% confidence interval (CI) 0.63, 0.96; P = 0.02. The treatment benefit at 104 weeks for eGFR was 0.75 ml min−1 1.73 m−2 (95% CI 0.43, 1.06; P < 0.001) overall and 2.19 ml min−1 1.73 m−2 (95% CI 1.00, 3.38; P < 0.001) in patients with baseline eGFR <60 ml min−1 1.73 m−2. These results suggest a benefit of semaglutide on kidney outcomes in individuals with overweight/obesity, without diabetes.ClinicalTrials.gov identifier: NCT03574597.

#2496 Effect of semaglutide on kidney outcomes in people with overweight or obesity and established cardiovascular disease in the SELECT trial

Abstract Background and Aims Obesity is an important risk factor for declining kidney function and albuminuria. Secondary analyses of cardiovascular outcome trials in people with type 2 diabetes suggest that the glucagon-like peptide-1 receptor agonist semaglutide has the potential to reduce kidney function deterioration. Semaglutide reduced the primary endpoint of major adverse cardiovascular events by 20% in the randomised controlled SELECT trial in people with overweight or obesity without diabetes. The present report is the prespecified analysis on secondary and exploratory kidney outcomes in SELECT. Method The main kidney endpoint was the time from randomisation to first occurrence of a 5-component nephropathy composite comprising: death from kidney causes; initiation of chronic kidney replacement therapy (dialysis or transplantation); onset of persistent estimated glomerular filtration rate (eGFR) &amp;lt;15 mL/min/1.73 m2; persistent ≥50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria. Persistence was defined as at least two measures at least 4 weeks apart. Patients were randomised to once-weekly subcutaneous semaglutide 2.4 mg or placebo. Blood and urine samples for eGFR and urinary albumin-to-creatinine ratio (UACR) were collected at screening, at 20, 52, 104, 156, 208 weeks of follow-up and at the end of treatment. Analyses were of in-trial data and used Cox regression and mixed models for repeated measures. Results A total of 8803 patients were assigned to semaglutide and 8801 to placebo. The median follow-up was 182 weeks. The main composite nephropathy endpoint occurred in fewer of those assigned semaglutide (1.8% [155/8803]) than placebo (2.2% [198/8801]): hazard ratio 0.78 [95% confidence interval (CI) 0.63, 0.96]; p = 0.02 (Fig. 1). This effect on the main endpoint was driven by the treatment effect on onset of macroalbuminuria and, to a lesser extent, persistent ≥50% reduction in eGFR. At the prespecified 104-week time point, eGFR had declined less in the semaglutide than placebo arm, giving a treatment effect of 0.75 mL/min/1.73 m2 [95% CI 0.43, 1.06]; p &amp;lt; 0.001 (Fig. 2A). The treatment effect on eGFR at 104 weeks was 0.57 mL/min/1.73 m2 [95% CI 0.26, 0.89] among those with eGFR ≥60 mL/min/1.73 m2 (N = 15 638) at baseline and was 2.19 mL/min/1.73 m2 [95% CI 1.00, 3.38] in those with eGFR &amp;lt;60 mL/min/1.73 m2 (N = 1908) at baseline. At 104 weeks the proportionate increase in UACR was less in the semaglutide than the placebo arm, with a treatment effect of –10.7% [95% CI –13.2, –8.2]; p &amp;lt; 0.001 (Fig. 2B). The treatment effect on UACR at 104 weeks was –8.1% [95% CI –10.6, –5.6], –27.2% [95% CI –35.3, –18.1] and –31.4% [95% CI –54.9, 4.3] in those with normo- (N = 14 848), micro- (N =1968) and macroalbuminuria (N = 325) at baseline, respectively. Semaglutide was not associated with any excess of acute kidney injury, regardless of baseline eGFR. Conclusion These prespecified secondary analyses suggest a beneficial effect of once-weekly subcutaneous semaglutide 2.4 mg on a composite kidney endpoint in people with overweight or obesity and established cardiovascular disease. Significant benefits for both eGFR and UACR were found, including clinically relevant lesser eGFR decline in those with baseline eGFR &amp;lt;60 mL/min/1.73 m2.

A Review and Meta-Analysis of the Safety and Efficacy of Using Glucagon-like Peptide-1 Receptor Agonists.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to reduce glucose levels in patients with type 2 diabetes mellitus since 2005. This meta-analysis discusses the mechanisms and potential benefits of several GLP-1 RAs. In particular, this meta-analysis focuses on the safety and associations with weight loss, glucose reduction, cardiovascular outcomes, heart failure, and renal outcomes of GLP-1 RAs to determine their benefits for patients with different conditions. In terms of glycemic control and weight loss, semaglutide was statistically superior to other GLP-1 RAs. In terms of cardiovascular outcomes, 14 mg of semaglutide taken orally once daily and 1.8 mg of liraglutide injected once daily reduced the incidence of cardiovascular death, whereas other GLP-1 RAs did not provide similar benefits. Moreover, semaglutide was associated with superior outcomes for heart failure and cardiovascular death in non-diabetic obesity patients, whereas liraglutide worsened heart failure outcomes in diabetic patients with a reduced ejection fraction. Additionally, semaglutide, dulaglutide, and liraglutide were beneficial in terms of composite renal outcomes: These GLP-1 RAs were significantly associated with less new or persistent macroalbuminuria, but not with improved eGFR deterioration or reduced requirement for renal replacement therapy. However, GLP-1 RAs may benefit patients with type 2 diabetes mellitus or obesity.

STUDY OF MICROALBUMINURIAAND ALBUMIN - CREATININE RATIO IN TYPE 2 DIABETES MELLITUS AND THEIR CORRELATION WITH GFR AND OTHER BIOCHEMICAL PARAMETERS

Diabetes mellitus (DM) is one of the primary risk factors for developing renal impairment globally. The development of microalbuminuria has been considered to be one of the rst clinical signs of a classic course of diabetic nephropathy, which leads to macroalbuminuria and then to progressive loss of glomerular ltration rate (GFR) and eventually end-stage renal disease. Both type 1 and type 2 DM may lead to chronic complication of diabetic nephropathy (DN). The development of microalbuminuria has been considered to be one of the rst clinical signs of a classic course of diabetic nephropathy, which leads to macroalbuminuria and then to progressive loss of glomerular ltration rate (GFR) and eventually end-stage renal disease. Persistent macroalbuminuria predicts loss of kidney function and, more importantly, interventions that reduce macroalbuminuria also slow the loss of glomerular ltration rate. this prospective observational study was designed in an attempt to evaluate the relationship between microalbuminuria, albumin-creatinine ratio with other biochemical parameters in type 2 DM and to examine whether this relation differs from that of non-diabet

Association of Fetuin-A with Thr256Ser exon polymorphism of α2-Heremans Schmid Glycoprotein (AHSG) gene in type 2 diabetic patients with overt nephropathy

BackgroundCirculatory Fetuin-A has been well reported to elevate the risk for Diabetic Nephropathy (DN) and is associated with many vascular complications. Compelling reports have well documented that the circulatory levels of Fetuin-A directly have an impact on its AHSG (α2- Heremans- Schmid Glycoprotein) gene single nucleotide polymorphisms (SNP). Thus, in this study among the South Indian T2DM population, we aim to explore the association of AHSG Thr256Ser (rs4918) SNP in subjects with DN and correlate with the circulatory levels of Fetuin-A at various stages of DN patients. MethodsA total of 975 subjects were recruited, such as Group-I, consisting of Controls (n = 300), Group-II, with normoalbuminuria (n = 300), Group-IIIa, with incipient microalbuminuria (n = 195), Group-IIIb, with persistent macroalbuminuria (n = 180)] and were subjected for genotyping using PCR-Restriction Fragment Length Polymorphism (RFLP). Circulatory Fetuin-A was measured using sandwich enzyme-linked immunosorbent assay (ELISA). ResultsThe ‘G’ allele of AHSG exon-7 (C/G) SNP is significantly concomitant and conferred significant risk for normoalbuminuria subjects. In the DN subjects, the ‘G' allele showed the risk for persistent macroalbuminuria. A noticeable stepwise decrease was evidenced in the circulatory Fetuin-A among persistent macroalbuminuria over incipient microalbuminuria from normoalbuminuria. Further, the circulatory Fetuin-A was lowered in DN subjects with mutant GG genotype than the wild CC. ConclusionAHSG Thr256Ser (rs4918) SNP was associated with renal complications among South Indian T2DM subjects.

Diabetic Kidney Disease in Childhood and Adolescence: Conventional and Novel Renoprotective Strategies

Diabetic kidney disease (DKD) is defined as a clinical syndrome consisting of persistent macroalbuminuria, progressive decline in glomerular filtration rate (GFR), hypertension, increased cardiovascular disease events, and the associated mortality of these conditions. The disease evolves from the microvascular complications of poorly controlled Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM). The pathogenic pathways comprise renal haemodynamic changes, ischaemia and inflammation, and overactive renin–angiotensin–aldosterone system (RAAS), through which several events cascade down from hyperglycaemia to renal fibrosis. Conventional and novel renoprotective strategies target modifiable DKD risk factors and specific stages of the pathogenic pathways, respectively. Although these strategies may slow DKD progression to end-stage kidney disease (ESKD), novel drugs are still undergoing trials for validation in human participants. This narrative review appraises these renoprotective strategies and highlights the current clinical staging and pathogenesis of the disease.

P1017A RANDOMIZED, PLACEBO-CONTROLLED MULTICENTER STUDY OF THE EFFECTS OF 12 WEEKS OF SODIUM ZIRCONIUM CYCLOSILICATE (SZC) ON ALBUMINURIA (UACR) IN PATIENTS WITH TYPE 2 DIABETES AND HYPERKALEMIA

Abstract Background and Aims Hyperkalemia is a frequent challenge in the treatment of type 2 diabetes and chronic kidney disease. It often leads to suboptimal dosing or discontinuation of renin-angiotensin (RAS) blockade, thus increasing the risk of renal disease progression. Furthermore, epidemiological findings indicate that high potassium levels impair the renoprotective effect of RAS blockade. We want to test whether adjunctive treatment with sodium zirconium cyclosilicate (SZC) a new treatment for hyperkalemia, improves the effect of standard RAS blocking treatment as measured by urinary albumin creatinine ratio (UACR) in individuals with type 2 diabetes. Method Randomized, double-blind placebo-controlled multicenter study with 2 sites in Denmark and 3 sites in Sweden. Individuals (n=100) with type 2 diabetes (age 18-85), persistent macroalbuminuria (UACR≥ 200 mg/g) on chronic RAS blocking treatment and documented hyperkalemia (plasma potassium ≥ 5.0 mmol/L at least once within 90 days of inclusion) will be enrolled in the study. Participants with plasma potassium &amp;gt;5.0 mmol/L at the last assessment before randomization will be randomized to receive SZC 10 g or placebo three times a day (tid) for 2 days followed by SZC 5g or placebo once a day (qd). Participants with serum potassium ≤ 5.0 mmol/L will be randomized to receive SZC qd or placebo qd.UACR will be measured in three consecutive morning spot urine collections at baseline and the end of study after 12 weeks of treatment with Lokelma or placebo. Results The primary outcome is change in geometric mean UACR from baseline to end of studySecondary outcomes include changes in estimated glomerular filtration rate (eGFR, calculated by CKD-EPI formula) and 24-h urinary sodium and potassium excretion.In an exploratory analysis the long-term effect of potassium reduction will be modelled using the PRE-SCORE risk calculator. In addition, changes in plasma aldosterone levels will be assessed, and safety will be monitored according to good clinical practice. Conclusion This study will test the concept of SZC as an add-on therapy to improve the renoprotective effect of standard RAS blocking treatment. This could provide future potential for keeping more individuals on optimal dosing of RAS blockade.

Variations in Risk of End-Stage Renal Disease and Risk of Mortality in an International Study of Patients With Type 1 Diabetes and Advanced Nephropathy.

OBJECTIVEPatients with type 1 diabetes and diabetic nephropathy are targets for intervention to reduce high risk of end-stage renal disease (ESRD) and deaths. This study compares risks of these outcomes in four international cohorts.RESEARCH DESIGN AND METHODSIn the 1990s and early 2000s, Caucasian patients with type 1 diabetes with persistent macroalbuminuria in chronic kidney disease stages 1–3 were identified in the Joslin Clinic (U.S., 432), Finnish Diabetic Nephropathy Study (FinnDiane) (Finland, 486), Steno Diabetes Center Copenhagen (Denmark, 368), and INSERM (France, 232) and were followed for 3–18 years with annual creatinine measurements to ascertain ESRD and deaths unrelated to ESRD.RESULTSDuring 15,685 patient-years, 505 ESRD cases (rate 32/1,000 patient-years) and 228 deaths unrelated to ESRD (rate 14/1,000 patient-years) occurred. Risk of ESRD was associated with male sex; younger age; lower estimated glomerular filtration rate (eGFR); higher albumin/creatinine ratio, HbA1c, and systolic blood pressure; and smoking. Risk of death unrelated to ESRD was associated with older age, smoking, and higher baseline eGFR. In adjusted analysis, ESRD risk was highest in Joslin versus reference FinnDiane (hazard ratio [HR] 1.44, P = 0.003) and lowest in Steno (HR 0.54, P < 0.001). Differences in eGFR slopes paralleled risk of ESRD. Mortality unrelated to ESRD was lowest in Joslin (HR 0.68, P = 0.003 vs. the other cohorts). Competing risk did not explain international differences in the outcomes.CONCLUSIONSDespite almost universal renoprotective treatment, progression to ESRD and mortality in patients with type 1 diabetes with advanced nephropathy are still very high and differ among countries. Finding causes of these differences may help reduce risk of these outcomes.

Practice pearl: liraglutide and cardiovascular and renal events in type 2 diabetes

ABSTRACTReview of:Marso S, Daniels G, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375: 311–322.Mann J, Orsted D, Brown-Frandsen K, et al. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med 2017; 377: 839–848.This comprehensive research project, LEADER, led to two reports, one focusing on the effect of liraglutide on cardiovascular events, and the second one reporting on the renal effects on the same study population. The study group included 9340 patients with type 2 diabetes. Patients were required to have type 2 diabetes and an age 50 with a previous cardiovascular problem or chronic heart failure, or an age of 60 with at least one cardiovascular risk factor. Patients were randomized to 1.8 mg (or the maximum tolerated dose) of liraglutide, or placebo. The median follow up was 3.8 years. The primary cardiovascular outcome, a combined endpoint of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, was seen in 13% (608 of 4668 patients) treated with liraglutide versus 14.9 % (694 of 4672 patients) in the placebo patients (HR 0.87; 95% confidence interval [CI] 0.78 to 0.97; P = 0.01 for superiority). Death from cardiovascular disease and death from any cause were also lower in the liraglutide group. The rates for nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were not significantly reduced. In the renal report, the renal outcome was reduced in the liraglutide versus the placebo group (268 of 4668 versus 337 out of 4672 in the placebo group; HR 0.78; CI 0.67 to 0.92; p = 0.003). This improvement was mainly driven by a lower rate of the new onset of persistent macroalbuminuria in the liraglutide patients (161 vs 215 patients; HR 0.74; 95% CI, 0.60 to 0.91; p = 0.004), while the rates of other renal adverse events were similar in both groups. When taken together these two reports are the first data to show that the glucagon-like peptide 1 (GLP-1) analogue liraglutide can reduce cardiovascular events and halt progression to macroalbuminuria in patients with Type 2 diabetes.

Liraglutide and Renal Outcomes in Type 2 Diabetes

BackgroundIn a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown.MethodsWe report the prespecified secondary renal outcomes of that randomized, controlled trial in which patients were assigned to receive liraglutide or placebo. The secondary renal outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The risk of renal outcomes was determined with the use of time-to-event analyses with an intention-to-treat approach. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed.ResultsA total of 9340 patients underwent randomization, and the median follow-up of the patients was 3.84 years. The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1000 patient-years), including the rate of acute kidney injury (7.1 and 6.2 events per 1000 patient-years, respectively).ConclusionsThis prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.)

Abstract 569: Albuminuria, the HDL Proteome, and Prevalent Coronary Artery Calcium in Type 1 Diabetes

Patients with type 1 diabetes (T1D) are at high risk of atherosclerotic cardiovascular disease (CVD). Albuminuria is strongly associated with CVD risk and fully accounts for the excess overall mortality risk in some T1D cohorts. One important contributor might be alterations of the HDL proteome. In the current study, we tested the hypotheses that albuminuria is associated with alterations in the HDL proteome in T1D, and that these alterations are associated with prevalent CVD. We performed a cross-sectional study of 191 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) participants selected according to levels of urine albumin excretion (67 persistent normoalbuminuria, 64 persistent microalbuminuria, and 60 persistent macroalbuminuria). We used targeted proteomics and isotope dilution tandem-mass spectrometry to quantify the concentration of 47 proteins in HDL. Adjusting for age, sex, DCCT treatment group, duration of diabetes, lipid-lowering medications, renin-angiotensin system inhibitors, smoking, BMI, and HbA1c, and after accounting for multiple comparisons, six proteins in HDL were significantly associated with albuminuria (2 increased and 4 decreased). For example, compared to normoalbuminuria, macroalbuminuria was associated with 57% and 177% higher AMBP ( P =0.0003) and PTGDS ( P =0.0006), respectively, and 28% and 27% lower PON1 ( P =0.002) and PON3 ( P =0.008), respectively. Furthermore, PON1 and PON3 in HDL were strongly and negatively associated with the presence of coronary artery calcium, with odds ratios per 1-SD difference of 0.63 (0.43-0.92, 95% CI, P =0.02) for PON1 and 0.59 (0.40-0.87, 95% CI, P =0.008) for PON3. Our observations indicate that the HDL proteome is remodeled in albuminuric patients with T1D, and that these alterations in HDL’s protein cargo may mediate, in part, the relationship of albuminuria with CVD. Because PON1 and PON3 are anti-atherogenic in hypercholesterolemic mice, our data suggest that low levels of PON1 and PON3 in HDL increase the risk of atherosclerosis in diabetic humans. In future studies, it will be important to determine whether reductions of PON1 and PON3 in HDL predict the risk of future CVD in subjects with T1D.

LEADER and the new ‘cardiovascular’ glucose‐lowering agents

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Adiponectin is associated with early diabetic kidney disease in adults with type 1 diabetes: A Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study

ObjectiveThe associations between elevated adiponectin and end-stage renal disease are well recognized and thought to be at least partially explained by reduced renal clearance. Conversely, the relationship between adiponectin and early diabetic kidney disease (DKD) with preserved glomerular filtration rate (GFR), including rapid GFR decline and incident chronic kidney disease (CKD) is unclear. We hypothesized that elevated adiponectin would be associated with early DKD in adults with type 1 diabetes. MethodsAdults with type 1 diabetes (n=646 at baseline, n=525 at 6years) had adiponectin and renal function by estimated GFR (eGFR) by CKD-EPI creatinine and albumin-excretion rate (AER) evaluated at baseline and 6years. Linear and logistic models evaluated the associations of baseline adiponectin with AER, macroalbuminuria (AER ≥200μg/min), eGFR, CKD (<60mL/min/1.73m2) and rapid GFR decline (>3mL/min/1.73m2/year). Models adjusted for age, sex, duration, HbA1c, SBP, LDL-C and current smoking. ResultsCompared to non-diabetics, adults with type 1 diabetes had significantly higher adiponectin, and the difference remained significant after adjusting for AER and/or eGFR (p<0.0001). Adiponectin at baseline was positively associated with rapid GFR decline (OR: 1.24, 95% CI 1.00–1.53), incident CKD (OR: 1.75, 1.14–2.70), and persistent macroalbuminuria and CKD (OR: 1.61, 1.10–2.36) over 6years in adjusted models. The associations also remained significant after further adjustments for CRP, estimated insulin sensitivity and ACEi/ARB therapy. ConclusionsAdults with type 1 diabetes have higher adiponectin than their non-diabetic peers, and elevated adiponectin at baseline is independently associated with greater odds of developing early DKD over 6years.

Impact of HbA1c, followed from onset of type 1 diabetes, on the development of severe retinopathy and nephropathy: the VISS Study (Vascular Diabetic Complications in Southeast Sweden).

HbA1c is strongly related to the development of diabetes complications, but it is still controversial which HbA1c level to strive for in the treatment of type 1 diabetes. The aim of the current study was to evaluate HbA1c, followed from diagnosis, as a predictor of severe microvascular complications and to formulate HbA1c target levels for treatment. A longitudinal observation study followed an unselected population of 451 patients diagnosed with type 1 diabetes during 1983-1987 before the age of 35 years in a region of Southeast Sweden. Retinopathy was evaluated by fundus photography and nephropathy data collected from medical records. HbA1c was measured starting from diagnosis and during the whole follow-up period of 20-24 years. Long-term weighted mean HbA1c was then calculated. Complications were analyzed in relation to HbA1c levels. The incidence of proliferative retinopathy and persistent macroalbuminuria increased sharply and occurred earlier with increasing long-term mean HbA1c. None of the 451 patients developed proliferative retinopathy or persistent macroalbuminuria below long-term weighted mean HbA1c 7.6% (60 mmol/mol); 51% of the patients with long-term mean HbA1c above 9.5% (80 mmol/mol) developed proliferative retinopathy and 23% persistent macroalbuminuria. Long-term weighted mean HbA1c, measured from diagnosis, is closely associated with the development of severe complications in type 1 diabetes. Keeping HbA1c below 7.6% (60 mmol/mol) as a treatment target seems to prevent proliferative retinopathy and persistent macroalbuminuria for up to 20 years.

Urinary elafin and kidney injury in hematopoietic cell transplant recipients.

Graft-versus-host disease (GVHD) is associated with kidney injury after hematopoietic cell transplantation (HCT). Because plasma elafin levels correlate with skin GVHD, this study examined urinary elafin as a potential marker of renal inflammation and injury. Urine was collected prospectively on 205 patients undergoing their first HCT from 2003 to 2010. Collections were done at baseline, weekly through day 100, and monthly through year 1 to measure elafin and urine albumin-to-creatinine ratio (ACR). Associations between urinary elafin levels and microalbuminuria, macroalbuminuria, AKI and CKD, and mortality were examined using Cox proportional hazards or linear regression models. Available kidney biopsy specimens were processed for immunohistochemistry. Mean urinary elafin levels to day 100 were higher in patients with micro- or macroalbuminuria (adjusted mean difference, 529 pg/ml; P=0.03) at day 100 than in those with a normal ACR (adjusted mean difference, 1295 pg/ml; P<0.001). Mean urinary elafin levels were higher in patients with AKI compared with patients without AKI (adjusted mean difference, 558 pg/ml; P<0.01). The average urinary elafin levels within the first 100 days after HCT were higher in patients who developed CKD at 1 year than in patients without CKD (adjusted mean difference, 894 pg/ml; P=0.002). Among allogeneic recipients, a higher proportion of patients with micro- or macroalbuminuria at day 100 also had grade II-IV acute GVHD (80% and 86%, respectively) compared with patients with a normal ACR (58%; global P<0.01). Each increase in elafin of 500 pg/ml resulted in a 10% increase in risk of persistent macroalbuminuria (hazard ratio, 1.10; 95% confidence interval [95% CI], 1.06 to 1.13; P<0.001) and a 7% increase in the risk of overall mortality (95% CI, 1.02 to 1.13, P<0.01). Renal biopsy specimens from a separate cohort of HCT survivors demonstrated elafin staining in distal and collecting duct tubules. Higher urinary elafin levels are associated with an increased risk of micro- and macroalbuminuria, AKI and CKD, and death after HCT.

Urinary adiponectin excretion rises with increasing albuminuria in type 1 diabetes

AimUrinary adiponectin (u-adiponectin) excretion has been suggested to reflect early glomerular damage. Inspired by this, we studied the levels of u-adiponectin in type 1 diabetic patients with different levels of urinary albumin excretion (UAE). MethodsU-adiponectin was analysed by ELISA in type 1 diabetic patients: Fifty-eight with normoalbuminuria (<30mg albumin/24h), 43 with persistent microalbuminuria (30–300mg/24h) and 44 with persistent macroalbuminuria (>300mg/24h). For comparison, a control group of 55 healthy individuals was included. ResultsU-adiponectin increased with increasing levels of UAE (p<0.01). U-adiponectin median (interquartile range): Normoalbuminuria 0.38 (0.14–1.31), microalbuminuria 1.12 (0.20–2.68), macroalbuminuria 9.20 (1.10–23.35) and controls 0.09 (0.06–0.24) μg/g creatinine. Levels were unrelated to sex, age, cholesterol, diastolic BP and BMI. U-adiponectin was weakly associated with increasing systolic BP and HbA1c (r2<0.1, p<0.05), but strongly related to increasing UAE (r2=0.57, p<0.001) and decreasing eGFR (r2=0.26, p<0.001). The relationship between UAE and u-adiponectin was significant in all groups and independent of eGFR, BMI, BP and HbA1c. Furthermore, u-adiponectin was associated with markers of tubular damage (p<0.01). ConclusionU-adiponectin rises with increasing levels of UAE in patients with type 1 diabetes. This is in accordance with the hypothesis that loss of adiponectin may reflect glomerular and/or tubular damage.

Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial

To address whether nondihydropyridine calcium-channel blocker added-on angiotensin-converting-enzyme inhibitor therapy ameliorates albuminuria and cardiovascular outcomes in type 2 diabetes patients. The Bergamo Nephrologic Diabetes Complications Trial-B was a multicentre, prospective, double-blind, parallel-group trial comparing renal and cardiovascular outcomes in 281 hypertensive type 2 diabetes patients with microalbuminuria randomized to at least 2-year VeraTran (verapamil/trandolapril 180 mg/2 mg daily) or trandolapril (2 mg daily, identical image) treatment. Main outcome was persistent macroalbuminuria (albuminuria >200 µg/min in two consecutive visits). Treatment targets were SBP/DBP less than 120/80 mmHg and HbA1C less than 7%. Over a median follow-up of 4.5 years, 18 patients (13%) on VeraTran vs. 15 (10.5%) on trandolapril [unadjusted hazard ratio (95% confidence interval [CI]) 1.07 (0.54-2.12), P = 0.852] progressed to macroalbuminuria, respectively; 62 (44.9%) vs. 71 (49.7%) [0.80 (0.57-1.12), P = 0.198] regressed to normoalbuminuria (urinary albumin excretion <20 µg/min), and 20 (14.5%) vs. 21 (14.7%) [hazard ratio 0.93 (0.50-1.72), P = 0.816] had major cardiovascular events. BP and metabolic control were similar between groups. Patients with cardiovascular events were significantly less [13 (9.8%) vs. 28 (18.9%), hazard ratio: 0.37 (0.19-0.71), P = 0.003] among those regressing to normoalbuminuria than those without regression. Difference was independent of treatment allocation and was significant also after adjusting for baseline characteristics [0.40 (0.20-0.79), P = 0.009], follow-up SBP [0.40 (0.20-0.80), P = 0.010] or DBP [0.36 (0.18-0.73), P = 0.004] BP or HbA1C [0.43 (0.21-0.88), P = 0.021]. In hypertensive type 2 diabetes patients with microalbuminuria, verapamil added-on trandolapril did not improve renal or cardiovascular outcomes. Independent of verapamil, trandolapril normalized albuminuria in half of patients and this translated into significant cardioprotection.

Risk Factors for Microvascular Complications of Diabetes Among South Indian Subjects with Type 2 Diabetes—The Chennai Urban Rural Epidemiology Study (CURES) Eye Study-5

This study assessed the relationship between and risk factors for microvascular complications of diabetes in an urban South Indian type 2 diabetes population. Subjects with diabetes (n = 1,736) were selected from the population-based Chennai Urban Rural Epidemiology Study (CURES) Eye Study conducted on a representative population of Chennai city in south India. Four-field stereo retinal color photography was done, and diabetic retinopathy (DR) was classified according to the Early Treatment DR Study grading system. Neuropathy was diagnosed if the vibratory perception threshold of the big toe using biothesiometry was ≥ 20V. Overt nephropathy was diagnosed if the subjects had persistent macroalbuminuria (urinary albumin excretion ≥ 300 μg/mg of creatinine) and microalbuminuria if it was between 30 and 299 μg/mg of creatinine. Among the 1,715 subjects with gradable fundus photographs, 1,608 individuals who had information on all test parameters were included. Overall, DR was present in 282 (17.5%), neuropathy in 414 (25.7%), overt nephropathy in 82 (5.1%), and microalbuminuria in 426 (26.5%) subjects. Eighteen subjects had all three microvascular complications of diabetes. The risk of nephropathy (odds ratio [OR] = 5.3, P<0.0001) and neuropathy (OR = 2.9, P<0.0001) was significantly higher among the subjects with sight-threatening DR compared to those without DR. Common risk factors identified for all the three microvascular complications of diabetes were age, glycated hemoglobin, duration of diabetes, and serum triglycerides. DR was associated with nephropathy after adjusting for age, gender, hemoglobin A1c, systolic blood pressure, serum triglycerides, and duration of diabetes (OR = 2.140, 95% confidence interval = 1.261-3.632, P = 0.005). This is the first population-based study from India to report on all microvascular complications of diabetes and reveals that the association between DR and nephropathy is stronger than that with neuropathy.

Tubular and Glomerular Injury in Diabetes and the Impact of ACE Inhibition

OBJECTIVEWe studied tubular and glomerular damage in type 1 diabetic patients by measuring urinary–liver fatty acid binding protein (U-LFABP) and albuminuria. Subsequently, we evaluated the effect of ACE inhibition on U-LFABP in patients with diabetic nephropathy.RESEARCH DESIGN AND METHODSWe studied Caucasians with type 1 diabetes: 58 with normoalbuminuria (urinary albumin <30 mg/24 h), 45 with persistent microalbuminuria (30–300 mg/24 h), and 45 with persistent macroalbuminuria (≥300 mg/24 h). A control group consisted of 57 healthy individuals. The groups were matched by sex and duration of diabetes. In addition, U-LFABP was measured in 48 type 1 diabetic patients with diabetic nephropathy in a randomized crossover trial consisting of 2 months of treatment with 20, 40, and 60 mg lisinopril once daily in random order.RESULTSIn the cross-sectional study, levels of U-LFABP were significantly higher in normoalbuminuric patients versus those in the control group (median 2.6 [interquartile range 1.3–4.1] vs. 19 [0.8–3.0] μg/g creatinine, P = 0.02) and increased with increasing levels of albuminuria (microalbuminuric group 4.2 [1.8–8.3] μg/g creatinine and nephropathy group 71.2 [8.1–123.4], P < 0.05 for all comparisons). U-LFABP correlates with the urinary albumin-to-creatinine ratio (R2 = 0.54, P < 0.001). In the intervention study, all doses of lisinopril significantly reduced urinary albumin excretion rate and U-LFABP from baseline. The reductions in U-LFABP were 43, 46, and 40% with increasing doses of lisinopril (NS).CONCLUSIONSAn early and progressive increase in tubulointerstitial damage as reflected by increased U-LFABP levels occurs in type 1 diabetic patients and is associated with albuminuria. Furthermore, ACE inhibition reduces the tubular and glomerular damage and dysfunction.