Anne T. Reutens

Epidemiology of Diabetic Kidney Disease

The increasing prevalence of diabetes has led to DKD becoming the leading cause of ESRD in many regions. The economic cost of DKD will grow to prohibitive amounts unless strategies to prevent its onset or progression are urgently implemented. In type 1 and type 2 diabetes, the presence of microalbuminuria and macroalbuminuria confers increased risk of developing ESRD and of death. Comparison of recent studies with earlier historical studies shows that the incidence of ESRD and death has decreased in DKD. Increased risk of albuminuria has been identified in certain non-European ethnic groups. However, the initial concept of progression of DKD as an albuminuric phenotype involving development of microalbuminuria, macroalbuminuria, and then ESRD has had to be modified. Albumin excretion frequently regresses, and GFR can decline without abnormality in albumin excretion. There is emerging evidence that changes in renal function occurring early in the course of diabetes predict future outcomes. The major challenges are to prevent DKD onset, to detect it early, and to improve DKD outcomes globally.

Sulodexide Fails to Demonstrate Renoprotection in Overt Type 2 Diabetic Nephropathy

Sulodexide, a mixture of naturally occurring glycosaminoglycan polysaccharide components, has been reported to reduce albuminuria in patients with diabetes, but it is unknown whether it is renoprotective. This study reports the results from the randomized, double-blind, placebo-controlled, sulodexide macroalbuminuria (Sun-MACRO) trial, which evaluated the renoprotective effects of sulodexide in patients with type 2 diabetes, renal impairment, and significant proteinuria (>900 mg/d) already receiving maximal therapy with angiotensin II receptor blockers. The primary end point was a composite of a doubling of baseline serum creatinine, development of ESRD, or serum creatinine ≥6.0 mg/dl. We planned to enroll 2240 patients over approximately 24 months but terminated the study after enrolling 1248 patients. After 1029 person-years of follow-up, we did not detect any significant differences between sulodexide and placebo; the primary composite end point occurred in 26 and 30 patients in the sulodexide and placebo groups, respectively. Side effect profiles were similar for both groups. In conclusion, these data do not suggest a renoprotective benefit of sulodexide in patients with type 2 diabetes, renal impairment, and macroalbuminuria.

Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: A randomized controlled trial

BACKGROUND Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (~80% ± 8%), high-molecular-weight heparin (~5% ± 3%), and dermatan (~20% ± 8%), with a mean molecular weight of ~9 kDa. The drug is absorbed orally and has no anticoagulant effect in the doses used. Small preliminary studies consistently showed sulodexide to be associated with decreased albuminuria in patients with diabetes. STUDY DESIGN We conducted a multicenter placebo-controlled double-blinded study to determine the effect of sulodexide on urine albumin excretion in patients with type 2 diabetic nephropathy. SETTING & PARTICIPANTS Patients with type 2 diabetes and urine albumin-creatinine ratios (ACRs) of 35-200 mg/g in men and 45-200 mg/g in women were enrolled. Serum creatinine level was <1.5 mg/dL. Blood pressure goal was 130/80 mm Hg. A maximum US Food and Drug Administration-approved dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for a minimum of 4 months before randomization was required. INTERVENTION The study drug was sulodexide, 200 mg/d. OUTCOME & MEASUREMENTS The primary end point was normoalbuminuria (ACR <20 mg/g and a decrease >25%) or 50% decrease in baseline ACR. RESULTS In 1,056 randomly assigned patients with a mean baseline ACR of 107.8 ± 83.7 mg/g, comparing the sulodexide versus placebo groups, the primary end point was achieved in 16.5% versus 18.4%; normoalbuminuria, in 7.9% versus 6.1%; and a 50% decrease in albuminuria, in 15.4% versus 17.6%. The relative probability of any given change in albuminuria was identical in both groups. LIMITATIONS We were unable to determine whether the administered sulodexide was absorbed from the gastrointestinal tract. CONCLUSION Sulodexide failed to decrease urine albumin excretion in patients with type 2 diabetic nephropathy and microalbuminuria.

Rationale for and study design of the sulodexide trials in Type 2 diabetic, hypertensive patients with microalbuminuria or overt nephropathy.

Background  Patients with Type 2 diabetes and albuminuria are at high risk to progress to end‐stage renal disease (ESRD). Although angiotensin receptor blockers confer renoprotection, many diabetic patients still develop overt nephropathy and reach ESRD. Glycosaminoglycans belong to the same family as heparin and heparinoids. Pilot studies with sulodexide, a glycosaminoglycan, have shown that sulodexide can reduce urinary albumin excretion rates in diabetic patients. No hard renal end‐point data are available.

The association between cystatin C and incident type 2 diabetes is related to central adiposity.

BACKGROUND Cystatin C has recently been shown to be associated with incident type 2 diabetes. This study aims to validate this association and to study the impact of baseline adiposity. METHODS We investigated the 3-year diabetes incidence in 2849 participants from the French Data of an Epidemiological Study on the Insulin Resistance syndrome study, without overt kidney disease. Odds ratios (ORs) associated with cystatin C were adjusted for classical diabetes risk factors and interactions between cystatin C and these risk factors were studied. RESULTS Baseline serum cystatin C was significantly associated with incident diabetes on univariate analysis (OR/1 SD of log cystatin C: 1.74; 95% confidence interval [CI] 1.33-2.28; P=0.0001) and after adjustment for age and gender (OR 1.55; 95% CI 1.15-2.10; P=0.0039). This association was independent of serum creatinine-derived measures of baseline renal function and independent of fasting plasma glucose and HbA1c. When body mass index (BMI), waist circumference or baseline insulin resistance index were used as covariates, there was an interaction with cystatin C level. Cystatin C was associated only with incident diabetes for people with BMI, waist circumference or insulin resistance index≥median value with OR (95% CIs), respectively: 1.35 (0.98-1.84, P=0.0625); 1.39 (1.01-1.91, P=0.0441) and 1.41 (1.02-1.94, P=0.0398). CONCLUSIONS Cystatin C was associated with 3-year incident diabetes but only in people with central adiposity or insulin resistance. This should be considered in further studies assessing the clinical relevance of its prognostic value.

Incidence of chronic kidney disease among people with diabetes: A systematic review of observational studies

The aim was to systematically review published articles that reported the incidence of chronic kidney disease among people with diabetes.

Type 2 diabetes strengthens the association between pulse pressure and chronic kidney disease: the AusDiab study

Objective Chronic kidney disease (CKD) is a serious disorder with significant public health impact. Identification of factors associated with risk of progression of kidney disease may help in earlier intervention in high-risk groups. We investigated whether brachial pulse pressure (PP) was associated with 5-year changes in estimated glomerular filtration rate (eGFR) and incident CKD and whether type 2 diabetes modified these associations. Methods In the population-based Australian Diabetes, Obesity and Lifestyle Study (AusDiab) 5554 individuals (5.8% with type 2 diabetes) who took part in the 5-year follow-up and had no CKD or microalbuminuria at baseline were included. Results After adjusting for baseline age, sex, eGFR and use of blood pressure-lowering medication, each baseline SD higher PP was associated with a decline in eGFR of 0.32 ml/min (P = 0.006) and an odds ratio (OR) for CKD of 1.29 [95% confidence interval (CI) 1.09–1.53] in individuals without type 2 diabetes. In individuals with type 2 diabetes, eGFR declined by 1.10 ml/min (P = 0.011) and the OR for incident CKD was 1.94 (1.14–3.29). Similar associations with eGFR decline were observed with systolic blood pressure and incident CKD in individuals without type 2 diabetes. In individuals with type 2 diabetes, higher systolic blood pressure was only significantly associated with eGFR decline if the diastolic blood pressure was 70 mmHg or less (P for interaction between systolic and diastolic blood pressure: 0.033). Conclusions PP is an important risk factor for eGFR decline and incident CKD over a 5-year period, especially in individuals with type 2 diabetes.

Residual proteinuria and eGFR predict progression of renal impairment within 2 years in type 2 diabetic patients with nephropathy who are receiving optimal treatment with angiotensin receptor blockers

Proteinuria and estimated glomerular filtration rate (eGFR) predict progression of renal impairment in type 2 diabetic nephropathy (DN) but are they still predictive when these patients are treated with angiotensin receptor blockers (ARB)? We investigated whether residual (after ≥3 months of ARB treatment) urinary protein/creatinine ratio (rPCR) or urinary albumin/creatinine ratio (rACR) and residual eGFR (reGFR), predict subsequent progression.

Proteinuria in Type 2 Diabetic Patients with Renal Impairment: The Changing Face of Diabetic Nephropathy

Type 2 diabetic nephropathy (type 2 DN) patients traditionally develop significant proteinuria prior to the development of renal impairment. However, this clinical paradigm, based on observations prior to the widespread usage of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), has recently been questioned. 2,303 patients enrolled in the Sulodexide Overt Nephropathy Study (OVERT) were analyzed. Prior therapy with ACEi and/or ARB at the time of screening was recorded in 951 patients. 22% of patients had significant renal impairment with a PCR at screening of <500 mg/g. Therapy with ACEi and/or ARB at the time of screening was recorded in 94%, where prior medication data was available. In patients with type 2 DN and advanced renal impairment, levels of proteinuria below that which traditionally defines overt diabetic nephropathy, are found in more than one fifth of patients. We suggest that the high prevalence of ACEi and ARB usage in patients with type 2 DN may be effecting the traditional clinical paradigm of type 2 DN.

Acute metabolic and cardiovascular effects of mirabegron in healthy individuals

To quantify acute energy expenditure, supraclavicular skin temperature and cardiovascular responses to four doses of the β3‐adrenoceptor agonist, mirabegron.