Persistent Macroalbuminuria Research Articles

Serum Uric Acid as a Predictor for Development of Diabetic Nephropathy in Type 1 Diabetes

OBJECTIVEExperimental and clinical studies have suggested that uric acid may contribute to the development of hypertension and kidney disease. Whether uric acid has a causal role in the development of diabetic nephropathy is not known. The objective of the present study is to evaluate uric acid as a predictor of persistent micro- and macroalbuminuria.RESEARCH DESIGN AND METHODSThis prospective observational follow-up study consisted of an inception cohort of 277 patients followed from onset of type 1 diabetes. Of these, 270 patients had blood samples taken at baseline. In seven cases, uric acid could not be determined; therefore, 263 patients (156 men) were available for analysis. Uric acid was measured 3 years after onset of diabetes and before any patient developed microalbuminuria.RESULTSDuring a median follow-up of 18.1 years (range 1.0–21.8), 23 of 263 patients developed persistent macroalbuminuria (urinary albumin excretion rate >300 mg/24 h in at least two of three consecutive samples). In patients with uric acid levels in the highest quartile (>249 μmol/l), the cumulative incidence of persistent macroalbumnuria was 22.3% (95% CI 10.3–34.3) compared with 9.5% (3.8–15.2) in patients with uric acid in the three lower quartiles (log-rank test, P = 0.006). In a Cox proportional hazards model with sex and age as fixed covariates, uric acid was associated with subsequent development of persistent macroalbuminuria (hazard ratio 2.37 [95% CI 1.04–5.37] per 100 μmol/l increase in uric acid level; P = 0.04). Adjustment for confounders did not change the estimate significantly.CONCLUSIONSUric acid level soon after onset of type 1 diabetes is independently associated with risk for later development of diabetic nephropathy.

Macroalbuminuria and Renal Pathology in First Nation Youth With Type 2 Diabetes

OBJECTIVETo determine the prevalence of macroalbuminuria and to describe the clinical and renal pathological changes associated with macroalbuminuria in a population of Canadian First Nation children and adolescents with type 2 diabetes.RESEARCH DESIGN AND METHODSWe conducted a retrospective chart review at a single tertiary care pediatric diabetes center, and a case series was constructed. We collected data on microalbuminuria (≥3 mg/mmol creatinine [26.5 mg/g]) and macroalbuminuria (≥28 mg/mmol creatinine [247.5 mg/g]), estimated glomerular filtration rate, renal pathology, and aggravating risk factors (poor glycemic control, obesity, hypertension, glomerular hyperfiltration, hypercholesterolemia, smoking, and exposure to diabetes in utero).RESULTSWe reviewed 90 charts of children and adolescents with type 2 diabetes. A total of 53% had at least one random urine albumin-to-creatinine ratio ≥3 mg/mmol (26.5 mg/g). There were 14 of 90 (16%) who had persistent macroalbuminuria at or within 8 years of diagnosis of diabetes. Of these 14 subjects, 1 had orthostatic albuminuria and 3 had spontaneous resolution of albuminuria. A total of 10 had renal biopsies performed. There were 9 of 10 who exhibited immune complex disease or glomerulosclerosis, and none had classic diabetic nephropathy.CONCLUSIONSThis study suggests that the diagnosis of renal disease in children with type 2 diabetes cannot be reliably determined by clinical and laboratory findings alone. Renal biopsy is necessary for accurate diagnosis of renal disease in children and adolescents with type 2 diabetes and macroalbuminuria. The additional burden of nondiabetic kidney disease may explain the high rate of progression to end-stage kidney failure in this population.

Kidney Outcomes in Long-Term Studies of Ruboxistaurin for Diabetic Eye Disease

A pilot study showed that ruboxistaurin (RBX), a protein kinase C beta inhibitor, significantly decreased albuminuria and stabilized kidney function over 1 yr in patients who had diabetic nephropathy and persistent macroalbuminuria despite receiving the current standard of care, including renin-angiotensin system inhibition. In contrast, in a trial of patients with diabetic retinopathy, investigators reported the adverse event "diabetic nephropathy" more frequently in patients who received RBX. The purpose of this study was to evaluate long-term effects of RBX on kidney outcomes among patients with diabetic eye disease in three diabetic retinopathy trials (n = 1157). Baseline-to-study end changes in estimated GFR (eGFR) were calculated. Kidney outcomes included doubling of serum creatinine, development of advanced chronic kidney disease (stages 4 to 5), and death. Baseline eGFR was 81.6 +/- 26.0 ml/min per 1.73 m(2). In the combined placebo and RBX treatment groups, eGFR decreased by 11.0 +/- 19.6 ml/min per 1.73 m(2) during median follow-up of 33 to 39 mo. At least one kidney outcome occurred in 11.3% of patients. Frequency of doubling of serum creatinine was 6.0%, progression to advanced chronic kidney disease was 4.1%, and death was 4.1%. Kidney outcome rates did not differ by treatment assignment. Long-term kidney outcomes in patients with diabetic eye disease were similar in placebo and RBX groups. In conclusion, large-scale, prospective trials in patients with diabetic nephropathy are needed to confirm safety and potential benefits of RBX on clinical outcomes.

Beneficial impact of spironolactone in diabetic nephropathy

Aldosterone has been suggested to play a role in the initiation and progression of diabetic nephropathy. Currently recommended treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers [renin-angiotensin system (RAS) blockade] does not suppress circulating aldosterone sufficiently. We therefore aimed to evaluate the short-term effect of aldosterone antagonism with spironolactone on albuminuria and blood pressure in diabetic nephropathy. Twenty Caucasian type 1 diabetic patients with persistent macroalbuminuria despite antihypertensive treatment, including RAS blockade, completed this double-masked, randomized cross-over trial. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for two months, respectively, on top of usual antihypertensive treatment. After each treatment period albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined. Spironolactone on top of usual antihypertensive treatment induced a 30% (95% CI 17 to 41) reduction in albuminuria from [geometric mean (95% CI)] 831 (624 to 1106) mg/24-hour on placebo treatment (P < 0.001), and a reduction in fractional albumin clearance of 35% (20 to 46, P < 0.001). Twenty-four-hour blood pressure showed an insignificant reduction of [mean reduction (95% CI)] 8 (-1 to 17)/3 (-0.2 to 7) mm Hg (P < 0.10). There was an insignificant reversible reduction in GFR during treatment with spironolactone. On spironolactone treatment, one patient was excluded due to hyperkalemia (plasma potassium 5.7 mmol/L) and one due to orthostatic dizziness. Otherwise treatment was well tolerated. Our results suggest that spironolactone treatment on top of recommended antihypertensive treatment reduces blood pressure and may offer additional renoprotection in type 1 diabetic patients with diabetic nephropathy.

The prevalence of coeliac disease in adult Danish patients with type 1 diabetes with and without nephropathy

To the Editor: Coeliac disease causes malabsorption due to small bowel villous atrophy, which normalises when gluten, which is found in wheat, rye and barley, is withdrawn from the diet. Coeliac patients should be treated with a gluten-free diet that corrects the intestinal malabsorption and protects against the development of osteoporosis and intestinal lymphoma. As shown in several studies (review [1]), type 1 diabetes is associated with a high prevalence (2–10%) of coeliac disease. This has, in part, been explained by genetic factors, in particular by increased frequencies of HLA-DR3 and HLA-DQ2 [2]. Coeliac symptoms are often absent or atypical in type 1 diabetic patients and the diagnosis is therefore often delayed. Diabetic nephropathy is the leading cause of end-stage renal disease and develops in approximately one-third of type 1 diabetic patients within the first 20 years of diabetes. The pathogenesis of diabetic nephropathy is only partially understood. In addition to genetic factors, haemodynamic, metabolic and growth factors are generally accepted to contribute [3]. As in diabetic nephropathy [4], reduced final height is a significant clinical manifestation of coeliac disease. In this study we investigated the prevalence of coeliac disease in adult Danish type 1 diabetes patients, with the specific aim of studying whether undiagnosed coeliac disease is more prevalent in type 1 diabetic patients with diabetic nephropathy than in type 1 diabetic patients without nephropathy. We studied 967 type 1 diabetic patients [5]. The patient population comprised a group of 462 patients with overt diabetic nephropathy (defined as persistent macroalbuminuria [>300 mg/24 h], retinopathy and no signs of other kidney or urinary tract disease; 284 men, median age 41 [range: 17–78] years, median serum creatinine 103 [range: 52–706] μmol/l) and a group of 505 patients with longstanding (23 [range: 10–63] years) type 1 diabetes and persistent normoalbuminuria (275 men, age 46 [range: 20– 81] years). Median age at onset of diabetes was 12 (range: 0–47) and 18 (range: 0–64) years in the nephropathy and normoalbuminuric groups respectively (p<0.001). Total serum IgA concentration (in-house ELISA; Statens Serum Institute, Copenhagen, Denmark) and IgA anti-transglutaminase concentration (anti-tTG, commercial ELISA, Celikey; Pharmacia, Freiburg, Germany) were measured in a single random blood sample. The specificity and sensitivity values of the IgA anti-tTG assays were 99 and 96% respectively. The presence of IgA anti-tTG is highly indicative of coeliac disease even in asymptomatic cases [6]. Patients positive after screening were referred to their local hospital for a possible small bowel biopsy procedure and instructions for a gluten-free diet. Sera from five subjects with IgA deficiency (<0.1 mg/ml) were analysed for IgG anti-gliadin antibodies and IgG anti-tTG. We collected clinical data and laboratory results using a questionnaire including questions concerning possible earlier diagnosis of coeliac disease and possible previous gluten-free diet. H. Skovbjerg (*) Department of Medical Biochemistry and Genetics, The Panum Institute, Blegdamsvej 3, 2200 Copenhagen N, Denmark e-mail: hsk@imbg.ku.dk Tel.: +45-353-27793 Fax: +45-353-67980

Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study

ObjectiveTo evaluate baseline predictors for the development of persistent microalbuminuria and macroalbuminuria prospectively in patients with type 1 diabetes.DesignProspective observational study of an inception cohort.SettingOutpatient diabetic clinic in a tertiary...

Prevalence of Microalbuminuria in Young Patients with Type 1 and Type 2 Diabetes Mellitus

This study was designed to determine the prevalence of microalbuminuria and the associated risk factors in patients with childhood-onset diabetes mellitus (DM). One hundred and sixty-three patients (141 with type 1 DM [DM1] and 22 with type 2 DM [DM21), aged 8 to 28 years, were evaluated for albumin excretion rate and HbA(1c). The mean duration of DM was 8.1 +/- 3.4 and 5.5 +/- 3.9 years in DM1 and DM2, respectively. Persistent microalbuminuria and macroalbuminuria were observed in 11.3% and 2.8% of patients with DM1, and 18.2% and 4.5% in patients with DM2, respectively. In DM1, the duration of DM, age of onset, and HbA(1c) levels were significant predictors of microalbuminuria. Our observations suggest that screening for microalbuminuria should be started from early adolescence in patients with DM1 and DM2.

Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus: prospective, observational study

Objective: To evaluate putative risk factors for the development of incipient diabetic nephropathy (persistent microalbuminuria) and overt diabetic nephropathy (persistent macroalbuminuria) in patients with non-insulin dependent diabetes.Design: Prospective, observational study...

Comparative Effects of Enalapril, Atenolol and Chlorthalidone on Blood Pressure and Kidney Function of Diabetic Patients Affected by Arterial Hypertension and Persistent Proteinuria

Arterial hypertension and proteinuric nephropathy are common features in diabetic patients. In streptozotocin-diabetic rats, it has been possible to reduce the blood pressure and proteinuria by converting enzyme inhibitors, and so slowing the decline of kidney function. These results have been confirmed in diabetic patients affected by arterial hypertension and persistent proteinuria. However, up to now it has not been clear if these favorable renal effects are related specifically to converting enzyme inhibition. In the attempt to clarify this last point, from a practical as well as from a speculative point of view, 12 type 2 diabetic outpatients affected by mild to moderate arterial hypertension and persistent macroalbuminuria (greater than 250 mg/daily, at least on three consecutive occasions) without any other signs of renal diseases were studied. In a randomized sequence and in a double blind fashion, after a washout period of 3 weeks, the patients underwent pharmacological treatment which consisted of enalapril 20 mg o.d., chlorthalidone 12.5 mg o.d., atenolol 50 mg o.d. and placebo o.d. Each treatment lasted 45 days. Kidney function, blood pressure and heart rate were checked at the beginning and at the end of each treatment, while urinary albumin excretion was measured at the end of the 4th, 5th, and 6th week of each treatment. Blood pressure significantly decreased in a similar fashion after each active treatment, while kidney function did not change significantly. Urinary albumin excretion rate significantly decreased after enalapril and atenolol, but did not change after chlorthalidone. According to these results we can hypothesize that the inhibition of tissue angiotensin formation and its related change on the glomerular permeability, rather than renal and systemic hemodynamic features, seem to be the common mechanisms by which both enalapril as well as atenolol decrease the albuminuria in our patients.

Systemic and renal effects of chronic angiotensin converting enzyme inhibition with captopril in hypertensive diabetic patients

Nine outpatients with mild to moderate arterial hypertension, type 2 diabetes mellitus and persistent macroalbuminuria were studied. After 1 month of placebo, the patients were treated with 50 mg captopril twice a day for the following 6 months. Blood pressure and urinary albumin excretion were significantly reduced but no relationship was found between these two variables. No changes were detected in the renal plasma flow, glomerular filtration rate, filtration fraction, renal vascular resistance or metabolic pattern. Captopril significantly reduced blood pressure and albuminuria without any change in the renal function. The decrease in albuminuria may be related to the reduction in blood pressure as well as to a direct effect of captopril on glomerular haemodynamics.