Persistent Microalbuminuria Research Articles

Urinary tubular biomarkers as predictors of kidney function decline, cardiovascular events and mortality in microalbuminuric type 2 diabetic patients.

Urinary levels of kidney injury molecule 1 (u-KIM-1) and neutrophil gelatinase-associated lipocalin (u-NGAL) reflect proximal tubular pathophysiology and have been proposed as risk markers for development of complications in patients with type 2 diabetes (T2D). We clarify the predictive value of u-KIM-1 and u-NGAL for decline in eGFR, cardiovascular events (CVE) and all-cause mortality in patients with T2D and persistent microalbuminuria without clinical cardiovascular disease. This is a prospective study that included 200 patients. u-KIM-1 and u-NGAL were measured at baseline and were available in 192 patients. Endpoints comprised: decline in eGFR > 30%, a composite of fatal and nonfatal CVE consisting of: cardiovascular mortality, myocardial infarction, stroke, ischemic heart disease and heart failure based on national hospital discharge registries, and all-cause mortality. Adjusted Cox models included traditional risk factors, including eGFR. Hazard ratios (HR) are provided per 1 standard deviation (SD) increment of log2-transformed values. Relative integrated discrimination improvement (rIDI) was calculated. During the 6.1years' follow-up, higher u-KIM-1 was a predictor of eGFR decline (n = 29), CVE (n = 34) and all-cause mortality (n = 29) in adjusted models: HR (95% CI) 1.68 (1.04-2.71), p = 0.034; 2.26 (1.24-4.15), p = 0.008; and 1.52 (1.00-2.31), p = 0.049. u-KIM-1 contributed significantly to risk prediction for all-cause mortality evaluated by rIDI (63.1%, p = 0.001). u-NGAL was not a predictor of any of the outcomes after adjustment. In patients with T2D and persistent microalbuminuria, u-KIM-1, but not u-NGAL, was an independent risk factor for decline in eGFR, CVE and all-cause mortality, and contributed significant discrimination for all-cause mortality, beyond traditional risk factors.

Maturity-Onset Diabetes of the Young (MODY) in a Racially Diverse Pediatric Population

Current practice guidelines recommend considering a diagnosis of MODY in patients with a strong family history but without typical features of type 2 diabetes (T2D) (i.e., obesity, insulin resistance, high-risk ethnicity) or type 1 diabetes (T1D) (i.e., islet autoantibodies). We aimed to test if these criteria apply to a racially diverse pediatric patient population. Using EPIC Population Health, we retrospectively reviewed electronic medical records (IRB H-41512) of youth diagnosed with MODY between 2013-2017 in a large academic pediatric hospital in Southwestern U.S. We found that, out of 46 patients with MODY, 50% (n=23) had MODY 2, 17.3% (n=8) MODY 3, 17.3% (n=8) MODY 5, 8.6% (n=4) MODY 1, 2.1% (n=1) MODY 4, and 8.6% of patients had a clinical diagnosis of MODY due to inability to perform molecular testing. The mean (SD, range) age of diabetes diagnosis was 10.1 years (4.4, 2-17); 52% of patients were females; 50% were non-Hispanic white, 32.5% Hispanic, 6.5% African American, 6.6% Lebanese, 2.2% Asian and 2.2% others/unknown. Notably, 15.2% (n=7, all with a molecular diagnosis of MODY) had positive islet antibodies, 8.6% (n=4) Hashimoto’s thyroiditis and 2.1% (n=1) vitiligo. Obesity/overweight was present in 23.8%, 15.2% had hypertension / prehypertension and 21.7% had dyslipidemia. Diabetes was absent in parents and siblings of 26% (n=12) of patients, although in 5 patients, the mother had gestational diabetes. Persistent microalbuminuria was found in 2 youth with MODY 2 and diabetic neuropathy in 1 patient with MODY 2. The mean (SD, range) time between the diagnoses of diabetes and MODY was 14.3 months (22.3, 1-120). In conclusion, youth with MODY often were of ethnic minorities, lacked a family history of diabetes and had characteristics typical of T1D or T2D, suggesting that the current guidelines to consider a diagnosis of MODY may not apply to a racially diverse U.S. pediatric population. Furthermore, in contrast to previous studies, we identified microvascular complications in youth with MODY 2. Disclosure S. Relan: None. F.C. Hessel: None. K.D. Timmons: None. R. Sonabend: None. M.J. Redondo: None.

MIKROALBUMIN AIR KEMIH (URIN) PASIEN DM TIPE 2

Diabetic Nephropathy is one of several chronic complication of type 2 DM that could lead to end stage renal disease (ESRD). In type2 DM patients, about 85% of ESRD caused by diabetic nephropathy. Persistent microalbuminuria can be predictor for nephropathy. Earlydetection of microalbuminuria could be useful in improving an aggressive treatment to avoid ESRD and other macrovasculer disorder intype 2 DM patients. The purpose of this study was to describe the microalbuminuria profile in type 2 DM patients. A cross sectional studywas taken on 21 type 2 DM patients. Data were analyzed by descriptive analyzed (distribution, frequency, mean, standard deviation, ttest). P value < 0.05 was considered significant. This study reveals that frequency microalbuminuria was 78.9%. There was no differentage between microalbuminuria and normoalbuminuria. Duration of diabetes in microalbuminuria patients were more longer. Themean time is 45.3 (41) months and normoalbuminuria 36(16) months. The systolic and diastolic pressure in microlabuminuria washigher than normoalbuminuria. The body mass index between microalbuminurian and normoalbuminuria (P < 0.05) was significantlydifferent. In patient with microalbuminuria the mean of HbA1c value was 7.9(2.5) and in normoalbuminuria patient it was 9(1.8).There were no significant different of lipid profile between both samples. In this study was only found significantly different of body massindex between microalbuminuria and normoalbuminuria patients.

Role of Kidney Biopsies for Biomarker Discovery in Diabetic Kidney Disease.

Although estimated glomerular filtration rate and albuminuria are well-established biomarkers of diabetic kidney disease (DKD), additional biomarkers are needed, especially for the early stages of the disease when both albuminuria and estimated glomerular filtration rate may still be in the normal range and are less helpful for identifying those at risk of progression. Traditional biomarker studies for early DKD are challenging because of a lack of good early clinical end points, and most rely on changes in existing imprecise biomarkers to assess the value of new biomarkers. There are well-characterized changes in kidney structure, however, that are highly correlated with kidney function, always precede the clinical findings of DKD and, at preclinical stages, predict DKD progression. These structural parameters may thus serve as clinically useful end points for identifying new biomarkers of early DKD. In addition, investigators are analyzing tissue transcriptomic data to identify pathways involved in early DKD which may have associated candidate biomarkers measurable in blood or urine, and differentially expressed microRNAs and epigenetic modifications in kidney tissue are beginning to yield important observations which may be useful in identifying new clinically useful biomarkers. This review examines the emerging literature on the use of kidney tissue in biomarker discovery in DKD.

Risk Factors Associated with Microalbuminuria in Children and Adolescents with Diabetes in Bangladesh.

Introduction:Diabetic nephropathy is leading cause of morbidity and mortality of type 1 diabetes mellitus (DM). Microalbuminuria is the first clinical sign of nephropathy.Methods:This was a cross-section study with longitudinal evaluation of urinary albumin xcretion in 199 children with type 1 diabetes attending CDiC Clinic in BIRDEM over a period of two years. The aim of the study was to assess the frequency of microalbuminuria and to determine other risk factors. We collected blood and early morning spot urinary sample and analyzed for HbA1c by Clover A1c and urinary microalbumin by a DCA analyzer. Children had urinary microalbumin 30-300 mg/L on at least two occasions were categorized as having persistent microalbuminuria. Demographic and clinical data were recorded including age at onset of diabetes, age during registration, gender and duration of diabetes which were compared between patients without microalbuminuria and with microalbuminuria.Result:Microalbuminuria developed in forty nine children and adolescents (25%). Among them 24% were Type 1, 27% were with Fibrocalculous pancreatic diabetes (FCPD) and 68% were Type 2 diabetes. Median HbA1c was higher 10.8 [9.4-12.4] vs 9.5 [8.0-11.2] (P.006) in adolescents with microalbuminuria. On logistic regression univariate analysis independent predictors of microalbuminuria were older age, systolic blood pressure, BMI SDS and mean HbA1c which remained significant in multivariate analysis as predictors of microalbuminuria.Conclusion:We found high prevalence of microalbuminuria which was associated with higher age, systolic blood pressure, BMI SDS and HbA1c.

Angiotensin-converting enzyme-inhibitor therapy in adolescents with type 1 diabetes in a regional cohort: Auckland, New Zealand from 2006 to 2016.

To review indications and use of angiotensin-converting enzyme-inhibitor (ACEI) therapy for the treatment of persistent microalbuminuria (MA) and/or hypertension (HTN) in adolescents with type 1 diabetes mellitus (T1DM). Retrospective chart review of adolescent patients with T1DM seen within the paediatric diabetes service in Auckland, New Zealand, from 2006 to 2016. MA, HTN, patient demographic characteristics and ACEI prescribing and monitoring indices were examined. Five hundred adolescents with T1DM were included. There were 26 patients (5%) with MA and/or HTN. MA alone was present in 16, HTN alone in 3 and both HTN and MA in 7. The 5-year MA/HTN-free rate was 98%, and the 10-year MA/HTN-free rate was 93%. Longer disease duration and earlier diagnosis were predictors of MA/HTN. There was no significant difference in standard clinical indices between study patients and others. ACEI was prescribed for 17 of 26 patients for either HTN or MA. Within 6 weeks of ACEI commencement, less than half of the subjects had repeat serum creatinine and MA screens and no record of repeat blood pressure measurement. Despite this, all patients had 3-monthly reviews within outpatient clinics where adjustments of ACEI doses were made. In our regional adolescent population with T1DM, there were low rates of both MA and/or HTN. In those who required treatment with ACEI, clinical monitoring post-commencement of therapy was inconsistent. Local consensus guidelines for the management of persistent MA in children and adolescents with diabetes mellitus were developed in response to this study.

Diabetes Mellitus, Microalbuminuria, and Subclinical Cardiac Disease: Identification and Monitoring of Individuals at Risk of Heart Failure.

BackgroundPatients with type 2 diabetes mellitus and elevated urinary albumin:creatinine ratio (ACR) have increased risk of heart failure. We hypothesized this was because of cardiac tissue changes rather than silent coronary artery disease.Methods and ResultsIn a case‐controlled observational study 130 subjects including 50 ACR+ve diabetes mellitus patients with persistent microalbuminuria (ACR >2.5 mg/mol in males and >3.5 mg/mol in females, ≥2 measurements, no previous renin–angiotensin–aldosterone therapy, 50 ACR−ve diabetes mellitus patients and 30 controls underwent cardiovascular magnetic resonance for investigation of myocardial fibrosis, ischemia and infarction, and echocardiography. Thirty ACR+ve patients underwent further testing after 1‐year treatment with renin–angiotensin–aldosterone blockade. Cardiac extracellular volume fraction, a measure of diffuse fibrosis, was higher in diabetes mellitus patients than controls (26.1±3.4% and 23.3±3.0% P=0.0002) and in ACR+ve than ACR−ve diabetes mellitus patients (27.2±4.1% versus 25.1±2.9%, P=0.004). ACR+ve patients also had lower E′ measured by echocardiography (8.2±1.9 cm/s versus 8.9±1.9 cm/s, P=0.04) and elevated high‐sensitivity cardiac troponin T 18% versus 4% ≥14 ng/L (P=0.05). Rate of silent myocardial ischemia or infarction were not influenced by ACR status. Renin–angiotensin–aldosterone blockade was associated with increased left ventricular ejection fraction (59.3±7.8 to 61.5±8.7%, P=0.03) and decreased extracellular volume fraction (26.5±3.6 to 25.2±3.1, P=0.01) but no changes in diastolic function or high‐sensitivity cardiac troponin T levels.ConclusionsAsymptomatic diabetes mellitus patients with persistent microalbuminuria have markers of diffuse cardiac fibrosis including elevated extracellular volume fraction, high‐sensitivity cardiac troponin T, and diastolic dysfunction, which may in part be reversible by renin–angiotensin–aldosterone blockade. Increased risk in these patients may be mediated by subclinical changes in tissue structure and function.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01970319.

Renal function preservation with Manidipine vs Amlodipine in type 2 diabetic hypertensive patients with persistent microalbuminuria

Renal function preservation with Manidipine vs Amlodipine in type 2 diabetic hypertensive patients with persistent microalbuminuria

Renal function preservation with Manidipine vs Amlodipine in type 2 diabetic hypertensive patients with persistent microalbuminuria

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

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.

Incident microalbuminuria and complement factor mannan‐binding lectin‐associated protein 19 in people with newly diagnosed type 1 diabetes

Evidence links the lectin pathway of complement activation to diabetic kidney disease. Upon carbohydrate-recognition by pattern-recognition molecules, eg, mannan-binding lectin (MBL), the MBL-associated serine protease (MASP-2) is activated and initiates the complement cascade. The MASP2 gene encodes MASP-2 and the alternative splice product MBL-associated protein 19 (MAp19). Both MAp19 and MASP-2 circulate in complex with MBL. We tested the hypothesis that MAp19 and MASP-2 concentrations predict the risk of incident microalbuminuria. Baseline MAp19 and MASP-2 were measured in 270 persons with newly diagnosed type 1 diabetes tracked for incidence of persistent microalbuminuria in a prospective observational 18-year-follow-up study. Seventy-five participants (28%) developed microalbuminuria during follow-up. MBL-associated protein 19 concentrations were higher in participants that later progressed to microalbuminuria as compared with those with persistent normoalbuminuria (268ng/mL [95% CI, 243-293] vs 236ng/mL [95% CI, 223-250], P=.02). Participants with MAp19 concentration within the highest quartile of the cohort had an increased risk of microalbuminuria as compared with participants with MAp19 concentration within the combined lower 3 quartiles in unadjusted Cox analysis, hazard ratio 1.86 ([95% CI, 1.17-2.96], P=.009). This remained significant in adjusted models, eg, adjusting for age, sex, HbA1c , systolic blood pressure, urinary albumin excretion, smoking, serum creatinine, and serum cholesterol. MBL-associated serine protease concentration was not associated with incidence of microalbuminuria. In conclusion, the results show an association between baseline MAp19 concentration and the incidence of microalbuminuria in an 18-year-follow-up study on persons with newly diagnosed type 1 diabetes.

Persistent proteinuria as an indicator of renal disease in HIV-infected children

Background Persistent proteinuria (microalbuminuria) has been reported to be a precursor of HIV-related renal disease. Screening allows for early management in order to prevent the progression of renal disease and decrease morbidity and mortality associated with chronic kidney disease in HIV. Several studies have been done on renal manifestation in HIV-infected children from American and African regions, but similar studies from Asia are lacking.Objective To determine the prevalence of persistent proteinuria in HIV-positive children on antiretroviral therapy (ARV) in Dr. Soetomo Hospital, Surabaya.Methods A cross-sectional study on children with HIV and treated with highly active antiretroviral therapy (HARRT) was done from August 2014 to February 2015. Microalbuminuria was measured by the ratio of urine albumin to creatinine (ACR), while proteinuria was measured by dipstick. Measurements were performed 3 times in 4-8 weeks. All subjects underwent complete evaluation of blood tests, serum creatinine, blood urea nitrogen (BUN), CD4 counts, and urinalysis. Data were analyzed using Chi-square and logistic regression tests.Results Of 38 children on HARRT enrolled in this study, 2 subjects developed acute kidney injury (AKI), 4 subjects were suspected to have urinary tract infection (UTI), and 1 subject was suspected to have urinary tract stones. The prevalence of persistent microalbuminuria was 2.6%. There was no correlation between immunological status, WHO clinical stage, or duration of ARV and the incidence of persistent proteinuria (P>0.05).Conclusion The prevalence of persistent proteinuria is lower in younger HIV-infected children at a non-advanced stage and HIV-infected children with normal immunological status who are on HAART. We provide baseline data on the renal conditions of HIV-infected children in the era of HAART, before tenovofir is increasingly used as an antiretroviral therapy regimen in Indonesia.

Urinary proteomics predict onset of microalbuminuria in normoalbuminuric type 2 diabetic patients, a sub-study of the DIRECT-Protect 2 study.

Early prevention of diabetic nephropathy is not successful as early interventions have shown conflicting results, partly because of a lack of early and precise indicators of disease development. Urinary proteomics has shown promise in this regard and could identify those at high risk who might benefit from treatment. In this study we investigate its utility in a large type 2 diabetic cohort with normoalbuminuria. We performed a post hoc analysis in the Diabetic Retinopathy Candesartan Trials (DIRECT-Protect 2 study), a multi centric randomized clinical controlled trial. Patients were allocated to candesartan or placebo, with the aim of slowing the progression of retinopathy. The secondary endpoint was development of persistent microalbuminuria (three of four samples). We used a previously defined chronic kidney disease risk score based on proteomic measurement of 273 urinary peptides (CKD273-classifier). A Cox regression model for the progression of albuminuria was developed and evaluated with integrated discrimination improvement (IDI), continuous net reclassification index (cNRI) and receiver operating characteristic curve statistics. Seven hundred and thirty-seven patients were analysed and 89 developed persistent microalbuminuria (12%) with a mean follow-up of 4.1 years. At baseline the CKD273-classifier predicted development of microalbuminuria during follow-up, independent of treatment (candesartan/placebo), age, gender, systolic blood pressure, urine albumin excretion rate, estimated glomerular filtration rate, HbA1c and diabetes duration, with hazard ratio 2.5 [95% confidence interval (CI) 1.4-4.3; P = 0.002] and area under the curve 0.79 (95% CI 0.75-0.84; P < 0.0001). The CKD273-classifier improved the risk prediction (relative IDI 14%, P = 0.002; cNRI 0.10, P = 0.043). In this cohort of patients with type 2 diabetes and normoalbuminuria from a large intervention study, the CKD273-classifier was an independent predictor of microalbuminuria. This may help identify high-risk normoalbuminuric patients for preventive strategies for diabetic nephropathy.

Characteristics of Type 2 Diabetes with Ketosis in Baoshan, Yunnan of China.

Objectives. The study provided data to demonstrate the characteristics of type 2 diabetes (T2D) with ketosis in rural parts of south-west border of China in order to help health professionals with optimizing diabetic care. Methods. All hospitalized adult diabetic patients consecutively between January 2011 and July 2015 in Baoshan People's Hospital, Yunnan province of China, were evaluated. T2D with ketosis, ordinary T2D (without ketosis), and type 1 diabetes (T1D) patients were analyzed according to the clinical and biochemical parameters and chronic complications in these subjects. Results. The prevalence of T2D with ketosis was 12% in the whole study subjects. Overweight and obese patients were predominant (49.1%) in T2D patients with ketosis. The mean HbA1c (13.3 ± 3.1%, P = 0.01), fasting plasma glucose (16.9 ± 6 mmol/L, P < 0.0001), and plasma triglyceride (4.0 ± 4.0 mmol/L, P < 0.0001) in T2D patients with ketosis were significantly higher than ordinary T2D patients without ketosis. Infections were the most common inducements in T2D patients with ketosis. Chronic complications including peripheral neuropathy (34.9%), retinopathy (12.7%), diabetic foot (18.1%), and persistent microalbuminuria (11.7%) were common in T2D patients with ketosis. Conclusions. This study indicated the poor glycemic control in diabetic patients in rural areas of south-west part of China. More efforts were urgently required to popularize public health education and improve medical quality in diabetic treatment in these regions.

Angiotensin Blockage with Losartan Is Associated with Decreased Albuminuria and Stable Renal Function in Adults and Children with HbSS on Hydroxyurea

Introduction: Sickle cell nephropathy (SCN) is a progressive complication of sickle cell disease (SCD) that begins in childhood and may result in renal failure and early mortality; yet the potential for prevention and reversal of SCN is not known. Urinary albumin/creatinine ratio (ACR) is a biomarker of glomerular damage but may not correlate with renal hemodynamic abnormalities that are indicative of early renal failure, e.g. glomerular filtration rate (GFR), renal plasma flow (RPF), and glomerular membrane permeability. We hypothesized that the angiotensin receptor blocker losartan will improve GFR and decrease excretion of high molecular weight (HMW) proteins that are restricted at the glomerulus, while not affecting abnormalities in markers of tubular injury and ischemia.Methods: Adults and children ≥10 years with HbSS who were on hydroxyurea (HU) for ≥6 months but had persistent microalbuminuria (MiA; ACR ≥30 mg/g) or macroalbuminuria (MA; ACR ≥300 mg/g) on ≥2 consecutive occasions were eligible. Target enrollment was 30 subjects (half with MA), with interim analysis after 15 enrolled. Losartan therapy was given for 12 months, titrated to 100 mg daily. At baseline and 2 time points after starting losartan (≥1 month, ≥12 months), GFR and RPF were measured by urinary clearance of intravenous iohexol and para-hippuric acid (PAH). Excretion rates of HWM proteins (albumin and immunoglobulin G (IgG)) were measured. Urinary levels of tubular proteins α1-microglobulin (α1M), β2-microglobulin (β2M), kidney injury marker-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) were measured by ELISA and expressed as the ratio of urinary protein/ creatinine to account for urine concentration.Results: At interim analysis, 12 subjects (9 male) have completed baseline and 1-month studies, and 5 have also completed 12-month studies; 3 subjects completed baseline only and are excluded from analysis. Mean age was 27.6 years (range 10.2 - 42.9). Median time on losartan was 44 days (27 - 210 days) at the first (≥1 month) renal function study and 426 days (393 - 519 days) at the last (≥12 month) study. Baseline GFR was 105 ml/min/1.73 m2 (range 71 - 147); 3 (25%) subjects had GFR <90 ml/min/1.73 m2 (stage 2 chronic kidney disease, CKD), and 6 (50%) had MA. At ≥1 month on losartan, the mean reduction in ACR was 51.0% (range 27.3% - 81.7%; p=0.006); the % reduction was similar for those with MA (60.1%) vs MiA (41.8%), p=0.32. Five of 6 with MA improved to MiA. Two of 3 with stage 2 CKD had improvement in GFR to >90 ml/min/1.73 m2 (stage 1 CKD). At ≥12 months on losartan, mean reduction in ACR was 34.5% from baseline (range -5.3% - 69.2%). The Table shows renal hemodynamics and urinary biomarkers at baseline and changes at 1 and 12 months. Excretion of albumin and IgG were significantly lower at ≥1 month. GFR and tubular biomarkers had no significant changes at either time point. There was no significant correlation of ACR with urinary biomarker ratios at baseline, nor any correlation of ΔACR with change in biomarkers at 1 month. No episodes of hyperkalemia or other adverse event occurred while on losartan therapy.Conclusions: In adults and children with HbSS and albuminuria (stage >=1 CKD) despite HU, losartan significantly reduced excretion of large proteins that are restricted at the glomerulus, with no changes in measured GFR. Markers of tubular injury and ischemic damage were unchanged by losartan, suggesting that losartan improves glomerular permability defects without significantly affecting the distal nephron. These findings warrant a larger, randomized controlled study of losartan with HU to determine if losartan prevents or slows progression to renal failure in SCD.Table 1Baseline(n=12)Change at ≥1 month(n=12)Change at ≥12 months(n=5)medianrangemedian95% CIpmedian95% CIpMAP (mm Hg)8668 - 109-5.0-15.3, 1.30.15-1.3-22.3, 61.0Albumin excretion (mcg/min)293.238.8 - 812.8-134.2-326.9, -66.80.006-196.2-493.5, 19.30.38IgG excretion (mcg/min)10.30.7 - 36.1-2.2-3.5, -1.60.0062.1-7.2, 3.21.0GFR (ml/min/1.73 m2)11271 - 1477.5-13, 200.391.0-23, 151.0RPF (ml/min/1.73 m2)881369 - 1217173-60, 4510.39-61-182, 910.38α1M (mg/g Cr)15.74.5 - 130.8-2.2-17.8, 1.50.15-17.1-23.0, -1.80.06β2M (mg/g Cr)20.011.3 - 45.4-6.2-17.6, 7.30.772.2-17.1, 28.81.0KIM-1 (pg/g Cr)383.071.9 - 122381.6-160, 2140.39192.8-181, 45211.0NGAL (ng/g Cr)5.21.9 - 29.00.2-4.6, 1.21.0-0.9-3.2, 1.70.38 DisclosuresOff Label Use: Losartan was given to patients for treatment of sickle cell nephropathy, defined as albuminuria with albumin/creatinine ratio >30 mg/g. Losartan is FDA approved for diabetic nephropathy and hypertension, but has no indications for sickle nephropathy..

RAGE and CYBA polymorphisms are associated with microalbuminuria and end-stage renal disease onset in a cohort of type 1 diabetes mellitus patients over a 20-year follow-up.

We investigated the association of polymorphisms of three genes implicated in oxidative stress: CYBA C242T, RAGE -374T/A and -429T/C, and ALOX12 Arg261Gln, with the delay of microalbuminuria onset in patients with type 1 diabetes mellitus (DT1). A total of 162 T1D patients presenting with diabetes for 32.9±9years were included in the study; 53 had persistent microalbuminuria (>30mg/l) and 109 did not. Onset of diabetes, microalbuminuria and end-stage renal disease (ESRD) were recorded as bio-clinical data. We determined polymorphism association of microalbuminuria with a Cox regression model. All polymorphisms respected the Hardy-Weinberg equilibrium. The Cox regression model validated four significant variables associated with microalbuminuria: RAGE 374AA (HR 4.19 [1.84-9.58] (p=0.001)), CYBA TT+TC (HR 2.1 [1.16-3.80], p=0.015), male sex (HR 1.92 [1.07-3.43], p=0.028) and diabetes diagnosis at the pediatric stage (HR 1.85 [1.03-3.32], p=0.039). The same association was found with ESRD (p=0.028 and p=0.033 for CYBA TC+TT and RAGE 374AA, respectively). CYBA C242T and RAGE 374T/A were not significantly associated with diabetic retinopathy. CYBA C242T and RAGE -374T/A correlate with microalbuminuria onset in the French DT1 cohort. The same correlation with ESRD onset supports the argument for the involvement of a genetic predisposition involving kidney-specific oxidative stress for diabetic nephropathy.

High hemoglobin A1c variability is associated with early risk of microalbuminuria in children with T1D.

To test the hypothesis that HbA1c variability, as measured by standard deviation (SD), is associated with increased risk for incident microalbuminuria and persistent microalbuminuria in pediatric type 1 diabetes (T1D). A retrospective analysis using data from electronic health records was performed on 1195 patients from a pediatric diabetes clinic network in the Midwest USA from 1993 to 2009 with ≥1 yr of T1D, ≥4 total HbA1c values, ≥2 HbA1c values/yr, ≥1 urine microalbumin. Microalbuminuria, the main outcome was defined as albumin excretion rate ≥20 mcg/min or 2 of 3 consecutive urine microalbumin/creatinine ≥30 mg/gm. Patients who had persistently high microalbumin or who were treated with an angiotensin-converting-enzyme inhibitor within 1 yr were considered to have persistent microalbuminuria. Sex, race, age, diagnosis age, and duration were covariates. Median numbers of per-patient HbA1c and microalbumin results were 14 and 3, respectively. Median intrapersonal mean HbA1c and SD were 8.62% (70.72 mol/mol) and 1.47% (16.07 mmol/mol), respectively. The median interquartile range (IQR) of diagnosis age was 9.4 yr (6.26-12.02) and diabetes duration was 4.97 yr (2.93-7.64). A total of 172 patients (14.4%) developed microalbuminuria; 55 (4.6%) had persistent microalbuminuria. Patients with higher SD of HbA1c had shorter time to microalbuminuria. In time-dependent Cox Proportional Hazard models, updated SD of HbA1c was significantly associated with microalbuminuria [univariate hazard ratio (HR) 1.48 (1.25-1.76); multivariable HR 1.28 (1.04-1.58)], whereas updated mean HbA1c was not [univariate HR 1.08 (0.97-1.22); multivariable HR 1.05 (0.92-1.2)]. Patients with persistent microalbuminuria had similar HRs. HbA1c variability is independently associated with development of microalbuminuria in children with T1D, highlighting the importance of maintaining stable glycemic control in pediatric patients.

Microalbuminuria en Pacientes Pediátricos Con Diagnóstico de síndrome Hemolítico Urémico

IntroductionHemolytic uremic syndrome (HUS) is characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. It is the leading cause of acute kidney failure in children under 3 years of age. A variable number of patients develop proteinuria, hypertension, and chronic renal failure. ObjectiveTo evaluate the renal involvement in pediatric patients diagnosed with HUS using the microalbumin/creatinine ratio. Patients and MethodsDescriptive concurrent cohort study that analyzed the presence of microalbuminuria in patients diagnosed with HUS between January 2001 and March 2012, who evolved without hypertension and normal renal function (clearance greater than 90ml/min using Schwartz formula). Demographic factors (age, sex), clinical presentation at time of diagnosis, use of antibiotics prior to admission, and need for renal replacement therapy were evaluated. ResultsOf the 24 patients studied, 54% were male. The mean age at diagnosis was two years. Peritoneal dialysis was required in 45%, and 33% developed persistent microalbuminuria. Antiproteinuric treatment was introduce in 4 patients, with good response. The mean follow-up was 6 years (range 6 months to 11 years). The serum creatinine returned to normal in all patients during follow up. ConclusionsThe percentage of persistent microalbuminuria found in patients with a previous diagnosis of HUS was similar in our group to that described in the literature. Antiproteinuric treatment could delay kidney damage, but further multicenter prospective studies are necessary.

Biomarkers of progression in diabetic nephropathy: The past, present and future.

More than 380 million people are currently suffering from diabetes. The International Diabetes Federation estimated that this would rise to 592 million within a generation. Despite this relentless increase in the prevalence of type 2 diabetes worldwide, with the advent of potent statins, there has been a gradual decline in mortality from macrovascular complications, such as stroke and coronary heart disease. However, this is not the situation in diabetic nephropathy, which remains a leading cause of end-stage renal disease (ESRD) globally, with its incidence being still on a rising trend. Notably, once nephropathy develops, approximately 20–40% of patients inevitably progress to ESRD. Therefore, we need biomarkers that would enable early risk stratification in diabetic nephropathy (Figure​(Figure1),1), so that those at higher risk of progression to ESRD are identified at early stages of nephropathy development. Long-term follow up of interventional studies, such as STENO-2, have clearly shown that, even at the stage of microalbuminuria, intensive multifactorial management targeting blood pressure (particularly with blockade of the renin–angiotensin system), glucose, cholesterol and lifestyle issues could reduce the progression to ESRD as well as the associated cardiovascular mortality. The availability of sensitive and well-validated biomarkers for nephropathy progression would allow targeted intensive management to be provided to those who would derive the most cost-effective benefits from such intervention.

The Micral-Test as a screening tool to detect microalbuminuria in children 5 - 15 years old with sickle cell anaemia, Lagos State University Teaching Hospital

Objective. To determine the sensitivity, specificity, and positive and negative predictive values of the Micral-Test in determination of microalbuminuria (MA). Methods. Eighty children aged 5 - 15 years with sickle cell anaemia (SCA) (HbSS) in a steady state attending the Lagos State University Teaching Hospital were recruited. The subjects were age-, sex- and social-class-matched with controls of genotype AA (HbAA). This prospective, descriptive and cross-sectional study lasted for 3 months, between October and December 2009. Morning random spot urine was used to assess the Micral-Test and the albumin/creatinine ratio (ACR). The performance of the Micral-Test was determined using the ACR as the gold standard. Result. The sensitivity and specificity of the Micral-Test were 84.6% and 81.0%, respectively. The sensitivity and specificity were 100% and 86.6%, respectively, in children 10 years old. The positive predictive value was 28.2% and the negative predictive value was 98% among the study subjects. Conclusion. The sensitivity and specificity of the Micral-Test make it a good screening tool to detect MA in children with SCA. The Micral- Test is cheaper than quantitative measurement of ACR. Patients with a single positive Micral-Test should be followed up with two more Micral-Tests over a 3-month period to confirm persistent MA.