Reduction In Urinary Albumin Excretion Research Articles

Reduction of urinary albumin excretion with empagliflozin in patients with type 2 diabetes and uncontrolled hypertension

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

SGLT2-inhibitors are effective and safe in the elderly: The SOLD study

Background and aimsSodium-glucose co-transporter-2 inhibitors (SGLT2i) may have important benefits for the elderly with type 2 diabetes (T2D), however some safety concerns still limit their use in patients over 70 years of age. The SOLD study (SGLT2i in Older Diabetic patients) is a multicenter study, aimed to evaluate the effectiveness and safety of SGLT2i in the older diabetic patients in a real-life setting. Materials and methodsWe analyzed a population of 739 adults (mean age 75.4 ± 3.9 years, M/F 420/319) with T2D, which started a SGLT2i-based treatment after the age of 70, with at least one year of follow-up. Data were collected at baseline, at 6 and 12 months of follow-up. ResultsSGLT2i (37.5% Empagliflozin, 35.7% Dapagliflozin, 26.1% Canagliflozin, 0.7% Ertugliflozin) were an add-on therapy to Metformin in 88.6%, to basal insulin in 36.1% and to other antidiabetic drugs in 29.6% of cases. 565 subjects completed the follow up, while 174 (23.5%) discontinued treatment due to adverse events which were SGLT2i related. A statistically significant reduction of glycated hemoglobin (baseline vs 12 months: 7.8 ± 1.1 vs 7.1 ± 0.8%, p < 0.001) and body mass index values (baseline vs 12 months: 29.2 ± 4.7 vs 28.1 ± 4.5 kg/m2, p < 0.001) were evident during follow-up. Overall, estimated glomerular filtration rate remained stable over time, with significant reduction of urinary albumin excretion. In the subgroup of patients which were ≥ 80 years, a significant improvement in glycated hemoglobin values without renal function alterations was evident. Overall discontinuation rate during the follow-up period was different across age groups, being urinary tract infections and worsening of renal function the most common cause. ConclusionSGLT2i are well-tolerated and safe in the elderly and appear as an effective therapeutic option, though some caution is also suggested, especially in more fragile subjects.

URINARY ALBUMIN EXCRETION CHANGES AFTER ADRENALECTOMY IN PATIENTS WITH PRIMARY ALDOSTERONISM

Objective: We aimed to evaluate changes in urinary albumin excretion (UAE) in patients with primary aldosteronism (PA) after adrenalectomy compared with those who remained with non-surgical treatment. Design and method: We evaluated 28 patients with PA diagnosed by adrenal venous sampling (AVS), attended by hypertension specialists or endocrinologists in Hospital del Mar, Barcelona. Office blood pressure (BP), body weight and laboratory parameters (estimated glomerular filtration rate by CKD-EPI equation (eGFR), plasma potassium (K) and UAE) were analyzed before and at 6 months after adrenalectomy (Adx group) or before and 6 months after AVS (non-Adx group). Results: Most patients (66.7%) were male and the mean age was 55.8 ± 9.6 years. Twelve patients (42.8%) underwent adrenalectomy and 16 (57.1%) remained on pharmacological treatment alone. Spironolactone was the principal antihypertensive treatment in the non-Adx group (84.6% of patients). The proportion of diabetes mellitus was similar in both groups (12.5% in Adx group vs 16.2% in non-Adx group, p = 0.6). The decrease in BP was statistically significant in both groups (table 1). Adx group patients showed a statistically significant reduction in the UAE (-7.7 [-33.2 to -4.0] mg/g, p = 0.002) compared to patients in non-Adx group (+0.1 [-6.5 to + 24.9], p = 0.8). After six months, the mean reduction in UAE (log-transformed) was significantly superior in the Adx group than in the non-Adx group. After adjusting by variation of systolic-BP and variation of body weight, a mean difference between the two groups of -0.966 mmHg (95% CI -1.746 to -1.182); p = 0.018 was observed. Conclusions: Patients with PA who underwent adrenalectomy presented a higher reduction in UAE than patients who remained on pharmacological treatment alone.

Effect of glucagon-like peptide-1 receptor agonists on renal function: A meta-analysis of randomized controlled trials.

The objective of this meta-analysis was to examine the impact of the GLP-1 RA on renal function parameters in randomized controlled trials. A systematic search was performed in PubMed-MEDLINE, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar databases. Meta-analysis was performed using a random-effects model and sensitivity analysis. Data from 18 randomized controlled trials involving 12 192 subjects, showed that treatment with GLP-1 RA had no effect on serum creatinine levels (weighted mean difference [WMD]: 0.00 mg/mL, 95% confidence interval [CI]: -0.01, 0.01, P = .83, I2 = 0%) and glomerular filtration rate (WMD: 1.01 mL/min/1.73 m2 , 95% CI: -1.61, 3.63, P = .45, I2 = 75%). On the other hand, a significant reduction in urinary albumin excretion (WMD: -18.01 mg/day, 95% CI: -31.20, -4.82, P = .007, I2 = 23%) and albumin-to-creatinine ratio (WMD: -6.74 mg/g, 95% CI: -12.64, -0.85, P = .03, I2 = 68%) was detected after GLP-1 RA therapy. Results of our meta-analysis revealed that GLP-1 RA treatment decreases urinary albumin excretion and albumin-to-creatinine ratio but it did not cause significant changes in creatinine levels and glomerular filtration rate.

Factor Xa inhibitor, edoxaban ameliorates renal injury after subtotal nephrectomy by reducing epithelial-mesenchymal transition and inflammatory response.

Chronic kidney disease (CKD) is an increasing and life‐threatening disease worldwide. Recent evidence indicates that blood coagulation factors promote renal dysfunction in CKD patients. Activated factor X (FXa) inhibitors are safe and first‐line drugs for the prevention of thrombosis in patients with atrial fibrillation. Here, we investigated the therapeutic effects of edoxaban on CKD using the mouse 5/6 nephrectomy model. Eight‐week‐old wild‐type mice were subjected to 5/6 nephrectomy surgery and randomly assigned to two groups, edoxaban or vehicle admixture diet. Edoxaban treatment led to reduction of urinary albumin excretion and plasma UN levels compared with vehicle group, which was accompanied with reduced glomerular cross‐sectional area and cell number. Edoxaban treatment also attenuated fibrinogen positive area in the remnant kidneys after subtotal nephrectomy. Moreover, edoxaban treatment resulted in attenuated tubulointerstitial fibrosis after 5/6 nephrectomy, which was accompanied by reduced expression levels of epithelial‐mesenchymal transition (EMT) markers, inflammatory mediators, and oxidative stress markers in the remnant kidneys. Treatment of cultured proximal tubular cells, HK‐2 cells, with FXa protein led to increased expression levels of EMT markers, inflammatory mediators, and oxidative stress markers, which were abolished by pretreatment with edoxaban. Treatment of HK‐2 cells with edoxaban attenuated FXa‐stimulated phosphorylation levels of extracellular signal‐regulated kinase (ERK) and NF‐κB. Our findings indicate that edoxaban can improve renal injury after subtotal nephrectomy by reducing EMT and inflammatory response, suggesting that FXa inhibition could be a novel therapeutic target for CKD patients with atrial fibrillation.

Non-purine selective xanthine oxidase inhibitor ameliorates glomerular endothelial injury in InsAkita diabetic mice.

Endothelial dysfunction represents a predominant early feature of diabetes, rendering patients with diabetes prone to renal complications, e.g., proteinuria. Recent studies have indicated a possible role for xanthine oxidase (XO) in the pathogenesis of vascular dysfunctions associated with diabetes. In the present study, we investigated the contribution of XO activation on the progression of diabetic nephropathy in a mouse model using selective XO inhibitors. Male Ins2Akita heterozygous mice were used with wild-type mice as controls. Akita mice were treated with topiroxostat (Topi) or vehicle for 4 wk. Serum uric acid levels were significantly reduced in Akita + Topi mice compared with Akita + vehicle mice. The Akita + Topi group had a significant reduction in urinary albumin excretion compared with the Akita + vehicle group. Mesangial expansion, glomerular collagen type IV deposition, and glomerular endothelial injury (assessed by lectin staining and transmission electron microscopy) were considerably reduced in the Akita + topi group compared with the Akita + vehicle group. Furthermore, glomerular permeability was significantly higher in the Akita + vehicle group compared with the wild-type group. These changes were reduced with the administration of Topi. We conclude that XO inhibitors preserve glomerular endothelial functions and rescue compromised glomerular permeability, suggesting that XO activation plays a vital role in the pathogenesis of diabetic nephropathy.

Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials

Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs. We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology. Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82-0·94; p<0·0001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0·88 (95% CI 0·81-0·96; p=0·003) for death from cardiovascular causes, 0·84 (0·76-0·93; p<0·0001) for fatal or non-fatal stroke, and 0·91 (0·84-1·00; p=0·043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0·88, 0·83-0·95; p=0·001), hospital admission for heart failure by 9% (0·91, 0·83-0·99; p=0·028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate [or increase in creatinine], progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0·83, 0·78-0·89; p<0·0001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer. Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes. None.

Effects of Treatment of Metabolic Acidosis in CKD: A Systematic Review and Meta-Analysis.

Metabolic acidosis is associated with progression of CKD and has significant adverse effects on muscle and bone. A systematic review and meta-analysis was conducted to evaluate the benefits and risks of metabolic acidosis treatment with oral alkali supplementation or a reduction of dietary acid intake in those with CKD. MEDLINE, Embase, and Cochrane CENTRAL were searched for relevant trials in patients with stage 3-5 CKD and metabolic acidosis (<22 mEq/L) or low-normal serum bicarbonate (22-24 mEq/L). Data were pooled in a meta-analysis with results expressed as weighted mean difference for continuous outcomes and relative risk for categorical outcomes with 95% confidence intervals (95% CIs), using a random effects model. Study quality and strength of evidence were assessed using Cochrane risk of bias and the Grading of Recommendations Assessment, Development and Evaluation criteria. Fourteen clinical trials were included (n=1394 participants). Treatment of metabolic acidosis with oral alkali supplementation or a reduction of dietary acid intake increased serum bicarbonate levels (14 studies, 1378 patients, mean difference 3.33 mEq/L, 95% CI, 2.37 to 4.29) and resulted in a slower decline in eGFR (13 studies, 1329 patients, mean difference -3.28 ml/min per 1.73 m2, 95% CI, -4.42 to -2.14; moderate certainty) and a reduction in urinary albumin excretion (very-low certainty), along with a reduction in the risk of progression to ESKD (relative risk, 0.32; 95% CI, 0.18 to 0.56; low certainty). Oral alkali supplementation was associated with worsening hypertension or the requirement for increased antihypertensive therapy (very-low certainty). Low-to-moderate certainty evidence suggest that oral alkali supplementation or a reduction in dietary acid intake may slow the rate of kidney function decline and potentially reduce the risk of ESKD in patients with CKD and metabolic acidosis.

Time of administration of treatment for hypertension in renal patients

Wang et al.1 make a valuable contribution to an aspect of blood pressure management often ignored. In 1961, in blood pressure studies over 24 h, we observed blood pressure did not fall at night in patients with malignant (accelerated) hypertension who had renal failure or were at risk of this.2 Wang et al.1 now provide a meta-analysis of subsequent studies and support our suggestion that ‘non-dipping’ hypertension is important in the generation of morbidity, and that evening administration of medication may be optimal. Their conclusion from the analysis is that evening dosing, when contrasted with morning administration, improves two surrogate markers of long-term benefit: restoring ‘dipping’ in ‘non-dipping’ hypertensives and decreasing urinary albumin. Information on renal function was provided in only two of six studies, totalling 138 patients. There was no significant change in kidney function when measured, but there was no information on the rate of progression of renal dysfunction. The studies did not follow patients for long enough to evaluate ‘hard’ endpoints, death and dialysis, and longer follow-up might have demonstrated renal function benefit from evening dosing. Another surrogate marker of prognosis in chronic kidney disease, urinary albumin excretion (UAE), was reported in only one study included in this meta-analysis. A reduction in UAE with evening dosing was highly correlated with the decrease in nocturnal blood pressure and with the increase in diurnal/nocturnal ratio of blood pressure but no rate of change in UAE was calculated. Renal function is usefully considered as the rate of deterioration. Plasma creatinine, expressed as the reciprocal of plasma creatinine, or the estimated glomerular filtration rate, often demonstrates linear progression, allowing calculation of rates of deterioration in individual patients. Future studies could usefully record more frequent measurements of plasma creatinine and UAE in each individual and identify those responding to changes in time of administration. Time series analysis, utilising Bayesian statistics with Kalman Filtering, were developed for my group to monitor progression of renal function and to detect and evaluate the probability of change.3 If this method is utilised in any prospective trial of change in administration time (or retrospectively if enough data points are available) many fewer subjects will be needed to confirm or refute the conclusions of this meta-analysis. My personal clinical experience provides examples of a change in the rate of progression of kidney failure in some patients when there were therapeutic changes to modify nocturnal blood pressure, I have proposed3, 4 that in the clinic records of renal function and of urinary albumin/creatinine ratio should be considered graphically and also analysed for changes in rate of deterioration when changes, including change in time of administration of medication, have been introduced.

Factors associated with the reduction of albumin excretion in diabetic hypertensive patients: differential effect of manidipine versus amlodipine.

In AMANDHA trial, the addition of manidipine, but not amlodipine, in diabetic patients with uncontrolled hypertension, microalbuminuria and preserved renal function resulted in a large decrease of urinary albumin excretion (UAE) despite similar blood pressure (BP) reductions. Factors associated with the reduction of UAE were analyzed. For this purpose, a multivariable analysis was performed. Although after 6 months of treatment, manidipine and amlodipine decreased BP to a similar extent, reductions of UAE were higher with manidipine. The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were associated with changes in UAE. The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were independently associated with changes in UAE. Compared with amlodipine, manidipine reduced UAE to a higher extent, independently of BP reduction.

On the top of ARB N/L typeCa channel blocker leads to less elevation of aldosterone.

The activation of the renin–angiotensin system (RAS) is one of the unfavourable characteristics of calcium channel blocker (CCB). N type calcium channel is thought to be involved in renin gene transcription and adrenal aldosterone release. Accordingly, N/L type CCB has a possibility of less elevation of plasma aldosterone concentrations (PAC) among CCBs. In a monotherapy study, we had already demonstrated that N/L type CCB leads to less activation of the RAS compared with L type CCB. The objective of this study is to substantiate the hypothesis that at the condition of additive administration on the top of an angiotensin receptor blocker (ARB), still N/L type CCB leads to less elevation of PAC compared with L type one. Subjects were 60 hypertensives administered with valsartan. As an open label study, amlodipine (L type) or cilnidipine (N/L type) were administered on the top of valsartan (ARB) in a cross-over manner. Results were as follows (valsartan+amlodipine compared with valsartan+cilnidipine): systolic blood pressure (SBP)/diastolic blood pressure (DBP) (mmHg): 132±10/76±10 compared with 131±10/77±9, P=0.95/0.48, plasma renin activity (PRA) (ng/ml·h): 2.41±2.67 compared with 2.00±1.50 P=0.20, PAC (pg/ml): 77.3±31.0 compared with 67.4±24.8, P<0.05, urinary albumin excretion (UAE) (mg/gCr): 105.9±216.1 compared with 73.9±122.2, P<0.05. Thus, PAC at cilnidipine was significantly lower than those at amlodipine in spite of the comparable BP reductions. Besides, UAE was significantly lower at cilnidipine. In conclusion, on the top of the ARB, it is suggested that cilnidipine administration might lead to less elevation of PAC and reduction in UAE compared with amlodipine.

Renoprotective Effect of Gemigliptin, a Dipeptidyl Peptidase-4 Inhibitor, in Streptozotocin-Induced Type 1 Diabetic Mice.

BackgroundDipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice.MethodsDiabetes was induced by intraperitoneal administration of a single dose of STZ. Mice with diabetes were treated without or with gemigliptin (300 mg/kg) for 8 weeks. Morphological changes of the glomerular basement membrane (GBM) were observed by electron microscopy and periodic-acid Schiff staining. In addition, we measured blood glucose and urinary albumin excretion and evaluated fibrotic markers using immunohistochemical staining, quantitative reverse transcription polymerase chain reaction analysis, and Western blot analysis.ResultsGemigliptin did not reduce the blood glucose levels of STZ-treated mice. In gemigliptin-treated mice with STZ, a significant reduction in urinary albumin excretion and GBM thickness was observed. Immunohistological examination revealed that gemigliptin attenuated renal fibrosis induced by STZ and decreased extracellular matrix protein levels, including those of type I collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type I collagen and fibronectin mRNA and protein levels via down-regulation of Smad3 phosphorylation.ConclusionOur data demonstrate that gemigliptin has renoprotective effects on DKD, regardless of its glucose-lowering effect, suggesting that it could be used to prevent DKD, including in patients with type 1 diabetes.

Meta-Analysis of the Effect of Dietary Sodium Restriction with or without Concomitant Renin-Angiotensin-Aldosterone System-Inhibiting Treatment on Albuminuria.

Urinary albumin excretion and/or albumin to creatinine ratio are associated with CKD and higher risk of cardiovascular events. Several studies investigated the effect of reduced dietary sodium intake on urinary albumin excretion and/or albumin to creatinine ratio in adult patient populations, but the majority was inconclusive because of insufficient statistical power. A meta-analysis of the randomized, controlled trials available could overcome this problem and lead to more definitive conclusions. A systematic search of the online databases available (from 1996 to October of 2014) was conducted of randomized, controlled trials that expressed urinary albumin excretion or albumin to creatinine ratio as the difference between the effects of two different sodium intake regimens. For each study, the mean difference and 95% confidence intervals were pooled using a random effect model. Heterogeneity, publication bias, subgroup, and meta-regression analyses were performed. Eleven studies met the predefined inclusion criteria and provided 23 cohorts with 516 participants and 1-6 weeks of follow-up time. In the pooled analysis, an average reduction in sodium intake of 92 mmol/d was associated with a 32.1% (95% confidence interval, -44.3 to -18.8) reduction in urinary albumin excretion. The effect of sodium restriction was higher in the cohorts including patients on concomitant renin-angiotensin-aldosterone system-blocking therapy, in the studies with intervention lasting at least 2 weeks, and among participants with evidence of kidney damage. A greater reduction of urinary albumin excretion was associated with a higher decrease in BP during the intervention. The analysis of changes in albumin to creatinine ratio provided similar results. This meta-analysis indicates that sodium intake reduction markedly reduces albumin excretion, more so during concomitant renin-angiotensin-aldosterone system-blocking therapy and among patients with kidney damage.

Renoprotective Effects of Fenofibrate via Modulation of LKB1/AMPK mRNA Expression and Endothelial Dysfunction in a Rat Model of Diabetic Nephropathy

This study was conducted to investigate whether the renoprotective effects of fenofibrate are mediated via attenuation of endothelial dysfunction and modulating the mRNA expression of adenosine monophosphate-activated protein kinase (AMPK) and its downstream kinase liver kinase B1 (LKB1) in rats with diabetic nephropathy (DN). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg kg^-1). Fenofibrate (100 mg kg^-1, p.o.) was given to diabetic rats daily for 12 weeks. Treatment with fenofibrate significantly improved the renal function as revealed by the significant reductions in urinary albumin excretion and serum levels of creatinine and urea, in addition to the significant increase in creatinine clearance compared with the diabetic control group. Hyperglycemia-induced oxidative damage was ameliorated by treatment with fenofibrate as indicated by the significantly increased levels of glutathione and catalase together with the significant decrease in lipid peroxidation. Administration of fenofibrate caused significant increases in renal nitric oxide (NO) production and mRNA expression of endothelial NO synthase (eNOS), AMPK and LKB1, reflecting improvement of endothelial function. Our results give further insights into the mechanisms underlying the protective role of fenofibrate in DN via modulation of AMPK, LKB1 and eNOS mRNA expression.

In Vivo Visualization of the Antialbuminuric Effects of the Angiotensin-Converting Enzyme Inhibitor Enalapril

Angiotensin-converting enzyme (ACE) inhibitors are commonly used antiproteinuric drugs. Here we assessed the effect of the ACE inhibitor enalapril on the glomerular sieving coefficient of albumin (GSCA) using intravital multiphoton microscopy. Munich Wistar Frömter (MWF) rats were used as a model of hypertension-related glomerular lesions. Young (9-week-old) MWF rats were nonproteinuric, similar to what was observed in control Wistar rats. However, urinary albumin excretion in the MWF rats gradually increased during aging, averaging 0.00062 ± 0.0001 at age 9 weeks and 0.0054 ± 0.0003 (mg/mOsmol per liter) at age 52 weeks (P < 0.0001). Albuminuria in aged MWF rats was accompanied by structural changes, which were indicative of glomerular lesions. The GSCA was low in young MWF rats but increased markedly during aging, averaging 0.00057 ± 4.7 × 10(-5) (n = 25) in young MWF rats and 0.0027 ± 0.00036 in 52-week-old MWF rats (n = 36; P < 0.0001). Treatment of proteinuric 12-month-old MWF rats with enalapril over a 4-week period reduced the GSCA from 0.0027 ± 0.00036 to 0.00139 ± 0.00013 (P = 0.0005). Similarly, urinary albumin excretion was reduced, averaging 0.0051 ± 0.0003 and 0.0036 ± 0.0005 mg/mOsmol per liter before and after enalapril administration, respectively (P = 0.0089). In parallel, enalapril treatment reduced the mean arterial blood pressure (144.6 ± 6.5 mm Hg in untreated versus 110.9 ± 0.6 mm Hg in enalapril-treated MWF rats) and increased the glomerular filtration rate from 1.64 ± 0.3 ml/min to 3.58 ± 0.3 ml/min (P = 0.0025 versus baseline). In summary, enalapril reduced the GSCA in proteinuric MWF rats, which was paralleled by a similar reduction in urinary albumin excretion. These data suggest that glomerular rather than tubular mechanisms account for the beneficial antiproteinuric effects of the ACE inhibitor.

Vitamin B and its derivatives for diabetic kidney disease.

Diabetes is a leading cause of end-stage kidney disease (ESKD) mainly due to development and progression of diabetic kidney disease (DKD). In absence of definitive treatments of DKD, small studies showed that vitamin B may help in delaying progression of DKD by inhibiting vascular inflammation and endothelial cell damage. Hence, it could be beneficial as a treatment option for DKD. To assess the benefits and harms of vitamin B and its derivatives in patients with DKD. We searched the Cochrane Renal Group's Specialised Register to 29 October 2012 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. We included randomised controlled trials comparing vitamin B or its derivatives, or both with placebo, no treatment or active treatment in patients with DKD. We excluded studies comparing vitamin B or its derivatives, or both among patients with pre-existing ESKD. Two authors independently assessed study eligibility, risk of bias and extracted data. Results were reported as risk ratio (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. Statistical analyses were performed using the random-effects model. Nine studies compared 1354 participants randomised to either vitamin B or its derivatives with placebo or active control were identified. A total of 1102 participants were randomised to single vitamin B derivatives, placebo or active control in eight studies, and 252 participants randomised to multiple vitamin B derivatives or placebo. Monotherapy included different dose of pyridoxamine (four studies), benfotiamine (1), folic acid (1), thiamine (1), and vitamin B12 (1) while combination therapy included folic acid, vitamin B6, and vitamin B12 in one study. Treatment duration ranged from two to 36 months. Selection bias was unclear in three studies and low in the remaining six studies. Two studies reported blinding of patient, caregiver and observer and were at low risk of performance and detection bias, two studies were at high risk bias, and five studies were unclear. Attrition bias was high in one study, unclear in one study and low in seven studies. Reporting bias was high in one study, unclear in one study, and low in the remaining seven studies. Four studies funded by pharmaceutical companies were judged to be at high risk bias, three were at low risk of bias, and two were unclear.Only a single study reported a reduction in albuminuria with thiamine compared to placebo, while second study reported reduction in glomerular filtration rate (GFR) following use of combination therapy. No significant difference in the risk of all-cause mortality with pyridoxamine or combination therapy was reported. None of the vitamin B derivatives used either alone or in combination improved kidney function: increased in creatinine clearance, improved the GFR; neither were effective in controlling blood pressure significantly compared to placebo or active control. One study reported a significant median reduction in urinary albumin excretion with thiamine treatment compared to placebo. No significant difference was found between vitamin B combination therapy and control group for serious adverse events, or one or more adverse event per patient. Vitamin B therapy was reported to well-tolerated with mild side effects in studies with treatment duration of more than six months. Studies of less than six months duration did not explicitly report adverse events; they reported that the drugs were well-tolerated without any serious drug related adverse events. None of the included studies reported cardiovascular death, progression from macroalbuminuria to ESKD, progression from microalbuminuria to macroalbuminuria, regression from microalbuminuria to normoalbuminuria, doubling of SCr, and quality of life. We were not able to perform subgroup or sensitivity analyses or assess publication bias due to insufficient data. There is an absence of evidence to recommend the use of vitamin B therapy alone or combination for delaying progression of DKD. Thiamine was found to be beneficial for reduction in albuminuria in a single study; however, there was lack of any improvement in kidney function or blood pressure following the use of vitamin B preparations used alone or in combination. These findings require further confirmation given the limitations of the small number and poor quality of the available studies.

Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease

BackgroundHypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin–angiotensin–aldosterone system, and progression of kidney disease.MethodsIn this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m2 of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting–enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume.ResultsThe annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril–telmisartan group and the lisinopril–placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (−1.17 vs. −0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002).ConclusionsIn early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686.)

COX-2 but not mPGES-1 contributes to renal PGE2 induction and diabetic proteinuria in mice with type-1 diabetes.

Prostaglandin E2 (PGE2) has been implicated to play a pathogenic role in diabetic nephropathy (DN) but its source remains unlcear. To elucidate whether mPGES-1, the best characterized PGE2 synthase, was involved in the development of DN, we examined the renal phenotype of mPGES-1 KO mice subjected to STZ-induced type-1 diabetes. After STZ treatment, mPGES-1 WT and KO mice presented the similar onset of diabetes as shown by similar elevation of blood glucose. Meanwhile, both genotypes of mice exhibited similar increases of urinary and renal PGE2 production. In parallel with this comparable diabetic status, the kidney injury indices including the urinary albumin excretion, kidney weight and the kidney histology (PAS staining) did not show any difference between the two genotypes. By Western-blotting and quantitative qRT-PCR, mPGES-1, mPGES-2, cPGES and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) remain unaltered following six weeks of diabetes. Finally, a selective COX-2 inhibitor celecoxib (50 mg/kg/day) was applied to the STZ-treated KO mice, which resulted in significant reduction of urinary albumin excretion (KO/STZ: 141.5±38.4 vs. KO/STZ + Celebrex: 48.7±20.8 ug/24 h, p<0.05) and the blockade of renal PGE2 induction (kidney: KO/STZ: 588.7±89.2 vs. KO/STZ + Celebrex: 340.8±58.7 ug/24 h, p<0.05; urine: KO/STZ 1667.6±421.4 vs. KO/STZ + Celebrex 813.6±199.9 pg/24 h, p<0.05), without affecting the blood glucose levels and urine volume. Taken together, our data suggests that an as yet unidentified prostaglanind E synthase but not mPGES-1 may couple with COX-2 to mediate increased renal PGE2 sythsesis in DN.

Abstract P121: Meta-analysis of the Randomized Controlled Trials of Sodium Intake Reduction and Urinary Albumin Excretion

Background: Urinary albumin excretion (UAE) is a predictor of chronic kidney disease and of higher cardiovascular morbidity and mortality. A number of studies investigated the effect of reduced dietary sodium intake on UAE but their results were not consistent. Therefore, our study assessed the effect of sodium restriction on UAE and/or on albumin/creatinine ratio (ACR) through an updated meta-analysis of the available randomised controlled trials (RCT). Methods: A systematic search of the on-line databases was conducted including RCTs that assessed UAE/ACR at the start and the end of the trial and outcomes expressed as difference between the effect of two different sodium intake regimens. For each study, the mean difference (MD) and 95% confidence intervals (95%CI) were extracted and pooled using a random effect model. Heterogeneity, publication bias, subgroup, and meta-regression analyses were performed. Results: Nine studies were identified, providing 21 cohorts with overall 454 participants and 1-6 weeks follow-up time. In the pooled analysis, lower sodium intake was associated with a 26.7% (95% CI: -40.7 to -12.6) reduction of UAE, with no evidence of publication bias.The effect of lower sodium intake was highest in the cohorts including patients on concomitant RAAS-blocking therapy (-37.7%; -56.5 to -19.9), in those with intervention lasting at least 2 weeks (-32.4%; -47.2 to -17.7), and among participants with evidence of kidney damage (-32.6%; -47.5 to -17.6). The changes in BP occurring during intervention were a significant source of heterogeneity. &gt;The analysis of changes in ACR, where available, provided similar results. Conclusions: This meta-analysis indicated that sodium intake reduction markedly reduces albumin excretion, more so among patients with hypertension and/or kidney damage and during concomitant RAAS-blocking therapy.

Fabry Disease

Fabry disease is an X-linked disorder resulting from mutations of the gene that encodes the lysosomal hydrolase α -galactosidase A, and leads to progressive lysosomal accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids.[1][1] In classically affected male patients, clinical