Diabetes Microalbuminuria Research Articles

Glycosaminoglycan Regulation by VEGFA and VEGFC of the Glomerular Microvascular Endothelial Cell Glycocalyx in Vitro

Damage to endothelial glycocalyx impairs vascular barrier function and may contribute to progression of chronic vascular disease. An early indicator is microalbuminuria resulting from glomerular filtration barrier damage. We investigated the contributions of hyaluronic acid (HA) and chondroitin sulfate (CS) to glomerular microvascular endothelial cell (GEnC) glycocalyx and examined whether these are modified by vascular endothelial growth factors A and C (VEGFA and VEGFC). HA and CS were imaged on GEnCs and their resynthesis was examined. The effect of HA and CS on transendothelial electrical resistance (TEER) and labeled albumin flux across monolayers was assessed. Effects of VEGFA and VEGFC on production and charge characteristics of glycosaminoglycan (GAG) were examined via metabolic labeling and liquid chromatography. GAG shedding was quantified using Alcian Blue. NDST2 expression was examined using real-time PCR. GEnCs expressed HA and CS in the glycocalyx. CS contributed to the barrier to both ion (TEER) and protein flux across the monolayer; HA had only a limited effect. VEGFC promoted HA synthesis and increased the charge density of synthesized GAGs. In contrast, VEGFA induced shedding of charged GAGs. CS plays a role in restriction of macromolecular flux across GEnC monolayers, and VEGFA and VEGFC differentially regulate synthesis, charge, and shedding of GAGs in GEnCs. These observations have important implications for endothelial barrier regulation in glomerular and other microvascular beds.

Efficacy and safety of linagliptin in type 2 diabetes subjects at high risk for renal and cardiovascular disease: a pooled analysis of six phase III clinical trials.

BackgroundIn patients with type 2 diabetes mellitus (T2DM), hypertension and microalbuminuria are predictive markers for increased renal and cardiovascular risk. This post hoc analysis of data from a global development program aimed to evaluate the efficacy and safety of linagliptin in a population with joint prevalence of these two vascular risk factors.MethodsData for patients with baseline microalbuminuria (urine albumin-to-creatinine ratio 30–300 mg/g) and hypertension (systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg and/or a history of hypertension; and/or an antihypertensive treatment at baseline) who participated in any of six randomized, placebo-controlled, phase III trials were analyzed. Participants received linagliptin 5 mg daily (alone or in combination with other oral antidiabetic drugs) or placebo for 18 to 24 weeks.ResultsOf 3,119 patients, 512 had both microalbuminuria and hypertension (linagliptin, 366; placebo, 146). Baseline mean (SD) HbA1c was 8.3 (0.9)% and 8.4 (0.9)%; median (range) urine albumin-to-creatinine ratio was 60 (30–292) mg/g and 64 (30–298) mg/g; mean (SD) systolic blood pressure was 138 (15) mm Hg and 135 (16) mm Hg; and mean (SD) diastolic blood pressure was 81 (10) mm Hg and 81 (10) mm Hg, for linagliptin and placebo, respectively. Placebo-corrected mean change in HbA1c from baseline to week 18 and week 24 was -0.57% (95% CI: -0.75, -0.39; P < 0.0001) and -0.59% (95% CI: -0.80, -0.39; P < 0.0001), respectively. Placebo-corrected mean change in FPG from baseline to week 24 was -21.3 mg/dl (95% CI: -31.0, -11.6; P < 0.0001). The incidence of drug-related adverse events was similar for linagliptin and placebo (10.4% and 8.2%, respectively). Changes in systolic and diastolic blood pressure, cholesterol and triglyceride levels were similar between linagliptin and placebo.ConclusionIn T2DM patients with the two common vascular risk factors of hypertension and microalbuminuria, linagliptin achieved significant improvements in glycemic control. In this vulnerable patient population at high risk for micro- and macrovascular complications, linagliptin was well tolerated.

Titration of telmisartan, but not addition of amlodipine, reduces urine albumin in diabetic patients treated with telmisartan–diuretic

Microalbuminuria is closely associated with an increased risk of renal and cardiovascular adverse outcomes. The present study tested the hypothesis that titration of telmisartan reduces urinary excretion of albumin more than does addition of amlodipine in patients treated with a standard dose of telmisartan combined with a low-dose diuretic for the same degree of blood pressure (BP) reduction. Hypertensive patients with type 2 diabetes mellitus and microalbuminuria under treatment with a combination of a standard dose of telmisartan (40 mg/day) and trichlormethiazide (1 mg/day) were randomly assigned to receive either an increased dose of telmisartan (80 mg/day) combined with trichlormethiazide [increased dose angiotensin receptor blocker (ARB) group, n = 20] or a combination consisting of telmisartan (40 mg/day), trichlormethiazide, and amlodipine (5 mg/day) (triple combination group, n = 20) for 6 months. The primary endpoint was a reduction in urinary albumin levels. Although BP was reduced to a similar extent by the two regimens, patients receiving the increased dose ARB showed a higher reduction in urinary albumin (-37.4 ± 16.9%) than those on the triple combination regimen (-8.9 ± 23.7%; P < 0.0001). The reduction in urinary albumin was correlated with the drop in BP in the latter group, but not in the increased dose ARB group. Uptitration of telmisartan more effectively reduces urinary albumin than addition of amlodipine in hypertensive patients with diabetes treated with a combination of telmisartan and diuretic for the same degree of BP reduction.

Ramipril

Ramipril

Targeting albuminuria in arterial hypertension and diabetes

Targeting albuminuria in arterial hypertension and diabetes

Macrophage Migration Inhibitory Factor Is a Possible Candidate for the Induction of Microalbuminuria in Diabetic &lt;i&gt;db&lt;/i&gt;/&lt;i&gt;db&lt;/i&gt; Mice

Preventing the onset of microalbuminuria in diabetic nephropathy is a problem that needs urgent rectification. The use of a mouse model for diabetes is vital in this regard. For example, db/db mice exhibit defects in the leptin receptor Ob-Rb sub-type, while the ob/ob strain exhibits defects in the leptin ligand. These mouse strains demonstrate type 2 diabetes, either with or without microalbuminuria, respectively. The purpose of the present study was to use DNA microarray technology to screen for the gene responsible for the onset of diabetic microalbuminuria. Using Affymetrix Mouse Gene ST 1.0 arrays, microarray analysis was performed using total RNA from the kidneys of ob control, ob/ob, db/m, and db/db mice. Microarray and quantitative reverse transcription-polymerase chain reaction (RT-PCR) indicated that transcription of the macrophage migration inhibitory factor (MIF) gene was significantly enhanced in the kidneys of db/db mice. Western blotting showed that levels of MIF protein was enhanced in the kidneys of both diabetic db/db and ob/ob mice. On the other hand, elevation of urinary MIF excretion detected by enzyme-linked immunosorbent assay (ELISA) was only in db/db mice and preceded the onset of microalbuminuria. Immunofluorescence studies revealed that MIF was expressed in mouse kidney glomeruli. While MIF expression was enhanced in the diabetic kidneys of both mouse strains, the elevated secretion from db/db mouse kidneys may be responsible for initiating the onset of microalbuminuria in diabetic nephropathy.

Endothelial progenitor cells in relation to endothelin-1 and endothelin receptor blockade: A randomized, controlled trial

Endothelial progenitor cells (EPC) represent an endogenous repair mechanism involving rendothelialization and neoangiogenesis. Patients with both diabetes and vascular disease have low numbers of circulating EPC. The endothelium-derived peptide, endothelin-1 (ET-1), is increased in patients with type 2 diabetes and vascular complications and has been suggested to contribute to endothelial dysfunction. Therefore, we investigated the relation between EPC and plasma ET-1 and the effect of dual ET-1 receptor antagonist treatment. In this double blind study patients with type 2 diabetes mellitus and microalbuminuria were randomized to treatment with the dual ETA/ETB receptor antagonist bosentan treatment (125mg bid; n=17) or placebo (n=19) for four weeks. Different EPC subpopulations were enumerated by flow cytometry using triple staining (CD34, CD133, KDR) at baseline at the end of treatment. Viability was assessed by 7AAD and Annexin-V-staining. Baseline ET-1 levels correlated significantly with C-reactive protein levels. Patients with ET-1 levels above the median value had higher levels of CD34(+)CD133(+) and CD34(+)KDR(+) EPC. There was no difference in CD34(+) and CD34(+)CD133(+)KDR(+) cells, markers of EPC apoptosis or circulating markers of endothelial damage between patients with ET-1 levels below or above the median. Four week treatment with bosentan did not change EPC levels. Among patients with type 2 diabetes and vascular disease, high plasma levels of ET-1 are associated with higher number of EPC. The recruitment of EPC does not seem to be regulated via ET-1 receptor activation since treatment with a dual ET-1 receptor blocker did not affect circulating EPC numbers.

Tromsø eye study: prevalence and risk factors of diabetic retinopathy

To determine the prevalence of visual impairment, retinopathy and macular oedema, and assess risk factors for retinopathy in persons with diabetes. The present study included 514 participants with diabetes aged 46-87 years from the Tromsø Eye Study, a sub-study of the population-based Tromsø Study in Norway. Visual acuity was measured using an auto-refractor. Retinal images from both eyes were graded for retinopathy and macular oedema. We collected data on risk factor exposure from self-report questionnaires, clinical examinations, laboratory measurements and case note reviews. Regression models assessed the cross-sectional relationship between potential risk factors and diabetic retinopathy. The prevalence of visual impairment (corrected Snellen visual acuity <20/60 in the better-seeing eye) was 1.6%. The prevalence of diabetic retinopathy was 26.8% and macular oedema 3.9%. In a multivariable logistic regression model, retinopathy was associated with longer diabetes duration (odds ratio, OR 1.07, 95% CI 1.03-1.11), insulin use (OR 2.14, 95% CI 1.19-3.85), nonfasting glucose (OR 1.07, 95% CI 1.00-1.15) and microalbuminuria (OR 1.89, 95% CI 1.28-2.81). Sub-group analyses showed association between retinopathy and even low levels of microalbuminuria (1.16 mg/mmol). The findings suggest that low levels of microalbuminuria may be a useful risk predictor for identifying individuals with diabetes at high risk of retinopathy. The study confirms previous findings that insulin use, longer diabetes duration and higher levels of blood glucose are associated with retinopathy in persons with diabetes. The prevalence of diabetic retinopathy was similar as reported in other studies.

Diagnostic accuracy of urine dipstick testing in screening for microalbuminuria in type 2 diabetes: a cohort study in primary care

Clinical guidelines recommend annual screening for microalbuminuria in diabetes. Detection of microalbuminuria is important because it is associated with increased morbidity and mortality. Dipstick tests for microalbuminuria may be convenient, but their accuracy is uncertain. To assess the utility of urine dipstick testing for microalbuminuria in type 2 diabetes. In a 6-week cohort study in four general practices in Oxfordshire, UK, first-pass urine samples were obtained at two weekly intervals from patients with type 2 diabetes and tested in the practice using Micral-Test and Microalbustix urine dipsticks. Parallel samples were sent for laboratory albumin-creatinine ratio (ACR) assay. Results of single dipstick tests and sequences of dipstick and laboratory tests were compared with a clinical testing strategy based on current guidelines to assess the accuracy and estimate costs of testing. The prevalence of microalbuminuria was 12.5% (n = 88). Mean (standard deviation) age was 68 (10) years, 56 (57%) were men. Median (interquartile range) diabetes duration was 6.2 (2.0-10.0) years. The sensitivity and specificity, respectively, of a single Micral-Test were 91.7% and 44.0% and of a Microalbustix test 33.3% and 92.0%. Testing strategies involving dipstick and laboratory ACR measurements or dipstick tests had similar accuracy. The costs of using dipstick tests were overall lower than laboratory ACR-based testing. Dipstick testing in this study did not reliably identify diabetes patients with microalbuminuria. Although dipstick testing would decrease testing costs, it could either fail to diagnose most patients with microalbuminuria or increase the numbers of patients retested depending on the dipstick used.

543 COMPRISON OF THE ANTIALBUMINURIC EFFECTS BETWEEN L-/N-TYPE AND L-TYPE CALCIUM CHANNEL BLOCKERS IN HYPERTENSIVE PATIENTS WITH DIABETES AND MICROALBUMINURIA

Background: It has been demonstrated that L-/N-type calcium channel blocker (CCB), cilnidipine, but not L-type CCB, decreased urinary protein in renin-angiotensin system (RAS) inhibitor-treated hypertensive patients with macroproteinuria. Design and Methods: To clarify whether L-/N-type CCB also has a greater renoprotective effect than L-type CCB in RAS inhibitor-treated hypertensive patients with diabetic microalbuminuria, we conducted a multi-center, open-labeled, randomized trial to compare changes in natural logarithm of albumin/creatinine (Cr) ratio in spot urine between the addition of cilnidipine and amlodipine in RAS inhibitor-treated hypertensive patients with type 2 diabetes and microalbuminuria. Serum Cr, estimated glomerular filtration rate (eGFR), blood pressure (BP) and pulse rate (PR) were also examined. Results: A total of 367 patients were randomly assigned to receive cilnidipine (n = 186) or amlodipine (n = 179) and final doses of cilnidpine and amlodipine were 10.3 ± 4.1 and 4.9 ± 2.1 mg/day, respectively. Both cilnidipine (from 146.6 ± 12.7/81.5 ± 10.3 to 130.4 ± 13.9/73.4 ± 10.2 mmHg) and amlodipine (from 145.4 ± 11.6/80.2 ± 9.8 to 129.7 ± 13.3/71.8 ± 9.8 mmHg) were equally decreased BP and its changes were not different between the two groups. Also, PR was similarly decreased by both drugs. Urinary albumin/Cr ratio was slightly decreased by cilnidipine (from 111.5 ± 139.0 to 107.9 ± 130.2 mg/g) but not by amlodipine (from 88.3 ± 63.5 to 89.1 ± 97.6 mg/g). Changes in natural logarithm of urinary albumin/Cr ratio were not different between the cilnidipine and amlodipine groups. Also, changes in serum Cr and eGFR were not different. Conclusions: The present trials did not demonstrate that cilnidipine has a greater antialbuminuric effect than amlodipine in RAS inhibitor-treated hypertensive patients with type 2 diabetes and microalbuminuria.

570 EFFECTS OF TITRATION OF TELMISARTAN VERSUS ADDITION OF AMLODIPINE ON ALBUMINURIA IN PATIENTSTREATED WITH TELMISARTAN PLUS DIURETIC

Background: Microalbuminuria is closely associated with an increased risk of renal and cardiovascular adverse outcomes.We investigated effects ofup-titration of telmisartan and addition of amlodipine on albuminuria in patients treated with a standard dose of telmisartan combined with a low dose diuretic. Design and Methods: Hypertensive patients with type 2 diabetes mellitus and microalbuminuria under treatment with a combination of a standard dose of telmisartan (40 mg/day) and a low dose of trichlormethiazide (1 mg/day) were randomly assigned to switch their antihypertensive medicationeither to a high dose of telmisartan (80 mg/day) combined with trichlormethiazide (1 mg/day) (high-dose ARB group) or to a combination consisting of telmisartan (40 mg/day), trichlormethiazide (1 mg/day), and amlodipine (5 mg/day) (triple combination group) for 6 months. The primary endpoint was a reduction in urinary albumin levels. Results: Although blood pressure (BP) was reduced to a similar extent in the two regimens, patients receiving high-dose ARB showed a greater reduction in urinary albumin (–37.4 ± 16.9%) than those on the triple combination regimen(–8.9 ± 23.7%; P < 0.0001). The reduction of urinary albumin was correlated with the drop ofBP in the triple combination, but not high-dose ARB, group. Conclusions: Up-titration of telmisartan more effectively reduces urinary albumin than addition of amlodipine in hypertensive patients with diabetes treated with a combination of telmisartan and diuretic for the same degree of BP reduction. The beneficial effect of up-titration of telmisartan is greater than that expected from its BP lowering effect.

Relationship between diabetic retinopathy, microalbuminuria and overt nephropathy, and twenty-year incidence follow-up of a sample of type 1 diabetic patients

PurposeTo determine the incidence and relationship of diabetic retinopathy (DR), microalbuminuria and overt nephropathy (ON). MethodA 20-year prospective study, in a cohort of 110 consecutive type 1 diabetes mellitus (DM) patients, without diabetic retinopathy or microalbuminuria at enrolment in 1990. ResultsThe 20-year incidence of any DR was 70.91%, microalbuminuria 42.72%, and ON was 23.63%. Regarding the risk factors: pre pubertal age at diagnosis was significant for DR and ON, LDL-cholesterol and CT/HDL-cholesterol were significant for DR but not for microalbuminuria or ON. The relationship between DR and ON demonstrated that DR was a significant risk factor for ON, but ON was significant for sight-threatening DR. At the end of the study, two major groups of patients were formed: patients with DR only and patients with DR and ON. For the development of only DR we can assume that the most important risk factor is the duration of DM, followed by the high levels of HbA1c, pre-pubertal age at onset, and arterial hypertension; and for the development of ON and DR simultaneously, risk factors are higher levels of HbA1c, arterial hypertension, DM duration and pre-pubertal age at onset. ConclusionsIn the current study, two major groups of patients have been formed, those who developed only DR and those who developed DR and ON. For the former, incidence increased as DM duration increased, and for the latter incidence appeared to be closely related to levels of HbA1c.

Spironolactone diminishes urinary albumin excretion in patients with type 1 diabetes and microalbuminuria: a randomized placebo‐controlled crossover study

Adding aldosterone receptor blockade to standard renoprotective treatment may provide additional renoprotection in patients with overt nephropathy. We expected an impact of spironolactone in early diabetic nephropathy, and for this hypothesis we studied the effect on markers of glomerular and tubular damage in patients with Type 1 diabetes and persistent microalbuminuria. A double-blind, randomized, placebo-controlled crossover study in 21 patients with Type 1 diabetes and microalbuminuria using spironolactone 25 mg or placebo once daily, for 60 days added to standard antihypertensive treatment. After each treatment period, the primary endpoint were evaluated: urinary(u)-albumin excretion/24 hour(h) and secondary endpoints; 24 h blood pressure, glomerular filtration rate (GFR) and markers of tubular damage: urinary liver-type fatty-acid binding protein (LFABP), neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1). All patients completed the study. During spironolactone treatment, urinary albumin excretion rate was reduced by 60% (range 21-80%), from 90 mg/24 h to 35 mg/24 h (P=0.01). Blood pressure (24 h) did not change during spironolactone treatment (P>0.2 for all comparisons). The GFR (SD) decreased from 78 (6) mL/min/1.73 m(2) to 72 (6) mL/min/1.73 m(2) (P=0.003). Urinary liver-type fatty-acid binding protein, neutrophil gelatinase-associated lipocalin and kidney injury molecule 1 did not change during treatment (P>0.3 for all comparisons). Treatment was well-tolerated, but two patients had severe hyperkalaemia (plasma potassium = 5.7 mmol/l), which was sufficiently treated with diuretics and dietary intervention. Spironolactone treatment in addition to standard renoprotective treatment lowers urinary albumin excretion in microalbuminuric patients with Type 1 diabetes, and thus may offer additional renoprotection independent of blood pressure.

Prevention of microalbuminuria in patients with type 2 diabetes and hypertension

We have previously demonstrated in the Randomized Olmesartan and Diabetes Microalbuminuria Prevention study that the angiotensin receptor blocker (ARB) olmesartan delays the onset of microalbuminuria in patients with type 2 diabetes. Now, we investigated the effect in the subpopulation with hypertension. Overall, 4020 patients with type 2 diabetes and hypertension at baseline (defined by a SBP/DBP ≥130/80 mmHg or use of antihypertensive medication) received either 40 mg olmesartan once daily or placebo for a median of 3.2 years in a randomized, double-blind, multicenter, controlled trial. Additional antihypertensive drugs (except angiotensin-converting enzyme inhibitors or ARBs) were used as needed to lower blood pressure (BP) to less than 130/80 mmHg. The average BP was 126.3/74.7 and 129.5/76.6 mmHg, respectively (P < 0.001). Olmesartan delayed the time to onset of microalbuminuria by 25% (hazard ratio = 0.75; 95% confidence interval = 0.61-0.92, P = 0.007). Patients with a baseline SBP above the median of 136.7 mmHg and a SBP reduction above the median of 17.45 mmHg had a lower incidence of microalbuminuria than patients with a SBP reduction of less than 17.45 (8.1 vs. 11.2%, P < 0.0001). Independent from the baseline BP and the degree of BP reduction a 15-39% increase in the time to onset of microalbuminuria was detectable by olmesartan treatment. Cardiovascular events were comparable and occurred in 93 (4.6%) patients taking olmesartan and 86 (4.4%) taking placebo. Patients with a better BP reduction are less likely to develop microalbuminuria. Treatment with olmesartan delayed the onset of microalbuminuria independent of the baseline BP and the degree of BP reduction.

Fasting APO B48 levels are associated with microalbuminuria in patients with type 2 diabetes

In view of the high incidence of macrovascular diseases in patients with type 2 diabetes mellitus and microalbuminuria, the study evaluates the association of microalbuminuria with fasting plasma Apo B48 levels, a marker of the residual presence of intestinally derived TRLs lipoproteins, thought to be highly atherogenic. We studied 50 patients with type 2 diabetes aged 35-75 years. Exclusion criteria were overt macrovascular disease, overt nephropathy (Glomerular filtration rate (GFR) <45 ml/min/1.73 m(2)), or use of hypolipidemic agents. Anthropometry, fasting plasma lipids, plasma creatinine, and HbA1c were measured. Urinary albumin excretion was measured on a morning urine sample with the ELISA and expressed as albumin/creatinine ratio. GFR was estimated using the MDRD formula. The plasma fasting Apo B48 was measured by ELISA. Age, gender distribution, fasting plasma lipids, HbA1c, smoking status, plasma creatinine, estimate GFR, and the proportion of patients treated with insulin or antihypertensive drugs were similar for patients with or without microalbuminuria. People with microalbuminuria had longer diabetes duration (borderline significance) and significantly higher Apo B48 (1.765 ± 1.379 μg/ml vs. 1.022 ± 0.692 μg/ml, p = 0.01) than those without microalbuminuria. Multivariate logistic regression analysis confirmed that fasting Apo B48 levels were significantly associated with microalbuminuria independent of major confounders measured in the study. In patients with type 2 diabetes, microalbuminuria is associated with elevated Apo B48 levels, independent of major confounders; this may partly explain the excess cardiovascular risk of these patients.

Glomerular hyperfiltration: a marker of early renal damage in pre-diabetes and pre-hypertension

Glomerular hyperfiltration is a characteristic functional abnormality in insulin-dependent diabetes mellitus and occurs in the large majority of young Type 1 diabetic patients. Hyperfiltration is hypothesized to be a precursor of intraglomerular hypertension leading to albuminuria. Glomerular filtration rate (GFR) then falls progressively in parallel with a further rise in albuminuria which may lead, in the long run, to end-stage renal failure. Experimental and clinical studies have shown that glomerular hyperfiltration can occur also in hypertension. However, whether hyperfiltration occurs also in early stages of hyperglycaemia and high blood pressure, such as in pre-diabetes and pre-hypertension, is not well known. In this issue of the Journal, Okada and Coll studied a large Japanese population showing that in pre-diabetic and pre-hypertensive subjects, the prevalence of hyperfiltration is proportional to the level of glucose and blood pressure, respectively. One main problem with the diagnosis of hyperfiltration is that no generally accepted definition is available due to the strong inverse correlation of GFR with age. To overcome this limitation, Okada et al. calculated the upper normal limit of GFR in a large healthy Japanese sample divided into 10-year age groups, providing ageand sex-specific reference values. For hyperfiltration to develop, the concomitant action of a variety of pathogenetic factors are needed including increased body mass index, hyperinsulinaemia, activation of the sympathetic nervous system, hyperleptinaemia, increased oxidative stress, inflammatory cytokines, etc. Another mechanism accounting for increased GFR in obese persons is increased NaCl intake. In addition, a significant role of increased Na reabsorption in the pathophysiology of glomerular hyperfiltration in obesity and hypertension has been described. Pharmacological agents with action on the renin–angiotensin system are effective in reducing glomerular hypertension which accounts for their efficacy in preventing progression of microalbuminuria in diabetes and hypertension. According to current guidelines, only low GFR and microalbuminuria or proteinuria should be considered as markers of renal dysfunction. Due to the strong association between hyperfiltration and risk of microalbuminuria found in diabetes and hypertension, hyperfiltration should be regarded as a precursor of nephropathy in these clinical conditions. More extensive use of markers of early organ damage may help clinicians to reach a more timely decision about the initiation of treatment and thus delay cardiovascular complications. Hyperglycaemia and high blood pressure in people with hyperfiltration should be treated earlier to prevent the progression of renal dysfunction to chronic kidney disease. Increased GFR, also called hyperfiltration, is a proposed mechanism for renal injury in several clinical conditions. According to the Brenner theory [1], low nephron number at birth explains why some individuals are prone to developing progressive renal damage later in life when other risk factors become operative. At the single-nephron level, hyperfiltration is hypothesized to be a precursor of intraglomerular hypertension leading to albuminuria. Increased glomerular capillary hydraulic pressure may be due to changes in systemic arterial pressure and/or changes in efferent and afferent arteriolar resistances. In the absence of therapeutic interventions, GFR then falls progressively in parallel with a further rise in albuminuria which may lead, in the long run, to end-stage renal failure (Figure 1). Human models of renal injury are in keeping with this pathogenetic view. Glomerular hyperfiltration has been observed in patients with unilateral renal agenesis [2], congenitally reduced nephron number [3] and acquired reduction in renal mass [4]. These individuals are prone to developing proteinuria early in life in association with glomerular sclerosis. It is suggested that this model of renal injury may apply to the early diabetic or hypertensive kidney.

Spironolactone treatment in patients with diabetic microalbuminuria and resistant hypertension

Resistant hypertension is common in diabetes. Spironolactone by inhibiting aldosterone not only exerts antihypertensive effect but also antiproteinuric effect. In this study, the mean decrease in systolic and diastolic blood pressure after 4 weeks of spironolactone was 25.5 ± 7.8 and 11.4 ± 3.5 mmHg respectively and it increased further at 8 weeks and at 12 weeks, while there was no significant change in blood pressure in the control group. At 12 weeks, significantly greater reductions in both the systolic and diastolic blood pressure were observed in patients treated with spironolactone having serum potassium less than 4 meq/l vs those having serum potassium more than 4 meq/l. Reduction in urine microalbumin, though higher in patients with serum potassium less than 4 meq/l was not significant at any intervals.

Mechanisms of Glomerular Albumin Filtration and Tubular Reabsorption

Albumin is filtered through the glomerulus with a sieving coefficient of 0.00062, which results in approximately 3.3 g of albumin filtered daily in human kidneys. The proximal convoluted tubule reabsorbs 71%, the loop of Henle and distal tubule 23%, and collecting duct 3% of the glomerular filtered albumin, thus indicating that the kidney plays an important role in protein metabolism. Dysfunction of albumin reabsorption in the proximal tubules, due to reduced megalin expression, may explain the microalbuminuria in early-stage diabetes. Meanwhile, massive nonselective proteinuria is ascribed to various disorders of the glomerular filtration barrier, including podocyte detachment, glomerular basement membrane rupture, and slit diaphragm dysfunction in focal segmental glomerulosclerosis, membranous nephropathy, and other glomerulonephritis. Selective albuminuria associated with foot process effacement and tight junction-like slit alteration is observed in the patients with minimal-change nephrotic syndrome, and the albumin uptake is enhanced in the podocyte cell body, possibly mediated by albumin receptors in the low-dose puromycin model. The role of enhanced podocyte albumin transport needs to be investigated to elucidate the mechanism of the selective albuminuria in minimal-change disease.

What is a preferred angiotensin II receptor blocker-based combination therapy for blood pressure control in hypertensive patients with diabetic and non-diabetic renal impairment?

Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular (CV) events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Given that most patients with hypertension require at least two antihypertensives to achieve blood pressure (BP) goals, identifying the most appropriate combination regimen based on individual risk factors and comorbidities is important for risk management. Single-pill combinations (SPCs) containing two or more antihypertensive agents with complementary mechanisms of action offer potential advantages over free-drug combinations, including simplification of treatment regimens, convenience and reduced costs. The improved adherence and convenience resulting from SPC use is recognised in updated hypertension guidelines. Despite a wide choice of SPCs for hypertension treatment, clinical evidence from direct head-to-head comparisons to guide selection for individual patients is lacking. However, in patients with evidence of renal disease or at greater risk of developing renal disease, such as those with diabetes mellitus, microalbuminura and high-normal BP or overt hypertension, guidelines recommend renin-angiotensin system (RAS) blocker-based combination therapy due to superior renoprotective effects compared with other antihypertensive classes. Furthermore, RAS inhibitors attenuate the oedema and renal hyperfiltration associated with calcium channel blocker (CCB) monotherapy, making them a good choice for combination therapy. The occurrence of angiotensin-converting enzyme (ACE) inhibitor-induced cough supports the use of angiotensin II receptor blockers (ARBs) for RAS blockade rather than ACE inhibitors. In this regard, ARB-based SPCs are available in combination with the diuretic, hydrochlorothiazide (HCTZ) or the calcium CCB, amlodipine. Telmisartan, a long-acting ARB with preferential pharmacodynamic profile compared with several other ARBs, and the only ARB with an indication for the prevention of CV disease progression, is available in two SPC formulations, telmisartan/HCTZ and telmisartan/amlodipine. Clinical studies suggest that in CV high-risk patients and those with evidence of renal disease, the use of an ARB/CCB combination may be preferred to ARB/HCTZ combinations due to superior renoprotective and CV benefits and reduced metabolic side effects in patients with concomitant metabolic disorders. However, selection of the most appropriate antihypertensive combination should be dependent on careful review of the individual patient and appropriate consideration of drug pharmacology.

Association of Helicobacter pylori infection with microalbuminuria in type 2 diabetic patients

As default, Helicobacter pylori infection may cause systemic inflammation and vascular endothelial damage. Therefore, it can be assumed that the glomerular damage as a result may lead to an increase in urinary albumin excretion. In this study, this hypothesis was set, and the relationship between Helicobacter pylori infection and microalbuminuria was examined. Ninety-three patients with type 2 diabetes were included in the study. These patients were divided into two groups as Helicobacter pylori infection-positive (Group 1) or -negative (Group 2). In all infected and non-infected patients, urinary albumin excretion and other parameters were compared. The presence of Helicobacter pylori infection was detected in 53 of 93 diabetic patients (56.98%). Diabetic patients infected by Helicobacter pylori (Group 1; 186.7±24.2 mg/24 h) showed significantly higher microalbuminuria than non-infected patients (Group 2; 131.2±11.6 mg/24 h) (p=0.012). Diabetics infected with Helicobacter pylori had significantly higher inflammation marker levels than non-infected patients (p<0.05). It has been concluded that the relation between microalbuminuria level and Helicobacter pylori infection in diabetics is independent from other study variables. Helicobacter pylori infection, because of the systemic inflammatory response, may play an important role in the progression of diabetic nephropathy or its development. In this study, demonstrating the relationship between Helicobacter pylori infection with diabetic microalbuminuria, due to the small number of patients, is inadequate. Therefore, clinical and molecular studies involving more patients should be supported.