Adrian Vlad

Proximal tubule dysfunction is associated with podocyte damage biomarkers nephrin and vascular endothelial growth factor in type 2 diabetes mellitus patients: a cross-sectional study.

Background There is an ongoing debate as to whether early diabetic nephropathy in Type 2 diabetes mellitus may be attributed to the glomerulus or to the proximal tubule. Urinary excretion of nephrin and vascular endothelial growth factor may increase even in the normoalbuminuria stage. In the course of diabetic nephropathy, the proximal tubule may be involved in the uptake of urinary nephrin and vascular endothelial growth factor. Materials and Methods Two groups of consecutive Type 2 diabetes mellitus outpatients (38 normo-, 32 microalbuminuric) and 21 healthy subjects were enrolled in a cross-sectional study and evaluated concerning the relation of proximal tubule dysfunction with the podocyte biomarkers excretion, assessed by ELISA methods. The impact of advanced glycation end-products on this relation was also queried. Results Urinary alpha1-microglobulin and kidney injury molecule-1 correlated with urinary albumin:creatinine ratio (R2u200a=u200a0.269; p<0.001; R2u200a=u200a0.125; p<0.001), nephrinuria (R2u200a=u200a0.529; p<0.001; R2u200a=u200a0.203; p<0.001), urinary vascular endothelial growth factor (R2u200a=u200a0.709; p<0.001; R2u200a=u200a0.360; p<0.001), urinary advanced glycation end-products (R2u200a=u200a0.578; p<0.001; R2u200a=u200a0.405; p<0.001), serum cystatin C (R2u200a=u200a0.130; p<0.001; R2u200a=u200a0.128; p<0.001), and glomerular filtration rate (R2u200a=u200a0.167; p<0.001; R2u200a=u200a0.166; p<0.001); nephrinuria and urinary vascular endothelial growth factor correlated with urinary albumin:creatinine ratio (R2u200a=u200a0.498; p<0.001; R2u200a=u200a0.227; p<0.001), urinary advanced glycation end-products (R2u200a=u200a0.251; p<0.001; R2u200a=u200a0.308; p<0.001), serum cystatin C (R2u200a=u200a0.157; p<0.001; R2u200a=u200a0.226; p<0.001), and glomerular filtration rate (R2u200a=u200a0.087; pu200a=u200a0.007; R2u200a=u200a0.218; p<0.001). Conclusions In Type 2 diabetes mellitus there is an association of proximal tubule dysfunction with podocyte damage biomarkers, even in the normoalbuminuria stage. This observation suggests a potential role of the proximal tubule in urinary nephrin and urinary vascular endothelial growth factor processing in early diabetic nephropathy, a fact which could be related to advanced glycation end-products intervention. Podocyte damage and proximal tubule dysfunction biomarkers could be validated as a practical approach to the diagnosis of early diabetic nephropathy by further studies on larger cohorts.

Cerebrovascular reactivity is impaired in patients with non-insulin-dependent diabetes mellitus and microangiopathy.

ZusammenfassungHINTERGRUND: Unter zerebrovaskulärer Reaktivität (ZVR) versteht man einen hämodynamischen Parameter, nämlich den normalerweise auftretenden Anstieg der zerebralen Durchblutung nach vasodilatorischem Stimulus (z.B. Hyperkapnie). ZIEL DER STUDIE: Erfassung der ZVR durch transkraniellen Doppler-Ultraschall vor und nach einem Atem-Anhalte-Test (AAT) bei normotensiven Patienten mit nicht-insulinunabhängigem Diabetes mellitus (NIDDM) und anschließende Evaluierung der Ergebnisse dieser ZVR nach Hyperkapnie in Bezug auf Risikofaktoren für eine zerebrale Mikroangiopathie. METHODEN: Die Studie wurde bei 34 normotensiven Patienten mit NIDDM und einem in der Alters- und Geschlechtsverteilung entsprechenden Kollektiv von 31 Personen, die als Kontrolle (NK) dienten, durchgeführt. Die NIDDM-Patienten wurden in eine Subgruppe A (n = 21, 12 Männer, 9 Frauen; Alter: 58,77 ± 8,91 (MW ± SD) Jahre) mit mikroangiopathischen Komplikationen und eine Subgruppe B (n = 13; 8 Männer; Alter 56,34 ± 9,83 Jahre) ohne solche Komplikationen unterteilt. Die NK Gruppe bestand aus 17 Männer und 14 Frauen (Alter: 58,43 ± 6,31). Es galten folgende Exklusionskriterien: Hypertonie und vergangene oder bestehende symptomatische zerebrovaskuläre Erkrankung. Der AAT bestand aus einer durch 20 Sekunden Luftanhalten erzeugte Hyperkapnie. Die ZVR wurde durch Messung des Anstiegs der mittleren Flussgeschwindigkeit (MFV) in beiden AA cerebri med. während Hyperkapnie im Vergleich zu der basal erhobenen MFV erhoben. ERGEBNISSE: In der Gruppe A war die CVR bei 71,42% signifikant vermindert, während in der Gruppe B nur 30,76% eine mild, bzw moderat verminderte ZVR aufwiesen. Die durch univariate Regressionananlyse ermittelten besten Prädiktoren einer relativ verminderten ZVR waren: Dauer des Diabetes mellitus (r = 0,802; p < 0,0001), Fibrinogen (r = 0,574, p < 0,0001), C-reaktives Protein (r = 0,525; P < 0,001), Proteinurie (r = 0,924, p < 0,0001), Serumkreatinin (r = 0,969; p < 0,0001). Die multivariate Regressionsanalyse zeigte, dass die Dauer des Diabetes mellitus (p < 0,0001), die Proteinurie (p < 0,0001) und das Serumkreatinin (p < 0,0001) signifikante Prädiktoren einer gestörten CVR waren. SCHLUSSFOLGERUNGEN: Die ZVR ist bei normotensiven NIDDM-Patienten vermindert. Diese Änderung der zerebralen Hämodynamik korreliert signifikant mit der Dauer des Diabets mellitus, mit Entzündungsparametern und mit dem Serumkreatinin.SummaryBACKGROUND: Cerebrovascular reactivity (CVR) is a hemodynamic parameter representing the increase in normal cerebral artery blood flow in response to a vasodilatory stimulus such as hypercapnia. MAIN PURPOSE: The aim of the study was to assess CVR using transcranial Doppler ultrasound and the breath-holding test (BHT) in normotensive patients with non-insulin-dependent diabetes mellitus (NIDDM). The cerebrovascular response to hypercapnia was evaluated in relation to risk factors for cerebral microangiopathy. METHODS: The study was carried out in a group of 34 normotensive NIDDM patients and a group of 31 sex- and age-matched normal controls. The NIDDM group was subdivided into 21 patients with microangiopathic complications (Group A, 12 men, 9 women; mean age 58.77 ± 8.91 years) and 13 patients with no such complications (Group B, 8 men, 5 women; mean age 56.34 ± 9.83 years). The control group comprised 17 men and 14 women (Group C, mean age 58.43 ± 6.31 years). Exclusion criteria were hypertension and past or present symptomatic cerebrovascular disease. The BHT consisted of spontaneous hypercapnia induced by holding the breath for 20 seconds. CVR was estimated in relation to the increase in the mean flow velocity (MFV) compared with the basal velocity in both middle cerebral arteries during hypercapnia. RESULTS: In Group A, the CVR was significantly decreased in 71.42% of patients, whereas in Group B only 30.76% of patients presented with mildly to moderately impaired CVR. Predictors for impaired % increase in the MFV during the BHT demonstrated by univariate regression analysis were: duration of diabetes (r = 0.802; P < 0.0001), fibrinogen (r = 0.574; P < 0.0001), C-reactive protein (r = 0.525; P < 0.001), proteinuria (r = 0.924; P < 0.0001) and serum creatinine (r = 0.969; P < 0.0001). Multivariate regression analysis showed as predictors: duration of diabetes (P < 0.0001), proteinuria (P < 0.0001) and serum creatinine (P < 0.0001). CONCLUSION: CVR is impaired in normotensive NIDDM patients. These cerebral hemodynamic changes correlate significantly with the duration of DM, parameters of inflammation, proteinuria and serum creatinine.

Nephro- and neuroprotective effects of rosiglitazone versus glimepiride in normoalbuminuric patients with type 2 diabetes mellitus: a randomized controlled trial

ZusammenfassungHINTERGRUND: Thiazolidinedione stellen eine neue Substanzklasse dar, die den Blutzucker durch Herabsetzung der Insulinresistenz bei Patienten mit Typ 2 Diabetes senken und auf verschiedenen Ebenen eine pleiotrope Wirkung ausüben. HAUPTZIEL DER STUDIE: Die neuro- und nephroprotektiven Effekte von Rosiglitazon wurden bei normalbuminurischen Typ 2 Diabetikern im Vergleich zu Glimepirid erhoben. Weiters wurde die Bedeutung verschiedener Biomarker bei der Diagnose einer beginnenden diabetischen Nephropathie und einer zerebralen Mikroangiopathie untersucht. METHODEN: Insgesamt wurden 34 normalbuminurische Typ 2 Diabetiker in eine einjährige offene, randomisierte, kontrollierte Studie eingeschlossen: In der Gruppe A wurden 17 Patienten (7 Männer, 10 Frauen; mittleres Alter 63 ± 8,07 Jahre) mit Rosiglitazon und Metformin behandelt; in der Gruppe B 17 Patienten (7 Männer, 10 Frauen, mittleres Alter 63,2 ± 7,19 Jahre) mit Glimepirid plus Metformin. Alle Patienten wurden am Beginn der Studie, nach 6 Monaten und am Ende der Studie untersucht. Dabei wurden folgende Parameter erhoben: Serum und Harn β2-Mikroglobulin, Harn alpha 1-Mikroglobulin, Serum Cystatin C, Serum Kreatinin, GFR, C-reaktives Protein, Fibrinogen, HbA1c, Cholesterin, Triglyceride, Haemoglobin, sowie der Albumin: Kreatinin Quotient (AK Qu) im Harn. Außerdem wurden jeweils folgende zerebrale hämodynamische Parameter erhoben: Pulsatilitätsindex und Widerstands Index in der A carotis interna und in der Arteria cerebri media, sowie die Intima Dicke in der Arteria carotis communis. ERGEBNISSE: Nach einem Jahr wurden bei folgenden Parametern Unterschiede zwischen den Gruppen gefunden: im Serum Cystatin C (P < 0,04), im Harn Beta2-Mikroglobulin (P < 0,004), im Harn Alpha1-Mikroglobulin (P < 0,0001), im C-reaktiven Protein (P < 0,0001), im Fibrinogen (P < 0,0001), Serum Kreatinin (P < 0,0024), in der GFR (P < 0,0010), im AKQu (P < 0,0001), und in den zerebralen hämodynamischen Indizes. Der Anstieg im Alpha1-Mikroglobulin und Beta2-Mikroglobulin trat vor dem Auftreten einer Mikroalbuminurie ein. Der AKQu korrelierte mit dem Harn Alpha-1 Mikroglobulin (r = 0,4867) und dem Serum Cystatin C (r = 0,3702). Die zerebrovaskulären Parameter besserten sich in Gruppe A im Vergleich zur Gruppe B und korrelierten mit dem Harn Beta2-Mikroglobulin, dem Harn Alpha1-Mikroglobulin, dem C-reaktiven Protein, dem Fibrinogen, und der GFR. SCHLUSSFOLGERUNG: Nach Ende der Beobachtungsperiode konnte der nephro- und neuroprotektive Effekt von Rosiglitazon bei Typ 2 Diabetikern bestätigt werden. Diese Wirkung war unabhängig von der Blutzuckersenkung. Das Alpha1- und das Beta2-Mikroglobulin im Harn sind signifikante Biomarker für eine beginnende diabetische Nephropathie und eine diabetische zerebrale Mikroangiopathie. Diese Biomarker zeigten, dass die Funktionsstörung des proximalen Tubulus vor dem Stadium der Mikroalbuminurie eintreten kann.SummaryBACKGROUND: Thiazolidinediones represent a novel class of drugs that exert pleiotropic effects at various levels and lower blood glucose through reduction of insulin resistance in patients with type 2 diabetes mellitus. MAIN PURPOSE: The nephro- and neuroprotective effects of rosiglitazone vs. glimepiride were evaluated in normoalbuminuric patients with type 2 diabetes mellitus. The relevance of several biomarkers in the diagnosis of incipient diabetic nephropathy and cerebral microangiopathy was also assessed. METHODS: A total of 34 normoalbuminuric patients with type 2 diabetes mellitus were enrolled in a 1-year open-label randomized controlled trial. Group A comprised 17 patients (7 men, 10 women, mean age 63 ± 8.07 years) treated with rosiglitazone plus metformin; Group B comprised 17 patients (7 men, 10 women, mean age 63.2 ± 7.19 years) treated with glimepiride plus metformin. All patients were assessed at initiation, at 6 months and by the end of the study concerning serum and urinary β2-microglobulin, urinary a1-microglobulin, serum cystatin C, serum creatinine, glomerular filtration rate, C-reactive protein, fibrinogen, glycated hemoglobin, cholesterol, triglycerides, hemoglobin, and the urinary albumin/creatinine ratio (UACR). Cerebral hemodynamic parameters were also measured: pulsatility index and resistance index in the internal carotid artery and middle cerebral artery, and intima-media thickness in the common carotid artery. RESULTS: At 1 year there were differences between groups A and B regarding serum cystatin C (P < 0.04), urinary β2-microglobulin (P < 0.004), urinary a1-microglobulin (P < 0.0001), C-reactive protein (P < 0.0001), fibrinogen (P < 0.0001), serum creatinine (P < 0.0024), glomerular filtration rate (P < 0.0010), UACR (P < 0.0001), and the cerebral hemodynamic indices. The increase in a1- and β2-microglobulin preceded the occurrence of microalbuminuria. UACR correlated with urinary a1- microglobulin (r = 0.4854), urinary β2-microglobulin (r = 0.4867), and serum cystatin C (r = 0.3702). The cerebrovascular parameters improved in group A vs. group B and correlated with urinary β2- and a1-microglobulin, C-reactive protein, fibrinogen, glomerular filtration rate, and duration of diabetes. CONCLUSION: Rosiglitazone demonstrated its nephro- and neuroprotective effects in normoalbuminuric patients with type 2 diabetes mellitus by the end of the follow-up period and these effects were beyond glycemic control. Urinary β2- and a1-microglobulin are significant biomarkers for incipient diabetic nephropathy and diabetic cerebral microangiopathy. These biomarkers showed that proximal tubule dysfunction may develop before the stage of microalbuminuria.

Proximal tubule dysfunction is dissociated from endothelial dysfunction in normoalbuminuric patients with type 2 diabetes mellitus: a cross-sectional study.

Introduction: The aim of our study was to clarify the hypothesis that proximal tubule (PT) dysfunction may be responsible for early diabetic nephropathy (DN), independently of preceding glomerular endothelial dysfunction. The pattern of endothelial dysfunction and its potential variability was evaluated in two vascular beds, the kidney and the brain. Methods: A total of 68 normoalbuminuric type 2 diabetes mellitus (DM) patients were enrolled in a cross-sectional study and the following parameters were assessed: urinary albumin:creatinine ratio (UACR), urinary α1-microglobulin, urinary β2-microglobulin, plasma asymmetric dimethyl-arginine (ADMA), serum creatinine, glomerular filtration rate (GFR), C-reactive protein (CRP), fibrinogen, HbA1c; pulsatility and resistance indices in the internal carotid artery and middle cerebral artery and intima-media thickness (IMT) in the common carotid artery; cerebrovascular reactivity was evaluated through the breath-holding test. Results: Plasma ADMA was increased in 12 patients (17.5%), urinary α1-microglobulin in 19 patients (27.9%) and urinary β2-microglobulin in 16 patients (23.5%). Cerebral hemodynamic indices correlated with plasma ADMA, CRP, fibrinogen, duration of DM, HbA1c and GFR. ADMA correlated with fibrinogen, CRP, HbA1c, duration of DM and GFR. There were no correlations between ADMA and UACR, and urinary α1-/β2-microglobulin. Also, no correlations were found between urinary α1-/β2-microglobulin and UACR, HbA1c, duration of DM and GFR. Conclusion: The increase in urinary α1-/β2-microglobulin precedes the stage of albuminuria. It may be assumed that early DN is related to PT dysfunction. Endothelial dysfunction plays a pivotal role in the brain vasculature, while its involvement in the development of early DN is not conditional on the occurrence of albuminuria.

Pioglitazone delays proximal tubule dysfunction and improves cerebral vessel endothelial dysfunction in normoalbuminuric people with type 2 diabetes mellitus

AIMnThe renal and cerebral protective effects of pioglitazone were assessed in normoalbuminuric patients with type 2 diabetes mellitus (DM).nnnMETHODSnA total of 68 normoalbuminuric type 2 DM patients were enrolled in a one-year open-label randomized controlled trial: 34 patients (pioglitazone-metformin) vs. 34 patients (glimepiride-metformin). All patients were assessed concerning urinary albumin: creatinine ratio (UACR), urinary alpha1-microglobulin, urinary beta2-microglobulin, plasma asymmetric dymethyl-arginine (ADMA), GFR, hsC-reactive protein, fibrinogen, HbA1c; pulsatility index, resistance index in the internal carotid artery and middle cerebral artery, intima-media thickness in the common carotid artery; cerebrovascular reactivity was evaluated through the breath-holding test.nnnRESULTSnAt 1 year there were differences between groups regarding ADMA, urinary beta2-microglobulin, urinary alpha1-microglobulin, parameters of inflammation, serum creatinine, GFR, UACR, the cerebral haemodynamic indices. Significant correlations were found between alpha 1-microglobulin-UACR (R(2)=0.143; P=0.001) and GFR (R(2)=0.081; P=0.01); beta2-microglobulin-UACR (R(2)=0.241; P=0.0001) and GFR (R(2)=0.064; P=0.036); ADMA-GFR (R(2)=0.338; P=0.0001), parameters of inflammation, HbA1c, duration of DM, cerebral indices. There were no correlations between ADMA-UACR, urinary alpha1-microglobulin and beta2-microglobulin.nnnCONCLUSIONnProximal tubule (PT) dysfunction precedes albuminuria and is dissociated from endothelial dysfunction in patients with type 2 DM. Pioglitazone delays PT dysfunction and improves cerebral vessels endothelial dysfunction in normoalbuminuric patients with type 2 DM.

Glycated peptides are associated with the variability of endothelial dysfunction in the cerebral vessels and the kidney in type 2 diabetes mellitus patients: a cross-sectional study

BACKGROUNDnDiabetic atherosclerosis and microangiopathy parallel diabetic nephropathy. The aim of our study was to evaluate the pattern of endothelial dysfunction in two vascular territories, the kidney and the brain, both affected by diabetic vasculopathic complications. The endothelial variability was evaluated in relation to advanced glycation end-products modified peptides.nnnMETHODSnSeventy patients with type 2 diabetes mellitus and 11 healthy subjects were assessed concerning urine albumin: creatinine ratio, plasma and urinary advanced glycation end-products, plasma asymmetric dimethyl-arginine, serum cystatin C, intima-media thickness in the common carotid arteries, the pulsatility index, the resistance index in the internal carotid arteries and the middle cerebral arteries, the cerebrovascular reactivity through the breath-holding test.nnnRESULTSnThe breath-holding index correlated with asymmetric dimethyl-arginine (R²=0.151; p<0.001), plasma advanced glycation end-products (R²=0.173; p<0.001), C-reactive protein (R²=0.587; p<0.001), duration of diabetes mellitus (R²=0.146; p=0.001), cystatin C (R²=0.220; p<0.001), estimated glomerular filtration rate (R²=0.237; p=0.001). Urine albumin: creatinine ratio correlated with urinary advanced glycation end-products (R²=0.257; p<0.001), but not with asymmetric dimethyl-arginine (R²=0.029; p=0.147).nnnCONCLUSIONSnIn type 2 diabetic patients endothelial dysfunction in the cerebral vessels appears to be dissociated from glomerular endothelial dysfunction in early diabetic nephropathy. Advanced glycation end-products could impact both the cerebral vessels and the glomerular endothelium.