The Effects of Renin Angiotensin System Blockage (RAS), Calcium Channel Blocker and Combined Drugs on TWEAK, PTX3 and FMD Levels in Diabetic Proteinuric Patients With Hypertension
Condition: Diabetes; Hypertension; Proteinuria
MeSH terms: Proteinuria; Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      Diabetic nephropathy (DN) is the most important complication of diabetes mellitus (DM) and
      the most common cause of end-stage renal disease (ESRD). Diabetic nephropathy is a clinical
      syndrome characterized by persistent albuminuria (> 300 mg/d or > 200 mcg/min) that is
      confirmed on at least 2 occasions 3 to 6 months apart, a relentless decline in the glomerular
      filtration rate (GFR), and elevated arterial blood pressure. In addition to the renal
      hemodynamic alterations, patients with overt diabetic nephropathy (dipstick-positive
      proteinuria and decreasing GFR) generally develop systemic hypertension. Hypertension is an
      adverse factor in all progressive renal diseases and seems especially so in diabetic
      nephropathy. The deleterious effects of hypertension are likely directed at the vasculature
      and microvasculature. Use of angiotensin converting enzyme (ACE) inhibitors and/or
      angiotensin receptor blockers (ARBs), strict glycemic control and use of antilipidemic drugs
      may improve progression of DN.

      TNF-like weak inducer of apoptosis (TWEAK, TNFSF12) is a member of the TNF superfamily of
      structurally related cytokines. The human TWEAK gene encodes a 249-amino acid type II
      transmembrane glycoprotein (30 kD). TWEAK may be expressed as a full-length, membrane-bound
      protein and as a 156-amino acid, 18-kD soluble protein, (sTWEAK) that results from
      proteolysis of TWEAK. TWEAK gene is expressed in many tissues, including brain, kidney,
      heart, arterial wall, monocytes and macrophages. Reduced soluble TNF-like weak inducer of
      apoptosis (sTWEAK) plasma levels have been reported both in patients with subclinical
      atherosclerosis and chronic kidney disease (CKD).

      Long pentraxin 3 (PTX3) is a multimeric inflammatory mediator. Increased serum PTX3 levels
      have been reported among end-stage renal disease patients. Moreover, PTX3 has been suggested
      to represent a novel mortality risk factor, and elevated PTX3 levels have been shown to
      accompany increased albuminuria among patients with chronic kidney disease (CKD).

      There is no data about the effects of Renin angiotensin system blockage (RAS), calcium
      channel blocker and combined drugs on TWEAK and PTX3 levels in diabetic proteinuric patients
      with hypertension. The aim of this study was to find out whether the beneficial effects of
      RAS blockage, calcium channel blocker and combined drugs in diabetic hypertensive proteinuric
      patients has any relation with the alteration of TWEAK and PTX3 levels. The investigators
      searched for the effects of angiotensin II (AII) receptor blocker (Valsartan 160 mg), calcium
      channel blocker (Amlodipine 10 mg) and AII receptor blocker plus calcium channel blocker
      (Valsartan 160 mg + Amlodipine 10 mg) on the clinical and laboratory parameters of diabetic
      hypertensive proteinuric patients.
    

Detailed description: 
      The patients who were non-obese (BMI<30kg/m2), non dyslipidemic (total cholesterol <200mg/dl,
      Triglyceride<150mg/dl), and free of cardiovascular events (negative medical history, negative
      ECG findings) were investigated for enrollment. CKD stage 1 patients older than 18 years of
      age and willing to participate to the study were screened. From the 375 patients with
      established type 2 diabetes mellitus+hypertension, 174 had proteinuria and/or hypertension
      (24 h protein excretion 1-2 g/day, systolic blood pressures ≥140mmHg and/or diastolic blood
      pressures ≥ 90 mmHg, respectively). All cases were first referrals and at the time of the
      study all were off treatment. Patients with history of coronary artery disease, smokers and
      those taking statins or renin-angiotensin blockers were excluded because of the effect of
      these factors on endothelial dysfunction. Of 174 screened patients 107 met the study criteria
      and were included in this study. The duration of proteinuria and diabetic nephropathy after
      initial diagnosis was not known.

      The exclusion criteria were as follows: A)Nephrotic syndrome, B)coronary heart disease
      (patients with ischemic ST-T alterations and voltage criteria for LVH on electrocardiogram,
      and with history of revascularization or myocardial infarction), C) elevated liver enzymes
      (AST or ALT levels ≥ 40U/L) and D) renal failure (serum creatinine levels > 1.3 mg/dl). In
      order to evaluate the effect of RAS blockade on plasma TWEAK and PTX3 concentrations,
      patients with proteinuria were given an AII receptor blocker (Valsartan 160 mg), calcium
      channel blocker (Amlodipine 10 mg) and combine drug (Valsartan 160 mg + Amlodipine 10 mg) for
      12 weeks. The effect of RAS blockade on insulin sensitivity and proteinuria was also
      investigated.

      After the intervention period, blood samples were obtained for assay of plasma TWEAK and PTX3
      concentrations, HbA1c , and insulin resistance scores (HOMA-IR).

      Urine samples were also collected over a 24-hour period to determine the degree of
      proteinuria.
    

Intervention name(s): Amlodipine; Valsartan
Intervention type(s): Drug; Drug
Intervention description(s): calcium channel blocker (Amlodipine 10 mg) during 12 weeks; AII receptor blocker inhibitor (Valsartan 160 mg) during 12 weeks
Intervention MeSH terms: Amlodipine; Valsartan
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: TWEAK; FMD; PTX3; Valsartan; Amlodipine; Renin Angiotensin System