Ewa Aleksandrowicz

Triple Pharmacological Blockade of the Renin-Angiotensin-Aldosterone System in Nondiabetic CKD: An Open-Label Crossover Randomized Controlled Trial

BACKGROUND Agents inhibiting the renin-angiotensin-aldosterone (RAAS) system have an important role in slowing the progression of chronic kidney disease. We evaluated the hypothesis that the addition of an aldosterone receptor antagonist to an angiotensin-converting enzyme (ACE) inhibitor and angiotensin II type 1 (AT-1) receptor blocker (ARB) (triple RAAS blockade) may provide an additional benefit compared with an ACE inhibitor and ARB (double RAAS blockade). DESIGN Randomized open controlled crossover study. SETTING & PARTICIPANTS 18 whites (7 women, 11 men) from the Outpatient Department of Nephrology with chronic nondiabetic proteinuric kidney diseases, mean age 42.4 +/- 1.9 years (SEM). INTERVENTIONS In the 8-week run-in period, all participants received the ACE inhibitor cilazapril (5 mg), the ARB telmisartan (80 mg), and the diuretic hydrochlorothiazide (12.5 mg) as double RAAS blockade to achieve the target blood pressure of less than 130/80 mm Hg. Participants were then randomly assigned to 2 treatment sequences, either the addition of spironolactone (25 mg) (triple RAAS blockade) through 8 weeks followed by double RAAS blockade through 8 weeks (sequence 1) or double RAAS blockade followed by triple RAAS blockade (sequence 2). MAIN OUTCOME MEASURES 24-hour urine protein excretion (primary end point) and markers of tubular injury and fibrosis (secondary end points). Analysis was performed using analysis of variance for repeated measurements. RESULTS At baseline, mean serum creatinine level was 1.16 +/- 0.09 mg/dL (103 +/- 8 micromol/L), estimated glomerular filtration rate was 107.8 mL/min (95% confidence interval, 93 to 140.9 [1.8 mL/s; 95% confidence interval, 1.55 to 2.35; Cockcroft-Gault formula), and 24-hour mean proteinuria was 0.97 +/- 0.18 g. Mean urine protein excretion was 0.7 g/24 h (95% confidence interval, 0.48 to 0.92) less after triple RAAS blockade than after double RAAS blockade (P = 0.01), without change in blood pressure. Urine excretion of N-acetyl-beta-d-glucosaminidase (P = 0.02) and amino-terminal propeptide of type III procollagen (P = 0.05) also significantly decreased. Potassium levels increased significantly after triple therapy (P = 0.02). However, no patient was withdrawn because of adverse effects. LIMITATIONS Absence of blinding, small sample size, short treatment period, absence of histological assessment. CONCLUSIONS Administration of an aldosterone receptor antagonist in addition to double RAAS blockade with an ACE inhibitor and ARB may slow the progression of chronic kidney disease. Additional studies are necessary to confirm this result.

Renal Allograft Protection with Angiotensin II Type 1 Receptor Antagonists

The renal benefits of agents inhibiting the renin‐angiotensin‐aldosterone system in renal transplant recipients, i.e. preventing the development of chronic graft nephropathy, are supposed but not finally proven. In a double‐blind, placebo‐controlled, cross‐over study, we evaluated the influence of losartan on surrogate markers of tubular injury, urine excretion of transforming growth factor β‐1 (TGF‐β1) and amino‐terminal propeptide of type III procollagen (PIIINP) in 16 patients after transplantation. The patients received randomly either losartan (50–100 mg daily) or the β‐blocker carvedilol (12.5–25 mg) for 8 weeks, allowing a placebo washout between treatments. The target office through blood pressure (BP) was below 130/85 mmHg. The BP did not differ in the treatment periods. Losartan significantly decreased N‐acetyl‐β‐d‐glucosaminidase and alfa‐1 microglobulin excretion relative to placebo and carvedilol. Urine excretion of TGF‐β1 and PIIINP was significantly lower after losartan. In conclusion, losartan reduces urine excretion of proteins associated with tubular damage and graft fibrosis.

The influence of ozonated autohemotherapy on oxidative stress in hemodialyzed patients with atherosclerotic ischemia of lower limbs

Ozonated autohemotherapy is used as a complementary medical approach in the treatment of vascular disorders. One of the greatest problems concerning an application of ozone in medicine is its induction of oxidative stress. The standards of ozonotherapy were elaborated recently making this treatment useful and probably non toxic. The aim of the present study was to investigate the influence of ozonated autohemotherapy on the oxidative stress extent in hemodialyzed patients, known to be particularly exposed to generation and deleterious effects of free radicals. Twelve continuously hemodialyzed subjects with atherosclerotic ischemia of the lower limbs were examined in a prospective, controlled, single blind study. Autohemotherapy with blood exposure to oxygen served as a control. The protein and lipid peroxidation products, the reduced glutathione level in red blood cells and free hemoglobin plasma concentration were measured. The study showed that ozonated autohemotherapy with ozone concentration 50 μg/ml per gram of blood induced a significant decrease in glutathione level after 9 sessions of this procedure. Therapy did not cause either the enhancement of protein and lipid peroxidation, or erythrocytes damage. It seems likely that the antioxidant defense system, part of which is glutathione, neutralizes oxidative properties of ozone in this concentration and protects against oxidative cell damage.

Relationship between uremic toxins and oxidative stress in patients with chronic renal failure

Objective. Uremic toxins play a critical role in the manifestation of the uremic syndrome. This is a consequence of retention of such substances in chronic renal failure patients and interactions between them. To date >100 uremic compounds have been discovered. The aim of this study was to elucidate potential relationships between N-methyl-2-pyridone-5-carboxamide (Me2PY) and N-methyl-4-pyridone-5-carboxamide (Me4PY), two uremic compounds, and different parameters of oxidative stress. Material and methods. Forty-three non-dialyzed patients at the Nephrological Outpatients Clinic of Gdansk were enrolled and divided into two groups: (i) 20 patients with a mean estimated glomerular filtration rate (eGFR) of 22.7 ml/min/1.73 m2; and (ii) 23 patients with a mean eGFR of 12.4 ml/min/1.73 m2. In both groups, the plasma concentrations of uremic toxins (Me2PY, Me4PY, creatinine), malonyldialdehyde (MDA) and carbonyl groups and the erythrocyte concentration of glutathione (GSH) were analyzed. Correlations between uremic toxins and oxidative stress markers were calculated using Pearsons correlation. Results. We observed significant correlations between serum creatinine and Me2PY (r=0.68; p=0.00001), eGFR and Me2PY (r=−0.55; p=0.00001), Me4PY and serum creatinine (r=0.64, p=0.00001), Me4PY and eGFR (r=−0.59; p=0.00008), MDA and Me2PY (r=0.42; p=0.006), MDA and Me4PY (r=0.38; p=0.02), GSH and Me2PY (r=−0.37; p=0.02) and GSH and Me4PY (r=−0.46; p=0.005), and in particular in patients with severe renal impairment. Conclusions. We conclude that there is a relationship between the novel uremic toxins described and oxidative stress markers. However, elucidation of the exact pathogenetic links requires further detailed studies.

The Effect of N-Acetylcysteine on Proteinuria and Markers of Tubular Injury in Non-Diabetic Patients with Chronic Kidney Disease

Background: Inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin II subtype 1 receptor antagonists (ARB) constitutes a strategy in the management of patients with chronic kidney disease. There is still no optimal therapy which can stop the progression of chronic kidney disease. Antioxidants such as N-acetylcysteine (NAC) have been reported as a promising strategy in this field. Methods: In a placebo-controlled, randomized, open, 2-period cross-over study, we evaluated the influence of NAC (1,200 mg/day) added to renin-angiotensin-aldosterone system blockade on proteinuria and surrogate markers of tubular injury and renal fibrosis in 20 non-diabetic patients with proteinuria (0.4–6.36 g/24 h) with normal or decreased kidney function (estimated glomerular filtration rate 61–163 ml/min). Subjects entered the 8-week run-in period during which the therapy using ACEI and/or ARB was established with blood pressure below 130/80 mm Hg. Next, patients were randomly assigned to 1 of 2 treatment sequences: NAC/washout/placebo or placebo/washout/NAC. Clinical evaluation and laboratory tests were performed at the randomization point and after each period of the study. Results: No significant changes in laboratory tests were observed. Conclusion: NAC had no effect on proteinuria, surrogate markers of tubular injury or renal fibrosis in non-diabetic patients with chronic kidney disease.

Renal Function and Solitary Kidney Disease: Wilms Tumour Survivors versus Patients with Unilateral Renal Agenesis

Aims: To test the hypothesis that Wilms tumour survivors (WTs) experience increased disturbance in renal function, even after prompt treatment, compared to patients with unilateral renal agenesis (URA). Methods: To assess the renal function of 30 WTs and 17 individuals with URA, the estimated glomerular filtration rate (eGFR) was calculated using the Schwartz and Filler formulas as well as the new Schwartz equation for chronic kidney disease. To measure kidney damage, serum levels and urine excretion of β2-microglobulin (B2M), cystatin C (Cys C), neutrophil gelatinase-associated lipocalin (NGAL) were tested, N-acetyl-β-glucosaminidase (NAG), and albumin urine excretion and urine sediment were examined. Blood pressure was measured. Results: No differences were found between the groups in terms of eGFR, serum Cys C, B2M and NGAL concentrations. The urine excretion of Cys C, NGAL and NAG was similar in both groups. URA patients had higher B2M excretion than WTs. Arterial hypertension was present in 7/30 (23%) WTs and 1/17 (6%) patients with URA. Conclusions: WTs have similar eGFR to individuals with URA and are more likely to have arterial hypertension. The patients with URA have signs of tubular damage. This study demonstrates the need for nephrological monitoring of individuals with a single kidney.

No effects of ozonated autohemotherapy on inflammation response in hemodialyzed patients.

BACKGROUND Ozone as a strong oxidant may induce an inflammatory response. AIM The hypothesis was verified as to whether ozonated autohemotherapy using an ozone dose in therapeutic range changes the plasma concentration of C-reactive protein and interleukin-6, markers of inflammation. METHODS In a controlled, single-blind, cross-over study, 12 chronically hemodialyzed patients with peripheral arterial disease were exposed to nine sessions of autohemotherapy with blood exposure to oxygen as a control followed by nine sessions of ozonated autohemotherapy with an ozone concentration of 50 microg/ml. RESULTS There was no statistical difference between C-reactive protein levels at baseline (1.53 +/- 1.01 mg/l), after nine sessions of control autohemotherapy (1.48 +/- 0.96 mg/l), and after nine sessions of ozonated autohemotherapy (1.55 +/- 0.84 mg/l). There was also no statistical difference between the interleukin-6 serum concentration at baseline (438 +/- 118 pg/ml), after nine sessions of control autohemotherapy (444 +/- 120 pg/ml), and after nine sessions of ozonated autohemotherapy (466 +/- 152 pg/ml). CONCLUSION The results of this study suggest that ozonated autohemotherapy using an ozone concentration of 50 microg/ml does not induce an inflammatory response.

Dual blockade of the renin-angiotensin-aldosterone system with high-dose angiotensin-converting enzyme inhibitor for nephroprotection : An open, controlled, randomized study

Objective. Despite the proven effectiveness of combination therapy with an angiotensin I-converting enzyme inhibitor (ACEI) and angiotensin II-receptor blockers (ARBs) for the prevention and treatment of kidney disease, it has not proved possible to inhibit the progress of chronic nephropathies completely. To improve renal outcome one may consider using increased dosages of ACEI above those usually recommended for hypertension. Material and methods. A randomized, open, controlled study was conducted to evaluate the influence of two combination therapies on proteinuria, markers of tubular injury and renal fibrosis. A total of 18 patients with a creatinine level of 109±36 µmol/l and proteinuria of 0.97±0.76 g/24 h were enrolled in the study. In the 8-week run-in period, an ACEI (cilazapril 5 mg once-daily) and an ARB (telmisartan 80 mg once-daily) were administered to achieve the target blood pressure of ≤130/80 mmHg. Next, the patients were randomly assigned to either an increased dose of cilazapril (10 mg) or the previous dose (5 mg) in two active-treatment periods, each lasting 8 weeks. Results. A significant increase in renin activity was observed after administration of cilazapril 10 mg (6.46±1.12 vs 4.67±0.7 ng/ml/h; p=0.028). Proteinuria, urine excretion of N-acetyl-β-D-glucosaminidase, and α1-microglobulin and amino-terminal propeptide of type III procollagen were unchanged. Conclusion. An increased dosage of cilazapril (twice the maximum recommended dose) in addition to combination therapy with telmisartan was associated with increased blockade of the renin–angiotensin–aldosterone system, with no additional effect on proteinuria, markers of tubular injury or renal fibrosis.

Renal function and low-molecular-weight proteins (cystatin C, β2-microglobulin, neutrophil gelatinase-associated lipocalin) in child and young adult cancer survivors.

Background: We sought to verify the hypothesis that children and young adults with cancer who have completed treatment differ according to the type and degree of renal damage. Procedure: This study included 144 children and young adults (73 female) who had completed treatment for leukemias and lymphomas (group L, n=45), Wilms tumor (group W, n=52) and other solid tumors (group S, n=47). The following parameters were evaluated: serum concentrations of creatinine, cystatin C, &bgr;2-microglobulin, neutrophil gelatinase-associated lipocalin and urine excretion of albumin, and urinalysis with sediment. Glomerular filtration rate (eGFR) was estimated using the classic Schwartz (eGFRSch), Schwartz redux (eGFRSchred), and Filler (eGFRFiller) formulas and with the new Schwartz equation for patients with chronic kidney disease (eGFRSchCKD). Results: Group S had the lowest eGFRSchCKD and eGFRFiller, the highest serum cystatin C and the highest albumin excretion compared with groups L and W. Groups S and W had lower eGFRSch and eGFRSchred and higher serum &bgr;2-microglobulin and neutrophil gelatinase-associated lipocalin compared with group L. Group W had lower eGFRSchCKD than group L. Conclusions: Children and young adults with cancer who have completed treatment differ in the type and degree of renal damage they sustain.

Effects of N-acetylcysteine on angiotensin-converting enzyme plasma activity in patients with chronic kidney diseases.

randomly assigned to one of two treatment sequences: 8 weeks NAC (1,200 mg/day)/8 weeks washout/ 8 weeks placebo (sequence 1) or 8 weeks placebo/8 weeks washout/8 weeks NAC (1,200 mg/day) (sequence 2). The dosages of any drugs once established in the run-in period, were left unchanged throughout the study, as well as in the washout period. Circulating ACE concentration was determined in plasma with a commercial ELISA system (Human ACE Immunoassay Quantikine, RD p = 0.036). A similar conclusion was reached previously in experimental conditions showing that different antioxidants including NAC may decrease local endothelial ACE activity [2] . The molecular and cellular mechanisms by which oxidative stress may mediate ACE activity are not clear so far. Given that increased endothelial expression of ACE plays an important role in cardiovascular remodeling [3] , one may indicate that NAC not only improves endothelial In one of the previous issues of Blood Purification Sahin et al. [1] reported that N-acetylcysteine (NAC) could improve endothelial dysfunction in patients with chronic kidney disease (CKD). The authors suggested that this effect is related to the action of NAC as an antioxidant, i.e. free-radical scavenger, or as a reactive sulfhydryl compound that increases the reducing capacity of the cell. Here, we would like to extend these observations and present the results of our recent clinical study which indicate that NAC could also interfere with the renin-angiotensin system reducing the concentration of circulating angiotensin-converting enzyme (ACE). In a placebo-controlled, randomized, open two-period cross-over study, we evaluated the influence of NAC on plasma concentration of ACE in 20 nondiabetic patients with persistent proteinuria (0.4–6.36 g per 24 h) with normal or slightly lowered kidney function (eGFR 61–163 ml/min). Subjects entered the 8-week run-in period during which antihypertensive therapy was settled with a target blood pressure below 130/80 mm Hg. Next, patients were Published online: May 19, 2008