Effects of angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist and calcium antagonist on urinary podocytes in patients with IgA nephropathy

The urinary podocyte is postulated to be a marker for estimation of the severity of active glomerular injury and a predictor of disease progression in children with glomerulonephritis. Non-dihydropyridine calcium antagonist, including verapamil, reduce proteinuria to an extent similar to that of the angiotensin-converting enzyme inhibitor (ACEI), including trandolapril, but to a greater extent than other antihypertensives. Angiotensin (Ang) II receptor antagonists, including candesartan cilexetil, show potent and long-term preventive effects against the progression of renal injury. The aim of the present study is to assess whether verapamil, trandolapril and candesartan cilexetil affect proteinuria and urinary podocytes in patients with IgA nephropathy. Thirty-two normotensive patients aged 18-54 years with biopsy-proven IgA nephropathy, nonnephrotic proteinuria (1-3 g/day), and normal renal function (creatinine clearance >80 ml/min) were studied. Twenty patients with diffuse mesangial proliferative glomerulonephritis (non-IgA PGN) and 20 healthy controls were also included in this study. The number of urinary podocytes in patients with advanced IgA nephropathy (n = 16) was significantly higher than that in patients with the disease in the mild stage (n = 16) (p < 0.01) or in patients with non-IgA PGN (p < 0.01). Urinary podocytes were not detected in healthy controls. The 32 patients with IgA nephropathy were randomly divided into four treatment groups: those treated with verapamil (120 mg/day, n = 8); those treated with trandolapril (2 mg/day, n = 8); those treated with candesartan cilexetil (8 mg/day, n = 8), and those given a placebo (n = 8). Treatment continued for 3 months. Antiproteinuric response in the trandolapril group was similar to that in the candesartan cilexetil group (-38 vs. -40%). The action of trandolapril or candesartan cilexetil was greater than that of verapamil (p < 0.01). Reduction in the number of urinary podocytes from baseline was significantly greater in patients treated with trandolapril or candesartan cilexetil than in patients treated with verapamil (p < 0.01). However, there was no difference between patients treated with trandolapril and those treated with candesartan cilexetil. Proteinuria and urinary podocytes were unaffected in the placebo group. These data suggest that urinary podocytes may be a marker of disease activity in adult patients with IgA nephropathy and that trandolapril and candesartan cilexetil are more effective than verapamil in reducing the number of podocytes.     

Blockade of renin-angiotensin system ameliorates renal injury in NIDDM model rats

Background. Recently, inhibition of the renin-angiotensin system has been reported to be effective for patients with diabetic nephropathy. In this study, we examined the renal protective effects of candesartan cilexetil (TCV-116) in Wistar fatty rats, a model of non-insulin-dependent diabetes mellitus (NIDDM) with renal injuries. Methods. Twelve-week-old Wistar fatty rats received candesartan cilexetil (0.3 or 1 mg/kg) or enalapril (10 mg/kg) daily, administered orally, for 16 weeks. Routine laboratory parameters, such as urinary albumin and total protein excretion, were measured every 4 weeks, and renal function tests and histopathological studies were carried out at the end of the experiment. Results. In the 12-week-old Wistar fatty rats, plasma glucose and insulin levels were significantly higher than those in age-matched Wistar lean rats (normal controls). Urinary albumin and total protein excretion was slightly but significantly increased as compared to these parameters in Wistar lean rats, and increased further with time. Daily administration of candesartan cilexetil or enalapril inhibited the increase in urinary albumin and total protein excretion without affecting plasma glucose and insulin levels. In histopathological studies, candesartan cilexetil (0.3 and 1 mg/kg) and enalapril (10 mg/kg) prevented the glomerular injury observed in vehicle-treated rats. Candesartan cilexetil (1 mg/kg) and enalapril also inhibited tubular changes. Systolic blood pressure in the drug-treated groups was significantly decreased compared with that in vehicle-treated rats. Conclusions. Inhibitors of the renin-angiotensin system ameliorated proteinuria and the pathological changes of renal injuries in this NIDDM model. Candesartan cilexetil may be useful for the treatment of NIDDM patients with renal damage. Received: March 1, 1999 / Accepted: June 13, 2000     

Candesartan cilexetil in children with hypertension or proteinuria: preliminary data

The angiotensin II receptor blockers irbesartan and losartan effectively reduce blood pressure and proteinuria in childhood. We were impressed by the neutral taste and the small size of the candesartan cilexetil tablets. This angiotensin II receptor blocker was used during 4 months in 17 pediatric patients (aged 0.5–16, median 4.5 years) with chronic arterial hypertension (n=6), overt proteinuria (n=2), or both (n=9). The initial candesartan dose of 0.23 (0.16–0.28) mg/kg body weight once daily (median and interquartile ranged) was doubled in ten patients [final dose 0.35 (0.22–0.47) mg/kg body weight]. No adverse clinical experiences were noted on candesartan. Candesartan increased plasma potassium by 0.3 (0.0–0.8) mmol/l (P<0.01). In children with arterial hypertension, blood pressure decreased by 9 (3–13)/9 (3–18) mmHg (P<0.01); in those with overt proteinuria the urinary albumin/creatinine ratio decreased by 279 (33–652) mg/mmol (P<0.05). In conclusion, in children candesartan reduces blood pressure and proteinuria with an excellent short-term tolerability profile.     

Effects of the angiotensin II type 1 receptor antagonist candesartan,compared with angiotensin-converting enzyme inhibitors,on the urinary excretion of albumin and type IV collagen in patients with diabetic nephropathy

Background. We previously reported that the angiotensin II type 1 receptor antagonist candesartan was effective in reducing blood pressure and microalbuminuria in hypertensive patients with diabetic nephropathy after angiotensin-converting enzyme (ACE) inhibitors were replaced due to side effects. In the present study, the clinical effects of candesartan were investigated and compared with ACE inhibitors in patients with stage 2 or 3A diabetic nephropathy, mainly with respect to the effects on the urinary excretion of albumin and type IV collagen. Methods. Forty-nine patients (26 males/23 females) with diabetic nephropathy (stage 2 or 3A), including normotensive patients, were the study subjects. The patients were treated with either an ACE inhibitor (23 patients) or candesartan (26 patients) for 11 ± 3 months. The urinary excretion of albumin and urinary type IV collagen was measured. Results. Posttreatment blood pressure tended to decrease, but such a decrease did not reach a statistically significant level, nor did it show any intergroup difference. The urinary albumin excretion was positively correlated with pretreatment mean blood pressure and left ventricular mass index, but the urinary type IV collagen excretion did not show such correlations. The urinary albumin excretion decreased significantly after treatment to a similar extent in both groups, whereas the urinary type IV collagen excretion decreased significantly only in the candesartan group. Conclusion. It was revealed that ACE inhibitors and candesartan reduced urinary albumin excretion to a similar extent in patients with diabetic nephropathy. From the results of the present study, it is inferred that the renoprotective effect of candesartan in diabetic nephropathy may partially differ from that of ACE inhibitors.     

Re-biopsy in a patient with IgA nephropathy showing success of treatment with cyclosporin A and angiotensin-II receptor blocker

We report a patient with IgA nephropathy (IgAN) showing reduction of proteinuria and histological improvement of renal injury with cyclosporin A (CsA) and angiotensin-II receptor blocker (ARB) therapy. The amount of urinary protein was reduced from 4.4 to 1.8 g/24 h after 2 months of CsA (150 mg/day) therapy, and further, to 0.4 g/24 h after 1 month of the combination therapy with ARB (candesartan, 4 mg/day). A renal re-biopsy, after treatment with CsA for 3 months and ARB for 1 month, demonstrated a reduction of IgA deposits, disappearance of crescents, re-separation of foot process fusion and decrease of interstitial cellular infiltration. After CsA therapy for 20 months and ARB for 18 months, the patient currently remains stable without deterioration of serum creatinine (1.7 mg/dl) and urinary protein excretion (0.5 g/day). These findings seem to indicate that combination therapy with CsA and ARB is effective for achieving histological improvement and protecting against deteriorated renal function, in addition to reducing proteinuria, in IgAN. Received: October 1, 2001 / Accepted: April 10, 2002     

Albuminuria and insulin resistance in children with biopsy proven non-alcoholic fatty liver disease

Insulin resistance may favor increased urinary albumin excretion (UAE), leading progressively to chronic kidney disease (CKD). A recent study on non-alcoholic fatty liver disease (NAFLD), a condition of insulin resistance, associated this disease with the incidence of CKD in patients with type 2 diabetes. The aim of our study was to determine whether there is an association between insulin resistance and kidney function, based on estimates of UAE and creatinine clearance in children with biopsy-proven NAFLD. Kidney function was assessed in 80 patients with NAFLD and 59 individuals of normal weight matched for age and sex. Insulin resistance was measured by means of the homeostatic model assessment-insulin resistance (HOMA-IR) and limited to NAFLD patients by using the whole-body insulin sensitivity index. The HOMA-IR was found to differ significantly between the two groups (2.69 ± 1.7 vs. 1.05 ± 0.45; p = 0.002), while UAE (9.02 ± 5.8 vs. 8.0 ± 4.3 mg/24 h; p = 0.9) and creatinine clearance (78 ± 24 vs. 80 ± 29 mg/min; p = 0.8) did not. We found a significant but weak inverse correlation between insulin sensitivity and creatinine clearance in NAFLD patients (r _s = –0.25;p = 0.02). No difference was observed in kidney function between NAFLD children presenting with or without metabolic syndrome, low or normal HDL-cholesterol, and different degrees of histological liver damage (grade of steatosis ≥2, necro-inflammation, and fibrosis). Patients with hypertension had increased levels of UAE (p = 0.04). A longer exposure to insulin resistance may be required to cause the increase in urinary albumin excretion and to enable the detection of the effect of the accelerated atherogenic process most likely occurring in children with fatty liver disease. Longitudinal studies are needed to rule out any causative relationship between insulin resistance and urinary albumin excretion.     

Safety and efficacy of a biliary-excreted angiotensin converting enzyme (ACE) inhibitor,temocapril, in combination with amlodipine in advanced diabetic nephropathy

Background. Diabetic patients with moderate to advanced renal failure have severe hypertension and often require multiple antihypertensive agents to control it. Nevertheless, no standardized therapy has been established. This study was designed to examine the safety and efficacy of the biliary-excreted angiotensin converting enzyme inhibitor temocapril in those patients whose blood pressure was not adequately decreased by calcium channel blocker monotherapy. Methods. Twenty-seven patients who did not reach the therapeutic goal of blood pressure (140/90 mm Hg) with amlodipine monotherapy were assigned to receive temocapril (2 mg) and amlodipine (5 mg) for 3 months. Blood samples for hematological and biochemical examinations were taken every month during treatment. Twenty-four-hour urine was collected to measure urinary protein excretion. Trough plasma concentrations and pharmacokinetics were measured during temocapril treatment. Results. Blood pressure was significantly decreased (P < 0.05) from 158 ± 14/91 ± 9 to 148 ± 15/83 ± 8 mm Hg by the addition of temocapril. The peak serum concentration (Cmax) was 86.3 ± 22.7 μg/l at 3.9 ± 1.6 h (Tmax) after administration. Mean area under curve for 0 to 24 h (AUC_0–24 h) was 1179 ± 273 μg/l · h. Trough levels showed a steady state. After temocapril therapy, the slope of the reciprocal of creatinine decreased compared with that before the addition of temocapril. Urinary protein excretion significantly decreased from 3100 ± 1100 to 2300 ± 1100 mg/day. There was no significant change in hematological and biochemical data. Conclusions. The present findings suggest that temocapril can be safely used in patients with advanced diabetic nephropathy, and in combination with dihydropyridine calcium channel blockers it decreases blood pressure and effectively retards the aggravation of renal insufficiency for 3 months in those patients. Received: April 3, 2002 / Accepted: August 29, 2002 Correspondence to:G. Yasuda     

Use of candesartan cilexetil decreases proteinuria in renal transplant patients with chronic allograft dysfunction

BACKGROUND: Posttransplant proteinuria and hypertension are difficult to treat after renal transplantation. Therefore, we examined whether candesartan cilexetil is effective in reducing urinary protein excretion or in controlling hypertension in patients with renal allograft dysfunction. METHODS: Sixty-two renal transplant recipients with proteinuria were enrolled in this study. They underwent kidney transplantation under cyclosporine or tacrolimus immunosuppression between February 1983 and December 1998. Causes of proteinuria were chronic rejection in 28, glomerulonephritis in 16, cyclosporine or tacrolimus nephrotoxicity in 9, and unknown in 9 recipients. The dose of candesartan cilexetil ranged from 4 to 12 mg/day. Eleven patients with proteinuria who had not been treated with candesartan cilexetil constituted a matched control population. RESULTS: Hypertension was well controlled by administration of candesartan cilexetil. Both systolic blood pressure and diastolic blood pressure significantly decreased from 141.7+/-14.8 mm Hg to 118.7+/-11.9 mm Hg and 121.2+/-11.6 mm Hg, and from 89.0+/-13.0 mm Hg to 72.0+/-10.4 mm Hg and 74.9+/-9.4 mm Hg, at 2 months and 1 year after administration, respectively. Urinary protein excretion was reduced from 0.93+/-1.2 g/day to 0.34+/-0.7 g/day and 0.43+/-1.2 g/day at 2 months and 1 year after administration, respectively. The levels of creatinine clearance were 55.7+/-28.9 mL/min before treatment, 50.9+/-24.8 mL/min at 2 months, and 52.6+/-24.8 mL/min at 1 year after treatment, respectively. There was no clinically significant difference between them. Regarding the calcineurin inhibitor levels, there was no significant difference between the levels before and 1 year after treatment. There was a significant difference in all examinations (systolic blood pressure, diastolic blood pressure, proteinuria, and renal function) between the patients with and without candesartan at 1 year after treatment. No significant adverse effects occurred. CONCLUSIONS: Candesartan cilexetil can effectively control hypertension and proteinuria without deterioration in renal allograft function. These data suggest that treatment with candesartan cilexetil may be useful for maintaining long-term renal allograft function.     

Quantification of osteopontin in the urine of healthy and stone-forming men

Osteopontin (OPN) is one of the most important components in calcium stone matrix, but its role in stone formation is not clear. Since quantitative data regarding the excretion of OPN are necessary to assess its role, we have developed a quantitative enzyme-linked immunosorbent assay (ELISA) for OPN, and measured the urinary OPN concentrations in urolithiasis patients. Forty-seven men with urinary stones composed chiefly of calcium oxalate participated in the study. The controls were 13 normal healthy male volunteers. Urine samples were collected early in the morning and analyzed by a quantitative ELISA employing purified polyclonal antibodies to synthesized OPN aminopolypeptides. The urinary ratio of the concentrations of OPN and creatinine (OPN/Cre) in the urolithiasis patients (0.039 ± 0.029) was significantly lower than that in the control subjects (0.062 ± 0.030) (P<0.05). Single stone formers (n = 26; 0.050 ± 0.020) had significantly higher OPN/Cre ratios compared with recurrent stone formers (n = 21; 0.031 ± 0.021) (P<0.05). The results show that OPN excretion in urolithiasis patients was lowered, presumably because of the incorporation of OPN by kidney stones. Received: 4 September 1998 / Accepted: 1 March 1999     

Candesartan Cilexetil on Regular Hemodialysis: Inability to Reduce Excessive Thirst,but Good Tolerance and Efficacy in Hypertensive Patients

It has been postulated that hypertension and interdialytic weight gain in hemodialysis patients are related to the activation of the renin-angiotensin system. Angiotensin II type 1 (AT1) receptor antagonists are new anti-hypertensive agents and are currently the most specific means of blocking the Renin-Angiotensin Enzymatic cascade. Recent studies show that candesartan cilexetil regulates thirst and hypertension in rodents, via cerebral AT1 receptor blockade. We therefore conducted a prospective open study of candesartan cilexetil in 21 hypertensive patients on long-term hemodialysis during 6 weeks, focusing on thirst regulation. We also performed a prospective follow-up study of tolerance of candesartan and its anti-hypertensive efficacy after this 6-week study, while the patients remained on this therapy. Weight gain between hemodialysis sessions did not differ between the periods before and during candesartan cilexetil therapy. Median absolute interdialytic weight gain was 2.35 kg (range: 0.55–5) before therapy, compared to 2.25 kg (range: 0.35–4.65) during therapy (p > 0.05, Wilcoxon test). The median interdialytic weight gain/dry weight index was 3.7% (range: 1.15–7) before therapy and 3.6% (range: 0.7–6.6) during candesartan therapy (p > 0.05, Wilcoxon test). The median dose of candesartan cilexetil was 12 mg/day (range: 4–24). The median total duration of therapy with candesartan (including the 6 weeks of the thirst study) was 12 months (range: 2–25). During candesartan cilexetil therapy, the number of concomitant anti-hypertensive drugs per patient fell significantly (median number of anti-hypertensive drugs before candesartan = 2 (range: 1–6); during candesartan = 1 (range: 1–5) (p < 0.02, Wilcoxon test). No anaphylactoid reactions occurred. A total of 161 episodes of hypotension (5%) occurred during 3074 hemodialysis sessions (including the 6 weeks of the thirst study) We conclude that, like angiotensin converting enzyme inhibitors and the other angiotensin receptor antagonists, candesartan cilexetil is unable to reduce interdialytic weight gain in hemodialysis patients. This study also shows that the irreversible angiotensin II receptor antagonist candesartan cilexetil is a safe and effective therapeutic option for hypertensive hemodialysis patients.     

Effect of carnitine supplementation on lipid profile and anemia in children on chronic dialysis

We prospectively evaluated the effects of L-carnitine supplementation on plasma free carnitine (FC) levels, serum lipid profile, and erythropoietin (rhEPO) requirement in 24 children treated with peritoneal dialysis (PD; n = 16) or hemodialysis (HD; n = 8). The study was divided into a 3-month observation period, and a 3-month treatment period during which patients received 20 mg/kg per day of L-carnitine given orally. Clinical, biochemical, and hematological data were collected every 3 months. FC levels were measured in plasma and peritoneal dialysate by tandem mass spectrometry. There were no statistically significant changes in lipid levels, hemoglobin, or rhEPO requirements during the course of the study. Fifteen patients (13 PD, 2 HD) had plasma FC levels measured before and after treatment; FC levels increased from 32.1 ± 14.1 μmol/l to 80.9 ± 38.7 μmol/l (P < 0.001). In PD patients, dialysate FC losses increased from 106 ± 78 μmol/day at baseline to 178 ± 119 μmol/day after supplementation. Positive correlations between FC plasma levels and dialysate levels (R = 0.507) or daily excretion (R = 0.603) were found after treatment. In our case series, an oral dose of 20 mg/kg per day of L-carnitine restored FC levels and produced a positive carnitine balance with no significant effects on hematological parameters or lipid profile over a 3-month period. Prolonged treatment duration may be required to obtain significant results.     

Risk of Calcium Oxalate Nephrolithiasis after Calcium or Combined Calcium and Calcitriol Supplementation in Postmenopausal Women

Although calcium supplementation can cause hypercalciuria, the risk of nephrolithiasis has been shown to decrease rather than increase among subjects who had a higher calcium intake. Hypercalciuria is also a well-established side effect of calcitriol administration. However, the risk of nephrolithiasis is not well defined. The present study was undertaken to prospectively determine the effect of calcium with or without calcitriol on physicochemical risk factors associated with calcium oxalate nephrolithiasis in Thai postmenopausal women with osteoporosis. Subjects consisted of 53 Thai women more than 10 years postmenopausal who were randomly allocated to receive 750 mg of calcium carbonate supplement alone (n= 28) or 750 mg of calcium carbonate plus 0.5 mg calcitriol (n= 25) daily. Mean ± SEM for age was 65.3 ± 1.1 years, body weight 53.5 ± 1.3 kg. Urine samples for biochemical assays were collected at baseline and 3 months after treatment. Supersaturation for calcium oxalate stone formation was assessed from the 24 h urine constituents by the Tiselius’s index, AP(CaOx). Three months of calcium supplement alone resulted in a modest, but not significant, increase in urinary calcium (baseline, 2.90 ± 0.43 mmol/day; after treatment 3.58 ± 0.54 mmol/day) with no change in urinary oxalate, citrate or magnesium. In contrast, calcium together with calcitriol caused a significant increase in urinary calcium (baseline, 2.87 ± 0.41 mmol/day; after treatment, 4.08 ± 0.57 mmol/day; p<0.05). No significant change in other urine constituents after treatment with calcium and calcitriol was detected. Therefore, AP(CaOx) did not significantly increase either after calcium alone (baseline, 1.17 ± 0.39; after treatment, 1.36 ± 0.28) or after calcium plus calcitriol (baseline, 1.09 ± 0.17; after treatment, 1.09 ± 0.19). However, after treatments, 12 subjects (23%) – 6 receiving calcium supplement alone and 6 receiving calcium plus calcitriol supplement – had high AP(CaOx) values (greater than the upper limit of 95% CI for AP(CaOx) derived from non-stone-forming Thai women). The post-treatment/baseline ratio was 3.21 ± 0.74 for urinary calcium, 1.01 ± 0.19 for urinary oxalate, and 2.23 ± 0.42 (median 1.15) for AP(CaOx). The post-treatment/baseline ratio of calcium, but not for urinary oxalate, had a significant correlation with the post-treatment/baseline ratio of AP(CaOx). Our findings suggest that the alteration in the risk of calcium oxalate nephrolithiasis based on urinary composition is related to the alteration in urinary calcium. The risk of calcium oxalate nephrolithiasis does not increase significantly after calcium or combined calcium and calcitriol supplement in the majority of postmenopausal women with osteoporosis. Received: 10 March 1999 / Accepted: 16 November 1999     

Tension-free vaginal tape,suprapubic arc sling,and transobturator tape in the treatment of mixed urinary incontinence in women

We evaluated the outcome at least 6 months after tension-free vaginal tape (TVT), suprapubic arc (SPARC) sling, or transobturator tape (TOT) procedure in women with mixed urinary incontinence and identified factors predicting the outcome in these patients. A total of 144 women, 29 to 77 years old (mean age 57.3), were included in the study; TVT (n = 72), SPARC (n = 22), and TOT (n = 50). The mean follow-up time was 10.9 months (range 6 to 52). There were no significant differences in the three groups in terms of the cure rate for stress urinary incontinence (SUI; TVT, 95.8%; SPARC, 90.0%; TOT, 94.0%; P = 0.625) and urinary incontinence (UUI; TVT, 81.9%; SPARC, 86.4%; TOT, 82.0%; P = 0.965). In the multivariate model, there is no influencing factor for treatment failure of SUI, while maximum urethral closure pressure (MUCP) and the diagnosis of uninhibited detrusor contraction during cystometry were independent risk factors for treatment failure of UUI. Decreasing MUCP was associated with an increased likelihood of treatment failure of UUI [odds ratio (OR), 0.974; 95% confidence interval (CI), 0.950–0.998; P = 0.034]. In the same model, uninhibited detrusor contraction was associated with 3.4-fold risk of treatment failure of UUI (OR, 3.351; 95% CI, 1.031–10.887; P = 0.044). Our findings suggest that low MUCP and the presence of uninhibited detrusor contraction during cystometry should be considered to be at high risk of treatment failure of UUI after surgery in these patients.     

Urinary endothelin excretion in the neonate: influence of maturity and perinatal pathology

The present study was undertaken to establish the developmental pattern of urinary endothelin-1 (ET-1) excretion and to define its possible role in mediating pathophysiological changes related to perinatal asphyxia/infection and dopamine treatment. Urinary ET-1 levels were measured by radioimmunoassay in 7 full-term neonates (mean gestational age 39.3 weeks) on days 1, 3 and 5, and in 9 pre-term neonates (mean gestational age 30.8 weeks) on days 1, 3, 5, 7 and weekly thereafter for 5 consecutive, weeks. The results were compared with those of three age-groups of 30 normal children (4–8 years, 9–12 years and 13–18 years); each group, consisted of 10 children. The influence of severe cardiopulmonary distress (n=16, mean gestational age 33.9 weeks, post-natal age 3.3 days) and dopamine administration in a dose of 2 g/min per kg (n=10, mean gestational and post-natal ages 32.1 weeks and 5.6 days, respectively) were also studied. In full-term infants, ET-1 concentration fell from 34.3±1.8 pmol/l on day 1 to 21.5±1.5 pmol/l on day 5 (P<0.01). In premature infants its absolute value and its post-natal fall were similar in the 1st week and no further change occurred in weeks 2–5; it stabilized at levels between 17.1±2.2 and 16.7±1.7 pmol/l. These concentrations tended to be lower than those of 25.5±1.3, 23.0±1.0 and 26.2±0.7 pmol/l measured in three groups of older children. During the 1st week, daily ET-1 excretion remained unchanged in term infants (3.1±1.0 vs. 3.7±1.5 pmol/m² per day), but there was a significant increase from 6.5±1.0 to 12.4±0.7 pmol/m² per day (P<0.01) in premature infants. During weeks 2–5, preterm infants excreted more ET-1 than older children (P<0.01). In response to perinatal ashphyxia/infection and dopamine therapy, urinary ET-1 excretion markedly rose and there was a significant positive correlation between urine flow rate and ET-1 excretion (P<0.001). We conclude that ET-1 concentration rather than excretion rate may have a role in mediating the changes in renal functions that occur soon after birth. The pathophysiological significance of the flow-dependent increase in urinary ET-1 excretion needs to be further studied.     

Urinary ET-1, AVP and sodium in premature infants treated with indomethacin and ibuprofen for patent ductus arteriosus

The relative potency and interrelationship between vasoactive and natriuretic mediators are thought to be important in the transition from fetal to neonatal life. The relationship between urinary vasoactive factors and sodium excretion has not been adequately addressed in premature infants receiving indomethacin and ibuprofen for therapy of patent ductus arteriosus. Excretion rates of AVP, ET-1 and sodium were measured in premature infants with RDS receiving indomethacin or ibuprofen. Forty-four RDS premature infants (<34-week gestation) with PDA received either ibuprofen (n=22) in an initial dose of 10 mg/kg followed by two doses of 5 mg/kg each after 24 and 48 h or 3 doses at 12-h intervals of indomethacin (n=24), 0.2 mg/kg, infused continuously over a period of 15 min. Urinary ET-1, AVP and sodium excretion were measured before and after treatment. Indomethacin treatment caused a significant decrease in urinary ET-1 and AVP excretion (UET-1/Ucr 0.14±0.01 vs. 0.10±0.05 fenton/mmol; P<0.05; 24.42±6.18 vs. 12.63±3.06 pg/mmol; P<0.05, respectively), along with a significant reduction in urinary sodium (92.1±36.1 vs. 64.8±35.6 mmol/l; P<0.01), fractional excretion of sodium (6.8±37.1 vs. 4.5±37.1%; P<0.01) and urinary osmolality (276.2±103.9 vs. 226.4±60.3 mOsmol/kg; P<0.05). Ibuprofen treatment caused a significant decrease in urinary AVP (UAVP/Ucr 24.5±3.4 vs. 16.3±2.04 pg/mmol; P<0.01), along with a significant decrease in urinary sodium (78.0±8.4 vs. 57.0±8.0 mmol/l; P<0.05) and in fractional excretion of sodium (7.5±1.3 vs. 3.9±3.0%; P<0.05), while it did not modify urinary ET-1 excretion. The association of renal ET-1 and AVP activity with sodium excretion in premature infants treated with indomethacin and ibuprofen supports the hypothesis that these factors may play a role in the physiologic changes in sodium excretion.     

Deoxyspergualin, an immunosuppressant, in patients suffering from nephropathies with crescent formation: an open-label trial to evaluate safety and efficacy

Background Crescent formation in glomeruli means an acute active lesion that develops a rapidly progressive course. Therapies using pulse methylprednisolone, oral corticosteroids, and cyclophosphamide are recommended, but no agreement has been reached on the optimal therapy. There have been no controlled trials, because of the severity of this condition and because withholding treatment would become an ethical issue. Methods We evaluated the safety and efficacy of deoxyspergualin (DSG), an immunosuppressant, in a multicenter, prospective trial of 44 patients with crescent formation in over 10% of glomeruli, who were randomly placed into groups that received daily doses of 0.1 mg/kg (n = 21) and 0.2 mg/kg (n = 23) of DSG, given by a 1-h infusion for 4 weeks, and who were then monitored for 3 months. All patients received DSG in this open-label prospective study. We evaluated the levels of urinary protein and hematuria, and examined renal function after the DSG treatment. Results Urinary protein significantly decreased with each dose after starting the DSG administration and this efficacy was sustained for 2 months after the discontinuation of DSG. In the groups receiving 0.1 mg/kg and 0.2 mg/kg, mean urinary protein levels were 2.1 g/day and 2.3 g/day at the initiation of the DSG administration, 1.4 g/day and 1.6 g/day at week 4, and 1.5 g/day and 1.3 g/day at week 12, respectively. Hematuria was markedly improved by a dose of 0.2 mg/kg and was not exacerbated following the termination of DSG. Exacerbation of renal dysfunction, as measured by creatinine clearance, serum creatinine, and blood urea nitrogen was prevented by both doses of DSG. The most common adverse reaction was reversible neutropenia. Conclusions Short-term treatment with DSG may be effective and tolerated in patients suffering from nephropathies with crescent formation. Participating investigators and study centers in the present trial of deoxyspergualin are listed in the Appendix.     

Urinary albumin and TGF β1 levels as renal damage indices in patients with congestive heart failure

Background. In patients with congestive heart failure (CHF), the pathogenic role of angiotensin II in the development of cardiovascular death has widely been accepted. To study the pathophysiological mechanisms of CHF-associated renal damage, we examined urinary albumin levels as a clinical marker of glomerular hyperfiltration and sclerosis, which may be attributed to the upregulated function of angiotensin II. Methods. Twenty outpatients with mild to moderate CHF without renal failure were examined. They were treated with various combinations of angiotensin-converting enzyme inhibitors (ACEI), (n = 9), calcium antagonists (n = 9), β-blockers (n = 6), and diuretics (n = 12). Urinary (u-) levels of albumin, N-acetyl-β-d-glucosaminidase (NAG), and transforming growth factor β-1 (TGF β1), and circulating levels of endothelin-1 (ET-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured and examined in relation to various clinical parameters and the mode of treatment. Results. (1) CHF patients showed significantly higher mean levels of u-albumin, u-NAG, u-TGF β1, plasma ET-1, and serum TIMP-1 than normal controls. In an age-matched comparison, the u-albumin levels in CHF patients were as high as those in diabetic patients without overt nephropathy and hypertension. (2) The u-albumin level tended to correlate with the u-NAG level (P = 0.051), however, there was no patient with high u-NAG in the subgroup with negative u-albumin levels. (3) The u-albumin level, like the u-TGF β1 and serum TIMP-1 levels, showed a significant positive correlation with the mean arterial pressure (MAP) level (each, P < 0.05), and showed slight, but nonsignificant correlations with the u-TGF β1 (P = 0.08) and serum TIMP-1 levels (P = 0.06). (4) The patients treated with an ACEI showed significantly lower levels of u-albumin (P < 0.01) and serum TIMP-1 (P < 0.05) than those not treated with an ACEI. Treatment with an ACEI tended to decrease positivity for u-TGF β1 (P = 0.09). Conclusions. The correlation between MAP and u-albumin levels and the ameliorative effect of ACEI on u-albumin excretion suggest that urinary albumin excretion may be caused by a glomerular hyperfiltration mechanism produced by both preloading of the systemic blood pressure and afterloading by angiotensin II-mediated constriction of efferent arterioles. In addition, the suppressive effects of ACEI on u-TGF β1 and serum TIMP-1 levels suggest that angiotensin II may accelerate TGF β1-mediated tissue remodeling, including nephrosclerosis, in CHF. Received: February 21, 2001 / Accepted: October 31, 2001     

A stable animal model of diet-induced calcium oxalate crystalluria

Twenty male Wistar rats, weighing 150 g, were placed in metabolic cages on a 30% sucrose diet for 7 days, before allocation to two groups: a control group (n = 5) and a lactose group (n = 15). They received respectively a 30% sucrose diet or a 30% lactose diet for 8 weeks, each containing 0.67% calcium and 0.38% phosphorus. After 4 (T1) and 8 (T2) weeks, the serum calcium (Ca) and citrate levels were significantly (P < 0.01) higher in rats fed the lactose diet. Serum alkaline phosphatase activity was increased in the lactose group (P < 0.01) at T1 and T2. The lactose-rich diet induced an increase in urinary Ca excretion at T1 and T2; citrate excretion was only enhanced at T2 (P < 0.001). No difference between the two groups was observed in urinary oxalate (Ox) excretion or creatinine clearance. Crystalluria analysis revealed a marked number (>300/mm³ at T1 and T2) of calcium oxalate dihydrate crystals (COD) in rats fed the lactose-rich diet, whereas no COD crystals were observed in sucrose-fed control rats at any time point. The formation of COD crystals in lactose-fed rats was related to an increase in calcium oxalate (CaOx) product (pCaOx), which was respectively 12.6 vs 3.9 at T1 and 10.5 vs 1.8 at T2, and an increase in CaOx ratio (Ca/Ox), which was 99.1 vs 7.5 and 67.5 vs 18.5 at T1 and T2, respectively. The high pCaOx and Ca/Ox ratios in the lactose group were due to hypercalciuria, in agreement with the number and the type of crystals. The present experimental model confirms that the ingestion of a 30% lactose diet increases urinary Ca excretion without changing urinary Ox excretion and shows for the first time that it induces a stable and marked crystalluria composed of COD. Such a non-nephrotoxic and stable model is of interest for the study of CaOx crystal formation secondary to hypercalciuria, and thus afterwards eventually for CaOx nephrolithiasis. Received: 27 January 1997 / Accepted: 16 July 1997     

Asymmetric Dimethylarginine (ADMA) and Progression of Nephropathy in Patients with Type 2 Diabetes

Diabetic nephropathy is the leading cause of kidney failure all over the world. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. ADMA is in part eliminated via urinary excretion. It is found to be elevated in end stage renal disease. Identification of the plasma concentrations of ADMA in patients with different stages of diabetic nephropathy compared with healthy age-matched control subjects for estimation of the role of ADMA as a marker of progression of kidney disease in diabetic patients. Seventy-five diabetic patients were divided into five groups: Group I: patients with normoalbuminuria (urinary albumin excretion UAE < 30 mg/d), Group II: patients with microalbuminuria (UAE: 30–300 mg/d), Group III: patients with macroalbuminuria (UAE > 300 mg/d), Group IV: patients one month after renal transplantation and Group V: patients on haemodialysis. Patients were compared to 15 healthy control subjects matched for age and sex. All subjects subjected to thorough clinical examination and laboratory investigations including: serum albumin, urea, creatinine, fasting and postprandial blood glucose, UAE, urinary albumin/creatinine ratio and serum ADMA level. All patients groups had significantly higher levels of ADMA when compared to control group P < 0.01. The levels of ADMA were positively correlated with disease progression and degree of proteinuria. ADMA can be used as a marker of progression of kidney disease among diabetic patients.     

Microalbuminuria in children with primary and white-coat hypertension

Microalbuminuria serves as an early marker of hypertension-related renal damage in adults. However, data on the prevalence of microalbuminuria in paediatric hypertensive patients in general and in children with white-coat hypertension (WCH) specifically are lacking. The aim of our study was to investigate the prevalence of microalbuminuria in children with primary hypertension (PH) and WCH, respectively. This was a retrospective case review of children with PH and WCH treated at three paediatric nephrology centres. Untreated children with either form of hypertension for whom measurements of urinary albumin excretion (UAE) had been performed were enrolled in the study. The study cohort comprised 52 children (39 boys) with hypertension (26 children with PH, 26 with WCH). Microalbuminuria (>3.2 mg/mmol creatinine) was present in 20% of children with PH and none of the children with WCH (p < 0.01). Children with PH had a higher median UAE than those with WCH (1.27 ± 1.92 vs. 0.66 ± 0.46 mg/mmol creatinine, p < 0.05). Based on these results, we suggest that children with PH have an increased prevalence of microalbuminuria, while children with WCH show no signs of hypertension-related renal damage.