ACE serum level and I/D gene polymorphism in children with obstructive uropathies and other congenital anomalies of the kidney and urinary tract.

AIM: The aim of this study was to investigate the association of an insertion/deletion (I/D) polymorphism in angiotensin-converting enzyme (ACE) gene with serum ACE level in relation to the type and severity of malformations from congenital anomalies of the kidney and urinary tract (CAKUT) spectrum. METHODS: A group of 134 Bulgarian children with CAKUT divided into four subgroups according to the leading malformation and 109 controls were genotyped by classical polymerase chain reaction. The quantitative determination of serum ACE was performed by ELISA method. RESULTS: A significant elevation of DD-genotype was observed in high-grade hydronephrosis compared to low-grade (43% vs. 9%). The carrying of DD-genotype was associated with higher risk for severe hydronephrosis with OR = 7.5 (95% CI: 1.242÷45.278; P = 0.028). Also, elevated serum ACE concentrations in patients with high-grade compared to low-grade hydronephrosis (237.4 ± 45 ng/mL vs 180.5 ± 64 ng/mL; P = 0.0065) were found. ACE level was significantly lower in patients with unilateral renal agenesis; hypo/dysplasia and multicystic dysplastic kidney (156.6 ± 54 ng/mL) than controls (200.6 ± 56.7 ng/mL; P = 0.005) and the remaining CAKUT subgroups. CONCLUSION: The DD genotype of I/D ACE polymorphism encodes the highest serum ACE level may be an additional genetic risk factor contributing to the severe hydronephrosis in Bulgarian patients with obstructive uropathies in contrast to other investigated categories of CAKUT malformations.

Caspase-4 may play a role in loss of proximal tubules and renal injury in nephropathic cystinosis.

Nephropathic cystinosis is characterized clinically by generalized proximal renal tubular dysfunction, renal Fanconi Syndrome and progressive renal failure. Glomerular-proximal tubule disconnection has been noted in renal biopsies from patients with nephropathic cystinosis. In vitro studies performed in cystinotic fibroblasts and renal proximal tubular cells support a role for apoptosis of the glomerulotubular junction, and we have further extended these studies to human native cystinotic kidney specimens. We performed semi-quantitative analysis of tubular density in kidney biopsies from patients with nephropathic cystinosis and demonstrated a significant reduction (p=0.0003) in the number of proximal tubules in the kidney tissue of patients with cystinosis compared to normal kidneys and kidneys with other causes of renal injury; this reduction appears to be associated with the over-expression of caspase-4. This study provides the first quantitative evidence of a loss of proximal tubules in nephropathic cystinosis and suggests a possible role of caspase-4 in the apoptotic loss of proximal tubular cells. Further work is needed to elucidate if this injury mechanism may be causative for the progression of renal functional decline in nephropathic cystinosis.

Changes of urinary enzyme activity after endoscopic treatment of vesico-ureteric reflux.

The urinary enzymes Gamma Glutamyl Transferase (GGT), Alkaline Phosphatase (ALP), Leucine-Arylamidase (LAS), and Dipeptidyl-Peptidase-IV (DPP-IV) were measured before and after endoscopic treatment of vesico-ureteric reflux (VUR) in two groups of twenty children. Ten patients had undergone successful endoscopic corrective surgery for VUR, another 10 patients had unsuccessful endoscopic intervention. After successful treatment the activity of LAS in the urine did not change, but GGT, ALP and DPP-IV activity in the urine was 2-5 times higher than before treatment (P < 0.03 for all three enzymes). Considerable changes of urinary enzyme activity were not observed following unsuccessful endoscopic treatment. Our data and the literature are contradictory. However, this contradiction might be explained by the differences in urine sampling methods. Our patients received the same chemoprophylactic drug at the time of both urine samplings, a point not considered by other researchers. The extent of increase of enzyme activity after endoscopic treatment of VUR did not reach the level that would permit the use of investigated enzymes for screening, because the observed changes did not exceed the limits of the normal range.

[Changes in urinary enzyme activity following silicon therapy of vesico-ureteral reflux]. / A vizeletenzimek aktivitásváltozása vesicoureteralis reflux szilikonnal végzett kezelésében.

The urinary enzymes Gamma Glutamyl Transferase (GGT), Alkaline Phosphatase (ALP), Leucine-Arylamidase (LAS) and Dipeptidyl-Peptidase-IV (DPP-IV) were measured before and after endoscopic treatment of vesico-ureteric reflux (VUR) in two groups of twenty children's. Ten patients had undergone successful endoscopic corrective surgery for VUR, another 10 patients had unsuccessful endoscopic intervention. After successful treatment the activity of LAS in the urine did not change, but that of GGT, ALP and DDP-IV activity in the urine was 2-5 times higher than before treatment (P < 0.03 for all three enzymes). Considerable changes of urinary enzymes' activity were not observed following unsuccessful endoscopic treatment. Our data and the literature are contradictory. However this contradiction might be explained by the differences in urine sampling methods. Our patients received the same chemoprofilactic drug at the time of both urine sampling, a point not considered by other researchers. The extent of increase of enzyme activity after endoscopic treatment of VUR did not reach the level that would permit the use of investigated enzymes for screening, because the observed changes did not exceed the limits of the normal range.

Serum levels of IgG antibodies against Tamm-Horsfall protein and urinary excretion of NAG and alpha-1-microglobulin as possible markers for tubular damage in patients with a continent ileal reservoir for urinary diversion.

Serum IgG antibodies against Tamm-Horsfall protein and urinary excretion of NAG and alpha-1-microglobulin were measured in 26 patients with a Kock reservoir for continent urinary diversion or orthotopic bladder reconstruction in order to detect any signs of tubular damage. None of these markers for tubular damage was correlated to the postoperative observation time ranging between 2 and 16 years. No correlation was found between these markers and signs of renal scarring or upper urinary tract dilatation as judged from urographies. A positive correlation was demonstrated between NAG excretion and antibodies against Tamm-Horsfall protein. The annual reduction in GFR was increased in patients with elevated alpha-1-microglobulin excretion but not in patients with elevated titres of antibodies against Tamm-Horsfall protein or increased NAG excretion. Patients with previous or present reflux nipple problems had elevated excretion of alpha-1-microglobulin. Regular determinations of alpha-1-microglobulin excretion appear to be of value in the follow-up of these patients.

Urinary levels of renal tubular enzyme N-acetyl-beta-D-glucosaminidase in relation to grade of vesicoureteral reflux.

Elevated urinary levels of the renal tubular enzyme N-acetyl-beta-D-glucosaminidase (NAG) have been shown to be associated with tubular damage. To determine whether urinary levels of NAG would be abnormal and/or vary with the severity of vesicoureteral reflux, bladder urine was obtained from 31 children without reflux and 32 children with various grades of reflux. Nonrefluxing controls were obtained from children undergoing evaluation for a history of infection, hematuria or voiding abnormality. Patients with evidence of obstruction, neuropathic bladder dysfunction, urinary tract infection or renal failure were excluded. Bladder (32 cases) and ureteral (5 cases) urine from children with reflux was obtained at cystography or at antireflux surgery. Control and reflux patients were not significantly different with regard to sex or age. The mean urinary NAG level in nonrefluxing control patients was 10.63 IU/mg. (range 0.94 to 26.61, standard error of mean 0.43). Mean urinary NAG for all patients with reflux was 16.47 IU/mg. (range 2.85 to 52.02, standard error of mean 0.9). Two children with intrarenal reflux had urinary NAG levels of 52 and 48 IU/mg. Urinary NAG levels are elevated with higher grades of reflux and this relatively simple assay may have clinical usefulness in the assessment of tubular dysfunction associated with reflux.

Urinary N-acetyl-beta-glucosaminidase and the selection of children for radiologic evaluation after urinary tract infection.

Urinary levels of N-acetyl-beta-glucosaminidase (NAG) were measured in 147 consecutively enrolled children younger than 13 years of age with urinary tract infection to determine whether elevated levels were a predictor of urologic abnormalities. The children were classified as having cystitis if results of 0 or 1 of the following tests were positive and as having pyelonephritis if results of greater than or equal to 2 tests were positive: (1) temperature greater than 38 degrees C, (2) serum C-reactive protein greater than 1 mg/dL, (3) erythrocyte sedimentation rate greater than 25 mm/h, and (4) 1-deamino-8-D-arginine vasopressin-renal concentrating protein less than 810 mOsm/kg. Urinary NAG to creatinine ratios did not distinguish cases of cystitis from those of pyelonephritis. Urinary NAG was useful in identifying children with cystitis who had vesicoureteral reflux of grades II through V. Of 6 children with cystitis and vesicoureteral reflux, 5 had levels of NAG more than 1 SD above the mean, whereas of 75 children without vesicoureteral reflux, only 15 had such an elevation (P = .003). Of those children with a normal NAG level, 60 (98.4%) had normal radiologic evaluation results, and only 1 child (1.6%) had vesicoureteral reflux. Levels of NAG did not identify children with pyelonephritis who had vesicoureteral reflux. It is concluded that (1) urinary NAG is of no value in localizing the site of urinary tract infection, and (2) an NAG level within 1 SD of the mean in a child with cystitis indicates a low risk of urologic abnormalities, and radiologic evaluation may be omitted unless infection recurs.