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PubMed2004

Nocturia and complementary indices: determination and quantification of the cause of nocturia by frequency-volume charts in women with lower urinary tract symptoms.

We evaluated differences between women with lower urinary tract symptoms (LUTS) with and without nocturia in terms of voiding habits, urine production and voided volumes in order to determine and quantify the cause of nocturia by using frequency-volume (FV) charts. At the initial visit, all patients underwent a detailed clinical evaluation including an International Prostate Symptom Score assessment, received a thorough explanation from the study coordinators, and were requested to complete a 3-day FV chart. Of the 123 women enrolled, 106 (86.2%) 20-83 years old (median age 55.0) completed the study. Nocturnal urine volume was higher in nocturics than in non-nocturics, but this was not statistically significant. Total daytime voided volume was lower in nocturics than in non-nocturics ( P=0.030) but with no detectable difference in total voided volume. To identify possible risk factors, we examined age and night time parameters including the nocturnal bladder capacity index (NBCI), nocturnal polyuria index (NPI) and nocturia index (NI) by univariate logistic analysis. When nocturia was defined as voiding at least twice per night, age and NI were found to be associated with it by univariate analysis. These two variables were further analyzed using a multivariate logistic model to determine their association with nocturia. In the multivariate analysis, a positive association was observed between age and nocturia. Patients 50 years or older had a 3.9-fold higher risk [odds ratio (OR) 3.86; 95% confidence interval (CI) 1.60-9.31; P=0.003] of voiding at least twice per night than those younger than 50 years. In the same model, patients with NI greater than 1.5 had a 4.5-fold higher risk of voiding at least twice per night (OR 4.59; 95% CI 1.80-11.17; P=0.001). FV charts are valuable for determining the cause of nocturia in women with LUTS. Our findings suggest that age and the NI may be important variables in the evaluation of nocturia in women with LUTS.

Adult↗
PubMed1998

Preclinical pharmacology of the natural product anticancer agent 10-hydroxycamptothecin, an inhibitor of topoisomerase I.

PURPOSE: 10-Hydroxycamptothecin (HCPT) is an indole alkaloid isolated from a Chinese tree, Camptotheca acuminata, and has a wide spectrum of anticancer activity in vitro and in vivo mainly through inhibitory effects on topoisomerase I. HCPT has been shown to be more potent and less toxic than camptothecin and has recently undergone clinical trials. To determine how HCPT might be best used as an anticancer agent, preclinical studies of the pharmacokinetics, tissue distribution, metabolism and elimination of HCPT in rats were undertaken. METHODS: HCPT was administered to rats by i.v. bolus injection at doses of 1, 3, and 10 mg/kg body weight. HCPT (lactone and carboxylate) and its metabolites in plasma, urine, feces, and various tissues were quantitated by reversed-phase HPLC. Pharmacokinetic parameters were then estimated. RESULTS: Following i.v. administration at doses of 3 or 10 mg/kg, the plasma concentration-time profile for lactone HCPT could be best described by a three-compartment model, with terminal elimination half-lives of 140.4 and 428.6 min, respectively. A two-compartment model was used to fit the plasma concentration-time curve at 1 mg/kg, with a terminal elimination half-life of 30.5 min. Carboxylate HCPT had a longer half-life than the lactone form of HCPT. During the initial 6 h after dosing, urinary excretion was the major route of elimination, and fecal excretion became the major route of elimination thereafter. HCPT was widely distributed to various tissues including the enterohepatic system, kidney, and bone marrow. The lactone form of HCPT was detectable in various tissues examined up to 72 h after dosing at all the three test doses. HCPT glucuronides were present in plasma, urine, feces and various tissues. No significant toxicity was observed at doses of 1 or 3 mg/kg. Polyuria and hematuria were observed only during the initial 3 h after dosing at 10 mg/kg. CONCLUSIONS: Prolonged elimination of HCPT in vivo may have a significant impact on its therapeutic effects. HCPT is metabolized to its carboxylate form and glucuronides. Dose-dependent toxicity was observed with i.v. administration of HCPT. The results of this study should be useful in the design of future human trials with this anticancer drug.

Animals↗
PubMed2005

Diabetes insipidus presentation before renal and pulmonary features in a patient with Wegener's granulomatosis.

We report a case of a 47-year-old woman with Wegener's granulomatosis complicated by central diabetes insipidus. The patient had initially seronegative polyarthritis which mostly responded well to methotrexate and steroid therapy. Eight months later the patient suffered from polyuria and polydipsia. There were no abnormalities of the anterior pituitary hormones. MR images showed only loss of brightness of the posterior pituitary. Extensive evaluation of the patient revealed the presence of ANCA, in c-ANCA pattern and also PR3 positivity. Three months later findings of glomerulonephritis, as suggested by an active urine sediment and gradual proteinuria, and, finally, asymptomatic pulmonary nodules completed the clinical picture of Wegener's disease within 1 year. Renal biopsy showed crescent formation in two glomeruli, consistent with ANCA-related glomerulonephritis which showed pauci-immün depositions by direct immunofluorescence. Diabetes insipidus symptoms mostly regressed; renal and pulmonary findings completely disappeared with glucocorticoid and pulse cyclophosphamide treatment. These findings show that diabetes insipidus may rarely develop early in the disease process and ANCA positivity was directly indicative of Wegener's granulomatosis before the classic clinical signs of the disease.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2004

Initial and long-term management of posterior urethral valves.

Posterior urethral valves are the most common cause of congenital obstructive uropathy, resulting in renal failure in childhood. Nowadays, in most cases, diagnosis is suggested by antenatal ultrasound. However, antenatal intervention has not resulted in a significantly improved outcome. Endoscopic valve ablation is the initial treatment in most of these neonates, but others procedures, like vesicostomy or ureterostomy, can also be justified in some particular cases in order to improve renal function prognosis. Different factors like bladder dysfunction, VUR, polyuria and proteinuria, can be responsible for the slow and progressive deterioration in renal function that some of these patients show over the years. By treating them all, we may prevent or delay the onset of end stage renal disease.

Algorithms↗
PubMed2005

Urinary nitrite excretion and urinary variables in patients with primary nocturnal frequency of micturition: effects of indomethacin suppositories.

Urinary nitrite excretion was measured in patients with primary nocturnal frequency of micturition (PNFM) and in normal individuals. Effects of indomethacin suppository on urine volume and other urinary variables were evaluated. The study comprised seven patients with PNFM and seven healthy control (age range 30-45 years). Nitrite was assayed in spot morning urine samples; urine volume, urine osmolality and electrolytes, serum osmolality and electrolytes and functional bladder capacity (FBC) were assayed. Both groups were then given 100 mg of indomethacin suppository daily for a maximum of 10 days and urinary variables were re-evaluated during day 10. Results showed that urinary nitrite excretion of patients with PNFM was greater than that of the normal subjects (230+/-62 umol/l vs. 42+/-30 umol/l, P<0.05). The mean (SD) 24 h urine volume and osmolality, the night urine volume and osmolality, serum osmolality, FBC, creatinine clearance, fractional excretion of sodium (FENa), fractional excretion of potassium (FEK), and urinary excretion of glucose and potassium were lower in patients with PNFM as compared with normal individuals, although not statistically significantly so, except for FBC that was significantly lower in the patients. Urinary excretion of sodium, calcium, chloride, phosphorus, magnesium, day-night urinary volume ratio, spot morning osmolality, nocturnal index, and nocturnal polyuria index were higher in patients with PNFM. Indomethacin decreased the 24 h urinary volume by 21%, creatinine clearance by 12%, osmolar clearance by 14% and urinary protein excretion by 38% in the patients. These variables decreased by 26, 45, 17 and 12% respectively in the healthy subjects, whereas 24 h urinary protein excretion increased mildly by 9%. Indomethacin increased day-night urinary volume ratio by 73% in the healthy subjects. It might be concluded that urinary nitrite excretion, urinary excretion of sodium, chloride, phosphorus, calcium, and magnesium increased and FBC decreased in patients with PNFM; Indomethacin decreased urinary volume, FENa, FEK, osmolar clearance, and free water clearance in the healthy subjects and the patients. These might explain the mechanism of action of indomethacin to reduce frequency of voiding. The possible interaction of prostaglandin and NO in the pathogenesis of PNFM is discussed.

Adult↗
PubMed2006

Acute fatty liver of pregnancy.

OBJECTIVE: Acute fatty liver of pregnancy (AFLP) is a rare and serious entity associated with significant maternal and neonatal mortality and morbidity. We describe our experience with the clinical diagnosis, management and course patients with AFLP. STUDY DESIGN: Medical records of patients with AFLP were reviewed over a 10-year period. Records were reviewed for symptoms, laboratory findings, clinical course, and maternal and perinatal outcomes. RESULTS: The incidence of AFLP was 1 in 7,270 births. The mean gestational age at onset was 34.6 +/- 4.9 weeks. Eight percent of the patients were multiparous with more than three pregnancies. The prodromic phase was variable; patients complained of nausea, abdominal pain, malaise, polyuria-polydipsia syndrome and headaches followed by jaundice. The laboratory results indicated coagulopathy, liver function abnormalities and hypoglycemia. Emergency cesarean section was performed in two cases. The diagnosis has been assessed by transcutaneous hepatic biopsies processed in all patients between the 4th and 15th day (8.4 +/- 4.3 days). Maternal morbidity included hypoglycaemia (40%), coagulopathy (50%) encephalopathy (30%) and renal failure (40%). There were no maternal deaths but fetal mortality is high 66%. CONCLUSION: The early recognition of AFLP cases and prompt progressive management, including early termination of pregnancy and large dose infusion of fresh frozen plasma, the prognosis of AFLP is obviously improved.

Acute Disease↗
PubMed1996

Renal type II Na/Pi-cotransporter is strongly impaired whereas the Na/sulphate-cotransporter and aquaporin 1 are unchanged in cadmium-treated rats.

The cellular mechanisms of cadmium (Cd) nephrotoxicity are poorly understood. In this study we investigated the cellular causes of the Cd-induced phosphaturia in the rat. Compared to controls, Cd-treated rats (2 mg Cd/kg body weight, s.c. for 14 days) showed a marked polyuria, proteinuria and phosphaturia. As studied by the rapid filtration technique in isolated cortical brush-border membrane vesicles (BBMV), Na+-gradient-driven uptake of phosphate ([32Pi]) and of [3H] glucose were markedly decreased in Cd-treated rats, whereas uptake of sulphate ([35S]) remained unchanged. By Western blotting of BBMV proteins and by indirect immunocytochemistry in 4-micron thick frozen fixed kidney sections, using an antibody against the type II Na/Pi-cotransporter (NaPi-2), we found a diminished expression of this protein in the brush-border membrane from Cd-treated rats. How ever, the expression of the water channel aquaporin 1, estimated from the specific antibody staining in brush-border membranes, remained unchanged by Cd. Northern blot analysis showed a strong reduction of 2.7 kb NaPi-2-related mRNA in Cd-affected kidneys. Our data indicate that: (1) Cd may reduce reabsorption of Pi in proximal tubules by affecting the expression of the functional Na/Pi-cotransporters in the luminal membrane, and (2) Cd effects on brush-border transporters are selective.

Animals↗
PubMed2003

Early oral cysteamine therapy for nephropathic cystinosis.

UNLABELLED: Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder in which intracellular cystine accumulates due to impaired transport out of lysosomes. The clinical manifestations include renal tubular Fanconi syndrome in the 1st year of life, with hypophosphatemic rickets, hypokalemia, polyuria, dehydration and acidosis, growth retardation, hypothyroidism, photophobia, renal glomerular deterioration by 10 years of age, and late complications such as myopathy, pancreatic insufficiency, and retinal blindnesss. The cystinosis gene, CTNS, codes for cystinosin, a 367 amino acid protein with seven transmembrane domains. More than 50 CTNSmutations have been identified, but approximately 50% of Northern European patients have a 57257-bp deletion which removes the first nine exons of CTNS. The mainstay of cystinosis therapy is oral cysteamine (Cystagon). This aminothiol can lower intracellular cystine content by 95%, and has proven efficacy in delaying renal glomerular deterioration, enhancing growth, preventing hypothyroidism, and lowering muscle cystine content. Its early and diligent use is critical; in one study, for every month of treatment prior to 3 years of age, 14 months' worth of later renal function were preserved. Several examples of individual patients treated early and having preserved renal function and normal growth are available. Newborn screening using a chip containing cDNA to detect common CTNSmutations may allow diagnosis and treatment in the first weeks of life. CONCLUSIONS: Early diagnosis and treatment of nephropathic cystinosis can change the course of this disease.

Administration, Oral↗
PubMed1999

Clinical symptoms, biochemical studies and therapeutic approaches in a sibship with a new congenital tubulopathy.

UNLABELLED: We report on two siblings suffering from a new congenital tubulopathy. Following normal pregnancies not complicated by polyhydramnios, severe renal losses of potassium, chloride, sodium and magnesium occurred in the first weeks after birth. Calcium metabolism was not affected. The distal tubular chloride reabsorption was considerably decreased in the two siblings (0.25 and 0.28, respectively). Secondary hyperaldosteronism, activation of the kallikrein-kinin system and elevated urinary prostaglandin excretion were observed. The effects of indomethacin, spironolactone and captopril on symptoms, electrolyte wasting, activation of renin-angiotensin-aldosterone and kallikrein-kinin system and prostaglandin synthesis were studied. In spite of persisting elevation of prostaglandin synthesis, captopril decreased electrolyte wasting, polyuria and hyperaldosteronism most effectively. CONCLUSION: We delineate an apparently new disorder characterized by a postnatal onset, an extremely decreased chloride reabsorption with extensive hyperchloriduria and hypermagnesiuria in the presence of normal calcium metabolism. The disorder can be distinguished from other tubulopathies with hypokalaemic alkalosis.

Absorption↗
PubMed1998

Evidence of an increased risk of hearing loss in heterozygous carriers in a Wolfram syndrome family.

Wolfram syndrome (MIM 222300) is characterized by juvenile-onset diabetes mellitus and optic atrophy. Previous linkage analyses in the United States and UK families have indicated that the gene for Wolfram syndrome (WFS) is localized on the short arm of chromosome 4. We herein confirm the linkage of the WFS locus to D4S3023 on 4p with a two-point LOD score of 3.42 in a large Japanese family with Wolfram syndrome. Multipoint linkage analysis revealed the maximum LOD score of 4.82 between D4S3023 and D4S394. We also evaluated putative health risks in carriers by multiple logistic analysis with independent variables, age, gender, and numbers of affected haplotypes and with dependent variables, such as hearing loss, diabetes mellitus, polyuria, incontinence, psychological illness, and visual acuity. The results showed that the putative disease haplotype increased a risk of hearing loss (odds ratio =35.68, 95% confidence interval =4.12-308.95) and diabetes mellitus (odds ratio =7.57, 95% confidence interval =2.03-28.23) independently. This is the first report of an increased health risk of illness in carriers, other than for psychiatric disease.

Adolescent↗
PubMed2002

Congenital mesoblastic nephroma associated with polyhydramnios and hypercalcemia.

Congenital mesoblastic nephroma (CMN) can present with atypical clinical and imaging findings. A premature male neonate was born to an 18-year-old woman after 33 weeks' gestation, which was complicated by polyhydramnios and placenta abruptio. A right abdominal mass was diagnosed antenatally. From the 1st day of life, the newborn had hypercalcemia with initially normal parathormone levels and polyuria for the first hours of life and normal urine output afterwards. Ultrasonographic study and magnetic resonance imaging of the abdomen showed at the upper pole of the right kidney a heterogeneous, solid, poorly defined mass, partially surrounded by a subcapsular fluid collection mimicking malignant rhabdoid tumor of the kidney. Surgical resection revealed a CMN of mixed, classic, and in areas, cellular type. One year after the resection, the patient is asymptomatic and normocalcemic. In conclusion, CMN may present with atypical clinical and imaging findings, necessitating an extensive work-up in order to exclude highly malignant renal tumors of the neonatal period.

Adolescent↗
PubMed2002

Follow-up of five patients with FHHNC due to mutations in the Paracellin-1 gene.

Familial hypomagnesemia, hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive inherited disorder that has recently been attributed to a defect in the paracellin-1 ( PCLN-1)gene, encoding for a protein responsible for the tubular reabsorption of magnesium and calcium. Limited information is available on clinical course, therapy and prognosis. We provide information on five patients with FHHNC and their follow-up at our institution. Polyuria, nephrocalcinosis and hyperuricemia were the main clinical findings of a diagnosis at a median age of 4.4 years. The clinical course of PCLN-1 mutations as presented in this study is highly variable, ranging from compensated renal failure to end-stage renal failure - as happened in two of our patients. The progression to renal failure cannot be deduced from the initial presentation. Medical treatment does not appear to influence the progression of the disease. Despite calcium and magnesium substitution, normal values could not be achieved in these patients. Early treatment with vitamin D and calcium was essential to maintain growth. Adequate treatment allows for a normal height and pubertal development.

Calcium↗
PubMed2003

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium (Mg) and calcium (Ca) in the thick ascending limb of Henle's loop. We have studied seven Arab patients with this syndrome who belong to four different families. The mean age at first presentation was 1.5+/-1.3 years (range 0.1-3 years) and at diagnosis 5.9+/-4.3 years (range 0.5-12 years). The presenting features were convulsions and carpopedal spasms (5 patients), polydipsia and polyuria (2 patients), rickets (2 patients), and recurrent urinary tract infections (1 patient). Bilateral nephrocalcinosis was observed in all patients. All patients had hypomagnesemia with a mean serum Mg of 0.45+/-0.09 mmol/l, an inappropriately high urine Mg of 2.07+/-0.73 mmol/24 h or fractional excretion of 15.3+/-7.1%, high urine Ca excretion of 4.1+/-1.2 mmol/24 h or urine Ca to creatinine ratio of 2.6+/-1.6, and normal serum potassium level of 4.4+/-0.34 mmol/l. All patients received Mg supplements and thiazide but exhibited slow worsening of their kidney function. After a mean follow-up of 4.4+/-3.9 years, one patient progressed to end-stage renal failure (ESRF). In conclusion, we report seven Arab patients with FHHNC syndrome. The clinical and biochemical data were similar to previous reports. However, they tend to show a slower rate of progression to ESRF.

Arabs↗
PubMed2003

Transient proximal tubular renal injury following Ecstasy ingestion.

Multiple renal adverse effects have been anecdotally reported with the ingestion of 3,4-methylenedioxymethamphetamine (Ecstasy), a widely used recreational drug. These side effects include acute renal failure, necrotizing vasculitis, and hyponatremia, the mechanisms for which are unknown. We report a case of transient acute proximal tubular injury and hyponatremia associated with Ecstasy use. An 18-year-old woman presented with new onset seizures and polydipsia. Her initial laboratory evaluation revealed hyponatremia (Na 117 mEq/L), polyuria (urine output >400 mL/h for several hours), renal glycosuria (blood glucose 120 mg/dL, urine glucose >1,000 mg/dL), and solute diuresis (urine osmolality 552 mOsm/kg H2O). Urine electrolyte values reflected a low tubular reabsorption of phosphorus (TRP) of 68.1% (expected TRP >85% at serum P 2.3 mg/dL) with an appropriate transtubular potassium gradient of 3.0 (serum K 3.7 mEq/L). Her hyponatremia was slowly corrected. A repeat TRP after 48 h had normalized to 86.5%, and her glycosuria resolved. An extensive toxin screen was later reported positive for Ecstasy. To our knowledge, this is the first example of an acute and transient proximal tubular injury with Ecstasy ingestion. This complication may become more apparent with increasing use of this drug.

Acute Disease↗
PubMed2003

Treatment of congenital nephrogenic diabetes insipidus by hydrochlorothiazide and cyclooxygenase-2 inhibitor.

A 1-month-old male infant presented with failure to thrive, polyuria, and severe hypernatremic dehydration. Based on family history, lack of response to vasopressin, and normal sonography of the urinary system, the diagnosis of congenital nephrogenic diabetes insipidus (cNDI) was established. The infant responded well to indomethacin in combination with hydrochlorothiazide (HCTZ), but quickly developed gastrointestinal bleeding. The substitution of indomethacin by amiloride and later by tolmetin was found to be ineffective. Treatment with HCTZ (3 mg/kg per day) and rofecoxib (1 mg/kg per day, both divided into three doses) combined with a low-salt formula resulted in a dramatic decrease in urinary free water losses. No side effects of the combination were noted. At age 8.5 months, the infant demonstrated catch-up growth and normal neurodevelopmental milestones. We conclude that the combination HCTZ/cyclooxygenase-2 inhibitor could be successfully used to treat infantile cNDI.

Cyclooxygenase 2↗
PubMed2003

In utero exposure to nonsteroidal anti-inflammatory drugs: neonatal renal failure.

We report a case of neonatal transient renal failure after maternal ingestion of diclofenac, paracetamol, and nimesulide during pregnancy. The baby girl was delivered at the 33 weeks gestation for complete absence of amniotic fluid. Acute renal failure was present. Urine output started 12 h after birth, increasing to polyuria on day 6, and then decreasing gradually to normal values. Serum creatinine normalized on day 6. Several cases of severe and sometimes irreversible renal problems have been described in neonates exposed to indomethacin, a non-selective cyclooxgenase (COX) inhibitor, during their fetal life. More recently, the use of nimesulide, a selective COX-2 inhibitor, as a tocolytic agent has been advocated. Although it is difficult to ascribe the observed side effects to one specific drug in our patient, using the Naranjo ADR probability scale, renal failure was probably related to nimesulide exposure. Paracetamol is considered safe at therapeutic doses, and there are no reports of prenatal diclofenac toxicity. However, recently there have been some reports of neonatal renal failure associated with maternal nimesulide consumption and probably modulated by genetic factors. Hence, cautious use of nimesulide during pregnancy must be advocated.

Acetaminophen↗
PubMed2004

Bartter syndrome: benefits and side effects of long-term treatment.

The present study reports clinical and laboratory data of patients with Bartter syndrome at diagnosis and follow-up with emphasis on the long-term benefits and side effects of the pharmacological therapy, which includes indomethacin and potassium supplementation. We followed 12 children, 6 boys, with a median age at diagnosis of 24.5 months (range 7-137 months) and at the end of the study 157.5 months (range 26.0-224.0 months). All children presented with polyuria and polydipsia, dehydration, and metabolic and electrolyte disturbances with failure to thrive. However, at study entry 5 of 12 patients also had hypophosphatemia, which disappeared after a mean time of 50+/-22.4 months, 3 of 12 had nephrocalcinosis, and 2 of 12 had typical renal cysts. Despite treatment, hypokalemia was persistent in some patients. During long-term follow-up we observed recovery of growth velocity and adequate metabolic and electrolyte balance. However, we noticed renal and gastrointestinal complications: 2 patients had a perforated gastric ulcer, 1 had a gastric ulcer, and gastritis was detected in 3 children. A decreased glomerular filtration rate was observed in 2 patients during follow-up. Our data emphasize the need for regular surveillance of renal function and gastrointestinal endoscopy in these patients. As an alternative to indomethacin, we present our satisfactory preliminary results with rofecoxib.

Bartter Syndrome↗
PubMed2005

Long-term outcome of kidney function after twin-twin transfusion syndrome treated by intrauterine laser coagulation.

Twin-twin transfusion syndrome (TTTS) is caused by unbalanced shunting of blood between monochorionic twins. It is well known that chronic hypotension and hypovolemia may cause renal insufficiency in the donor twin. The long-term outcome of kidney function after TTTS has not previously been delineated in the literature, however. The aim of this study was to evaluate the long-term outcome of kidney function in children after intrauterine laser treatment for severe TTTS. Eighteen surviving twin pairs after intrauterine laser treatment for TTTS were involved in the study. Their gestational age at birth was 29-39 weeks, their median birth weight was 2050 g, and their median age at evaluation was 3 years 1 month, range 1 year 9 months to 4 years 5 months. Serum creatinine, cystatin C, and beta 2-microglobulin, sodium, potassium, and phosphate excretion, and urine albumin and alpha-1-microglobulin were measured. Creatinine clearance was calculated by use of the Schwartz formula. The laboratory findings for all 36 children were within normal limits. There were no significant differences between donors and recipients. Despite severe alteration of renal function before the laser treatment (anuria-polyuria) no long-term impairment of renal function could be detected in any of the 18 twin pairs.

Child Development↗