George A. Richard

Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III

Analysis of patients with inherited hypokalaemic alkalosis resulting from salt–wasting has proved fertile ground for identification of essential elements of renal salt homeostasis and blood–pressure regulation. We now demonstrate linkage of this phenotype to a segment of chromosome 1 containing the gene encoding a renal chloride channel, CLCNKB. Examination of this gene reveals loss–of–function mutations that impair renal chloride reabsorption in the thick ascending limb of Henles loop. Mutations in seventeen kindreds have been identified, and they include large deletions and nonsense and missense mutations. Some of the deletions are shown to have arisen by unequal crossing over between CLCNKB and the nearby related gene, CLCNKA. Patients who harbour CLCNKB mutations are characterized by hypokalaemic alkalosis with salt–wasting, low blood pressure, normal magnesium and hyper– or normocalciuria; they define a distinct subset of patients with Bartters syndrome in whom nephrocalcinosis is absent. These findings demonstrate the critical role of CLCNKB in renal salt reabsorption and blood–pressure homeostasis, and demonstrate the potential role of specific CLCNKB antagonists as diuretic antihypertensive agents.

A randomized trial of short-course ciprofloxacin, ofloxacin, or trimethoprim/sulfamethoxazole for the treatment of acute urinary tract infection in women

PURPOSE Bladder infections are very common in otherwise healthy women, and short-course antimicrobial treatment appears effective for many episodes of cystitis. This study reports the results of short-course ciprofloxacin, ofloxacin, and trimethoprim/sulfamethoxazole therapy. PATIENTS AND METHODS We performed a randomized, double-blind study of the efficacy and safety of a 3-day course of oral ciprofloxacin 100 mg twice daily, ofloxacin 200 mg twice daily, or trimethoprim/sulfamethoxazole 160/800 mg twice daily in women with acute, uncomplicated, symptomatic lower urinary tract infection. RESULTS A total of 866 patients were enrolled, of whom 688 (79%) were evaluated for the efficacy of treatment (229 treated with ciprofloxacin, 228 treated with trimethoprim/sulfamethoxazole, and 231 treated with ofloxacin). The most frequent reason for exclusion was the failure to identify a pretreatment pathogen. The most commonly isolated pathogen was Escherichia coli (81%). Eradication of the pretreatment pathogen at the end of therapy occurred in 94% of ciprofloxacin, 93% of trimethoprim/sulfamethoxazole, and 97% of ofloxacin-treated patients. At follow-up evaluation at 4 to 6 weeks, recurrence rates (relapse or reinfection) were 11% in the ciprofloxacin, 16% in the trimethoprim/sulfamethoxazole, and 13% in the ofloxacin treatment group. Clinical success at the end of therapy was 93% in the ciprofloxacin, 95% in the trimethoprim/sulfamethoxazole, and 96% in the ofloxacin treatment groups. The frequency of all adverse events was 31% for ciprofloxacin, 41% for trimethoprim/sulfamethoxazole, and 39% for ofloxacin-treated patients (P = 0.03). Premature discontinuation of study drug due to an adverse event was more common in trimethoprim/sulfamethoxazole-treated patients (n = 9) compared with those given ciprofloxacin (n = 2) or ofloxacin (n = 1; P = 0.02). CONCLUSION Ciprofloxacin, ofloxacin, and trimethoprim/sulfamethoxazole had similar efficacy when given for 3 days to treat acute, symptomatic, uncomplicated lower urinary tract infection in women.

Correlation of Prenatal Renal Pelvic Anteroposterior Diameter with Outcome in Infancy

PURPOSE We attempted to correlate prenatal renal pelvic anteroposterior diameter with outcome in infancy. MATERIAL AND METHODS Between May 1992 and March 1994 we identified 27 cases of fetal hydronephrosis in which renal pelvic anteroposterior diameter was 4 mm. or greater before 33 weeks of gestation and 7 mm. or greater at or after 33 weeks of gestation. RESULTS Hydronephrosis was bilateral in 18 fetuses and unilateral in 9. Shortly after birth radiological assessment revealed vesicoureteral reflux in 6 neonates, ureteropelvic junction obstruction in 6, extrarenal pelves in 3 and persistent nonobstructive hydronephrosis in 4. Radiological evaluation was normal in 8 newborns. CONCLUSIONS When these screening criteria for hydronephrosis are met prenatally a complete radiological assessment should be done following birth.

Single-dose fluoroquinolone therapy of acute uncomplicated urinary tract infection in women: results from a randomized, double-blind, multicenter trial comparing single-dose to 3-day fluoroquinolone regimens

OBJECTIVES To compare the efficacy and safety of single-dose and 3-day fluoroquinolone treatment of uncomplicated urinary tract infection (UTI). METHODS Adult women with acute uncomplicated UTI were randomized to receive either a single dose of gatifloxacin (400 mg), 3 days of gatifloxacin (200 mg daily), or 3 days of ciprofloxacin (100 mg twice daily). Patients were assessed at four points during the study: before treatment (within 48 hours before the initiation of the study medication), at the end of treatment (by telephone contact on day 3), and twice after treatment completion (5 to 9 days after treatment [test-of-cure visit] and 29 to 42 days after treatment [only patients with a bacteriologic response of eradication at the test-of-cure visit]). RESULTS The bacterial eradication rate for the single-dose gatifloxacin, 3-day gatifloxacin, and 3-day ciprofloxacin groups was 90%, 95%, and 89%, respectively; the clinical efficacy rate was 93%, 95%, and 93%, respectively, for microbiologically assessable patients at the test-of-cure visit. Eradication of the most common uropathogens, including Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, was achieved with gatifloxacin and ciprofloxacin. Single-dose gatifloxacin was equivalent to 3-day ciprofloxacin in both microbiologic and clinical efficacy. CONCLUSIONS Single-dose and 3-day gatifloxacin were microbiologically and clinically equivalent to 3-day ciprofloxacin for the treatment of acute UTI among women. Single-dose gatifloxacin may offer advantages over 3-day fluoroquinolone therapy for uncomplicated UTI by decreasing secondary use of medical resources and improving patient compliance.

A double-blind, multicenter, comparative study of the safety and efficacy of cefixime versus amoxicillin in the treatment of acute urinary tract infections in adult patients

In this 31-site multicenter trial, 565 adult patients with urinary tract infections were randomly assigned to receive either a 10-day course of cefixime 400 mg once daily (n = 279) or amoxicillin 250 mg three times daily (n = 286). Although all patients were included in the safety analysis, only 93 (33 percent) cefixime-treated and 99 (35 percent) amoxicillin-treated patients were fully evaluable for the efficacy analysis. One week after therapy, the evaluable patients treated with cefixime demonstrated a 90 percent clinical cure rate and a 92 percent eradication rate of the baseline pathogen. This compared with an 83 percent clinical cure rate and an 84 percent bacterial eradication rate in the amoxicillin-treated group. The most frequently isolated pathogen was Escherichia coli (80 percent) followed by Proteus mirabilis (10 percent). One hundred thirty-seven (49 percent) of the 279 cefixime-treated and 126 (44 percent) of the 286 amoxicillin-treated patients reported at least one adverse experience during the study. Adverse reactions associated with cefixime were similar to those reported for other beta-lactam antibiotics. The most frequent adverse experiences reported by cefixime-treated patients were diarrhea (15 percent) and stool changes (12 percent). Headaches (11 percent) and diarrhea (9 percent) were the most frequently reported adverse reactions by the amoxicillin-treated patients. Eleven cefixime-treated patients (3.9 percent) and 10 amoxicillin-treated patients (3.5 percent) discontinued therapy because of adverse experiences. Results of this study demonstrate that a once-daily regimen of cefixime is as safe and effective as a three-times-daily regimen of amoxicillin in the treatment of acute urinary tract infections. Although the incidence of bowel changes was somewhat higher in the cefixime treatment group, these events usually resolved when therapy was discontinued.

Age-related radiological imaging in children with acute pyelonephritis

Abstract. Accurate diagnosis of acute pyelonephritis (APN) using clinical and laboratory parameters is often difficult in children. The aims of this retrospective study were twofold. Firstly, to correlate the clinical and laboratory manifestations of APN with the results of the dimercaptosuccinic acid (DMSA) renal scan in different age groups. Secondly, to compare the DMSA renal scan, renal ultrasonography (RUS), and voiding cystourethrography (VCUG) in patients with clinical APN. The DMSA renal scan was utilized as the gold standard for renal involvement. We determined the sensitivity of these tests in febrile urinary tract infections (UTI) in three age groups: group I less than 2 years; group II 2–8 years; group III older than 8 years. During the period January 1992 through December 1998, 222 children presented with a febrile UTI. All patients had a DMSA renal scan, 208 had contrast VCUG, and 163 had RUS. The clinical and laboratory manifestation of pyelonephritis correlated better with a positive DMSA renal scan in the older children than in the younger children; 85% of the DMSA renal scans were positive in group III; 69% in group II; 48% in group I (P<0.001). Vesicoureteral reflux detected by contrast VCUG was more prevalent in the younger age groups. Although high grades of reflux (grade IV–V) correlated better with a positive DMSA renal scan, it did not reach a level of statistical significance (P>0.05). RUS did not correlate with a positive DMSA renal scan in any age group.

Pattern of response to prednisone in idiopathic, minimal lesion nephrotic syndrome as a criterion in selecting patients for cyclophosphamide therapy

Twenty-three children with idiopathic, relapsing minimal lesion nephrotic syndrome were divided according to their pattern of response to prednisone: (1) steroid dependent, if the relapse occurred while the dosage of prednisone was being decreased; and (2) frequent relapser, if the relapse occurred at variable periods of time (one week to two months) after discontinuing prednisone therapy. All patients received cyclophosphamide for eight weeks in a single daily dose of 2 mg/kg, in order to prolong the length of the remission. The percentage of patients who continued in remission at the end of the first year and thereafter was greater in the frequent relapser group (P = 0.05). This study suggests that the pattern of response to prednisone may be another criterion for the selection of patients who will benefit from cyclophosphamide therapy.

Spectrum of multicystic renal dysplasia: diagnosis and management.

Multicystic renal dysplasia represents a spectrum of pathologic states, from unilateral multicystic kidney through segmental and focal multicystic dysplasia to bilateral multicystic kidney. Diagnosis can be established with low-risk procedures with reasonable accuracy. Treatment may be nonoperative in selected cases, but the physician must be responsible for long-term follow-up of the child until more is known about the natural history of this process.

Nephritis in systemic lupus erythematosus in children

Twenty-five patients, aged six to 18 years, with lupus nephritis, followed for two to 103 months (median 22 months), have been classified according to renal histology into groups with diffuse proliferative glomerulonephritis (18), focal proliferative nephritis (2), and membranous nephropathy (5). Correlations have been made among specific histologic groups, clinical findings, renal function studies, urinary findings, and response to therapy. In sequential renal biopsies, lesions progressed in most patients with diffuse proliferative and membranous changes; however, chronic renal failure occurred in only one patient and the five-year survival rate (60.9%) is better than previously reported in pediatric patients.

Cat scratch disease and acute rejection after pediatric renal transplantation

Abstract: Cat scratch disease (CSD) can lead to unexplained fever, generalized lymphadenopathy and organomegaly in immunocompetent individuals. CSD has rarely been reported in immunocompromised transplant recipients, where its clinical features would mimic the more common post‐transplant lymphoproliferative disease (PTLD). We report three cases of CSD seen recently in children who had received prior kidney transplants. The three children were between 7 and 9 yr old, and had received kidney transplants 2–4 yr prior, with stable renal function. In each case, there was unexplained fever with either lymphadenopathy or organomegaly. The diagnosis of CSD was suggested by a history of new cats being introduced into each household and confirmed in all cases by the serological presence of a significant titer (> 1 : 64) of IgM antibodies to Bartonella henselae. Tests for other bacterial infections, cytomegalovirus and Epstein–Barr virus infections were negative. All the patients showed a clinical improvement with anti‐microbial therapy. In patients A and B, the CSD was associated with an acute rejection episode shortly after diagnosis. The rejection episodes were reversed by intravenous steroid pulse therapy. Only four cases of CSD have been previously reported following solid organ transplantation. Acute rejection following CSD has not been previously reported. CSD should be included in the differential diagnosis of fever in the post‐transplant setting, especially where PTLD is suspected.