Relationship between age at initiation of cysteamine treatment, adherence with therapy, and glomerular kidney function in infantile nephropathic cystinosis.

Infantile nephropathic cystinosis, due to impaired transport of cystine out of lysosomes, occurs with an incidence of 1 in 100-200,000 live births. It is characterized by renal Fanconi syndrome in the first year of life and glomerular dysfunction progression to end-stage kidney disease by approximately 10 years of age. Treatment with oral cysteamine therapy helps preserve glomerular function, but affected individuals eventually require kidney replacement therapy. This is because glomerular damage had already occurred by the time a child is diagnosed with cystinosis, typically in the second year of life. We performed a retrospective multicenter study to investigate the impact of initiating cysteamine treatment within the first 2 months of life in some infants and comparing two different levels of adherence in patients diagnosed at the typical age. We collected 3983 data points from 55 patients born between 1997 and 2020; 52 patients with 1592 data points could be further evaluated. These data were first analyzed by dividing the patient cohort into three groups: (i) standard treatment start with good adherence, (ii) standard treatment start with less good adherence, and (iii) early treatment start. At every age, mean estimated glomerular filtration rate (eGFR) was higher in early-treated patients than in later-treated patients. Second, a generalized additive mixed model (GAMM) was applied showing that patients with initiation of treatment before 2 months of age are expected to have a 34 ml/min/1.73 m2 higher eGFR than patients with later treatment start while controlling for adherence and patients' age. These data strongly suggest that oral cysteamine treatment initiated within 2 months of birth preserves kidney function in infantile nephropathic cystinosis and provide evidence of the utility of newborn screening for this disease.

Monitoring of urinary calcium and phosphorus excretion in preterm infants: comparison of 2 methods.

OBJECTIVES: Premature babies require supplementation with calcium (Ca) and phosphorus (P) to prevent metabolic bone disease of prematurity. To guide mineral supplementation, 2 methods of monitoring urinary excretion of Ca and P are used: urinary Ca or P concentration and Ca/creatinine (Crea) or P/Crea ratios. We compare these 2 methods in regards to their agreement on the need for mineral supplementation. METHODS: Retrospective chart review of 230 premature babies with birth weight <1500 g, undergoing screening of urinary spot samples from day 21 of life and fortnightly thereafter. Hypothetical cutoff values for urine Ca or P concentration (1 mmol/L) and urine Ca/Crea ratio (0.5 mol/mol) or P/Crea ratio (4 mol/mol) were applied to the sample results. The agreement on whether to supplement the respective minerals based on the results with the 2 methods was compared. Multivariate general linear models sought to identify patient characteristics to predict discordant results. RESULTS: A total of 24.8% of cases did not agree on the indication for Ca supplementation, and 8.8% for P. Total daily Ca intake was the only patient characteristic associated with discordant results. CONCLUSIONS: With the intention to supplement the respective mineral, comparison of urinary mineral concentration with mineral/Crea ratio is moderate for Ca and good for P. The results do not allow identifying superiority of either method on the decision as to which babies require Ca and/or P supplements.

Gout in pediatric renal transplant recipients.

Clinical gout has rarely been described after pediatric renal transplantation (RTx), although asymptomatic hyperuricemia is common in these patients. We describe three male pediatric patients who presented with gouty arthritis 7-8.5 years following RTx. Since receiving allopurinol, all patients had been free of gouty symptoms. To prevent severe bone marrow depletion, the dosage of azathioprine, an immunosupressant drug, was reduced by 50% to prevent interaction with allopurinol. Because atypical presentation of gout can occur, a high index of suspicion is needed to allow appropriate diagnosis of this disease in patients with skeletal pain after RTx.

Hemolytic-uremic syndrome in Switzerland: a nationwide surveillance 1997-2003.

Hemolytic-uremic syndrome (HUS) is a leading cause of acute renal failure in childhood. In its typical presentation, it is preceded by an episode of diarrhea mostly due to Shiga-toxin-producing Escherichia coli. There is important geographical variation of many aspects of this syndrome. Nationwide data on childhood HUS in Switzerland have not been available so far. In a prospective national study through the Swiss Pediatric Surveillance Unit 114 cases (median age 21 months, 50% boys) were reported between April 1997 and March 2003 by 38 pediatric units (annual incidence 1.42 per 10(5) children < or =16 years). Shiga-toxin-producing E. coli were isolated in 32 (60%) of tested stool samples, serotype O157:H7 in eight. Sixteen children presented with only minimal renal involvement, including three with underlying urinary tract infection. Six patients presented with atypical hemolytic-uremic syndrome, and six with HUS due to invasive Streptococcus pneumoniae infection. Mortality was 5.3%, including two out of six children with S. pneumoniae infection. The severity of thrombocytopenia and the presence of central nervous system involvement significantly correlated with mortality. In conclusion, childhood HUS is not rare in Switzerland. Contrasting other countries, E. coli O157:H7 play only a minor role in the etiology. Incomplete manifestation is not uncommon.

Hypokalemic rhabdomyolysis in congenital tubular disorders: a case series and a systematic review.

Hypokalemia is a recognized cause of rhabdomyolysis but very few reports document its association with inborn renal tubular disorders. We report our experience with hypokalemic rhabdomyolysis in 5 pediatric patients affected by inborn renal tubular disorders and the results of a careful review of the literature disclosing 9 further cases for a total of 14 patients (8 male and 6 female subjects, aged between 1.6 and 46, median 16 years). The inborn renal tubular disorders underlying rhabdomyolysis were classic distal renal tubular acidosis (n = 7), Gitelman syndrome (n = 5), classic Bartter syndrome (n = 1), and antenatal Bartter syndrome (n = 1). In 8 patients rhabdomyolysis followed an acute intestinal disease, an upper respiratory illness or the discontinuation of regular medication. Five patients experienced two or more episodes of rhabdomyolysis. In 10 patients the underlying renal tubular disorder was recognized concurrently with the episode of rhabdomyolysis or some weeks later. In conclusion some congenital renal tubular disorders predispose to hypokalemic rhabdomyolysis. Prevention of discontinuation of regular medication and electrolyte repair in the context of acute intercurrent illnesses might avoid the development of hypokalemic rhabdomyolysis.

Childhood extraordinary daytime urinary frequency-a case series and a systematic literature review.

Childhood extraordinary daytime urinary frequency is likely a common but underreported condition characterized by daytime frequent voiding and typically not linked with complaints of burning, urinary incontinence, altered urinary stream, changes in the nighttime voiding pattern, excessive fluid intake and excessive urinary volume. To determine the features and outcome of extraordinary daytime urinary frequency, we report our experience with 14 children and the results of a formal systematic analysis of peer-reviewed English-language literature on this topic. Nineteen case series were found (together with 16 mostly pertinent comments), with each case series providing details on from one to 119 children. On the basis of our experience and the findings of our systematic analysis, we conclude that, in general practice, extraordinary daytime urinary frequency is a common cause of urinary frequency, that the age of such patients is, on average, 6 years and that the micturation abnormalities persist for an average of 6 months. The results of this review must be viewed with an understanding of the limitations of the analysis process, which incorporated data exclusively from case series.

Ambulatory arterial stiffness index is increased in hypertensive childhood disease.

Arterial hypertension in adults is often associated with an increased arterial stiffness, which correlates with the ambulatory arterial stiffness index (AASI) as derived from ambulatory blood pressure (BP) measurements. The purpose of this study was to demonstrate whether children with diagnosed hypertension have an increased AASI as in hypertensive adults. AASI was calculated from 185 ambulatory BP measurements of 114 hypertensive and 71 normotensive, healthy children. Hypertensive children had higher AASI values compared with their normotensive healthy counterparts (0.370 +/- 0.120 versus 0.204 +/- 0.199, p < 0.0001). Children with longer duration of hypertension or a history of primary or secondary aortic coarctation displayed even more elevated AASI values. A receiver operator curve derived cut-off of AASI set at 0.301 distinguished (p < 0.0001) hypertensive from normotensive children with an odds ratio of 8.2, a sensitivity of 81%, and a specificity of 65%. Moreover, AASI correlated with pulse and systolic BP. In conclusion, AASI is elevated in hypertensive children and correlates with the duration and the origin of hypertension in childhood.

Src inhibition ameliorates polycystic kidney disease.

Despite identification of the genes responsible for autosomal dominant polycystic kidney disease (PKD) and autosomal recessive PKD (ARPKD), the precise functions of their cystoprotein products remain unknown. Recent data suggested that multimeric cystoprotein complexes initiate aberrant signaling cascades in PKD, and common components of these signaling pathways may be therapeutic targets. This study identified c-Src (pp60(c-Src)) as one such common signaling intermediate and sought to determine whether Src activity plays a role in cyst formation. With the use of the nonorthologous BPK murine model and the orthologous PCK rat model of ARPKD, greater Src activity was found to correlate with disease progression. Inhibition of Src activity with the pharmacologic inhibitor SKI-606 resulted in amelioration of renal cyst formation and biliary ductal abnormalities in both models. Furthermore, the effects of Src inhibition in PCK kidneys suggest that the ErbB2 and B-Raf/MEK/ERK pathways are involved in Src-mediated signaling in ARPKD and that this occurs without reducing elevated cAMP. These data suggest that Src inhibition may provide therapeutic benefit in PKD.

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.

Better renoprotective effect of angiotensin II antagonist compared to dihydropyridine calcium channel blocker in childhood.

BACKGROUND: The dihydropyridine calcium channel blocker amlodipine and the angiotensin II antagonist irbesartan effectively reduce blood pressure in hypertensive children. METHODS: Eligible for the open-label, randomized study were nephropathic children between 6.0 and 18 years of age with plasma creatinine <177 micromol/L, overt proteinuria, untreated arterial hypertension (systolic, 5 to 30 mm Hg; and diastolic, 1 to 15 mm Hg;>95th centile) and stable immunosuppressive treatment. The initial dose of amlodipine was 5 mg (body weight, 20 to 40 kg) and 10 mg (body weight,>40 kg), respectively, that of irbesartan, which was 75 mg (body weight, 20 to 40 kg) and 150 mg (body weight,>40 kg), respectively. The dosage was doubled if necessary. RESULTS: A total of 26 children aged 6.1 to 17 years were allocated to receive either amlodipine (N = 13) or irbesartan (N = 13) for 16 weeks. Severe edema and headache occurred in two patients on amlodipine who withdrew from the study. No adverse experiences were noted in patients given irbesartan. Amlodipine [by 12 (10 to 14)/7 (5 to 10) mm Hg; median and interquartile range, respectively] and irbesartan [by 13 (9 to 16)/9 (7 to 11) mm Hg, respectively] reduced blood pressure (P < 0.01) in a similar fashion. Heart rate, plasma sodium, and creatinine did not change. Irbesartan slightly increased plasma potassium [by 0.1 (0.0 to 0.2) mmol/L; P < 0.05]. Plasma albumin and the urinary albumin/creatinine ratio were similar before and with amlodipine. On the contrary, irbesartan increased plasma albumin [by 4 (3 to 5) g/L; P < 0.03] and decreased the urinary albumin/creatinine ratio [by 242 (68 to 312) mg/mmol; P < 0.03]. CONCLUSION: The study demonstrates that in children the effect of angiotensin II antagonists on proteinuria is better than that of dihydropyridine calcium channel blockers.

Behavioral and functional abnormalities linked with recurrent urinary tract infections in girls.

BACKGROUND: Most girls with recurrent urinary tract infections do not have major urinary tract abnormalities. Recent studies focus on predisposing behavioral and functional abnormalities: infrequent voiding, inadequate fluid intake, stool retention, poor genital hygiene and voiding dysfunction. METHODS: Complete history, bladder and bowel questionnaire, physical examination, voiding-drinking diary, sonography and uroflowmetry were used to assess infrequent voiding, functional stool retention, poor fluid intake, inadequate hygiene, or voiding dysfunction in girls referred for evaluation of three or more symptomatic urinary tract infections (with a first infection at the age of more than 36 months). RESULTS: A total of 141 girls aged 3.9 to 18 years were evaluated between 1996 and 1999; 212 abnormalities were noted in 120 patients: infrequent voiding (isolated, 16; combined with other abnormalities, 47), poor fluid intake (isolated, 10; combined, 50), functional stool retention (isolated, 5; combined, 25), inadequate hygiene or toilet habits (isolated, 3; combined, 24), dysfunctional voiding (isolated, 15; combined, 10), bladder overactivity (isolated, 5; combined, 2). CONCLUSIONS: Most girls referred for evaluation of three or more urinary tract infections have host-mediated predisposing abnormalities: infrequent voiding, poor fluid intake, functional stool retention or voiding dysfunction. Poor genital hygiene and toilet habits were almost always combined with other abnormalities, suggesting that infections are not necessarily related to poor genital hygiene or toilet habits. Two or more indications of predisposing behavior often concur in the same patient.

How good is blood pressure control among treated hypertensive children and adolescents?

BACKGROUND: Since good control of arterial hypertension is of paramount importance, the present study was carried out to evaluate blood pressure control in pediatric patients with hypertension receiving regular medical care. STUDY DESIGN: The charts of 80 hypertensive children receiving medical care were reviewed. Their antihypertensive medication had been stable during three or more separate clinic visits and during 3 or more months. Patients with office hypertension were excluded. RESULTS: Blood pressure values higher than the corresponding 95th centiles were noted in 20 of the 80 patients. Hypertension was systolic in seven, diastolic in four and both systolic and diastolic in nine patients. The number of prescribed antihypertensive drugs and the number of doses/day of prescribed antihypertensive drugs was similar in patients with good and in those with poor blood pressure control. Plasma creatinine was higher in patients with poor than in those with good blood pressure control. CONCLUSIONS: The present survey indicates that the goal of antihypertensive medication is not achieved in a noticeable number of pediatric patients with treated hypertension.

Long-term calcineurin inhibition and magnesium balance after renal transplantation.

Regulation of magnesium balance is achieved by a steady-state mechanism in which intake and output are maintained at an equal level. Dietary magnesium intake, total and ionized plasma magnesium levels, and urinary magnesium were assessed in 46 renal transplant recipients treated with cyclosporine, nine transplant recipients who had never been on cyclosporine, and 31 healthy volunteers. Dietary magnesium intake [13.5 (11.0-15.1) mmol/day vs 13.0 (11.1-16.0) mmol/day and 13.7 (11.4-16.7) mmol/day, respectively; median and interquartile range] and urinary magnesium excretion [4.31 (3.57-5.89) vs 4.39 (3.56-6.02) and 5.01 (3.73-6.01) mmol/day, respectively] were similar in renal transplant recipients treated with cyclosporine, transplant recipients who had never been on cyclosporine, and control subjects. Total [0.74 (0.70-0.78) vs 0.80 (0.74-0.84) and 0.81 (0.79-0.87) mmol/l), respectively] and ionized [0.49 (0.46-0.52) vs 0.53 (0.50-0.58) and 0.54 (0.52-0.59) mmol/l, respectively] plasma magnesium were significantly lower in renal transplant recipients on cyclosporine than in transplant recipients without cyclosporine, and healthy controls. These observations indicate a modified magnesium steady state in renal transplant recipients treated with cyclosporine.

Effectiveness and safety of the angiotensin II antagonist irbesartan in children with chronic kidney diseases.

BACKGROUND: Studies in adults with chronic kidney diseases demonstrate that the orally available angiotensin II antagonist irbesartan reduces arterial pressure and pathological proteinuria, mostly with an excellent tolerability profile. Little information is available on irbesartan in childhood. METHODS: A total of 44 pediatric outpatients with chronic kidney disease (27 male and 17, aged 3.7 to 18 years, median 10 years) were given irbesartan once a day during 18 weeks for arterial hypertension (N = 23), proteinuria (N = 8), or both (N = 13). RESULTS: In patients with hypertension, the use of irbesartan 4.1 (3.1-5.3) mg/kg body weight daily (median and interquartile range) was associated with a decrease (P <.005) in arterial pressure by 17 (13-22)/10 (7-12) mm Hg. In patients with overt proteinuria the urinary protein excretion decreased (P <.01) during treatment with irbesartan (2.9 [2.0-4.8] mg/kg body weight) by 52 (0-75) mg/[m(2) x h]), whereas plasma albumin increased (P <.05) by 4 (1-5) g/L. The frequency of abdominal pain, constipation, cough, diarrhea, dizziness, edema, fatigue, headache, insomnia, myalgia, orthostasis, and rash was similar before and with irbesartan. Plasma sodium slightly decreased, whereas plasma potassium increased, with irbesartan (P <.01). CONCLUSIONS: In pediatric patients with chronic kidney diseases, irbesartan given once a day for 18 weeks significantly reduces arterial pressure and proteinuria, with an excellent tolerability and side effect profile.