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.
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 m
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.
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 usedurinary 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.
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.
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder caused by
CLDN16
mutations.
CLDN16
encodes the renal tight junction protein ...claudin-16, which is important for the paracellular reabsorption of calcium and magnesium in the thick ascending limb of Henle's loop. That FHHNC is frequently associated with progressive renal failure suggests additional roles for claudin-16 in the maintenance of tight junction integrity. An investigation of 32 patients with FHHNC and 17 different mutations was previously reported; here, the analysis is expanded to 39 additional patients and 12 new mutations. Expression studies revealed that five of the 12 new mutations led to partial loss of claudin-16 function and the remaining seven led to complete loss of function. The 23 patients who had mutations resulting in complete loss of function of both alleles were significantly younger at the onset of symptoms than the 46 patients who had at least one mutant allele providing partial function (2.2
versus
5.6 years;
P
< 0.01). In addition, those with complete loss of function had a more rapid decline in GFR (7.3
versus
2.9 ml/min per 1.72 m
2
/y;
P
< 0.01), leading to 54% requiring renal replacement therapy by age 15 compared with 20% of those with residual function (
P
< 0.05). These data suggest that residual function of claudin-16 may delay the progression of renal failure in FHHNC.
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 ≤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.
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.
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.
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.
Better renoprotective effect of angiotensin II antagonist compared to dihydropyridine calcium channel blocker in childhood.
The dihydropyridine calcium channel blocker amlodipine and the angiotensin ...II antagonist irbesartan effectively reduce blood pressure in hypertensive children.
Eligible for the open-label, randomized study were nephropathic children between 6.0 and 18 years of age with plasma creatinine <177 μmol/L, overt proteinuria, untreated arterial hypertension (systolic, 5 to 30mm Hg; and diastolic, 1 to 15mm Hg;>95th centile) and stable immunosuppressive treatment. The initial dose of amlodipine was 5mg (body weight, 20 to 40 kg) and 10mg (body weight,>40 kg), respectively, that of irbesartan, which was 75mg (body weight, 20 to 40 kg) and 150mg (body weight,>40 kg), respectively. The dosage was doubled if necessary.
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.
The study demonstrates that in children the effect of angiotensin II antagonists on proteinuria is better than that of dihydropyridine calcium channel blockers.
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