Aim: To identify risk factors for a child with Henoch‐Schönlein purpura (HSP) either to develop nephritis (HSPN) or to contract progressive course and to obtain the currently available evidence on ...the efficacy of treatment options in both preventing and treating the established renal disease.
Method: Review of the literature published over the last two decades.
Results: Persistent or recurrent purpura, severe abdominal symptoms and an older age proved as the most significant risk factors for later HSPN. The risks of long‐term renal impairment are the highest in children having at presentation nephritic/nephrotic syndrome and/or more than 50% of glomeruli occupied by large crescents or sclerosing lesions. Randomized controlled trials (RCT) do not support short course prednisone at presentation of HSP in preventing persistent renal disease. Many uncontrolled studies using various treatment regimens have reported outcomes considered better than expected. However, the data from RCTs are sparse and no treatment options for the established renal disease can be currently recommended based on RCTs.
Conclusion: Severity and/or duration of extrarenal HSP symptoms and an older age are the most significant risk factors for developing HSPN, whereas clinical and histological severity at HSPN onset are in general predictive of a long‐term renal impairment. The existing evidence does not support of short course prednisone in preventing persistent renal disease. A well‐designed RCTs are needed in children with moderately severe or rapidly progressive (crescentic) HSPN.
Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease. CAKUT can be caused by monogenic mutations; however, data are ...lacking on their frequency. Genetic diagnosis has been hampered by genetic heterogeneity and lack of genotype–phenotype correlation. To determine the percentage of cases with CAKUT that can be explained by mutations in known CAKUT genes, we analyzed the coding exons of the 17 known dominant CAKUT-causing genes in a cohort of 749 individuals from 650 families with CAKUT. The most common phenotypes in this CAKUT cohort were vesicoureteral reflux in 288 patients, renal hypodysplasia in 120 patients, and unilateral renal agenesis in 90 patients. We identified 37 different heterozygous mutations (33 novel) in 12 of the 17 known genes in 47 patients from 41 of the 650 families (6.3%). These mutations include (number of families): BMP7 (1), CDC5L (1), CHD1L (5), EYA1 (3), GATA3 (2), HNF1B (6), PAX2 (5), RET (3), ROBO2 (4), SALL1 (9), SIX2 (1), and SIX5 (1). Furthermore, several mutations previously reported to be disease-causing are most likely benign variants. Thus, in a large cohort over 6% of families with isolated CAKUT are caused by a mutation in 12 of 17 dominant CAKUT genes. Our report represents one of the most in-depth diagnostic studies of monogenic causes of isolated CAKUT in children.
Type 1 diabetes mellitus (T1DM) commonly occurs in childhood or adolescence, although the rising prevalence of type 2 diabetes mellitus (T2DM) in these age groups is now being seen worldwide. ...Diabetic nephropathy (DN) develops in 15–20% of subjects with T1DM and in similar or higher percentage of T2DM patients, causing increased morbidity and premature mortality. Although overt DN or kidney failure caused by either type of diabetes are very uncommon during childhood or adolescence, diabetic kidney disease in susceptible patients almost certainly begins soon after disease onset and may accelerate during adolescence, leading to microalbuminuria or incipient DN. Therefore, all diabetics warrant ongoing assessment of kidney function and screening for the earliest manifestations of renal injury. Pediatric health care professionals ought to understand about risk factors, strategy for prevention, method for screening, and treatment of early DN. This review considers each form of diabetes separately, including natural history, risk factors for development, screening for early manifestations, and strategy recommended for prevention and treatment of DN in children and adolescents.
Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40–50 % of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated ...CAKUT have been described, explaining ~12 % of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in
SRGAP1
in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2–ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene
SLIT2
for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in
SLIT2
or
SRGAP1
were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that
SRGAP1
is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with
ROBO2
in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in
SRGAP1
lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the
SLIT2
mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.
ABSTRACT
Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib‐polydactyly ...syndromes, Jeune, Sensenbrenner, and Mainzer‐Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating thoracic dystrophy (JATD) and two Mainzer‐Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end‐stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono‐renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy.
Jeune Asphyxiating Thoracic Dysplasia (JATD) is a rare recessive ciliary chondrodysplasia associated with death in infancy due to respiratory failure, and extraskeletal symptoms also occur in some patients. This large next generation sequencing study in 66 JATD and Mainzer‐Saldino syndrome (MSS) families reveals that mutations in the intraflagellar transport protein IFT140 cause MSS and are a frequent cause of JATD with retinal and kidney symptoms but mild thorax phenotype, providing for the first time a clinically significant genotype‐phenotype association in JATD.
Eight boys aged 2–12 weeks with urinary tract malformations (UTMs) exhibited features of transient type 1 pseudo-hypoaldosteronism (TPHA1) in the course of urinary tract infection (UTI). Hyponatremia ...(120.9 ± 5.8 mmol/l), hyperkalemia (6.9 ± 0.9 mmol/l), metabolic acidosis (plasma bicarbonate 11 ± 1.4 mmol/l), and a rise in serum creatinine levels (145 ± 101 μmol/l) were associated with high urinary sodium (Na) and low potassium (K) excretion. Tubular resistance to aldosterone was indicated by high plasma aldosterone concentrations (170.4 ± 100.5 ng/dl), high levels of the plasma aldosterone to potassium ratio (25.2 ± 15.6), and diminished urinary K/Na values (0.31 ± 0.19). With appropriate therapy, serum electrolytes, creatinine, and acid–base balance normalized within 2 weeks. A Medline search revealed another 85 cases of TPHA1 reported to date. All of the 93 patients were less than 7 months of age and 90% were less than 3 months of age, 90.3% suffered from UTM, with associated UTI in 89% of them, 11% had UTM in the absence of UTI, and 9.7% showed isolated UTI. These findings indicate that early infancy is the main contributing factor for TPHA1 to occur and that UTI and UTM are additional factors, with at least one being required for its development.
Aim of the study was to determine if carotid intima media thickness in children with idiopathic nephrotic syndrome is greater than in healthy subjects, and to assess whether carotid intima media ...thickness in children with nephrotic syndrome is associated with clinical (including disease duration, cumulative dose of steroids, number of relapses) and biochemical parameters.
A cross-sectional study included 40 patients with nephrotic syndrome (mean age 11.7±4.7 years). Steroid dependent nephrotic syndrome was established in 32 patients (80%), while 8 (20%) had steroid resistant nephrotic syndrome. Control group consisted of 20 age and gender matched healthy children. Blood pressure based on 24-h ambulatory blood pressure monitoring (ABPM), carotid intima media thickness, fasting glucose, insulin, HbA1c, lipid concentrations were measured in all children.
A significant difference was detected in carotid intima media thickness values (P=0.036). Children with nephrotic syndrome had significantly greater carotid intima media thickness compared with healthy children (0.42±0.06 and 0.38±0.03mm). Carotid intima-media thickness was positively associated with duration of nephrotic syndrome (r=0.45; P=0.004), body mass index (r=0.48; P=0.002), daytime systolic blood pressure (r=0.46; P=0.003) and night-time systolic blood pressure (r=0.52; P=0.001). Multiple linear regression showed that duration of nephrotic syndrome was the only independent predictor of carotid intima media thickness in children with nephrotic syndrome (R2=0.244; β=0.327; P=0.037).
The findings of the present study suggest subclinical vascular damage in patients with nephrotic syndrome. Duration of nephrotic syndrome was the only independent predictor of carotid intima media thickness.
Severe and reproducible low-renin hypertension responsive to salt restriction and amiloride–thiazide therapy in a 13-year-old otherwise asymptomatic boy suggested Liddle syndrome. This assumption was ...strengthened by a positive family history of hypertension poorly responsive to conventional treatment or sudden deaths under 40 years of age in four generations. DNA analysis of the beta and gamma subunits of the epithelial sodium channel revealed a heterozygous mutation c.C1852T (p.Pro618Ser) in the
SCNN1B
gene in the patient and in both his hypertensive mother and uncle. A PubMed search revealed 21 different disease-causing mutations reported to date, all but two clustering in the cytoplasmic C-terminal regions of either beta (16 mutations) or gamma (5) subunit, leading to a three- to eightfold increase in the amiloride-sensitive sodium current. Inter- and intrafamilial variability in both hypertension and hypokalemia were disclosed, which may not be obligatory among the subjects carrying a Liddle mutation.
Conclusion
: Liddle syndrome should be considered as a cause of hypertension in children or adolescents particularly with suppressed renin activity. Early diagnosis and appropriately tailored treatment avoid complications of long-term unrecognized or inappropriately managed hypertension.
Aim
This studied reviewed renovascular hypertension (RVH) due to renal artery stenosis (RAS) in two Serbian paediatric centres from 2001 to 2013.
Methods
The patients' demographic data, underlying ...syndromes, blood pressure (BP), antihypertensive treatments and outcomes were reviewed.
Results
The incidence of RVH was 1.9 per million children per year during the study period, and there were 25 patients with RAS, aged 10.4 ± 5.2 years. At presentation, their mean blood pressure (BP) standard deviation scores were 6.9 ± 3.4 systolic and 5.2 ± 2.6 diastolic. BP loads on 24‐hour ambulatory BP were 88 ± 14% systolic and 80 ± 29% diastolic. We found that 72% had fibromuscular dysplasia and 28% had underlying syndromes. RAS was unilateral in 64% and bilateral in 28%, and 8% had RAS of a single kidney. Antihypertensive treatment included antihypertensive drugs (100%), percutaneous transluminal angioplasty (92%), renal auto‐transplantation (16%), surgical revascularisation (12%) and nephrectomy (12%). After 4.4 ± 3.6 years of follow‐up, high BP was cured in 40% of the patients and 39.4% of the kidneys and improved in 48% (75.7%), with BP decreases of 20.3 ± 3.7% systolic and 16.3 ± 6.2% diastolic.
Conclusion
Fibromuscular dysplasia was the most common cause of RVH in this study, and hypertension was cured or improved in 88% of the patients.
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