Histologic and Clinical Factors Associated with Kidney Outcomes in IgA Vasculitis Nephritis.

BACKGROUND: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. METHODS: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. RESULTS: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. CONCLUSIONS: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

Treatment of idiopathic nephrotic syndrome at onset: a comparison between 8- and 12-week regimens in everyday clinical practice.

BACKGROUND: Optimal steroid treatment at onset of idiopathic nephrotic syndrome is still debated. The aim of this study was to analyze the clinical outcome at 24 months of follow-up in patients admitted to our unit for the first episode of steroid-sensitive nephrotic syndrome comparing two different steroid regimens. METHODS: We collected data on patients treated from 1992 to 2007 with prednisone according to the International Study on Kidney Diseases in Children 8-week regimen and since 2008 according to the Arbeitsgemeinschaft fur Padiatrische Nephrologie 12-week regimen. The primary outcome was to evaluate cumulative prednisone dosage at 12 and 24 months of follow-up in the two groups. As secondary outcomes, we considered mean relapse rate per patient; number of children without relapses at 6, 12, and 24 months; and number of patients who developed frequent relapses and steroid-dependent disease. RESULTS: Data were collected on 127 patients. Sixty-one subjects received the 8-week regimen and 66 the 12-week regimen. The mean cumulative prednisone dose at 12 and 24 months was not different, and the rate of patients without relapses was lower at 6 and 12 months in patients treated with the 8-week course, while no difference was observed at 24 months. CONCLUSIONS: Despite the limitations of a retrospective study with limited follow-up, our data indicate that switching treatment from a shorter to a longer scheme did not improve the clinical outcome at 24 months of observation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Parathyroid hormone and phosphate homeostasis in patients with Bartter and Gitelman syndrome: an international cross-sectional study.

BACKGROUND: Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies. METHODS: Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN). RESULTS: A total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs -0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate-standard deviation score < -2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting. CONCLUSIONS: Hyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.

Cardiac Abnormalities in Children with Autosomal Recessive Polycystic Kidney Disease.

BACKGROUND: No previous study has defined the prevalence of cardiac geometric and mechanical function abnormalities through the analysis of advanced echocardiographic parameters in children with autosomal recessive polycystic kidney disease (ARPKD). AIM: The purpose of this study was to evaluate cardiac geometry and function through advanced echocardiography in a well-characterized sample of pediatric patients with ARPKD. METHODS: Standard echocardiograms were obtained in 27 children with ARPKD (0-18 years) and in 88 healthy children of similar age, gender distribution, and body build. Left ventricular (LV) hypertrophy was defined as LV mass > 45g/(m2.16 + 0.09) and cardiac remodeling was defined by age-adjusted relative wall thickness (RWT). Systolic function was assessed by ejection fraction, midwall fractional shortening (mFS), and global longitudinal (GLS) and circumferential strain (GCS). RESULTS: Patients with ARPKD exhibited a higher LV mass index as compared to controls, and a more concentric LV geometry (both p < 0.001). Accordingly, the prevalence of abnormal LV geometry was significantly higher in ARPKD (33 vs. 0%; p < 0.005). No differences could be observed in the two groups for ejection fraction or GLS (both p = n.s.), while a significantly lower mFS (p < 0.05) as well as GCS (p < 0.001) could be observed. In the analysis of covariance, both LV mass index and RWT remained significantly higher in the ARPKD group, while mFS and GCS remained significantly lower (all p < 0.05). The prevalence of subclinical systolic dysfunction was significantly higher in patients with ARPKD as compared with control subjects (33 vs. 0%; p < 0.001). CONCLUSIONS: Children with ARPKD show significantly impaired cardiac phenotype, characterized by high rates of LV abnormal geometry paired with systolic mechanical dysfunction.

Growth Hormone (GH) Therapy During the Transition Period: Should We Think About Early Retesting in Patients with Idiopathic and Isolated GH Deficiency?

To investigate growth hormone (GH) secretion at the transition age, retesting of all subjects who have undergone GH replacement therapy is recommended when linear growth and pubertal development are complete to distinguish between transitional and persistent GH deficiency (GHD). Early retesting of children with idiopathic and isolated GHD (i.e., before the achievement of final height and/or the adult pubertal stage) can avoid possible over-treatment. Here, we report data from our population with idiopathic and isolated GHD to encourage changes in the management and timing of retesting. We recruited 31 patients (19 males) with idiopathic GHD who received recombinant GH (rGH) for at least 2 years. All of the patients were retested at the transition age at least 3 months after rGH discontinuation. Permanent GHD was defined as a GH peak of <19 ng/mL after administration of growth hormone⁻releasing hormone (GHRH) + arginine as a provocative test. Permanent GHD was confirmed in only five of 31 patients (16.13%). None of these patients presented low serum insulin-like growth factor (IGF)-1 levels (<-2 standard deviation score (SDS)). Only one male patient with an IGF-1 serum level lower than -2 SDS showed a normal GH stimulation response, with a GH peak of 44.99 ng/mL. Few patients with idiopathic and isolated GHD demonstrated persistence of the deficit when retested at the transition age, suggesting that the timing of retesting should be anticipated to avoid overtreatment.

Inhibin B in healthy and cryptorchid boys.

BACKGROUND: Cryptorchidism, the most common male genital abnormality observed in paediatrics, might often be associated with long-term functional consequences and can even reoccur after a successful orchidopexy. Serum markers that identify cryptorchid boys with gonadal dysfunction early should be useful in a decision-making process. Inhibin B, produced during all of childhood but altered in cryptorchid subjects, appears strictly related to Sertoli cells, and its levels directly reflect the status of the testis germinative epithelium. Unfortunately, its precise roles in bilateral and unilateral cryptorchidism are still debated and being unravelled. Herein, we report the most current knowledge about inhibin B in both healthy boys and those with cryptorchidism to discuss and clarify its potential clinical applications. DISCUSSION: Inhibin B represents a simple and repeatable serum marker and it seems to well asses the presence and function of the testicular tissue. Testicular tissue in prepubertal age is largely made up of Sertoli cells; inhibin B, coming from working Sertoli cells, allows to indirectly evaluate their function. Besides, inhibin B is produced throughout childhood, even before puberty, in contrast with central hormones, and it is not influenced by androgens during puberty, in contrast with other testicular hormones. Although further studies are needed, low levels of inhibin B have been related with low testicular score and/or with consistent alterations of testicular parameters at histological examination. This means that inhibin B could be an indirect marker of testicular functions that could even replace testicular biopsies, but current data are inconsistent to confirm this potential role of inhibin B in cryptorchidism. CONCLUSION: Inhibin B represents an effective candidate for early identification of testicular dysfunction after orchidopexy for cryptorchidism. Unfortunately, current data cannot exactly clarify the real role of inhibin B as a predictor of future testicular function in cryptorchidism and future long-term follow-up studies, with repeated inhibin B checks both in cryptorchid and in formerly cryptorchid children and adolescents, will permit to assess if previous normal levels of inhibin B would match with future normal pubertal development and fertility potential.

Report of a Novel SHOX Missense Variant in a Boy With Short Stature and His Mother With Leri-Weill Dyschondrosteosis.

Heterozygous mutations in the SHOX gene or in the upstream and downstream enhancer elements are associated with 2-22% of cases of idiopathic short stature (OMIM #300582) and with 60% of cases of Leri-Weill dyschondrosteosis (OMIM #127300) with which female subjects are generally more severely affected. Approximately 80-90% of SHOX pathogenic variants are deletions or duplications, and the remaining 10-20% are point mutations that primarily give rise to missense variants. The clinical interpretation of novel variants, particularly missense variants, can be challenging and can remain of uncertain significance. Here, we describe a novel missense variant (c.1044 G>T, p.Arg118Met) in a Moroccan boy with a disproportionately short stature and without any radiological traits or bone deformities and in his mother, who had a disproportionately short stature and a Madelung deformity. This variant has not been reported to date in the updated SHOX allelic variant or Human Gene Mutation Databases nor is it listed as a polymorphism in the ExAC browser, dbSNP, or 1000G. This mutation was predicted to be deleterious by three different bioinformatics tools since it modifies an amino acid in a highly conserved DNA-binding domain of the SHOX protein. Based on this evidence, the patient was treated with recombinant human growth hormone.

The Effect of Bisphenol A on Puberty: A Critical Review of the Medical Literature.

Many scientific studies have revealed a trend towards an earlier onset of puberty and have disclosed an increasing number of children that display precocious puberty. As an explanation, some authors have considered the global socio-economic improvement across different populations, and other authors have considered the action of endocrine disrupting chemicals (EDCs). Among these, bisphenol A (BPA), an aromatic compound largely used worldwide as a precursor of some plastics and chemical additives, is well known for its molecular oestrogen-like and obesogenic actions. We reviewed the medical literature of the previous 20 years that examined associations between BPA exposure and the age of puberty in humans, considering only those referring to clinical or epidemiological data. Of 19 studies, only 7 showed a correlation between BPA and puberty. In particular, the possible disruptive role of BPA on puberty may be seen in those with central precocious puberty or isolated premature breast development aged 2 months to 4 years old, even if the mechanism is undefined. Some studies also found a close relationship between urinary BPA, body weight, and early puberty, which can be explained by the obesogenic effect of BPA itself. The currently available data do not allow establishment of a clear role for BPA in pubertal development because of the conflicting results among all clinical and epidemiological studies examined. Further research is needed to fully understand the potential role of exposure to EDCs and their adverse endocrine health outcomes.

True Precocious Puberty Following Treatment of a Leydig Cell Tumor: Two Case Reports and Literature Review.

Leydig cell testicular tumors are a rare cause of precocious pseudopuberty in boys. Surgery is the main therapy and shows good overall prognosis. The physical signs of precocious puberty are expected to disappear shortly after surgical removal of the mass. We report two children, 7.5 and 7.7 year-old boys, who underwent testis-sparing surgery for a Leydig cell testicular tumor causing precocious pseudopuberty. During follow-up, after an immediate clinical and laboratory regression, both boys presented signs of precocious puberty and ultimately developed central precocious puberty. They were successfully treated with gonadotropin-releasing hormone (GnRH) analogs. Only six other cases have been described regarding the development of central precocious puberty after successful treatment of a Leydig cell tumor causing precocious pseudopuberty. Gonadotropin-dependent precocious puberty should be considered in children treated for a Leydig cell tumor presenting persistent or recurrent physical signs of puberty activation. In such cases, therapy with GnRH analogs appears to be the most effective medical treatment.