Growth promoting effects of growth hormone and IGF-I are additive in experimental uremia.

Exogenous growth hormone (GH) stimulates the endogenous production of IGF-I and improves growth in uremia. We investigated whether exogenous IGF-I is also able to improve uremic growth failure in rats and whether the growth promoting effects of GH and IGF-I are additive. In female 150 g uremic (subtotal nephrectomy, NX) Sprague-Dawley rats, both rhGH in doses from 2 X 1.25 to 2 X 10 IU/kg bid s.c. and rhIGF-I in doses from 2 X 0.5 to 2 X 4.0 mg/kg bid s.c. caused a dose-dependent increase in weight gain and length gain. However, endogenous production of GH was suppressed by both agents. Peptide hormone treatment did not affect cumulative food intake, but significantly increased food efficiency ratio (weight gain/food intake). Concomitant s.c. treatment with maximally effective doses of rhGH (12 X 5 IU/kg bid) and of rhIGF-I (2 X 2 mg/kg bid) resulted in additive growth promoting effects in NX and pair-fed control (CO) animals during the observation period of 12 days. Cumulative length gain was 3.2 +/- 0.5 cm in solvent-treated NX-animals, 4.1 +/- 0.5 cm with rhGH (+ 28% above solvent), 4.2 +/- 0.6 cm with rhIGF-I (+ 31%) and 4.9 +/- 0.5 cm with both peptides (+ 53%). The food efficiency ratio was 0.16 +/- 0.05 in solvent NX, 0.33 +/- 0.04 with rhGH (+ 106% above solvent), 0.23 +/- 0.02 with rhIGF-I (+ 44%), and 0.38 +/- 0.02 with both peptides (+ 138%). Histomorphometric analysis and measurements of length gain by fluorescence microscopy in the upper tibial metaphysis confirmed the growth promoting effects of both peptide hormones. The serum concentrations of IGF binding protein (BP)-4 (Western ligand blotting analysis) and of IGFBP-2 (immunoblot) were increased in uremic animals whereas IGFBP-3 was unchanged. Treatment with IGF-I and/or rhGH increased serum concentration of IGF-I but did not change the IGFBP pattern. rhIGF-I lowered blood glucose levels within one to two hours after injection. The effect was most pronounced during the first treatment day and declined thereafter. Concomitant treatment with rhGH attenuated the glucose lowering effect of rhIGF-I (glucose serum concentration at day one: 120 +/- 11 mg% in solvent NX, 50 +/- 21 mg% with rhIGF-I, 80 +/- 24 mg% with both peptides). It is concluded that: (i) IGF-I is able to stimulate growth in NX animals but suppresses endogenous GH production in the long run; (ii) the concomitant treatment with IGF-I and GH has additive effects on growth; and (iii) concomitant treatment with rhGH prevents hypoglycemia that is noted with rhIGF-I alone

Prevalence and potential relevance of hyperuricemia in pediatric kidney transplant recipients—a CERTAIN registry analysis

Background: Asymptomatic hyperuricemia is frequently observed in pediatric kidney transplant recipients; symptomatic hyperuricemia, however, is a rare complication. Only few data are available in this patient population. We, therefore, investigated the prevalence of hyperuricemia and its association with kidney transplant function and blood pressure in a multicenter cohort of pediatric kidney transplant recipients. Methods: This is a retrospective, observational multicenter registry study. All pediatric kidney transplant recipients in the CERTAIN database with at least one documented serum uric acid level and a follow-up of 5 years posttransplant were eligible. We identified 151 patients with 395 measurements of serum uric acid. We calculated the prevalence of hyperuricemia, analyzed potential risk factors and clinical consequences such as elevated blood pressure and reduced estimated glomerular filtration rate (eGFR). Statistical analysis was performed using IBM SPSS Statistics 26. Results: One hundred and ten of 395 (27.8%) serum uric acid levels were above 416 µmol/L (7.0 mg/dL), defined as the upper limit of normal. Univariate analysis showed a significant (p = .026) inverse association of serum uric acid with eGFR overtime. There was no significant association of serum uric acid concentrations with body mass index (z-score), blood pressure (z-score), or sex. No episodes of gout were documented. Conclusion: This study shows that hyperuricemia is present in a considerable number of patients sometime after pediatric kidney transplantation and is associated with lower eGFR. Whether hyperuricemia contributes to faster decline of graft function or to the overall cardiovascular risk of these patients remains to be elucidated. Keywords: gout; long-term outcome; pediatric kidney transplantation; uric acid; uric acid-lowering therapy

Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis

Introduction: Nephronophthisis (NPH) comprises a group of rare disorders accounting for up to 10% of end-stage kidney disease (ESKD) in children. Prediction of kidney prognosis poses a major challenge. We assessed differences in kidney survival, impact of variant type, and the association of clinical characteristics with declining kidney function. Methods: Data was obtained from 3 independent sources, namely the network for early onset cystic kidney diseases clinical registry (n = 105), an online survey sent out to the European Reference Network for Rare Kidney Diseases (n = 60), and a literature search (n = 218). Results: A total of 383 individuals were available for analysis: 116 NPHP1, 101 NPHP3, 81 NPHP4 and 85 NPHP11/TMEM67 patients. Kidney survival differed between the 4 cohorts with a highly variable median age at onset of ESKD as follows: NPHP3, 4.0 years (interquartile range 0.3–12.0); NPHP1, 13.5 years (interquartile range 10.5–16.5); NPHP4, 16.0 years (interquartile range 11.0–25.0); and NPHP11/TMEM67, 19.0 years (interquartile range 8.7–28.0). Kidney survival was significantly associated with the underlying variant type for NPHP1, NPHP3, and NPHP4. Multivariate analysis for the NPHP1 cohort revealed growth retardation (hazard ratio 3.5) and angiotensin-converting enzyme inhibitor (ACEI) treatment (hazard ratio 2.8) as 2 independent factors associated with an earlier onset of ESKD, whereas arterial hypertension was linked to an accelerated glomerular filtration rate (GFR) decline. Conclusion: The presented data will enable clinicians to better estimate kidney prognosis of distinct patients with NPH and thereby allow personalized counseling

Working Towards a Treat-to-Target Protocol in Juvenile Proliferative Lupus Nephritis - A Survey of Pediatric Rheumatologists and Nephrologists in Germany and Austria.

BackgroundTo describe treatment practices for juvenile proliferative lupus nephritis (LN) class III and IV of pediatric rheumatologists and nephrologists in Germany and Austria in preparation for a treat-to-target treatment protocol in LN.MethodsSurvey study by members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Pediatric Nephrology (GPN) on diagnostics and (concomitant) therapy of LN.ResultsFifty-eight physicians completed the survey. Overall, there was a considerable heterogeneity regarding the suggested diagnostics and management of juvenile proliferative LN. Increased urinary protein excretion, either assessed by 24 h urine collection or spot urine (protein-creatinine ratio), and reduced estimated glomerular filtration rate were specified as important parameters for indication of kidney biopsy to diagnose proliferative LN and monitoring of therapy. Corticosteroids were generally proposed for induction and maintenance therapy, most often in conjunction with either mycophenolate mofetil (MMF) or cyclophosphamide (CP) as steroid-sparing immunosuppressants. MMF was clearly preferred over CP for induction therapy of LN class III, whereas CP and MMF were equally proposed for LN class IV. MMF was most often recommended for maintenance therapy in conjunction with oral corticosteroids and continued for at least 3 years and 1 year, respectively, after remission. Hydroxychloroquine was widely accepted as a concomitant measure followed by renin-angiotensin system inhibitors in cases of arterial hypertension and/or proteinuria.ConclusionThe majority of pediatric rheumatologists and nephrologists in Germany and Austria propose the use of corticosteroids, most often in combination with either MMF or CP, for treatment of proliferative LN in children. The considerable heterogeneity of responses supports the need for a treat-to-target protocol for juvenile proliferative LN between pediatric rheumatologists and nephrologists

Estudo experimental do uso de rebolos convencionais na usinagem do aço VP-50 utilizado na retificação cilíndrica, por meio de diferentes métodos de lubrirrefrigeração

A retificação é um processo de usinagem preciso, sendo uma das etapas mais caras na fabricação dos moldes para injeção de termoplásticos. Na retificação o rebolo é a ferramenta abrasiva responsável pela retirada do material. O número de tipos de abrasivos e granulometrias disponíveis são bastante grandes e junto com a quantidade de ligas possíveis, estruturas e durezas, além dos formatos, fazem com que se chegue a um número enorme de produtos. O conhecimento das suas características técnicas, vantagens, defeitos e condições de trabalho são fundamentais para os engenheiros de produto, de processos e, naturalmente, para os gerentes de área industrial, identificarem qual o rebolo mais indicado para realização do processo de retificação. Dentre os aços utilizados na fabricação de moldes para injeção de termoplásticos destaca-se o aço VP-50, o qual foi o aço usado neste experimento, sendo usinado pelo processo de retificação cilíndrica. No processo de retificação, também foi adotado para fins de experimento dois métodos de lubrirrefrigeração, sendo eles o método convencional com lubrirrefrigeração abundante e o MQL que é a técnica com mínima quantidade de lubrirrefrigeração. O objetivo deste trabalho foi analisar de forma comparativa o desempenho de corte executado com três tipos de rebolos convencionais: rebolo de óxido de alumínio branco, rebolo de carbureto de silício verde e rebolo de carbureto de silício preto com óxido de alumínio branco. Os resultados foram analisados e comparados pelas variáveis de saída dos três tipos de rebolos, tipo de refrigeração e espessura equivalente de corte

Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy

Background Nephronophthisis associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic kidney diseases that includes nephronophthisis (NPHP), Senior-Loken syndrome (SLS), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). To date, causative mutations in NPHP-AC have been described for 18 different genes, rendering mutation analysis tedious and expensive. To overcome the broad genetic locus heterogeneity, a strategy of DNA pooling with consecutive massively parallel resequencing (MPR) was devised.Methods In 120 patients with severe NPHP-AC phenotypes, five pools of genomic DNA with 24 patients each were prepared which were used as templates in order to PCR amplify all 376 exons of 18 NPHP-AC genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L, NEK8, TMEM67, INPP5E, TMEM216, AHI1, ARL13B, CC2D2A, TTC21B, MKS1, and XPNPEP3). PCR products were then subjected to MPR on an Illumina Genome-Analyser and mutations were subsequently assigned to their respective mutation carrier via CEL I endonuclease based heteroduplex screening and confirmed by Sanger sequencing.Results For proof of principle, DNA from patients with known mutations was used and detection of 22 out of 24 different alleles (92% sensitivity) was demonstrated. MPR led to the molecular diagnosis in 30/120 patients (25%) and 54 pathogenic mutations (27 novel) were identified in seven different NPHP-AC genes. Additionally, in 24 patients only single heterozygous variants of unknown significance were found.Conclusions The combined approach of DNA pooling followed by MPR strongly facilitates mutation analysis in broadly heterogeneous single gene disorders. The lack of mutations in 75% of patients in this cohort indicates further extensive heterogeneity in NPHP-AC