Pubertal testicular volume references for ruler, orchidometer, and ultrasonography measurements based on a longitudinal follow-up.

BACKGROUND: Testicular volume is a marker of male pubertal development. Various clinical conditions and their treatments may influence testicular growth. OBJECTIVES: To create ruler-based age-dependent pubertal testicular volume references that enable calculation of standard deviation (SD) scores. MATERIALS AND METHODS: Study cohort comprised 65 boys who attended clinical examination twice a year from the age of 8.5 years until the attainment of final testicular size. Forty-nine (75.4%) boys completed the follow-up and 16 (24.6%) boys dropped out before the attainment of final post-pubertal testicular size. At each follow-up visit testicular size was measured with a ruler, orchidometer, and ultrasonography. LMS or LMSP method served as the technique for creating reference growth curves for testicular volumes. Using the novel references for ruler measurements, development of SD scores was assessed in a cohort of boys with unilateral cryptorchidism. RESULTS: Reference growth curves were constructed separately for ruler, orchidometer, and ultrasonography measurements. Median orchidometer volume of 4 mL, marker of male pubertal onset, occurred at the age of 11.7 years, whereas +2SD curve surpassed 4 mL at 10.2 years and -2SD curve at 13.7 years. Modeled ages at the attainment of 4 mL testicular volume based on ruler measurements were 9.7 years for +2SD curve, 11.5 years for median curve, and 13.6 years for -2SD curve. Ultrasonography-based volume of 1.3 mL corresponded with the median modeled orchidometer-based volume of 4 mL. In boys with unilateral cryptorchidism, ruler-based SD scores decreased during puberty in undescended testes, but not in descended testes. DISCUSSION AND CONCLUSION: The present study provides reference values for pubertal testicular volume measured with a ruler enabling an age-dependent assessment of testicular size. Comparison with measurements by an orchidometer and ultrasonography is also presented.

Outcome of immunosuppression in children with IgA vasculitis-related nephritis.

BACKGROUND AND HYPOTHESIS: IgA vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Treatment recommendations are, due to a lack of evidence, based on expert opinion resulting in variation. The aim of this study was to describe clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy proven IgAVN to identify prognostic risk factors and signals of treatment efficacy. METHODS: Retrospective data were collected on 1148 children with biopsy proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analyzed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow up. RESULTS: The median follow up was 3.7 years (IQR 2-6.2). At last follow up, 29% of patients had an eGFR < 90 ml/min/1.73m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second line immunosuppressive regimen to be superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow up. CONCLUSION: In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.

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.

Therapeutic exposures and pubertal testicular dysfunction are associated with adulthood milestones and paternity after childhood cancer.

BACKGROUND: Childhood cancer therapy may cause long-term effects. This cross-sectional study evaluated adulthood milestones in male childhood cancer survivors (CCS). METHODS: The study population comprised 252 male CCS with 6 to 42 years of survival diagnosed at the Children's Hospital in Helsinki (1964-2000) at the age of 0 to 17 years. Sex-, age-, and area of residence-matched population controls were randomly selected from the Finnish national registries. Data on moving away from the parental home, marital status, offspring, and adoption in CCS were compared with the population controls. We analyzed the influence of chemotherapy and radiation exposures and testicular dysfunction (ever nontestosterone-substituted serum follicle stimulating hormone >15 IU/L, luteinizing hormone >15 IU/L, testosterone <2 ng/mL (5 nmol/L), need of testosterone replacement therapy, or testicular volume <12 mL at the end of puberty) during pubertal maturation on long-term social outcomes. RESULTS: CCS moved away from their parental home as frequently as population controls (97.8% vs. 98.5%, p = .45). CCS were less likely to marry or live in a registered relationship (46.4% vs. 57.5%, p < .001), especially when diagnosed at a young age (<4 years). Among those married, the probability of divorce was similar between CCS and population controls (27.4% vs. 23.8%, p = .41). Survivors were less likely to sire a child (38.5% vs. 59.1%, p < .001) and more likely to adopt (2% vs. 0.4%, p = .015). Lower probability of paternity was associated with hematopoietic stem cell therapy, testicular radiation dose >6 Gy, pubertal signs of testicular dysfunction (nontestosterone-substituted serum follicle stimulating hormone >15 IU/L, luteinizing hormone  >15 IU/L, testosterone <2 ng/mL (5 nmol/L), or need of testosterone replacement therapy during puberty, or testicular volume <12 mL at the end of puberty) or azoospermia after puberty. CONCLUSIONS: This study emphasizes the value of pubertal monitoring of testicular function to estimate future probability of paternity. If no signs of dysfunction occurred during pubertal follow-up, paternity was comparable to population controls. Testicular radiation dose >6 Gy appeared to be the strongest risk factor for decreased paternity. PLAIN LANGUAGE SUMMARY: Treatment with intensive therapies, including hematopoietic stem cell therapy, testicular radiation dose >6 Gy, and signs of testicular dysfunction, during puberty are important risk factors for lower rates of fertility. Intensive therapies and testicular dysfunction itself do not similarly hamper psychosocial milestones in adulthood; cancer diagnosis at a very young age (<4 years) lower the probability of marriage. This study accentuates the importance of monitoring of pubertal development, emphasizing on testicular function, not only sperm analysis, to estimate future fertility among male childhood cancer survivors.

HLA-DQ and HLA-DRB1 alleles associated with Henoch-Schönlein purpura nephritis in Finnish pediatric population: a genome-wide association study.

BACKGROUND: The pathophysiology of Henoch-Schönlein purpura (HSP) is still unclear, but several findings suggest that genetic factors may influence disease susceptibility. We aimed to perform a genome-wide association study (GWAS) in pediatric HSP patients with an emphasis on severe HSP nephritis. METHODS: The study included 46 HSP patients, 42 of whom had undergone kidney biopsy. Forty-nine pediatric patients with an inflammatory bowel disease (IBD) served as an autoimmune disease control group while Finnish bone marrow and blood donors represented the general reference population (n = 18,757). GWAS was performed for HSP and IBD samples in a case-control manner against the reference population. The analysis also included imputation of human leukocyte antigen (HLA) alleles. RESULTS: GWAS analysis in HSP revealed several polymorphisms from the HLA region that surpassed the genome-wide significance level. Three HLA class II alleles were also significantly more frequent in HSP than in the reference population: DQA1*01:01, DQB1*05:01, and DRB1*01:01. Haplotype DQA1*01:01/DQB1*05:01/DRB1*01:01 occurred in 43.5% of HSP patients, whereas its frequency was 8.2% in IBD patients and 15.0% in the reference population. HSP patients with this haplotype showed similar baseline clinical findings and outcome as HSP patients negative for the haplotype. In IBD patients, no polymorphism or HLA allele appeared significant at the genome-wide level. CONCLUSIONS: Our results suggest that haplotype DQA1*01:01/DQB1*05:01/DRB1*01:01 is associated with susceptibility to HSP, but not with the severity of the kidney involvement. These HLA associations did not occur in IBD patients, suggesting that they are specific to HSP and not related to susceptibility to autoimmune diseases in general.

Prediction of renal outcome in Henoch-Schönlein nephritis based on biopsy findings.

BACKGROUND: In Henoch-Schönlein nephritis (HSN), a risk factor for unfavorable outcome is prolonged proteinuria, but the value of renal biopsies in prognosis assessment is debatable. METHODS: We evaluated serial renal biopsies from 26 HSN patients. Follow-up biopsy occurred at median 2.1 years after diagnostic biopsy. Patients formed two groups at the follow-up biopsy: patients without proteinuria (group I; n = 11) and with proteinuria (group II; n = 15). Biopsies underwent evaluation according to three classifications: International Study of Kidney Disease in Children (ISKDC), Oxford (MEST-C), and semiquantitative classification (SQC) including an activity and chronicity score. Analysis also included expression of pro-fibrotic (alpha-smooth muscle actin and vimentin) and inflammatory (P-selectin glycoprotein ligand-1) molecules in the diagnostic biopsy specimens. Definition of unfavorable outcome was active renal disease or reduced renal function at last follow-up. RESULTS: Between the biopsies, SQC chronicity score increased in 22 (85%) patients, whereas activity score and ISKDC grade decreased in 21 (81%) and 17 (65%), respectively. Of the MEST-C parameters, endocapillary proliferation (from 83 to 13%; p < 0.001) and crescents (from 63 to 25%; p = 0.022) showed significant reduction, and segmental glomerulosclerosis (from 38 to 79%; p = 0.006) significant increment. These changes occurred similarly in groups I and II. Expression of the pro-fibrotic and inflammatory molecules showed no clinically significant differences between groups I and II. None in group I and five (33%) patients in group II had unfavorable outcome (p = 0.053). CONCLUSIONS: Our results suggest that follow-up biopsies provide limited additional information to clinical symptoms in HSN outcome prediction.

Methylprednisolone or cyclosporine a in the treatment of Henoch-Schönlein nephritis: a nationwide study.

BACKGROUND: Optimal treatment of Henoch-Schönlein purpura nephritis (HSN) remains unclear. We evaluated outcome of pediatric HSN patients treated initially with either methylprednisolone (MP) or cyclosporine A (CyA) in Finland between 1996 and 2011. METHODS: Outcome of 62 HSN patients was evaluated by screening urine and blood samples (n = 51) or by collecting clinical parameters from medical charts until last follow-up visit (n = 11). Sixty (97%) patients had nephrotic-range proteinuria and/or ISKDC grade ≥ III before initial treatment. Patients were initially treated with either MP pulses (n = 42) followed by oral prednisone or with CyA (n = 20). Fifty-nine (95%) patients received angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers. RESULTS: Mean follow-up time was 10.8 years (range 3.2-21.2 years). One patient developed end-stage renal disease and another had decreased renal function (eGFR < 60 mL/min/1.73m2), both initially treated with MP (3%). Six patients (5 MP, 1 CyA) had eGFR between 60 and 89 mL/min/1.73m2 (10%). Eighteen patients (13 MP, 5 CyA) had proteinuria and/or hematuria (29%) and four of them had proteinuria > 0.5 g/day at end of follow-up. Sixteen (38%) MP-treated and two (10%) CyA-treated patients needed additional immunosuppressive treatment (RR 3.81, 95% CI 1.16-14.3, p = 0.035). Late initiation of treatment was associated with an increased risk for persistent proteinuria. CONCLUSIONS: Long-term outcome was relatively good in both treatment groups. However, since urinary abnormalities may persist or develop, long-term follow-up of HSN patients is mandatory. Early initiation of treatment had a favorable effect on proteinuria.

The ISKDC classification and a new semiquantitative classification for predicting outcomes of Henoch-Schönlein purpura nephritis.

BACKGROUND: Histological findings from primary kidney biopsies were correlated with patient outcomes in a national cohort of paediatric Henoch-Schönlein nephritis (HSN) patients. METHODS: Primary kidney biopsies from 53 HSN patients were re-evaluated using the ISKDC (International Study of Kidney Disease in Children) classification and a modified semiquantitative classification (SQC) that scores renal findings and also takes into account activity, chronicity and tubulointerstitial indices. The ISKDC and SQC classifications were evaluated comparatively in four outcome groups: no signs of renal disease (outcome A, n = 27), minor urinary abnormalities (outcome B, n = 18), active renal disease (outcome C, n = 3) and renal insufficiency, end-stage renal disease or succumbed due to HSN (outcome D, n = 5). For the receiver operating characteristic and logistic regression analyses, outcomes A and B were considered to be favourable and outcomes C and D to be unfavourable. The median follow-up time was 7.3 years. RESULTS: The patients with an unfavourable outcome (C and D), considered together due to low patient numbers, had significantly higher total biopsy SQC scores and activity indices than those who had a favourable one (groups A and B). The chronicity and tubulointerstitial indices differed significantly only between group C + D and group A. The difference in areas under the curve between the total biopsy SQC scores and ISKDC findings was 0.15 [p = 0.04, normal-based 95% confidence interval (CI) 0.007-0.29, bias-controlled 95% CI -0.004 to 0.28]. CONCLUSIONS: Our results suggest that the modified SQC is more sensitive than ISKDC classification for predicting the outcome in HSN cases.