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

BACKGROUND: Immunoglobulin A vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Due to a lack of evidence, treatment recommendations are based on expert opinion, resulting in variation. The aim of this study was to describe the clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy-proven IgAVN in order 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 analysed 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 (interquartile range 2-6.2). At last follow-up, 29% of patients had an eGFR <90 mL/min/1.73 m2, 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 being 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.

Survival of endodontically treated teeth in public dental service in Northern Finland: a practise-based register study.

OBJECTIVE: The aim of this study was to explore the factors associated with the survival of root canal treated teeth in a practise-based study setting in a 5-year period. MATERIAL AND METHODS: This retrospective study used data from the electronic patient registration system of the public dental services of the City of Oulu, Finland. The inclusion criteria for this study were patients aged ≥ 20 years who had root canal treatment (RCT) that was initiated in 2014. One RCT per patient was included in the study. A total of 713 patients met the inclusion criteria. The outcome variable for this study was the extraction of the RCT tooth during the 5-year period. Explanatory variables included age, diagnosis, tooth type (incisive, canine, premolar, molar), RCT technique (manual, motorized), time from RCT initiation to final restoration and type of final restoration (composite, glass ionomer, fixed dental prosthesis). To evaluate the association between the outcome variable and explanatory variables, Cox regression analyses were performed. RESULTS: The overall survival rate was 91%. The middle-aged (40-59-years-old) and the oldest (60 and older) patients had a two-fold risk of extraction compared to younger (20-40-years-old) patients. Similarly, a short length of time from RCT initiation to final restoration (0-14 days) resulted in a nearly three times higher risk of extraction compared to a longer period (≥ 90 days). CONCLUSIONS: The 5-year survival rate of RCTs seems high. Extractions were more common among patients over 40 years of age and if the RCT was completed shortly after its initiation.

Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings.

Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency due to the homozygous PCK1 variant has recently been associated with childhood-onset hypoglycemia with a recognizable pattern of abnormal urine organic acids. In this study, 21 children and 3 adult patients with genetically confirmed PEPCK-C deficiency were diagnosed during the years 2016 to 2019 and the available biochemical and clinical data were collected. All patients were ethnic Finns. Most patients (22 out of 24) had a previously published homozygous PCK1 variant c.925G>A. Two patients had a novel compound heterozygous PCK1 variant c.925G>A and c.716C>T. The laboratory results showed abnormal urine organic acid profile with increased tricarboxylic acid cycle intermediates and inadequate ketone body production during hypoglycemia. The hypoglycemic episodes manifested predominantly in the morning. Infections, fasting or poor food intake, heavy exercise, alcohol consumption, and breastfeeding were identified as triggering factors. Five patients presented with neonatal hypoglycemia. Hypoglycemic seizures occurred in half of the patients (12 out of 24). The first hypoglycemic episode often occurred at the age of 1-2 years, but it sometimes presented at a later age, and could re-occur during school age or adulthood. This study adds to the laboratory data on PEPCK-C deficiency, confirming the recognizable urine organic acid pattern and identifying deficient ketogenesis as a novel laboratory finding. The phenotype is expanded suggesting that the risk of hypoglycemia may continue into adulthood if predisposing factors are present.

Long-term outcome of biopsy-proven idiopathic tubulointersitial nephritis with or without uveitis in children-a nationwide follow-up study.

BACKGROUND: Only a few studies reporting the long-term outcome of children with idiopathic tubulointerstitial nephritis (TIN) and uveitis syndrome (TINU) are available. We studied the long-term kidney and ocular outcome in a nationwide cohort of children with TIN or TINU. METHODS: All patients followed up for a minimum of 1 year by a paediatrician and an ophthalmologist were enrolled. The data on plasma creatinine (P-Cr), estimated glomerular filtration rate (eGFR), proteinuria, hypertension and uveitis were collected retrospectively. RESULTS: Fifty-two patients were studied. Median age at time of diagnosis was 13.1 (1.8-16.9) years and median follow-up time was 5.7 (1.1-21.2) years. Forty-five (87%) patients were initially treated with glucocorticoids. The median of the maximum P-Cr was 162 µmol/l (47-1,016) and that of eGFR 47 ml/min/1.73m2 (8-124). Uveitis was diagnosed in 33 patients (63%) and 21 (40%) patients developed chronic uveitis. P-Cr normalised in a median of 2 months. Eleven (21%) patients had nephritis recurrence during or after discontinuation of glucocorticoids. At the latest follow-up, 13 (25%) patients had eGFR < 90 ml/min/1.73m2 (median 83; 61-89 ml/min/1.73m2). Six patients had tubular proteinuria; all presented with TIN without uveitis. Seven (13%) patients were hypertensive. Eleven (21%) patients had uveitis. One patient developed uraemia and was later transplanted. CONCLUSIONS: Our study questions the previously reported good long-term kidney and ocular outcome of patients with TIN/TINU. Decreased kidney function and/or ocular co-morbidities may persist for several years; thus, both kidney and ocular follow-up for at least 1 year is warranted. A higher resolution version of the Graphical abstract is available as Supplementary information.

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.

Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli in children: incidence, risk factors, and clinical outcome.

BACKGROUND: Hemolytic uremic syndrome (HUS) is a multisystemic disease. In a nationwide study, we characterized the incidence, clinical course, and prognosis of HUS caused by Shiga toxin (Stx)-producing Escherichia coli (STEC) strains with emphasis on risk factors, disease severity, and long-term outcome. METHODS: The data on pediatric HUS patients from 2000 to 2016 were collected from the medical records. STEC isolates from fecal cultures of HUS and non-HUS patients were collected from the same time period and characterized by whole genome sequencing analysis. RESULTS: Fifty-eight out of 262 culture-positive cases developed verified (n = 58, 22%) STEC-HUS. Another 29 cases had probable STEC-HUS, the annual incidence of STEC-HUS being 0.5 per 100,000 children. Eleven different serogroups were detected, O157 being the most common (n = 37, 66%). Age under 3 years (OR 2.4), stx2 (OR 9.7), and stx2a (OR 16.6) were found to be risk factors for HUS. Fifty-five patients (63%) needed dialysis. Twenty-nine patients (33%) developed major neurological symptoms. Complete renal recovery was observed in 57 patients after a median 4.0 years of follow-up. Age under 3 years, leukocyte count over 20 × 109/L, and need for dialysis were predictive factors for poor renal outcome. CONCLUSIONS: Age under 3 years, stx2, and stx2a were risk factors for HUS in STEC-positive children. However, serogroup or stx types did not predict the renal outcome or major CNS symptoms.

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.

FOXP3+ T cells are present in kidney biopsy samples in children with tubulointerstitial nephritis and uveitis syndrome.

BACKGROUND: Tubulointerstitial nephritis (TIN) is an inflammatory disease of unknown pathogenesis. To evaluate a possible role of regulatory T cells (Tregs) in the pathophysiology of TIN with (TINU) and without uveitis, we investigated the presence and quantity of FOXP3+ T regulatory lymphocytes in diagnostic kidney biopsies from pediatric patients. METHODS: A total of 33 patients (14 TIN and 19 TINU) were enrolled. The quantity of CD4+, FOXP3+ and double-positive T cells in formalin-fixed kidney biopsies was determined using double label immunohistochemistry with anti-human CD4 and FOXP3 antibodies. RESULTS: FOXP3 staining was successful in all 33 patients. In patients with chronic uveitis, the density of FOXP3+ cells was significantly lower (p = 0.046) than in TIN patients without uveitis or with uveitis lasting <3 months. CD4+ staining was successful in 23 patients. The density of all lymphocytes (CD4+, CD4+FOXP3+ and FOXP3+ cells) was significantly lower (p = 0.023) in patients with chronic uveitis than in other patients. CONCLUSIONS: FOXP3+ T cells are present in kidney biopsy samples from TIN and TINU patients. In patients with chronic uveitis, the density of FOXP3+ T cells is significantly lower than in other patients, suggesting a different pathomechanism for these clinical conditions.

Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal pattern of urine metabolites and liver dysfunction.

Clinical and laboratory data were collected from three Finnish patients including a sibling pair and another unrelated child with unexplained childhood hypoglycemia. Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis. Exome sequencing was performed for the patients and their parents. A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all affected individuals. COS-1 cells transfected with mutant PCK1 transcripts were used to study the pathogenic nature of the detected variant. The COS-1 transfected cells showed the mutant gene to be incapable of producing a normally functioning cytosolic phosphoenolpyruvate carboxykinase (PEPCK) enzyme. This report further delineates the clinical phenotype of isolated cytosolic PEPCK deficiency and offers a metabolic pattern helping to recognize these patients. Cytosolic PEPCK deficiency should be considered in the differential diagnosis of children presenting with hypoglycemia, hepatic dysfunction and elevated tricarboxylic acid intermediates in urinary organic acid analysis.

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.

Novel NPHS2 variant in patients with familial steroid-resistant nephrotic syndrome with early onset, slow progression and dominant inheritance pattern.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a common cause of end-stage renal disease in children but also occurs as an adult-onset condition. In a subset of SRNS patients, pathogenic variants are found in genes coding for podocyte foot process proteins. The aim of this study was to define the role of pathogenic variants in Finnish patients with familial and sporadic SRNS. METHODS: We analyzed SRNS-related genes NPHS1, NPHS2, NEPH1, ACTN4, TRPC6, INF2, WT1, CD2AP, LAMB2, and PLCE1 for disease-causing variants using direct sequencing of exons and intron/exon boundaries in all members of a family with dominant SRNS with early onset and slow progression to end-stage renal disease. We carried out a whole genome sequencing in two affected and two healthy family members. The function of found podocin variant was studied using co-immunoprecipitation and immunohistochemistry. Podocyte gene sequences were analyzed in a cohort of Finnish non-familial SRNS patients. RESULTS: A heterozygous de novo deletion, c.988_989delCT in NPHS2, was found in all affected family members and in none of their healthy relatives, non-familial patients or controls. No other SRNS-related gene variant, coding or non-coding co-segregated with the disease phenotype in the family. While the truncated podocin remained able to bind nephrin, the expression of nephrin was fragmented and podocin expression reduced. The gene analysis of the non-familial SRNS patients revealed few variants. CONCLUSION: The role of podocin variants in nephrotic syndrome may be more varied than previously thought.

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.

Tubulointerstitial nephritis and uveitis syndrome in children: a prospective multicenter study.

PURPOSE: To evaluate the occurrence and characteristics of uveitis related to tubulointerstitial nephritis (TIN) in children. DESIGN: Prospective, observational, multicenter, partly placebo-controlled treatment trial. PARTICIPANTS: Nineteen children with a biopsy-proven TIN. METHODS: Patients were treated with prednisone or followed without treatment. In addition to the nephrologic evaluations, the prospective follow-up included structured ophthalmological examinations at the onset of TIN and at 3 and 6 months after the diagnosis. MAIN OUTCOME MEASURES: Occurrence, clinical features, and outcome of uveitis. RESULTS: Some 84% (16/19) of the patients had uveitis, 83% (5/6) in the nontreatment group and 82% (9/11) in the prednisone-treated group. The remaining 2 patients, originally in the nontreatment group, were switched to the prednisone group after 2 weeks. Both of them developed uveitis. Altogether, 3 patients developed uveitis during prednisone treatment and 2 patients showed worsening of uveitis despite the systemic corticosteroid. Some 50% (8/16) of the patients with uveitis presented with no ocular symptoms; 88% (14/16) of the patients had a chronic course of uveitis. Two patients were diagnosed with uveitis before nephritis; nephritis and uveitis were diagnosed within 1 week from each other in 7 patients, and uveitis developed 1 to 6 months after the diagnosis of TIN in 7 patients. CONCLUSIONS: There was no statistically significant difference in the occurrence of uveitis in patients with TIN in the prednisone and nontreatment groups. In this study, the occurrence of uveitis associated with TIN was considerably higher than previously reported. Uveitis related to TIN may develop late and is often asymptomatic. The ophthalmological follow-up of all patients with TIN is warranted for at least 12 months starting with 3-month intervals. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any material discussed in this article.

Prednisone in the treatment of tubulointerstitial nephritis in children.

BACKGROUND: Patients with tubulointerstitial nephritis (TIN) may develop permanent renal impairment. However, there are no prospective studies available on the treatment of TIN. METHODS: The effect of prednisone in the treatment of TIN was evaluated in a total of 17 patients who received prednisone or who were followed up without medication. The patient group was subdivided based on the initial plasma creatinine (PCr), below or above 150 µmol/l. RESULTS: All prednisone-treated patients had normal plasma creatinine (PCr) after 1 month of treatment (median 59.1 [45-85] µmol/l) whereas only 50 % of patients in the non-treatment group had normal creatinine (median 81.0 [42-123] µmol/l) at the same time point (p = 0.025). During 6 months' follow-up, PCr decreased in all patient groups; however, it decreased significantly only in prednisone-treated patients with baseline PCr >150 µmol/l (p < 0.001). At the end of follow-up, no difference in PCr, glomerular filtration rate (GFR), or low molecular weight (LMW) proteinuria could be found between the study groups. A considerable number of patients in both groups had subnormal GFR and/or persistent LMW proteinuria at the 6-month follow-up visit. Eighty-two percent of the patients had uveitis. CONCLUSIONS: Prednisone speeds up the recovery from renal symptoms of TIN, especially in patients with severe nephritis. The renal function did not differ significantly between prednisone and control patients after 6 months' follow-up.

Transmembrane collagen XVII is a novel component of the glomerular filtration barrier.

The kidney filtration barrier consists of the capillary endothelium, the glomerular basement membrane and the slit diaphragm localized between foot processes of neighbouring podocytes. We report that collagen XVII, a transmembrane molecule known to be required for epithelial adhesion, is expressed in podocytes of normal human and mouse kidneys and in endothelial cells of the glomerular filtration barrier. Immunoelectron microscopy has revealed that collagen XVII is localized in foot processes of podocytes and in the glomerular basement membrane. Its role in kidney has been analysed in knockout mice, which survive to birth but have high neonatal mortality and skin blistering and structural abnormalities in their glomeruli. Morphometric analysis has shown increases in glomerular volume fraction and surface densities of knockout kidneys, indicating an increased glomerular amount in the cortex. Collagen XVII deficiency causes effacement of podocyte foot processes; however, major slit diaphragm disruptions have not been detected. The glomerular basement membrane is split in areas in which glomerular and endothelial basement membranes meet. Differences in the expression of collagen IV, integrins α3 or ß1, laminin α5 and nephrin have not been observed in mutant mice compared with controls. We propose that collagen XVII has a function in the attachment of podocyte foot processes to the glomerular basement membrane. It probably contributes to podocyte maturation and might have a role in glomerular filtration.

Outcome of Henoch-Schönlein purpura 8 years after treatment with a placebo or prednisone at disease onset.

BACKGROUND: Corticosteroids have been shown not to prevent the development of Henoch-Schönlein nephritis. However, long-term follow-up data are scarce. METHODS: The long-term outcome of patients in a randomized placebo-controlled prednisone study was evaluated 8 years later with a health questionnaire completed by 160/171 (94%) patients and by urine and blood pressure screening (138/171, 81%). RESULTS: Twelve patients had hematuria and/or proteinuria and seven had hypertension. The patients with nephritis at onset of Henoch-Schönlein purpura (HSP) had an increased risk of hypertension and/or urine abnormalities (odds ratio 3.6, p = 0.022, 95% confidence interval 1.3-10.0). There were no differences between the prednisone and placebo groups. Recurrences of purpura were reported by 15 patients, with some recurrences continuing for 10 years. All five reported pregnancies were complicated by proteinuria. Four patients presented with hematuria and/or proteinuria at the control visit, and four had hypertension. Of these, two had a decreased estimated glomerular filtration rate. CONCLUSIONS: HSP has a good long-term prognosis in unselected patients, although skin relapses with/without late-onset nephritis may occur, even a decade after the initial disease. Urine and blood pressure abnormalities 8 years after HSP are associated with nephritis at its onset. Early prednisone treatment does not affect the outcome and should not be routinely used.

Renal Phenotype in Mitochondrial Diseases: A Multicenter Study.

Aims: This study aimed to investigate associations between renal and extrarenal manifestations of mitochondrial diseases and their natural history as well as predictors of renal disease severity and overall disease outcome. The secondary aim was to generate a protocol of presymptomatic assessment and monitoring of renal function in patients with a defined mitochondrial disease. Methods: A multicenter, retrospective cohort study was performed by the Mitochondrial Clinical and Research Network (MCRN). Patients of any age with renal manifestations associated with a genetically verified mitochondrial disease were included from 8 expert European centers specializing in mitochondrial diseases: Gothenburg, Oulu, Copenhagen, Bergen, Helsinki, Stockholm, Rotterdam, and Barcelona. Results: Of the 36 patients included, two-thirds had mitochondrial DNA-associated disease. Renal manifestations were the first sign of mitochondrial disease in 19%, and renal involvement was first identified by laboratory tests in 57% of patients. Acute kidney injury occurred in 19% of patients and was the first sign of renal disease in the majority of these. The most common renal manifestation was chronic kidney disease (75% with stage 2 or greater), followed by tubulopathy (44.4%), the latter seen mostly among patients with single large-scale mitochondrial DNA deletions. Acute kidney injury and tubulopathy correlated with worse survival outcome. The most common findings on renal imaging were increased echogenicity and renal dysplasia/hypoplasia. Renal histology revealed focal segmental glomerulosclerosis, nephrocalcinosis, and nephronophthisis. Conclusion: Acute kidney injury is a distinct renal phenotype in patients with mitochondrial disease. Our results highlight the importance to recognize renal disease as a sign of an underlying mitochondrial disease. Acute kidney injury and tubulopathy are 2 distinct indicators of poor survival in patients with mitochondrial diseases.

Clinical outcome and occurrence of uveitis in children with idiopathic tubulointerstitial nephritis.

Acute idiopathic tubulointerstitial nephritis (TIN) is considered a condition with a good long-term prognosis. However, there is evidence that some patients develop permanent renal impairment. The aim of this study was to evaluate the clinical characteristics of TIN at the time of diagnosis in children and determine whether the findings upon presentation predict renal outcome. The clinical data and biopsy findings from 26 children with idiopathic TIN admitted to four Finnish university hospitals were analyzed retrospectively. Twenty-five patients (96%) manifested renal insufficiency. After the mean follow-up time of 2.75 years (SD 2.5; 0.9-13.5), 4 patients (15%) had permanent renal insufficiency and 8 patients (31%) had persistent low-molecular weight proteinuria. Uveitis was found in 12 patients (46%). Four of these patients (33%) developed chronic uveitis. Our analysis showed that none of the laboratory or biopsy findings upon presentation prognosticated renal outcome. No correlation between renal disease and uveitis could be found either. The occurrence of uveitis among TIN patients was higher than previously reported. Uveitis may develop late and without recurrence of renal dysfunction. Therefore, follow-up by a pediatrician and by an ophthalmologist is warranted in children with acute TIN for at least 12 months from diagnosis.