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IgA nephropathy (IgAN) is the most common primary glomerulonephritis (GN) worldwide. The disease course fluctuates, and the most important challenge is the considerable variation in the time lag between diagnosis and the development of a hard clinical end point, such as end-stage kidney disease (ESKD). The reaction of renal tissue to damage resembles the common wound-healing response. One part of this repair in IgAN is the expansion of lymphatic vessels known as lymphangiogenesis. The aim of this work was to establish the prognostic value of the density of lymphatic vessels in the renal biopsy at the time of diagnosis, for predicting the risk of ESKD in a Spanish cohort of patients with IgAN.We performed a retrospective multicenter study of 76 patients with IgAN. The end point of the study was progression to ESKD. The morphometric analysis of lymphatic vessels was performed on tissue sections stained with antipodoplanin antibody.Density of lymphatic vessels was significantly higher in patients with IgAN with mesangial hypercellularity50%, segmental sclerosis, higher degrees of interstitial fibrosis, and tubular atrophy. Patients with more lymphatic vessels had significantly higher values of proteinuria and lower estimated glomerular filtration rate (eGFR). A density of lymphatic vessels ≥8 per mmThis study contributes to the understanding of the natural history of the progression to ESKD in patients with IgAN revealing the density of lymphatics vessels may optimize the prognostic value of the International IgA predicting tool to calculate the risk of ESKD, favoring the evaluation of new targeted therapies.

Background Activation of parietal–epithelial cells (PECs) with neo-expression of CD44 has been found to play a relevant role in the development of focal and segmental glomerulosclerosis (FSGS). The aim of this study was to analyse whether the expression of CD44 by PECs in biopsies of minimal change disease (MCD) is associated with the response to corticosteroids, with kidney outcomes and/or can be considered an early sign of FSGS. Methods This multicentric, retrospective study included paediatric and adult patients with MCD. Demographic, clinical and biochemical data were recorded, and biopsies were stained with anti-CD44 antibodies. The association between PECs, CD44 expression and the response to corticosteroids, and kidney outcomes were analysed using logistic, Kaplan–Meier and Cox regression analyses. Results A total of 54 patients were included: 35 (65%) Conclusions In patients with a light microscopy pattern of MCD, CD44-positive staining of PECs is associated with a higher prevalence of steroid resistance and worse kidney outcomes, and can be considered an early sign of FSGS.

Background and Aims To report the response to different treatments and the renal prognosis in a cohort of patients with corticosteroid-resistant nephrotic syndrome (CRNS). Method Retrospective observational study in patients with CRNS. For this, the results of the histology, the different treatment guidelines used in each case and the evolution of renal function were collected, determining the results in terms of remission and renal survival in the different groups. Results Of the initial cohort of 37 patients, 33 were included, excluding 4 patients with Finnish-type genetic CRNS. The mean age at diagnosis was 6.1 years. 54.5% were women. Regarding the initial biopsy, 45.5% corresponded to minimal changes (15 patients), 27.3% (9) focal and segmental glomerulosclerosis, 15.1% (5) diffuse mesangial proliferation and 12.1% (4) others. The mean follow-up was 53 months (3-115 months). 27 patients (84.4%) received cyclosporine (CyA), 66.7% (18) of them presented complete remission and 22.2% (6) partial response. Of the patients in complete remission, 33% had at least one relapse after 17 months of treatment (7–27 months). Rituximab was administered in 12 patients (37.5%), of which 7 had not previously responded to immunosuppressants. 100% of frequent relapsers presented complete remission after administration of Rituximab, although 3 had subsequent relapses (60%) after 21 months of treatment (12-34 months). 57% of the patients who did not respond to immunosuppressants did not respond to Rituximab either, with Ofatumumab allowing complete remission in one of them. When relating the results with the histology, we saw how the remission in minimal changes and diffuse mesangial proliferation was 100% and 80%, respectively, although it was 33.3% in focal and segmental glomerulosclerosis. Similarly, renal failure was more frequent in patients with focal segmental glomerulosclerosis (77.7%). Of the remissions (24; 72.7%), 3 were partial (9.1%) and 6 (18.2%) did not respond to any immunosuppressive treatment, with the need for kidney transplantation in 2 of them (6%) and with 1 deceased due to an infectious cause (3%). Conclusion Histology and, especially, focal and segmental glomerulosclerosis, play a prognostic role in the CRNS with a lower remission rate and a greater deterioration in renal function and the need for associated kidney transplantation.

Background and Aims Ofatumumab (OFA) is an anti-CD-20 monoclonal antibody useful in nephrotic syndrome refractory to conventional treatments and rituximab (RTX). Our objective is to evaluate the response and safety in patients with nephrotic syndrome (NS) treated with Ofatumumab. Method A prospective descriptive study of 2 years duration (2017-2019) in children with NS refractory to first-line therapies who received treatment with anti-CD20 monoclonal antibodies. To do this, we divided the cohort into 3 groups: Patients with corticodependent NS (CDNS) without response or with adverse effects associated with first-line treatment that preclude its use (Group 1); Corticosteroid-resistant SN (CRNS) (Group 2) and SN with post-transplant recurrence (Group 3). In them, the results of safety and remission rate were evaluated. Results Thirty-three patients (21 with SNCD, 11 with SNCR, and 1 with SN recurrence in transplantation) were included and administered anti-CD20. The male / female ratio was 2: 1 and the mean age at diagnosis was 5.2 years. 100% of the children (33) received RTX and 18.2% (6) OFA. The RTX achieved complete remission in 87.9% (29) and 48.3% of these did not present new relapses after 70 months of follow-up. 100% of Group 1 presented complete remission after RTX, although 52.4% (11) presented at least 1 relapse after 22.9 months (mean 2.5 relapses). In group 2, 72.72% (8) complete remission and 27.2% (3) partial, with persistent proteinuria. 36.4% (4) presented relapse after 17 months of treatment (mean 1 relapse). Of the 6 who received OFA, 83.3% presented complete remission (1 SNCR and 4 SNCD) and 1 patient (SNCD) presented relapse at 24 months (mean follow-up 1 year). The other case, a 13-year-old girl with recurrence of focal segmental glomerulosclerosis (FSGS) in kidney transplantation, presented partial remission after one year of treatment in association with immunoadsorption sessions. Regarding safety, adverse reactions occurred in 6% (2): allergic reaction with 2nd dose of RTX and cytokine release syndrome with 1st dose of OFA. Conclusion Ofatumumab in our series has proven to be an effective and safe drug in difficult-to-manage NS, achieving complete remission in 5 patients who had not previously responded to Rituximab

Background Data on the activation of the acute inflammatory response and its clinicopathological associations in idiopathic nephrotic syndrome (INS) are scarce and discordant. Objective To analyse the associations between the activation of the inflammatory response, the clinicopathological characteristics of disease and the response to treatment with steroids in patients with INS. Methods A total of 101 patients with INS due to minimal change disease (MCD; n = 44), focal segmental glomerulosclerosis (FSGS; n = 33) and membranous nephropathy (MN; n = 24) and 50 healthy controls were included. At diagnosis, we measured the levels of haemopexin (Hx), haptoglobin (Hgl), interleukin-6 (IL-6), soluble urokinase-type plasminogen activator receptor (suPAR), tumour necrosis factor-α (TNF-α), soluble IL-1 receptor, interferon-γ and C-reactive protein. We analysed their clinicopathological associations. In MCD and FSGS patients, we determined the association between the levels of these variables and steroid resistance. Results The levels of Hx, Hgl, TNF-α, suPAR and IL-6 were higher in patients with INS than in healthy controls, and were not associated with proteinuria, estimated glomerular filtration rate or serum albumin. In MCD and FSGS patients, Hx, Hgl, IL-6 and TNF-α levels were similar and significantly higher than in MN patients. In patients with MCD and FSGS, multivariate analyses identified FSGS and the levels of Hx, Hgl or IL-6 as independent predictors of steroid resistance. Conclusions The activation of the inflammatory response in patients with INS is heterogeneous and more prevalent in MCD or FSGS patients than in those with MN. In MCD and FSGS, elevated levels of Hx, Hgl or IL-6 are independently associated with steroid resistance.

Background and Aims Determine evolution of renal function in nephronophthisis patient cohort, prognosis and variability of clinical presentation. Method Retrospective observational study to determine evolution of renal function in our cohort(n=13) between 4.5-20 years affected by different syndromes associated with nephronophthisis complex in last 20 years. We compared clinical-analytical parameters to diagnosis with current ones, including needs for kidney transplantation and results of genetics. Results Chronic-Kidney-Disease (CKD) prevalence at diagnosis was between 0.9-8.5 years (mean 5.3 years), staging of CKD was: 30.7% stage 2, 15.38% stage 3a and 1 patient stage 3b. 23.07% in stages 4 and 5. 69.23% needs first kidney transplantation and even a second one 15.38%. The average age at first transplantation was 6.04 years(2-11.67 years). The mean age to enter in renal replacement therapy program was 1.3 years(0.1-3.67 years). Among non-transplant, from diagnosis to present its being 0.5-7.25 years(median, 4.24 years). Most frequent symptom at the onset of the disease was delay in weight gain and height(84.61%) and also in cognitive development(53.84%), followed by polyuria-polydipsia(46.15%) and other signs/symptoms such as ataxia, pigmentary retinitis, hepatic insufficiency or skeletal alterations. In fact, in up to 54% of cases, renal involvement was a casual finding. Even with this, the most frequent form of presentation was purely renal(38.46%), followed by Joubert's Syndrome(30.77%), RHYNS(15.38%), Senior-Loken(7.7%) and Maizner-Saldino(7.7%). Currently, calculated glomerular filtration rate ranges between30.2-90.21 ml/min/1.73 m2 among recipient, with majority in the CKD stages: 3a(56%) and in between 30-128 ml/min/1.73 m2 among non-transplant patients, with predominance CKD 2 (50%). Conclusion The prognosis of renal function in the short-medium term in nephronophthisis is unfortunate. The possible initial symptomatic renal silence, the need (>50%) of multidisciplinary management and the frequency of CKD advanced to the diagnosis make necessary the knowledge of the disease and its possible associations, as well as its active search.

Background and Aims Deficit of phosphomanomutase-(PMM2-CDG) is the most frequent congenital N-glycosylation defect, producing cerebellar syndrome with intellectual deficit and “stroke-like” episodes. It has been associated with renal alterations such as proteinuria, diffuse cortical hyperechogenicity and malformations. We evaluated efficacy, safety and renal repercussion of acetazolamide as a new therapeutic tool. Method First clinical trial in phase II including PMM2-CDG patients (5-21-years). First phase: 6 months treatment group with acetazolamide. Second phase: 5 weeks randomized withdrawal in responders (acetazolamide vs placebo), assessing renal functionality and effects of this medication. Dosing acetazolamide by 8 to 30mg/kg/day in 2-3 doses. Controls were performed at 3, 6, 14, 25 and 30 weeks determining acid-base balance, ionogram, renal function (creatinine) and Pr/Cr, Ca/Cr index and B2-microglobulin in first morning urine. All patients underwent in a bone densitometry study and renal ultrasound. Results 24 patients were included (mean age 12.3 ± 4.5 years). Bicarbonate levels and plasma pH were significantly lower at week 25(p Conclusion The efficacy of acetazolamide in the neurological symptoms of PMM2-CDG, due to an enzymatic stimulation mechanism mediated by acidosis, generates the possibility of chronic treatment with the drug in this group of patients, with possible renal adverse effects associated with long-term, overshadowing the skeletal and renal prognosis.

Background and Aims Identify hypocalcemia and hemodynamic disorders related to apheresis in pediatrics either complications in vascular access or related to anticoagulation and adverse reactions with replacement fluid. Method Prospective and descriptive study of 171 sessions for therapeutic apheresis in pediatrics during 2018. Inclusion criteria was based on the 2016 Clinical-Practice-of-Therapeutic-Apheresis-guidelines(ASFA). The apheresis technique was selected also based on the 2016 ASFA Guidelines and the expertise in our center. Results The 171 sessions were distributed as follows: 73% were immunoadsorption(IA), 12% were cytoapheresis, 10.5% were LDL-apheresis and 4.5% therapeutic plasma exchange(TPE). The average age was 9 years and 58% were women. 50, 33 and 17% were due to Nephrological, Neurological and Digestive pathology respectively. 83% of the nephrological indications correspond to a category I of the ASFA Guidelines, as well as 25% of the neurological indications and all indications of Digestive pathology correspond to a category II. 58, 25 and 17% used temporary catheter, permanent catheter and needles respectively. Only one patient is accidentally removed from the temporary jugular catheter and it has not been related to vascular access or by the apheresis technique itself. Sixty-six percent had individual anticoagulation with citrate/calcium plus heparin and the remaining 33%, only once. Any case of bleeding related to catheter or others. Only 3 sessions of IA in the hypocalcemia objective, being symptomatic in only one of them. Of all 8 sessions of TPE, we performed 6 with frozen fresh plasma as replacement fluid with no adverse reactions. Conclusion The apheresis techniques in pediatrics had been presented with few complications in our center, none derived from vascular access, anticoagulation, infections or adverse effects due to use of replacement fluid. The training of medical and nursing staff is essential to identify risk situations. The use of protocols and international guidelines ensure safety in pediatrics.

Ciliopathies are a wide and heterogeneous group of diseases affecting intraflagellar transport. Among them, Mainzer-Saldino syndrome (MSS) shows phalangeal cone-shaped epiphysis, renal disease and retinal involvement. Short stature, cerebellar ataxia and hepatic fibrosis might also be found. IFT140 is the most commonly reported mutation in MSS. We will report on the case of a patient with a clinical diagnosis of Mainzer-Saldino syndrome due to IFT144 dysfunction. This mutation has not been previously related to MSS but it has been found in other ciliopathies and both syndromic and non-syndromic retinitis pigmentosa. At birth our patient showed trigonocephaly, early progressive renal failure requiring transplant, intrahepatic biliary duct dilation, cone-shaped epiphyses, growth retardation and retinitis pigmentosa with mild ophthalmic impairment. The best corrected visual acuity reached 0.15/0.22 LogMAR. The posterior pole showed abnormal macular reflex, mild vascular attenuation in the periphery and diffuse pigmentary changes. Autofluorescence showed bull's eye signal increase. Computerized optic tomography assessed the absence of external retinal layers in the extrafoveal macula. In conclusion, IFT144 genetic study may be involved in MSS and thus must be considered for diagnosis. Mild ophthalmic symptomatology despite early onset retinitis pigmentosa in the context of MSS has been found in this case caused by IFT144 mutation.

This corrects the article DOI: 10.1038/pr.2015.243.

Segmental renal infarction (SRI) is a rare condition that causes renovascular hypertension (RVH), which accounts for 8-10% of all causes of pediatric hypertension. We report the clinical course of two children with idiopathic SRI who suffered severe arterial hypertension associated with hyponatremia. Hypertension was diagnosed during the study of hematuria in the first case and due to a hypertensive emergency in the second case. The etiology was found to be renovascular in both patients, involving the occlusion of small renal arteries and causing SRI. Our first patient was treated with partial nephrectomy, and the second patient was treated with antihypertensive medication given the impossibility of removing the infarcted renal area. The occlusion of small renal arteries is a rare disease of unknown origin in which the gold standard for diagnosis is selective renal arteriography. The definitive treatment is surgical segmentectomy. If segmentectomy is not feasible because of the localization of the infarcted area, as in our second patient, medical treatment is required. In view of the importance of RVH in children and the rareness of the particular etiology here reported (SRI), a review of the literature was done.

Journal Article; Research Support, Non-U.S. Gov't; Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive tubular disorder characterized by excessive renal magnesium and calcium excretion and chronic kidney failure. This rare disease is caused by mutations in the CLDN16 and CLDN19 genes. These genes encode the tight junction proteins claudin-16 and claudin-19, respectively, which regulate the paracellular ion reabsorption in the kidney. Patients with mutations in the CLDN19 gene also present severe visual impairment. Our goals in this study were to examine the clinical characteristics of a large cohort of Spanish patients with this disorder and to identify the disease causing mutations. We included a total of 31 patients belonging to 27 unrelated families and studied renal and ocular manifestations. We then analyzed by direct DNA sequencing the coding regions of CLDN16 and CLDN19 genes in these patients. Bioinformatic tools were used to predict the consequences of mutations. Clinical evaluation showed ocular defects in 87% of patients, including mainly myopia, nystagmus and macular colobomata. Twenty two percent of patients underwent renal transplantation and impaired renal function was observed in another 61% of patients. Results of the genetic analysis revealed CLDN19 mutations in all patients confirming the clinical diagnosis. The majority of patients exhibited the previously described p.G20D mutation. Haplotype analysis using three microsatellite markers showed a founder effect for this recurrent mutation in our cohort. We also identified four new pathogenic mutations in CLDN19, p.G122R, p.I41T, p.G75C and p.G75S. A strategy based on microsequencing was designed to facilitate the genetic diagnosis of this disease. Our data indicate that patients with CLDN19 mutations have a high risk of progression to chronic renal disease. Yes