KEY POINTS:Single-molecule real-time sequencing with the PacMUC1 script resolved exact MUC1 variable tandem repeat structure and full allelic variation. In 300 individuals, the protocol identified 215 distinct MUC1 tandem repeat alleles with 80 repeat units and nine frameshift mutation types. Probe extension assay identified 90% of families with frameshift mutations, detection of frameshifted mucin-1 aided genetically unresolved cases. BACKGROUND:ADTKD- MUC1 is caused by frameshift mutations in the MUC1 gene, producing a frameshifted neoprotein (MUC1fs) toxic to kidney cells. The gene's variable number of tandem repeats (VNTR), with approximately 80% guanine/cytosine content, has made it largely inaccessible to standard short-read sequencing, leaving the reference sequence and natural variation poorly defined and complicating mutation detection. METHODS:Using single-molecule real-time (SMRT) sequencing, we characterized MUC1 VNTR in 300 individuals, including 279 from 143 families suspected of having ADTKD- MUC1 , assessing VNTR length, repeat structure, and frameshift mutations. Results were compared with the Clinical Laboratory Improvement Amendments-approved probe-extension assay, detecting the prevalent 59dupC mutation, and with MUC1fs immunohistochemistry, which detects the pathogenic protein independent of the underlying genomic change. RESULTS:We identified 215 unique VNTR alleles composed of 80 distinct repeat units, 46 (58%) of which were novel, and nine distinct frameshift mutations present on 52 mutated alleles. Overall, MUC1 frameshift mutations were identified in 71 of 143 families (50%) with suspected ADTKD- MUC1 , comprising 135 affected individuals (48%). The SMRT assay outperformed the probe-extension assay by identifying frameshift mutations in two families with previously inconclusive results and in eight additional families whose mutations were undetectable by the probe-extension design. When successful, SMRT assay showed 100% concordance with probe-extension assay at the family level and 98% at the individual level, with discordance attributable to allelic dropout inherent to both long-range PCR amplification and long-read sequencing. Analysis of the mutational spectrum confirmed 59dupC as the most prevalent mutation, affecting approximately 90% of families, while the other eight mutation types occurred at most twice. CONCLUSIONS:The SMRT assay outperformed the Clinical Laboratory Improvement Amendments-approved probe-extension assay by detecting essentially all VNTR-associated frameshift mutations. The probe-extension assay identified approximately 90% of affected families. MUC1fs immunohistochemistry added diagnostic value in genetically unresolved cases by detecting the pathogenic protein independent of the underlying mutation.

Granulomatous interstitial nephritis (GIN) is a rare form of tubulointerstitial nephritis being generally associated to infection, drugs or immune mediated disease. Sarcoidosis is the most frequent disease responsible for GIN, but conversely granulomatous inflammation can also be associated with immunodeficiency. Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by impaired B cell differentiation with defective immunoglobulin production. It is the most prevalent form of significant antibody deficiency affecting both children and adults and can present later in life. Besides recurrent infections, immune dysregulation seen in CVID can lead to autoimmunity, presenting with cytopenia and granulomatous infiltrations of several organs, namely the lungs, liver and lymphoid organs. Kidney involvement is rare in CVID and GIN has been reported in less than 5 cases worldwide to our knowledge. We report the case of a 58-year-old man with a past medical history of type 2 diabetes mellitus, hypertension and of two major skin infections (arm infection with compartment syndrome in childhood and Fournier gangrene at adult age). He presented with anorexia, asthenia, nausea and weight loss (12 Kg in the previous 3 months). Physical examination was unremarkable. Laboratory workup identified leucopenia, lymphopenia, rapidly progressive renal insufficiency (Scr 0.98 mg/dL to 3.5 mg/dL in 2 months), with bland urinary sediment, and urinary protein-to-creatinine ratio of 512.4 mg/g. Additionally, we identified hypercalcemia 11 mg/dL (normal PTH), normal erythrocyte sedimentation rate and increased angiotensin converting enzyme level (ACE 282 U/L). Auto-antibodies screening and complement were normal. Virology (including viral load of EBV and CMV) and tuberculosis quantiferon were also negative. Protein electrophoresis revealed hypoproteinemia with normal albumin and hypogammaglobulinemia and monoclonal gammopathy was excluded. IgG (374 mg/dL) and IgM (17 mg/dL) were below normal range, with normal IgA level. IgG 1 and IgG 2 sub-classes were also markedly decreased as also specific antibodies titters for pneumococcus. Vaccine response was not tested because of the urgent need to begin immunosuppressive treatment. Peripheral blood lymphocyte immunophenotyping showed a slight decrease in B cell proportion (CD19: 4.2%), and analysis of other B and T cell subpopulations in the peripheral blood was not possible due to the urgent need of treatment. Imagiology workup with CT scan revealed multiple adenopathies, lung parenchyma with septal diffuse and irregular thickening and hepatosplenomegaly. Renal biopsy was performed and revealed tubulointerstitial nephritis with noncaseous granulomas. Lung function was normal and broncofibroscopy with biopsy revealed also noncaseous granulomas and excluded infection or neoplasm. There was absence of B cells in the in the bronchoalveolar lavage. Following multidisciplinary discussion with immunoallergology and pneumology, CVID was considered and presented with related complications as granulomatous–lymphocytic infiltration, in the lungs and kidneys, cytopenias, hepatosplenomegaly and persistent diffuse adenopathies, making sarcoidosis diagnosis less probable. Considering immunodeficiency, intravenous immunoglobulin (IVIg) was added to glucocorticoid (GC) therapy (prednisolone 1 mg/kg) with significant pulmonary improvement, decrease in adenopathy size, renal function recovery (Scr 1.2 mg/dL without proteinuria 1 month later) and normalization of ACE and calcium. Although GIN is usually associated with sarcoidosis, finding primary hypogammaglobulinemia with defective specific antibody production should raise the suspicion of an underlining immunodeficiency. Although GC are used as first line treatment for both, IVIg replacement treatment is essential to avoid potential severe infections. As such and as our case underlines, evaluation of immunoglobulin serum levels is of paramount importance before considering immunosuppressive treatment, especially in granulomatous disease.

Background:ADTKD-MUC1 is caused by frameshift mutations in MUC1 gene that produce a frameshifted protein (MUC1fs) toxic to kidney cells. The gene's variable number of tandem repeats (VNTR), with high GC content, makes it largely inaccessible to standard sequencing. As a result, both the reference sequence and natural variation in this region remain poorly defined, complicating mutation detection and data interpretation. Standard methods also fail to pinpoint the exact VNTR unit affected, limiting insight into mutation mechanisms and genotype-phenotype correlations. Methods:We employed Single Molecule, Real-Time (SMRT) sequencing and characterized the genomic sequence of MUC1 in 300 individuals including 279 individuals from 143 families suspected of having ADTKD-MUC1. We compared these results to those obtained using the CLIA-approved mass spectrometry-based probe extension (PE) assay, which specifically detect the most prevalent 59dupC mutation. We correlated the structural features of the MUC1 VNTR with the rate of kidney function decline in affected individuals. Results:We identified MUC1 consensus sequences for 205 unique VNTR alleles, with 9 distinct types of frameshift mutations present on 52 distinct mutated VNTR alleles. MUC1 frameshift mutations were identified in 71 of 143 families (50%) with suspected ADTKD, comprising 135 genetically affected individuals (48%). The SMRT assay exhibited complete concordance and revealed that the PE assay is capable of detecting frameshift mutations in approximately 85% of affected families. The constellation of VNTR structures supports a genotype-progression model, in which fast progressors exhibit a significantly lower number of repeat units on the wild-type allele and a higher number of repeats on the mutation-bearing allele, including an increased number of frameshifted repeat units. Conclusions:SMRT sequencing outperforms current diagnostic methods for ADTKD-MUC1 and reveals the prognostic value of VNTR structures. Although their contribution to disease progression is modest (~6% variance explained), it remains biologically and clinically meaningful.

Type IV collagen is a key structural component of the glomerular basement membrane (GBM). Variants in COL4A3, COL4A4, and COL4A5 genes disrupt GBM integrity, leading to genetic kidney diseases (KD) such as Alport syndrome and thin basement membrane nephropathy. These variants impair collagen assembly, leading to hematuria, proteinuria, and progressive kidney dysfunction. Recently, an expanded spectrum of clinical phenotypes has been attributed to type IV collagen variants, namely proteinuria, focal and segmental glomerulosclerosis and cystic KD. Advances in molecular genetics are improving understanding of the genetic and phenotypic spectrum of type IV collagen-related nephropathies. Genetic and phenotypic characterization of the COL4 renal disease cohort of patients in the adult Nephrogenetics’ Clinic of a tertiary-level care hospital, between 2014 and 2024. Genetic testing was performed through next generation sequencing gene panels based on whole exome sequencing. Of the 332 screened patients, 41 patients (27 families) presented variants in the type IV collagen gene. Variants were reported in COL4A3 (n = 14), COL4A5 (n = 14), COL4A4 (n = 11), COL4A1 (n = 3) and COL4A6 (n = 1). Two patients had more than one identified mutation. According to American College of Medical Genetics and Genomics criteria, variants were classified as follows: 7 pathogenic (P); 23 likely pathogenic (LP); 11 variants of uncertain significance (VUS) and 2 as likely benign. A total of 30 patients had P/LP variants: 10 in COL4A5 (heterozygous), 1 COL4A5 heterozygous deletion, 11 in COL4A3 (10 heterozygous, 1 homozygous), 8 in COL4A4 (heterozygous). The majority of patients were female (n = 24), and mean age at diagnosis was 48.7 ± 15.8 years. Most (n = 27) had positive family history for CKD. The most common renal presentations included chronic kidney disease (n = 23) and hematuria and/or proteinuria in the remaining patients. Six patients had kidney cysts. Hypoacusia was reported in 6 patients, and one had reduced visual acuity. Of note, we highlight co-existing variants in other genes, in addition to P/LP COL4 variants: heterozygous CFHR3/CFHR1 deletion (2 patients); NADSYN1 LP variant (1 patient), CC2D2A LP variant (1 patient), MYH9 VUS (1 patient), KIAA0586 LP variant (1 patient). Genetic testing for mutations in type IV collagen is crucial for early diagnosis, accurate classification, and prognostic assessment of hereditary kidney diseases. Genetic diagnosis also enables personalized Nephrology care in the era of precision medicine, namely for actionable genes as COL4.

Background Prognostic assessment after starting hemodialysis is challenging, with mortality in the first year estimated to be 15%. Clark et al. developed the Recovery and Death Outcome risk score, which accurately predicted the likelihood of renal recovery to dialysis independence and of death within 1 year after in-hospital dialysis initiation, respectively. We aimed to validate the Death Outcome risk score to predict one-year mortality after dialysis start in our population. Methods Retrospective analysis of hospitalized patients starting hemodialysis in a tertiary-care hospital from January 1st, 2016, to December 31st, 2019. All-cause mortality risk one year after discharge was calculated according to the ReDO Death score. Patients were classified into death outcome risk groups and Cox regression was used to determine if the risk score was predictive of one-year mortality. The discriminatory ability for the ReDO Death score to predict mortality was determined using the receiver operating characteristic (ROC) curve. Results Three hundred sixty-nine patients were included, mostly male (59.9%), with mean age 71.1±14.3 years and median Charlson score 7±3. The one-year mortality rate was 22.2%. The ReDO Death score accurately predicted the one-year risk of mortality, with an area under the ROC of 0.741 [95% CI (0.687–0.794), p<0.001]. The optimal REDO Death risk cut-off was >30%, with a hazard ratio of 6.57 [95% CI (3.48–12.2), p<0.001] for one-year mortality risk (sensitivity 78.0% and specificity 60.6%). Conclusion We validated the ReDO Death score for 1-year mortality prediction after starting hemodialysis during hospitalization in a Portuguese population. This score can be used as a tool to inform goals-of-care discussion at the time of transition to out-of-hospital care.

BACKGROUND AND HYPOTHESIS:Podocytopathy associated with likely pathogenic/pathogenic variants of Transient receptor potential cation channel subfamily C member 6 (TRPC6) (TRPC6-AP) has been recognized for about 20 years. As a result of its rarity however, the spectrum of clinical phenotypes and genotype-phenotype correlation of TRPC6-AP remains poorly understood. Here, we characterized clinical, histological and genetic correlates of familial and sporadic patients with TRPC6-AP. METHODS:In this multicentre observational study, an online questionnaire followed by a systematic literature review was performed to create a cohort with comprehensive data on genetic and clinical outcomes [age of onset, clinical presentation, treatment response, kidney biopsy findings and progression to kidney failure (KF)]. Logistic regression, Cox proportional hazards model and Kaplan-Meier analyses investigated the associations between genetic variants and disease progression. RESULTS:Among 87 families (96 familial and 45 sporadic cases), 31 distinct missense TRPC6 variants (including 2 novel) were identified, with c.2683C>T p.(Arg895Cys) and c.523C>T p.(Arg175Trp) the commonest variants. Proteinuric kidney disease/nephrotic syndrome was the most common clinical presentation (83.7%), while focal segmental glomerulosclerosis was the most common histological finding (89.4%). By 33 (interquartile range 17-40) years, 48.9% (69/141) of patients had progressed to KF. Sporadic TRPC6-AP demonstrated an earlier progression to KF than familial cases (P = .001) and were more likely to present with nephrotic syndrome [odds ratio 4.34 (1.85-10.15); P = .001]. Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs 44.4%; P = .004). Compared with patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to KF earlier [median kidney survival of 21 years, hazard ratio 2.985 (95% confidence interval 1.40-5.79); and 38 years, hazard ratio 1.65 (95% confidence interval 1.01-2.81), respectively, log-rank P = .005]. CONCLUSION:Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.

Continuous advances in molecular genetics have enabled the diagnosis of an increasing number of genetic kidney diseases in recent years. Establishing a Nephrogenetics' Clinic aims to contribute to better renal care, especially in the era of precision medicine. We present our experience over the past 15 years. We conducted a retrospective analysis of genetic testing performed in adult patients since 2010. Since 2015, all patients have been studied with targeted panels based on whole exome sequencing, progressively amplified according to the state of the art. MUC1 was analyzed using Snapshot since 2014 and PKD1 with PCR long range (since 2020). Pre and post genetic counselling were performed by nephrologists and geneticists. Variants of uncertain significance (VUS) were evaluated by geneticists for segregation studies and periodically reclassified. Negative results were reviewed regularly and reanalyzed when relevant. A total of 369 index patients were studied, 173 (47%) females, mean age 51.5 years. Until mid-2023, genetic panels with ≤ 85 genes were used. Among 220 patients tested, 15.4% (n = 34) were found to have pathogenic (P) or likely pathogenic (LP) variants. The remaining patients either had VUS or a single pathogenic variant in a gene with autosomal recessive inheritance (n = 85), or their results were negative (n = 101). All reported VUS were reinterpreted, with 17 being reclassified: 8 patients had their VUS upgraded to LP, while 9 were downgraded to benign. In 2023, broader genetic panels, including copy number variation (CNV) analysis, were implemented. Since then, 29.6% (n = 24) of the 81 index cases tested with these broader panels revealed LP/P variants. We identified both a deletion and a microduplication that would have been missed without CNV analysis. Additionally, reanalysis of 24 negative samples using broader panels resulted in positive findings in four of them (17%). Phenotypes at presentation were: 38% glomerular disease, 29% uncharacterized chronic kidney disease (CKD), 18% tubulo-interstitial, 11% cystic and 4% others. Positive results (P and LP variants) in 69 index patients, of which we highlight: 30 COL4; 5 MUC; 1 biallelic REN; 4 UMOD; 2 INF2, 3 PAX2, 4 PKD1, 5 HNF1β; 15 high-risk APOL1 genotypes. Additionally, 1 family (4 patients) was studied for the MUC1 variant by PacBio with positive results. Of note, COL4 variants were the most frequent genetic cause of monogenic CKD. ADPKD is probably under-represented in our cohort due to selective testing of atypical cases. The use of broader gene panels and the systematic re-evaluation of variant classifications are pivotal in nephropathy genetic testing. These approaches enable accurate initial diagnoses, facilitating effective patient treatment, family screening, and counseling.

Abstract Background and Aims Amyloidosis is a disease caused by the extracellular deposition of amyloid material that leads to organ dysfunction. Renal involvement is frequent and is characterized by amyloid fibrils pathologic deposition in glomeruli, vessels and interstitium. The most common presentation is nephrotic-range proteinuria or nephrotic syndrome and can progress to end stage kidney disease (ESKD). Prognosis is usually poor, especially with cardiac and severe renal involvement that requires renal replacement therapy. The goal of this study was to analyse the outcomes of patients with amyloidosis followed at the nephrology clinic in our centre. Method Descriptive analysis of all confirmed amyloid patients, followed by the Nephrology department from January 2015 to June 2023. Results We identified 49 patients with a mean age of 64 ± 16 years [18-88], mainly Caucasian (n = 47, 82%) and male (n = 28, 57%). The majority of patients were diagnosed through renal biopsy (26, 53%). The most common amyloid type was AL (n = 18, 38%), followed by ATTR (n = 16, 33%) and AA (n = 12, 25%). In 3 patients the amyloid type couldn't be characterized. Renal presentation was mostly as CKD 28/49 (57%), 15/49 (30.6%) as nephrotic syndrome and 6/49 (12%) patients as AKI. At presentation, almost half of the patients (24/49, 49%) had nephrotic-range proteinuria, with a mean proteinuria of 6.72 ± 6.12 g/d [0.103-19.8] and mean sCr was 2.6 ± 3.1 mg/dl [0.5-18.9]. AL amyloidosis had an almost equal distribution between lambda (9/18, 50%) and kappa chain (8/18, 44%, one unknown). Extrarenal involvement was frequent, mainly cardiac (12/18, 67%). Also 12/18 (67%) patients needed dialysis after a mean of 9 ± 15 months post-diagnosis, 16/18 (89%) received treatment and mortality was 61%, in mean 16 ± 17 months post-diagnosis, mainly due to disease progression. AA amyloidosis was secondary to chronic infection in 7/12 (58%), 3/12 (25%) autoimmune diseases and in 2/12 (17%) unknown. Extrarenal involvement was less frequent, also mainly cardiac (3/12, 25%). 7/12 (58%) patients needed dialysis after a mean of 97 ± 117 months post-diagnosis and mortality was 58%, in mean 46 ± 66 months post-diagnosis, mainly due to acute infection. Two patients were diagnosed already on dialysis. Regarding ATTR amyloidosis, all patients had a positive genetic test, extrarenal involvement was very frequent (13/16, 81%), mostly cardiac and peripheric nervous system. No patients required dialysis during follow-up, and one patient died of unknown cause. Conclusion In our cohort, renal AL and AA amyloidosis had poor prognosis, with a high progression to ESKD and very significant mortality, irrespective of treatment. Conversely, ATTR amyloidosis patients had lower progression to dialysis and death, probably as a consequence of disease-modifying therapies instituted in recent years.

Abstract Background and Aims Rituximab (RTX) has been reported as an effective treatment alternative in primary forms of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) associated with steroid dependence and frequent relapses. However, the optimal RTX regimen and the outcomes of further doses of RTX remain unclear. This study aimed to evaluate the use of induction and maintenance RTX therapy for adults with primary podocytopathies. Method We performed a retrospective case series on adult patients with steroid-dependent podocytopathies who received an induction RTX therapy. Maintenance therapy was performed at physician's discretion. Remission and relapse rates, concomitant corticosteroids and immunosuppressants use, B-cell depletion and adverse events were analyzed. Results Fourteen patients (mean age at start of RTX 29.1 ± 21.9 years) with MCD (n = 7) or FSGS (n = 7) were treated with 2 doses of 1000 mg 2 weeks apart (n = 13) or four doses of 375 mg/m2 (n = 1) of RTX. At last follow-up (mean 47.3 ± 101.7 months) ten patients were in complete remission and two remained in partial remission. A reduction in the number of relapses, number of patients under corticosteroids and immunosuppressants, and dose of prednisolone was observed when compared to baseline [14 (100%) vs 5 (35.7%); 8/14 (57.1%) vs 4/12 (33.3%); 13/14 (92.9%) vs 7/12 (58.3%); 20 mg/day vs 5.25 mg/day, respectively]. Maintenance RTX therapy was used in six patients, with sustained complete remission. Infusion reactions were observed in four patients (one required treatment withdrawal). Conclusion Our findings support the use of RTX for a steroid-free remission in podocytopathies and suggest that maintenance RTX is well-tolerated and associated with prolonged remission. Further studies are needed to confirm its efficacy and safety and establish the optimal induction and maintenance RTX regimen in steroid-dependent podocytopathies.

Abstract Background and Aims Mortality within the first year after dialysis start is estimated to be 20-30%, and it is mostly due to cardiovascular disease. Prognostic assessment after starting hemodialysis is challenging. Clark et al. developed the Recovery and Death Outcome risk score, which accurately predicted the likelihood of renal recovery to dialysis independence and of death within 1 year after discharge from in-hospital dialysis initiation. These models can be used at discharge or soon after patients start outpatient dialysis. We aimed to validate the Death Outcome risk score to predict one-year mortality after dialysis start in our population. Method .Retrospective analysis of hospitalized patients who initiated hemodialysis in a tertiary care hospital (Unidade Local de Saúde Santa Maria), from January 1st of 2016 to December 31st of 2019, and were discharged to outpatient dialysis. The risk of death within one year of discharge was calculated according to the ReDO score. We evaluated all-cause mortality within one year of hospital discharge. We classified patients into death outcome risk groups (labeled D1 to D4) according to the ReDO predictive score. Cox regression method was used to determine if the risk score was predictive of mortality within the first year after discharge. The discriminatory ability for the ReDO score to predict mortality was determined using the receiver operating characteristic (ROC) curve. Results 369 patients were included, with a mean age of 71.1 ± 14.3 years. The majority were male (59.9%, n = 221) and 87% were Caucasian (n = 321). The median Charlson score was 7 ± 3. The mortality rate within one year after discharge was 22.2% (n = 82). The one-year survival was significantly lower in patients with the highest probability of death (D4 = 61.3% vs. D3 = 67.6% vs. D2 = 81.3% vs. D4 = 97.3%, p &lt; 0.001). The ReDO Death score accurately predicted the one-year risk of mortality, with an area under the ROC curve of 0.741, [95% CI (0.687–0.794), p &lt; 0.001] (Fig. 1). The optimal REDO Death risk cut-off was &gt;30%, with a hazard ratio of 6.57 [95% CI (3.48–12.2), p &lt; 0.001] for one year risk of death, with a sensitivity of 78.0% and specificity of 60.6%. Conclusion We validated the ReDO score for 1-year mortality prediction after starting hemodialysis during hospitalization in a Portuguese population. This score can be used as a tool to inform goals of care discussion at the time of transition to out-of-hospital care, involving the in-hospital nephrology care team, the patient, and, if applicable, the future care team, as it can enlighten clinical decisions and, in some cases, lead to better end-of-life planning.

Abstract Background and Aims Genetic kidney diseases (GKD) are rarely seen in pregnancy and some diagnosis will only be made during gestation, due to a high proportion of chronic kidney diseases (CKD) of unknown etiology and recent advances in genetic testing. Genetic counseling and, when possible, preimplantation genetic testing (PGT) should be offered pre-pregnancy to this specific CKD population. Method Retrospective analysis of maternal, obstetric and perinatal outcomes of pregnant women with GKD surveilled at Hospital Santa Maria, at the nephro-obstetric clinic from 2011 to 2023. Results We evaluated 34 pregnancies in 28 women, mean maternal age 30±6 years-old [21-37], 89% Caucasian. Molecular genetic testing was performed pre-pregnancy, during and post-pregnancy in 12/19, 2/19 and 5/19 patients, respectively. At baseline, mean serum creatinine (SCr) and proteinuria (Pr) was 1.0±0.9 mg/dL and 222±516 mg/g, with CKD stage 1/2/3/4/5 in 27/2/2/1/2 gestations and chronic hypertension (HTN) in 11/34 pregnancies. Only 1/28 patients performed PGT, while 1/28 patient declined it. De novo or increased Pr occurred in 10/34 gestations and de novo or worsening HTN in 5/34 gestations. Deterioration of renal function occurred in one patient (CKD3) without recovery and one patient (CKD5) induced dialysis 4 months post-pregnancy. Nephrotic Pr developed in 4/34 gestations. One patient (FSGS APOL1) was treated with tacrolimus and low dose steroids. The patient with TSC re-started sirolimus on week 22 to treat severe fetal ventricular rhabdomyoma. Miscarriage occurred in 2 pregnancies. The C section rate was 21,8%. There were 7 preterm deliveries of which 3 before 32 weeks of pregnancy, mainly due to severe preeclampsia. Mean gestational age at delivery was 37,6 ± 4 weeks (26-41), mean birth weight 2756 ± 831 g (560-3835). Eight newborns were admitted to neonatal ICU due prematurity, fetal TSC, and feeding difficulties. Pulmonary hemorrhage and sepsis caused the death of 2 newborns. We found 1 maternal death, due to rupture of a cerebral aneurism 1 month postpartum (PKD patient). Conclusion Our cohort was very heterogenous regarding CKD etiologies, but generally with good kidney function, which allowed overall good obstetric outcomes. Still, maternal, obstetric and fetal complications, namely HTN, Pr, PE and prematurity had an increased incidence compared to pregnancy in healthy patients. This particular population should be approached by an experienced multidisciplinary team in CKD pregnancy care to optimize outcome.

Introduction:Rituximab (RTX) has been reported as an effective treatment alternative in primary forms of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) associated with steroid dependence and frequent relapses. However, the optimal RTX regimen and the outcomes of further doses of RTX remain unclear. This study aimed to evaluate the use of induction and maintenance RTX therapy for adults with primary podocytopathies. Methods:We performed a retrospective case series on adult patients with steroid-dependent podocytopathies who received an induction RTX therapy. Maintenance therapy was performed at physician's discretion. Remission and relapse rates, concomitant corticosteroids and immunosuppressants use, B-cell depletion and adverse events were analyzed. Results:Fourteen patients (mean age at start of RTX 29.1 ± 21.9 years) with MCD (n = 7) or FSGS (n = 7) were treated with 2 doses of 1,000 mg 2 weeks apart (n = 13) or four doses of 375 mg/m2 (n = 1) of RTX. At last follow-up (mean 47.3 ± 101.7 months), 10 patients were in complete remission and two remained in partial remission. A reduction in the number of relapses, number of patients under corticosteroids and immunosuppressants, and dose of prednisolone was observed when compared to baseline (14 [100%] vs. 5 [35.7%]; 8/14 [57.1%] vs. 4/12 [33.3%]; 13/14 [92.9%] vs. 7/12 [58.3%]; 20 mg/day vs. 5.25 mg/day, respectively). Maintenance RTX therapy was used in 6 patients, with sustained complete remission. Infusion reactions were observed in 4 patients (one required treatment withdrawal). Conclusions:Our findings support the use of RTX for a steroid-free remission in podocytopathies and suggest that maintenance RTX is well-tolerated and associated with prolonged remission. Further studies are needed to confirm its efficacy and safety and establish the optimal induction and maintenance RTX regimen in steroid-dependent podocytopathies.

Sepsis-associated kidney injury is common in critically ill patients and significantly increases morbidity and mortality rates. Several complex pathophysiological factors contribute to its presentation and perpetuation, including macrocirculatory and microcirculatory changes, mitochondrial dysfunction, and metabolic reprogramming. Recovery from acute kidney injury (AKI) relies on the evolution towards adaptive mechanisms such as endothelial repair and tubular cell regeneration, while maladaptive repair increases the risk of progression to chronic kidney disease. Fundamental management strategies include early sepsis recognition and prompt treatment, through the administration of adequate antimicrobial agents, fluid resuscitation, and vasoactive agents as needed. In septic patients, organ-specific support is often required, particularly renal replacement therapy (RRT) in the setting of severe AKI, although ongoing debates persist regarding the ideal timing of initiation and dosing of RRT. A comprehensive approach integrating early recognition, targeted interventions, and close monitoring is essential to mitigate the burden of SA-AKI and improve patient outcomes in critical care settings.

Abstract Background and Aims Congenital abnormalities of the urinary tract (CAKUT) represent a broad range of disorders that occur due to abnormal kidney development. Maternal, obstetric, and perinatal outcome in pregnant woman with CAKUT have not been extensively evaluated, although small series report an increased incidence of urinary tract infections (UTI) and obstructive uropathy. Method Retrospective analysis of maternal, obstetric, and perinatal outcomes in pregnant patients with CAKUT (including genetic cystic kidney disease) that were surveilled in our tertiary center by a nephro-obstetric team between 2011 and June 2023. Information was obtained from medical records. Results We evaluated 47 gestations in 41 patients, with mean age of 31 ± 5 years [17-40], 89% were Caucasian, 11% black; 40% were nulliparous, 36% had hypertension (HT) and 42% a previous history of UTI. Regarding CAKUT specificity, 17/41 patients had genetic cystic diseases, 10/41 ureteropelvic junction obstruction (UPJ), 4/41 duplicate collecting system, 5/41 vesicourethral reflux, 2/41 ectopic kidney, 3/41 renal hypoplasia. Genetic testing was done before, during or after pregnancy in 2/4/4 patients, respectively. Teratogenic therapy exposure occurred in 25% of gestations. Most patients were CKD stage 1 (33/41), with 2/4/1/1 with patients in CKD stage 2/3/4/5, respectively. Mean baseline SCr was 0.99 ± 0.8 mg/dL [0.4-4.6] and mean proteinuria was 194 ± 357 mg/g [22-1500]. Renal function (RF) deterioration occurred in 9/47 (19%) women due to pre-eclampsia (PE), pregnancy hyperfiltration (PH) and hydronephrosis in 3/3/3 patients, respectively. Urologic intervention was needed in 2 patients due to hydronephrosis, and one of the patients required transient dialysis. All patients fully recovered RF except for the 1 CKD stage 3 patients that had partial RF recovery. De novo and worsening proteinuria occurred in 7/47 gestations due to PE (3/7) and PH (4/7). De novo or aggravation of HTN occurred in 25% gestations, UTI in 19% and PE in 6% gestations. Regarding fetal outcomes, mean duration of gestation was 38 ± 2 weeks [32-41] and mean birth weight 2910 ± 634 g [1360-4600]. There was 1 miscarriage and 1 medical termination of pregnancy at 17 weeks (neural tube defect). Cesarean was performed in (8/47, 17%) gestations and 10/47 (17%) newborns were admitted to the neonatal care unit (NICU) mainly due to prematurity, sepsis and feeding intolerance. Conclusion Our cohort of CAKUT patients was very heterogenous and only 19.5% had CKD stage 2-5. Still, we found a significant incidence of maternal, obstetric, and perinatal complications, namely HT UTI, PE, and the need for NICU. UPJ obstruction can evolve with RF deterioration and the need for intervention during pregnancy. This study underlines the importance of the management of these patients by a multidisciplinary team.