Extrarenal Complications Research Articles

THE IMPORTANCE OF KLOTHO PROTEIN IN THE DIAGNOSIS OF CHRONIC KIDNEY DISEASE

Chronic kidney disease (CKD) is an intrinsically systemic infection that alludes to a long-term misfortune of kidney work. The movement of CKD has repercussions for other organs, driving to numerous sorts of extrarenal complications. Seriously ponders are presently being attempted to uncover the hazard components and pathophysiological component of this malady. Amid the past 20 a long time, expanding prove from clinical and fundamental ponders has shown that klotho, which was at first known as an anti-aging quality and is primarily communicated within the kidney, is altogether connected with the improvement and movement of CKD and its complications. Here, we talk about in detail the part and pathophysiological suggestions of klotho in particle clutters, the aggravation reaction, vascular calcification, mineral bone clutters, and renal fibrosis in CKD. Based on the pathogenic component of klotho insufficiency and klotho decrease in pee early in CKD organize 2 and indeed prior in CKD stage 1, it isn't troublesome to get it that solvent klotho can serve as an early and delicate marker of CKD. Besides, the anticipation of klotho decay by a few components can weaken renal wounds, impede CKD movement, enhance extrarenal complications, and make strides renal work. In this audit, we center on the capacities and pathophysiological suggestions of klotho in CKD and its extrarenal complications as well as its potential applications as a demonstrative and/or prognostic biomarker for CKD and as a novel treatment methodology to progress and diminish the burden of comorbidity in CKD.

Unusual familial cystic kidney disease: combining fine radiologic and genetic evaluation to solve the case

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease, characterized by enlarged kidneys with numerous cysts, high blood pressure, and a variety of extrarenal complications. This disease is a significant cause of renal failure and requires accurate differentiation from other cystic kidney diseases, especially when family history does not clearly indicate ADPKD. This is crucial due to differences in prognosis, treatment, and familial implications. Advanced molecular genetics and imaging techniques are employed to diagnose and assess the prognosis of patients and their families.Case presentationThe case study revolves around three patients from the same family—two sisters and one daughter—referred to a nephrology department for ADPKD management. The initial proband, a 42-year-old woman, experienced abdominal discomfort leading to an ultrasound that suggested ADPKD. However, MRI findings indicated standard-sized kidneys with bilateral parapelvic cysts, and no genetic markers for ADPKD were found. Her sister, presenting with controlled hypertension and similar ultrasound findings, also had her initial ADPKD diagnosis refuted by MRI and genetic testing, which revealed no significant mutations. The daughter, however, exhibited a different scenario with enlarged kidneys and multiple cysts characteristic of early-stage ADPKD. Genetic testing confirmed a deleterious PKD1 mutation, suggesting a de novo mutation, as her father showed no signs of the disease.ConclusionThis study highlights the complexity and necessity of thorough diagnostic processes in suspected ADPKD cases to prevent misdiagnosis. The initial symptoms and imaging might misleadingly suggest ADPKD, as seen in the cases of the two older patients. Still, further detailed imaging and genetic analyses revealed no ADPKD, preventing inappropriate treatment and stress. In contrast, the younger patient's distinctive clinical and genetic profile confirmed ADPKD, illustrating the variability within even closely related individuals. Such detailed assessments are crucial in guiding correct treatment decisions and providing accurate familial counseling, emphasizing the importance of considering a broader spectrum of renal cystic disorders before confirming a diagnosis of ADPKD.

A comprehensive review of Alport syndrome: definition, pathophysiology, clinical manifestations, and diagnostic considerations.

Alport syndrome, a rare genetic disorder affecting around 1 in 50,000 individuals, primarily presents as microscopic hematuria and chronic kidney disease (CKD) with associated extrarenal complications. The Alport syndrome results from mutations in COL4A3, COL4A4, and COL4A5 genes, disrupting the formation of the α3-α4-α5 chain in the collagen IV network. The etiology involves X chromosome-related, autosomal dominant, autosomal recessive, and digenic inheritance patterns. The disease primarily manifests as kidney involvement, featuring persistent hematuria, proteinuria, and a progressive decline in renal function. Hearing loss, ocular abnormalities, and extrarenal manifestations further contribute to its complexity. Genotype-phenotype correlations are relatively evident, with distinct presentations in X-linked, autosomal recessive, and autosomal dominant cases. Diagnosis relies on urinalysis, histologic examination, and genetic testing with advancements in next-generation sequencing aiding identification. Although no specific treatment exists, early diagnosis improves outcomes, emphasizing the importance of genetic testing for prognosis and familial screening. The purpose of this review is to advance knowledge and enhance understanding of Alport syndrome.

The Impact of Autosomal Dominant Polycystic Kidney Disease in Children: A Nephrological, Nutritional, and Psychological Point of View.

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder characterized by the formation of numerous fluid-filled cysts in the kidneys, leading to progressive renal failure and various extrarenal complications, including hypertension. This review explores the genetic basis of ADPKD, including emerging evidence of epigenetic mechanisms in modulating gene expression and disease progression in ADPKD. Furthermore, it proposes to examine the pathological characteristics of this condition at the nephrological, cardiovascular, nutritional, and psychological levels, emphasizing that the follow-up of patients with ADPKD should be multidisciplinary from a young pediatric age.

#2245 ECYSCO, a European cystinosis cohort

Abstract Background and Aims Cystinosis is a rare multisystem lysosomal storage disease due to variants in the CTNS gene, coding for the carrier protein cystinosin, a lysosome membrane transporter, causing cystine accumulation. Specific treatment by cysteamine decreases renal and extrarenal complications frequency in cystinosis patients but data on long-term manifestations of the disease are lacking. The aim of the ECYSCO cohort is to describe the natural history of the disease and the effect of treatments. Methods We set up a European, multi-centre, longitudinal, non-interventional cohort, ECYSCO, that uses observational study methods to collect uniform data. 243 patients with a confirmed diagnosis of cystinosis and followed in 25 French and 5 European centers (Belgium, Italy, Spain and Germany) were included. Data are collected on the secure RaDiCo platform, via an e-CRF (REDCap). Results Data from 177 patients (50.8% male) were analyzed. Median age at diagnosis was 1.3 years [IQ 0.9; 1.8], with earlier diagnosis since the 1980s, but no further improvement in the 2000s. Genetic analysis was available for 158 patients: 46 (31.9%) presented with homozygous 57kb deletion in the CTNS gene, 57 (39.6%) with heterozygous 57kb deletion associated with another variant and 46 (26.4%) with other variants. The type of variant had no impact on the age at diagnosis. Median age at cysteamine start was 1.6 years (IQ 1.0-3.0). An improvement on age at treatment start was observed after the 1990s. All but 7 patients were treated with cysteamine. Sixty-seven patients received immediate release formulation (Cystagon®) and 103 received extended release formulation (Procysbi®). Median white blood cell cystine level was 1.2 nmol ½ cystine/mg protein (IQ 0.6; 2.2). The median duration of treatment was 21.5 years [IQ 11.7; 31.1]. 165 (93,2%) patients also received cysteamine ocular gel, Cystadrops®. Median age at inclusion was 18.4 years (IQ 10.4; 30.6). At that time, 104 patients (57.8%) had reached kidney failure (KF). There was no impact of genotype on age at KF. Median age at KF was 12.9 years [IQ 9.9; 18.0]. A 5-year gain in renal survival was observed after the 1990s. 102 patients (56.7%) received a kidney transplant. Among these transplanted patients: 76 (74.5%) received 1 transplant, 23 (22.5%) received 2 consecutive transplants, and 3 (2.9%) received 3. Median eGFR in the remaining patients was 58.9 ml/min [IQ 40.4; 82.2]. Extrarenal manifestations included hypothyroidism in 29 (16.4%) patients, diabetes mellitus in 15 (8.4%), skeletal manifestations in 89 (53.6%), myopathy in 28 (17.9%), and neurological disorders in 21 (13.5%). Skeletal manifestations involved patients before dialysis/transplantation in 46% of cases. The main complications in these patients were genu valgum (62.9%), genu varum (11.1%), kyphosis (21.2%), fractures (20.4%), and 12.6% required surgery. Patients with myopathy were dialysed or transplanted in 58.8% of cases. Conclusion Cystinosis is a good example of a pediatric disease with multiorgan involvement extending into adult care. More than half of patients are adults and have reached kidney failure even if age at renal replacement therapy start has increased. The high frequency of extra-renal manifestations demonstrates the importance of a multidisciplinary follow up of these patients.

#2723 10-hydroxy-trans-2-decenoic and nonanoic acid delayed senescence in adult renal progenitor cells and increased the anti-aging Klotho protein secretion

Abstract Background and Aims Recent investigations have elucidated the complex system involving human adult renal stem/progenitor cells (ARPCs) and their pivotal role in maintaining homeostasis and in facilitating regenerative processes within the adult kidneys. CD133+/CD24+ ARPCs can repair several kinds of renal damage but their reparative properties can be compromised by the cell senescence, contributing to renal aging and impaired damage repair. The functional marker CD133 inversely correlates with cellular senescence and plays a crucial role in the ARPC regulation. Decreased protective factors, hypoxia, and microenvironmental stress drive increasingly cell senescence, disordered inflammation and renal fibrosis. The resulting fibrosis, senescence, and microvascular rarefaction exacerbate damage and promote chronic kidney disease (CKD) progression. In this study, we explore the impact of natural molecular compounds and drugs on slowing down and delaying ARPC senescence. Method ARPCs were treated with the following compounds for 48 hours: nonanoic acid (1 mM), 3-decenoic acid (1 mM), 10-hydroxy-trans-2-decenoic acid (10-HDA, 25uM), and Valproic acid (VPA, 1 mM), either individually or in combination. Lipid microvesicles were used to transmit the bioactive molecules. FACS was used to determine the CD133 levels. the β-galactosidase assays were used to determine cell senescence status. Western blots were performed to assess p16, p53 and p21 markers. Results Cytofluorimetry results demonstrated an increase in the expression of CD133, the inverse cell senescence marker, both following stimulation with decenoic (fold change = 1.8, p = 0.0053) and nonanoic acid (FC = 1.3, p = 0.0056), and with VPA (FC 2, p = 0.0036). Simultaneously, the number of senescent cells decreased, as confirmed by the β-galactosidase assay (FC = 0.13, p = 0.0005). The treatment with decenoic and nonanoic acid also restored high levels of the lncRNA HOTAIR (FC = 14.6 for nonanoic acid and 12.7 for 10-HDA; p = 0.05), that in turn promoted the secretion of the α-Klotho anti-aging protein (FC = 3.1; p = 0.01). Additionally, the western blot analysis revealed that the 10-HDA decreased the expression of cell senescence markers, p16 (FC = 1.6, p = 0.05), p53 (FC = 1.8, p = 0.05) and p21 (FC= 3.7, p = 0.05). Moreover, the nonanoic acid reduced the expression of p16 (FC = 1.8, p = 0.05), p53 (FC = 2, p = 0.05) and p21 (FC= 2.6, p = 0.0007). Also, their combination contributes to decrease p16 (FC = 1.9, p = 0.05), p53 (FC = 1.3, p = 0.05) and p21 (FC= 2.5, p = 0.05). Conclusion This study identifies specific molecules capable of reducing or delaying ARPC senescence. In particular, the two natural compounds 10-HDA and nonanoic acid can also enhance the capacity of renal progenitors to secrete the α-Klotho protein whose decline prevention by several mechanisms can attenuate renal injuries, retard CKD progression, ameliorate extrarenal complications, and improve renal function. These findings present potential therapeutic avenues for delaying or mitigating the progression of CKD.

Mitigative role of cysteamine against unilateral renal reperfusion injury in Wistar rats.

Ischemia-reperfusion injury (IRI) is unavoidable during kidney transplant and it is responsible for delayed or non-function after kidney transplantation. Cysteamine is the standard drug in the management of nephropathic cystinosis and its extra-renal complications. Thus, we designed this study to investigate its potential against renal reperfusion injury. Significant elevation of H2O2, MDA, and nitrite and reduced GPx, GSH, and protein thiol in the Ischemia-reperfusion injury rats was reversed by cysteamine (50 and 100mg/kg). Serum MPO, TNF-α, IL-1β, creatinine, and AOPP were significantly elevated in IRI while rats treated with cysteamine revealed a significant decrease (p < 0.05) in the activities of these pro-inflammatory and renal injury markers. Based on its activity against inflammation, apoptosis, and free radical-induced stress, cysteamine has great potential to be used as a kidney transplant pre-operative drug to prevent renal reperfusion injury.

Assessment of Individualized Mean Perfusion Pressure Targets for the Prevention of Cardiac Surgery-Associated Acute Kidney Injury-The PrevHemAKI Randomized Controlled Trial.

Retrospective studies support that mean perfusion pressure (MPP) deficit in cardiac surgery patients is associated with a higher incidence of acute kidney injury (CS-AKI). The aim of our study was to apply an algorithm based on MPP in the postoperative period to determine whether management with an individualized target reduces the incidence of CS-AKI. Randomized controlled trial of patients undergoing cardiac surgery with extracorporeal circulation. Adult patients submitted to valve replacement and/or bypass surgery with a high risk of CS-AKI evaluated by a Leicester score >30 were randomized to follow a target MPP of >75% of the calculated baseline or a standard hemodynamic management during the first postoperative 24 h. Ninety-eight patients with an eGFR of 54 mL/min were included. There were no differences in MAP and MPP in the first 24 h between the randomized groups, although a higher use of noradrenaline was found in the intervention arm (38.78 vs. 63.27, p = 0.026). The percentage of time with MPP < 75% of measured baseline was similar in both groups (10 vs. 12.7%, p = 0.811). MAP during surgery was higher in the intervention group (73 vs. 77 mmHg, p = 0.008). The global incidence of CS-AKI was 36.7%, being 38.6% in the intervention group and 34.6% in the control group (p = 0.40). There were no differences in extrarenal complications between groups as well. An individualized hemodynamic management based on MPP compared to standard treatment in cardiac surgery patients was safe but did not reduce the incidence of CS-AKI in our study.

When hemorrhagic enterititis can cause anemia and thrombocytopenia without significant kidney damage.

A healthy 9-years-old boy was brought to the Emergency Department for widespread abdominal pain associated with bloody diarrhoea and significant tenesmus, in the absence of fever. Blood tests were compatible with an acute gastroenteritis, even though microbiological tests on stools resulted negative. Given the haemorrhagic dysentery, the boy was hospitalized to start empiric antibiotic therapy and intravenous rehydration. Abdominal ultrasound showed a thickening of colonic walls, mimicking an inflammatory intestinal disease at the onset (subsequently denied by gastro-colonoscopy). Seven days after the onset of symptoms, blood tests revealed microangiopathic anaemia with negative Coombs test, associated with thrombocytopenia. Urine dipstick revealed haematuria and proteinuria in nephritic range. No contraction of diuresis or alteration of renal function were observed (being creatinine values always within the normal range). Laboratory tests were consistent with the diagnosis of Haemolytic Uremic Syndrome (Hus) at the onset. Approximately 1% of paediatric patients with bloody diarrhoea can develop Hus. Positivity for Escherichia coli is not always evident in the stools. Thus, the triad of haemolytic anaemia, thrombocytopenia and renal failure could be present in only 60% of Hus at the onset. The finding of haematuria and/or proteinuria on the urine dipstick may be indicative of early kidney damage, allowing for careful monitoring and a rehydration program that can prevent progression of kidney damage and extrarenal complications.

Vascular polycystin proteins in health and disease.

PKD1 (polycystin 1) and PKD2 (polycystin 2) are expressed in a variety of different cell types, including arterial smooth muscle and endothelial cells. PKD1 is a transmembrane domain protein with a large extracellular N-terminus that is proposed to act as a mechanosensor and receptor. PKD2 is a member of the transient receptor potential (TRP) channel superfamily which is also termed TRPP1. Mutations in the genes which encode PKD1 and PKD2 lead to autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most prevalent monogenic disorders in humans and is associated with extrarenal and vascular complications, including hypertension. Recent studies have uncovered mechanisms of activation and physiological functions of PKD1 and PKD2 in arterial smooth muscle and endothelial cells. It has also been found that PKD function is altered in the vasculature during ADPKD and hypertension. We will summarize this work and discuss future possibilities for this area of research.

Autosomal Dominant Polycystic Kidney Disease: Is There a Role for Autophagy?

Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disorder initiated by mutations in either PKD1 or PKD2 genes, responsible for encoding polycystin 1 and polycystin 2, respectively. These proteins are primarily located within the primary cilia. The disease follows an inexorable progression, leading most patients to severe renal failure around the age of 50, and extra-renal complications are frequent. A cure for ADPKD remains elusive, but some measures can be employed to manage symptoms and slow cyst growth. Tolvaptan, a vasopressin V2 receptor antagonist, is the only drug that has been proven to attenuate ADPKD progression. Recently, autophagy, a cellular recycling system that facilitates the breakdown and reuse of aged or damaged cellular components, has emerged as a potential contributor to the pathogenesis of ADPKD. However, the precise role of autophagy in ADPKD remains a subject of investigation, displaying a potentially twofold impact. On the one hand, impaired autophagy may promote cyst formation by inducing apoptosis, while on the other hand, excessive autophagy may lead to fibrosis through epithelial to mesenchymal transition. Promising results of autophagy inducers have been observed in preclinical studies. Clinical trials are warranted to thoroughly assess the long-term safety and efficacy of a combination of autophagy inducers with metabolic and/or aquaferetic drugs. This research aims to shed light on the complex involvement of autophagy in ADPKD, explore the regulation of autophagy in disease progression, and highlight the potential of combination therapies as a promising avenue for future investigations.

NONALCOHOLIC FATTY LIVER DISEASE AND ALBUMINURIA : A SYSTEMATIC REVIEW

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with the dysregulation of multiple metabolic and inflammatory pathways. These can lead to extrahepatic disorders involving the kidney, a vulnerable organ responsible for extra-renal complications. Evaluating the association between NAFLD and low-grade albuminuria as a renal complication would be helpful to better understand the pathophysiology and extra-hepatic complications of NAFLD.The aim: This study aims to show incidence, correlation of nonalcoholic fatty liver disease and albuminuria Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2013 and 2023 were taken into account. Several different online reference sources, like Pubmed and SagePub, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: Non-alcoholic fatty liver disease (NAFLD) is associated with the dysregulation of multiple metabolic and inflammatory pathways. These can lead to extrahepatic disorders involving the kidney, a vulnerable organ responsible for extra-renal complications. Evaluating the association between NAFLD and low-grade albuminuria as a renal complication would be helpful to better understand the pathophysiology and extra-hepatic complications of NAFLD. Conclusion: Understanding the incidence, correlation of nonalcoholic fatty liver disease and allbuminuria

Screening for Chronic Kidney Disease in Type 2 Diabetic Patients: Single Centre Study

Abstract Background Diabetes mellitus is the most common cause of chronic kidney disease in the world, leading to multiple complications including end-stage renal disease, cardiovascular disease and even death so, Screening is an important strategy to address the burden of CKD in diabetic population. International clinical guidelines recommend CKD screening for individuals with risk factors such as diabetes, using laboratory assessments of glomerular filtration rate (GFR) and urine albumin excretion. Objective This study describes the implementation and outcomes of screening programme for chronic kidney disease in type 2 diabetic patients to assess the burden of renal disease in diabetic population. Patients and Methods The present study included two hundred type 2 diabetic patients complicated with diabetic nephropathy. Fifty five percent of the studied patients were males. Age ranged from 42 to 82 years with mean ± SD of 60.09 ± 8.55 years. They were screened in Alagouza Hospital for CKD by using urinary ACR and average eGFR. Patients with CKD were further investigated for extrarenal diabetic complications as PVD, amputation and cardiovascular complications by using LL arterial duplex and echocardiography. Results As regard diabetic complications, nephropathy came in the 1st rank with 106 patients (53%) presented with either average eGFR&amp;lt;60 ml/min/1.73 m2(10.5%), ACR &amp;gt;30 mg albumin/gm creatinine (30%) or both(12.5%). That was followed by history of neuropathy which represented 44.5% of the studied patients. Retinopathy evidenced in fundus examination compromised about 34.516% out of our studied population. Patients with past history of stroke represented 17.5% of the studied population Peripheral neuropathy was more common in patients with nephropathy 69.7 % (n = 62) (4 patients with decline eGFR, 36 patients with albuminuria and 22 patients with both), compared to only 30.3 % (n = 27) non- nephropathic diabetic patients gave positive history of neuropathy. retinopathy was more common in patients with nephropathy (11 patients with declined GFR, 25 patients with albuminuria and 25 patients with albuminuria and declined GFR), versus only 8 patients in among the non-nephropathic diabetic patients had retinopathy evidenced in fundus examination. Stroke was more common among patients with nephropathy (4 patients with decline eGFR, 6 patients with albuminuria and 12 patients with albuminuria and declined eGFR), versus 13 patients with positive stroke history in non- nephropathic diabetic patients. Patients with nephropathy were further investigated for the presence of extra renal diabetic complications as PVD and cardiovascular complications. Arterial LL duplex revealed PVD in 32.1% (34 patients) with 3 patients underwent amputation. As regard cardiovascular complications, 17.9 % (19 patients) were found to have abnormal findings in echocardiography examination including heart failure and ischemic changes. Conclusion From our study, we showed the high burden of diabetic complications among the patients with type 2 diabetes especially renal diabetic complications. Therefore, screening of diabetic nephropathy in patients with type 2 diabetes mellitus can help in early treatment and avoid its more serious complications not only the progression to ESRD but also development of other extra-renal diabetic complications.

Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life

Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause of chronic kidney disease (CKD) and the need for kidney replacement therapy (KRT) in children. Although more than 60 genes are known to cause CAKUT if mutated, genetic etiology is detected, on average, in only 16% of unselected CAKUT cases, making genetic testing unproductive. Whole exome sequencing (WES) was performed in 100 patients with CAKUT diagnosed in the first 1000 days of life with CKD stages 1 to 5D/T. Variants in 58 established CAKUT-associated genes were extracted, classified according to the American College of Medical Genetics and Genomics guidelines, and their translational value was assessed. In 25% of these mostly sporadic patients with CAKUT, a rare likely pathogenic or pathogenic variant was identified in 1 or 2 of 15 CAKUT-associated genes, including GATA3, HNF1B, LIFR, PAX2, SALL1, and TBC1D1. Of the 27 variants detected, 52% were loss-of-function and 18.5% de novo variants. The diagnostic yield was significantly higher in patients requiring KRT before 3 years of age (43%, odds ratio 2.95) and in patients with extrarenal features (41%, odds ratio 3.5) compared with patients lacking these criteria. Considering that all affected genes were previously associated with extrarenal complications, including treatable conditions, such as diabetes, hyperuricemia, hypomagnesemia, and hypoparathyroidism, the genetic diagnosis allowed preventive measures and/or early treatment in 25% of patients. WES offers significant advantages for the diagnosis and management of patients with CAKUT diagnosed before 3 years of age, especially in patients who require KRT or have extrarenal anomalies.

Neonatal Onset Distal Renal Tubular Acidosis: Description of Two Novel Variants on the ATP6V0A4 Gene and Review of the Literature on Associated Extrarenal Manifestations.

Distal renal tubular acidosis (dRTA) is an extremely rare disease that affects the distal tubule's ability to excrete proton cations, acidify urine, and maintain the acid-base balance. The clinical presentation of dRTA typically includes normal anion gap metabolic acidosis with decreased serum bicarbonate levels, hypokalemia, hypercalcemia, nephrocalcinosis, and alkaline urine. Hereditary causes of dRTA include pathogenic variants in ATP6V1B1 , ATP6V0A4 , SLC4A1 , FOXI1 , and WDR72 genes, which encode different transmembrane proteins on the apical surface of type A intercalated cells in the distal tubule. Variants in these genes lead to various defects in the function of the encoded proteins and can also account for extrarenal manifestations of dRTA due to the expression of these proteins in other organs, such as the stria vascularis of the inner ear. However, the literature on extrarenal manifestations, associated renal complications of hereditary dRTA, and appropriate investigations, and follow-up for patients with dRTA is scarce. In this article, we present a challenging case of neonatal-onset dRTA and contribute two novel variants of the ATP6V0A4 gene and a novel phenotype associated with a pathogenic variant on ATP6V0A4 to the scientific community. We also review the existing literature on hereditary causes of dRTA, with emphasis on associated renal and extrarenal complications.

Duration of prodromal phase and severity of hemolytic uremic syndrome.

Some data have recognized an association between shorter prodromal phase and severe episode of Shiga toxin-producing Escherichia coli-related hemolytic uremic syndrome (STEC-HUS). Our aims were to confirm such association and analyze characteristics of STEC-HUS patients according to duration of the prodromal phase. Patients treated from 2000 to 2022 were compared according to the presence of severe (> 10days of dialysis and/or extra-renal complications) or non-severe disease. Association between prodromal phase duration and disease severity was assessed by ROC curve and by classifying the cohort in 3 groups according to time to diagnosis. Non-severe (n = 145) and severe (n = 71) cases were compared. The latter had shorter prodromal phase, higher leukocyte count, hemoglobin, lactic dehydrogenase, liver enzymes, C-reactive protein, urea and creatinine, and lower albumin and sodium; only prodromal phase duration (p = 0.02) and leukocyte count (p = 0.02) remained significant in multivariate analysis. By ROC curve analysis, time to diagnosis resulted in a poor predictor of outcomes (AUC = 0.27). Since prodromal phase duration was 5days (IQR 3-7), we divided the cohort into Groups A (1-2days), B (3-7days), and C (≥ 8days). Rates of severe disease were 75.8%, 29.6%, and 11.4%, respectively. Taking Group B as reference, Group A patients had higher risk of complications (p = 0.00001; OR 7.4, 95% CI: 2.98-18.7) while Group C ones had significantly less risk (p = 0.02; OR 0.3, 95% CI: 0.1-0.91). This study found that duration of prodromal phase is an independent predictor of complicated STEC-HUS and confirms that shorter prodromal phase is associated with worse prognosis. A higher resolution version of the Graphical abstract is available as Supplementary information.

General recommendations for the management of glomerular diseases-2023

Glomerular diseases are associated with extrarenal complications, such as thromboembolism, cardiovascular events and particularly infections. A thorough knowledge of the various immunosuppressants and their associated toxicity profile is therefore of great importance. While nephrologists usually have extensive experience with calcineurin inhibitors and antimetabolites, two other compounds (rituximab, in severe cases cyclophosphamide) are used comparatively infrequently and will be discussed in more detail. Moreover, practical recommendations for the prevention of thromboembolism in states of nephrosis and for the prophylaxis of Pneumcystic jirovecii pneumonia are provided.

#4432 ECYSCO: A EUROPEAN COHORT DEDICATED TO CYSTINOSIS

Abstract Background and Aims Cystinosis is a rare multisystem lysosomal storage disease due to variants in the CTNS gene, coding for the carrier protein cystinosine, a lysosome membrane transporter causing cystine accumulation with a reported incidence of 1:180,000 live births. Specific treatment by cysteamine decreases renal and extrarenal complications frequency and increases life expectancy. Recently, new treatments for cystinosis entered into the European market with an extended-release formulation of cysteamine and a new formulation of eye drops. The aim of this project is to describe the natural history of the disease and long-term clinical manifestations. Method We set up a European, multi-centre, longitudinal, non-interventional cohort, ECYSCO, that uses observational study methods to collect uniform data. 243 patients with a confirmed diagnosis of cystinosis and followed in 25 French and 5 European centers (Belgium, Italy, Spain and Germany) were included. Data are collected on the secure RaDiCo platform, via an e-CRF (REDCap). Results Data from 180 patients (50.0% male) were analyzed. Median age at diagnosis was 1.3 years [IQ 0.8; 1.9], with earlier diagnosis since the 1980s, but no further improvement in the 2000s. Genetic analysis was available for 174 patients: 57 (32.8%) presented with homozygous 57kb deletion in the CTNS gene, 71 (40.8%) with heterozygous 57kb deletion associated with another variant and 46 (26.4%) with other variants. The type of variant had no impact on the age at diagnosis. Median age at cysteamine start was 1,6 years (IQ 1.0-3.0). An improvement on age at treatment start was observed after the 1990s. All but 6 patients were treated with cysteamine. 71 patients received immediate release formulation (Cystagon®) and 103 received extended release formulation (Procysbi®). Median white blood cell cystine level was correct at 1.2 nmol ½ cystine/mg protein (IQ 0.59; 2.20). The median duration of treatment was 21.5 years [IQ 11.7; 31.1]. 167 (95,9%) patients also received cysteamine ocular gel, Cystadrops®. Median age at inclusion was 19.08 years (IQ 10.43; 31.41). At that time, 104 patients (57.8%) had reached end-stage renal disease (ESRD). There was no impact of genotype on age at ESRD. Median age at ESRD was 12.9 years [IQ 9.9; 18.0]. A 5-year gain in renal survival was observed after the 1990s. 102 patients (56.7%) received a kidney transplant. Among these transplanted patients: 76 (74.5%) received 1 transplant, 23 (22.5%) received 2 consecutive transplants, and 3 (2.9%) received 3. Median eGFR in the remaining patients was 58.9 ml/min [IQ 40.4; 82.2]. Extrarenal manifestations included hypothyroidism in 61 (33.9%) patients, diabetes mellitus in 11 (6.1%), skeletal manifestations in 73 (40.5%), myopathy in 32 (17.8%), and neurological disorders in 22 (12.2%). At inclusion, 36 patients had no ESRD and no extra-renal complication. Conclusion Cystinosis is a good example of a pediatric disease with multiorgan involvement extending into adult care. More than half of patients are adults and have reached ESRD even if age at renal replacement therapy start has increased. The high frequency of extra-renal manifestations demonstrates the importance of a multidisciplinary follow up of these patients.

Hyperhydration to Improve Kidney Outcomes in Children with Shiga Toxin-Producing E. coli Infection: a multinational embedded cluster crossover randomized trial (the HIKO STEC trial)

BackgroundShiga toxin-producing E. coli (STEC) infections affect children and adults worldwide, and treatment remain solely supportive. Up to 15–20% of children infected by high-risk STEC (i.e., E. coli that produce Shiga toxin 2) develop hemolytic anemia, thrombocytopenia, and kidney failure (i.e., hemolytic uremic syndrome (HUS)), over half of whom require acute dialysis and 3% die. Although no therapy is widely accepted as being able to prevent the development of HUS and its complications, several observational studies suggest that intravascular volume expansion (hyperhydration) may prevent end organ damage. A randomized trial is needed to confirm or refute this hypothesis.MethodsWe will conduct a pragmatic, embedded, cluster-randomized, crossover trial in 26 pediatric institutions to determine if hyperhydration, compared to conservative fluid management, improves outcomes in 1040 children with high-risk STEC infections. The primary outcome is major adverse kidney events within 30 days (MAKE30), a composite measure that includes death, initiation of new renal replacement therapy, or persistent kidney dysfunction. Secondary outcomes include life-threatening, extrarenal complications, and development of HUS. Pathway eligible children will be treated per institutional allocation to each pathway. In the hyperhydration pathway, all eligible children are hospitalized and administered 200% maintenance balanced crystalloid fluids up to targets of 10% weight gain and 20% reduction in hematocrit. Sites in the conservative fluid management pathway manage children as in- or outpatients, based on clinician preference, with the pathway focused on close laboratory monitoring, and maintenance of euvolemia. Based on historical data, we estimate that 10% of children in our conservative fluid management pathway will experience the primary outcome. With 26 clusters enrolling a mean of 40 patients each with an intraclass correlation coefficient of 0.11, we will have 90% power to detect a 5% absolute risk reduction.DiscussionHUS is a devastating illness with no treatment options. This pragmatic study will determine if hyperhydration can reduce morbidity associated with HUS in children with high-risk STEC infection.Trial registrationClinicalTrials.gov NCT05219110. Registered on February 1, 2022.

Kidney Transplantation in Patients With Monoclonal Gammopathy of Renal Significance.

Monoclonal gammopathy of renal significance (MGRS) defines disorders characterized by direct or indirect kidney injury caused by a monoclonal immunoglobulin produced by a B-cell or plasma-cell clone that does not meet current hematologic criteria for therapy. MGRS-associated kidney diseases are diverse and can result in the development of end-stage kidney disease. The current paradigm states that the underlying hematologic condition should be treated and in deep remission before kidney transplantation can be performed because recurrence has been reported for all MGRS-associated kidney diseases. However, we suggest that decisions regarding kidney transplantation in MGRS patients should be individualized considering many factors such as the subtype of MGRS-associated kidney disease, patient age and comorbidity, presence and risk of extrarenal complications, estimated waiting time, the availability of a living kidney donor, and previous hematological treatment and response. Thus, kidney transplantation should be considered even in treatment-naive patients, with hematological treatment initiated after successful kidney transplantation.