Tubular Disorders Research Articles

Clear cell sarcoma of the kidney in Austrian children: Long-term survival after relapse.

Clear cell sarcoma of the kidney (CCSK) is a rare malignant childhood renal tumour. Recently, the central nervous system (CNS) was found to be the most frequent site of relapse associated with a poor outcome. Optimal treatment strategies are scarce. Retrospective data analysis of all Austrian children with CCSK. They were enrolled in the Austrian-Hungarian Wilms Tumour Study (AHWTS) 1989, the SIOP93-01 or the SIOP2001 study between 1990 and 2019. Demographic, diagnostic, treatment-related variables and survival data were analysed. We identified 12 children with CCSK (M=7, F=5; median age 1.6years). All had localised disease (stage I: 2; stage II: 2; stage III: 8) at diagnosis, and a first complete remission (CR1) was achieved in 12/12. Six patients are in an ongoing CR1 (median follow-up 10years). Six other patients had a relapse (local 1; brain 5) a median time of 2.4years from diagnosis. Two patients died of the disease 4months and 2.8years after first relapse. Four of five patients with CNS relapse are in CR2 with a median follow-up time of 9.3years after relapse diagnosis. Relapse treatment included a combination of chemotherapy, radiation and surgery. Two children received high-dose chemotherapy followed by autologous stem cell rescue, and one child received intrathecal mafosphamide. Long-term side effects after treatment were impaired tubular renal function (n=4), cardiomyopathy (n=1) and growth disorders (n=1). In this series, the brain was the most common site of relapse. Long-term survival after recurrence was achievable with intensive multimodal therapy.

Fumaric acid ester-induced renal Fanconi syndrome: evidence of mitochondrial toxicity.

BackgroundFumaric acid esters (FAEs) are used to treat chronic plaque psoriasis. Fumarate is a crucial component of the Krebs cycle and mitochondrial function. Proximal tubule cells have high energy demands and rely on aerobic respiration. Proximal tubular dysfunction can cause renal Fanconi syndrome and acute kidney injury. We sought to better understand the mechanism for this in the context of FAE therapy.MethodsWe describe a case series of 10 patients with FAE-associated Fanconi syndrome. Patients were diagnosed and managed at a tertiary renal tubular disorder clinic, with examination of serum and urine biochemistry. Five patients had a renal biopsy with examination of the specimens by electron microscopy.ResultsThe median age was 36.5 years [interquartile range (IQR) 32.25–54.25]. The median dose of FAE was 720 mg/day (IQR 390–720). There was low molecular weight proteinuria: the median urinary retinol-binding protein (RBP) at presentation was 8385 μg/mL (IQR 2793–14 600) and the RBP:creatinine ratio was 710 (IQR 390–2415). All patients had hyperphosphaturia [median fractional excretion of phosphate 24.2% (IQR 20.8–26.9), normal range <20%] as well as relative hypophosphataemia, with a median serum phosphate concentration of 0.93 mmol/L (IQR 0.83–0.97). Renal histology showed proximal tubular damage and abnormal mitochondrial morphology. Two patients had a favourable biochemical response to treatment with probenecid.ConclusionsWe document for the first time that FAE-associated renal Fanconi syndrome is associated with mitochondrial damage visible on electron microscopy. This effect may be ameliorated by antagonism of the organic anion transporter with probenecid.

Positive correlation between renal tubular flattening and renal tubular injury/interstitial fibrosis in murine kidney disease models.

The number of patients with chronic kidney disease (CKD) is growing continuously globally. In order to study pathogenesis and mechanisms, many animal models have been developed, including spontaneous, genetic, and induced models. Although each type of CKD shows disease-specific tissue changes in the early stages, tubular disorder and interstitial fibrosis histologically occur in the course of progression to end-stage renal failure. Therefore, the quantification of tubular disorder and interstitial fibrosis in CKD research using animal models is essential for measuring the degree of CKD severity and, thus, efficacy of therapeutic agents. Several strategies have been used to quantify interstitial fibrosis. Among scoring factors, renal tubular flattening can be quantitatively evaluated easily and inexpensively. However, the diagnostic value of renal tubular flattening evaluation has not been investigated previously. Therefore, in this study, we investigated the correlation between renal tubular flattening and interstitial fibrosis or renal tubular injury markers. We observed a strong correlation between the degree of tubular injury/interstitial fibrosis and renal tubular flattening in three types of mouse renal disease model. This is advantageous because rapidly advancing technologies such as artificial intelligence and image processing can be easily applied; hence, a more precise, objective, and quantitative diagnosis should be possible in the future.

Isolated Glycosuria in a Child in Sri Lanka

Renal glycosuria or benign glycosuria is a rare autosomal recessive condition where glucose is excreted from the urine while having normal serum glucose levels, as a result of a defect in low affinity sodium glucose transporter (SGLT2) in the proximal convoluted tubule (PCT) of the nephron. Benign glycosuria or renal glycosuria has been described as an autosomal recessive disorder. It is usually benign and most of the time asymptomatic and considered as an incidental finding. However, childhood glycosuria is associated with many other tubular disorders such as an Fanconi’s syndrome, Cystinosis, Wilson’s disease, Lowe’s syndrome, Tyrosinaemia and the initial presentation of childhood diabetes mellitus

Clinical Gitelman Syndrome with Periodic Paralysis and Anemia

Gitelman syndrome is a rare, autosomal recessive, renal tubular salt-wasting disorder characterized by hypokalemia andmetabolic alkalosis combined with hypomagnesemia and hypocalciuria. A 13-year-old male patient came with acute flaccidparalysis, pain, and weakness in limb muscles. Laboratory results showed hypokalemia, hypocalcemia, hypomagnesemia,and metabolic alkalosis accompanied by anemia and elevated serum transaminases. An electrocardiogram test showed aprolonged QT wave. Physical examination showed blood pressure 118/68 mmHg; heart rate 95x/minute; respiration rate 262 x/minute; temperature 37.6⁰C, weight 80 kg, height 160 cm, and BMI 31.25 kg/M . Neurological examination weakness inthe lower limb, negative pathological reflex. Hematology examination showed Hb 9.8 g/dL, MCV 82.3 fL, MCH 26.8 pg,MCHC 32.5 g/dl, WBC 16.87x10³/μL, platelets 320 x10 /μL, serum iron 47 mg/dL, TIBC 229 mg/dL, ferritin 38.45 ng/mL.Peripheral blood smear showed hypochromic microcytic anemia. Blood gas pH 7.47; pCO2 39 mmHg; pO2 44 mmHg;HCO3- 28.4 mmol/l; Beecf 4.7 mmol/l; SO2 83%; AaDO2 114; thus supporting metabolic alkalosis. Cortisol level was 11.39ug/dL, ANA test result was positive at 17.2 IU/mL, the complement level was normal, dsDNA antigen was negative. Due tohypokalemia, hypocalcemia, hypomagnesemia, and metabolic alkalosis, this patient was diagnosed with Gitelmansyndrome with anemia. The diagnosis should be confirmed by molecular DNA diagnostic studies to identify mutations ofthe gene encoding the thiazide-sensitive Na-Cl-cotransporter.

Gitelman syndrome, a rare condition: three clinical cases and pathophysiology review

Introduction: Gitelman syndrome (GS) is a renal tubular disorder characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. Clinical manifestations are nonspecific. Herein are reported three cases of GS with different age of onset, clinical manifestations, and management.Case Reports: Case 1 was a sixteen-year-old female, while Cases 2 and 3 presented at an atypical age (seven and eight years). Clinical manifestations mainly consisted of abdominal pain with vomits, together with past history of muscular weakness in Case 1. Diagnosis was based on usual electrolyte abnormalities, such as metabolic alkalosis with hypokalemia. Genetic diagnosis was confirmed in Case 3. Patients were treated with oral potassium, magnesium, and spironolactone, with symptom and electrolytic profile improvement.Discussion/Conclusions: GS is a rare condition that should be considered in cases of metabolic alkalosis and hypokalemia and all pediatricians should be aware of. Diagnosis is established based on biochemical profile and treatment response.

Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay.

BackgroundFamilial renal glucosuria is a rare renal tubular disorder caused by SLC5A2 gene variants. Most of them are exonic variants and have been classified as missense variants. However, there is growing evidence that some of these variants can be detrimental by affecting the pre-mRNA splicing process. Therefore, we hypothesize that a certain proportion of SLC5A2 exonic variants can result in disease via interfering with the normal splicing process of the pre-mRNA.MethodsWe used bioinformatics programs to analyze 77 previously described presumed SLC5A2 missense variants and identified candidate variants that may alter the splicing of pre-mRNA through minigene assays.ResultsOur study indicated six of 7 candidate variants induced splicing alterations. Variants c.216C > A, c.294C > A, c.886G > C, c.932A > G and c.962A > G may disrupt splicing enhancer motifs and generate splicing silencer sequences resulting in the skipping of exon 3. Variants c.305C > T and c.1129G > A probably disturb splice sites leading to exon skipping.ConclusionTo our knowledge, we report, for the first time, SLC5A2 exonic variants that produce alterations in pre-mRNA. Our research reinforces the importance of assessing the consequences for putative point variants at the mRNA level. Additionally, we propose that minigenes function analysis may be valuable to evaluate the impact of SLC5A2 exonic variants on pre-mRNA splicing without patients’ RNA samples.

A Pediatric Case of Long-term Untreated Distal Renal Tubular Acidosis

Distal renal tubular acidosis (dRTA) is a rare renal tubular disorder characterized by normal anion gap metabolic acidosis, hypokalemia, and high urine pH. It can be inherited or acquired. In untreated pediatric patients with dRTA, rickets and growth retardation are common. We report the case of a 12-year-old Lao girl who presented with typical clinical features of dRTA with severe bone deformities that developed after a bed-ridden state due to a bicycle accident at the age of 8 years. Initial laboratory tests revealed metabolic acidosis with a normal anion gap, hypokalemia, and alkali urine. Renal ultrasonography revealed bilateral medullary nephrocalcinosis. Whole exome sequencing revealed no pathogenic mutations. After treatment with oral alkali, potassium, and vitamin D, she could walk and run. Later, she underwent corrective orthopedic surgeries for bony deformities. Thus, in pediatric dRTA patients, despite severe symptoms remaining untreated, accurate diagnosis and proper management can improve quality of life. Key words: Distal renal tubular acidosis; Failure to thrive; Bony deformity; Muscle paralysis

Eight novel KCNJ1 variants and parathyroid hormone overaction or resistance in 5 probands with Bartter syndrome type 2

PurposeBartter syndrome type 2 (BS2) is an autosomal recessive renal tubular disorder, which is caused by the mutations in KCNJ1. This study was designed to analyze and describe the genotype and clinical features of five Chinese probands with BS2. MethodsIdentify KCNJ1 gene variants by the next generation sequencing and evaluate their mutation effects according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines. ResultsTen variants including eight novel ones of KCNJ1 gene were found, the most common type was missense variant. The common symptoms and signs from high to low incidence were: polydipsia and polyuria (5/5), one of them (1/5) presented with diabetes insipidus; maternal polyhydramnios and premature delivery (4/5); growth retardation (3/5). Two patients presented with hypochloremic metabolic alkalosis and hypokalemia; whereas the acid-base disturbance was absent in the others. One patient had evident parathyroid hormone (PTH) resistance (hypocalcemia, hyperphosphatemia and markedly elevated PTH levels), three presented with PTH overacting (hypercalcemia, hypophosphatemia and mild elevated PTH levels), and one showed normal blood calcium and phosphorus concentrations with high-normal PTH levels. All patients had nephrocalcinosis and/or hypercalciuria, and one of them complicated with nephrolithiasis. Indomethacin has significant therapeutic effect on the growth retardation, polydipsia and polyuria and treatment was associated with a decrease in urine calcium excretion, normalization of electrolyte disturbance and PTH parameters. ConclusionsTen variants of KCNJ1 gene were identified in five Chinese probands. These patients had atypical BS phenotype lacking evident metabolic alkalosis and/or manifesting with PTH overaction/resistance, which reminds clinicians to carefully differentiate BS2 with other parathyroid disorders. This is the first report of BS2 from Chinese populations.

Bartter Syndrome in Children; A Cause of Severe Hypokalemic Metabolic Alkalosis: Clinical Case Report and Literature Review

Bartter syndrome is an inherited renal tubular disorder caused by a defective salt reabsorption in the thick ascending limb of loop of Henle. It characterized by urinary loss of sodium, potassium, and chloride; hypokalemic metabolic alkalosis; normal blood pressure, high plasma levels of renin and aldosterone. There is phenotypical and genetic variability of Bartter syndrome since were identified five genes responsible for five different forms of Bartter syndrome. The objective of this work is to report a clinical case to study the pathophysiological, clinical, biological and therapeutic features of this syndrome.&#x0D; Materials and Methods: We reported a case of 04-month-old male infant admitted for acute dehydration secondary to polyuro-polydipsia syndrome and vomiting. In clinical presentation the patient had a dysmorphic syndrome with triangular face, protruding ears and flattened nasal root. Laboratory tests revealed hypokalemia, hyponatremia, metabolic alkalosis and hypercalciuria. Treatment with indomethacin was started at 1 mg/kg per day with favorable outcome.

EFFICACY AND SAFETY OF EVEROLIMUS IN KOREAN KIDNEY TRANSPLANT RECIPIENTS: RESULTS FROM A PROSPECTIVE, OPEN LABEL, MULTICENTER, SINGLE ARM TRIAL

Purpose: This research was planned as a part of regulatory post marketing surveillance according to the Standard for Re-examination of New Drugs to reconfirm the safety and efficacy of everolimus (Certican®) combined with reduced Cyclosporine A (CsA) after renal transplantation, by investigating incidence of any serious adverse event and adverse event early (12 weeks) after administration. Methods: This study involving 4 centers in Korea was performed from 17 Mar 2012 to 8 Oct 2013. In this prospective, open-label, multicenter, single-arm study, 54 patients were followed up for 12 weeks after administration of the study drug. The concentration of everolimus was adjusted to be 3-8 ng/ml. The concentration of CsA was adjusted to be 100-200 ng/ml till 4 weeks after then to be 75-150 ng/ml. The primary endpoints was incidence of serious adverse events and secondary endpoints was incidence of adverse events, presence or absence of acute rejection, and renal function were measured. Results: Of 54 patients enrolled in the study, 1 patient (consent withdrawal) and 4 patients (other reasons) were withdrawn and 49 in total completed the study. The subjects of Intention to treat (ITT) analysis were 52. Forty nine (94.23%) of 52 patients reported 165 adverse events during the study period. The overall incidence of biopsy-proven acute rejection within 12 weeks after transplantation was 4 patients (7.69 %). A total of 17 serious adverse events were reported in 12 patients (23.08 %). The most frequent of serious adverse events were Urinary tract infection, Blood creatinine increased, Lymphocele (3.85 %) followed by Bronchopneumonia (1.92 %), Gastritis, Nephropathy toxic, Oliguria, Renal necrosis, Renal tubular disorder, Cerebral infarction, Convulsion, Compression fracture, and Transplant rejection (1.92 %). Of 17 serious adverse events reported this time, 5 cases (29.41 %) were serious adverse drug reactions whose causality to the study drug could not be ruled out. The most frequent serious adverse drug reactions was Lymphocele (3.85 %) (Table 1). The analysis of renal function in the ITT set showed mean e-GRF was 7.51 ± 3.06 mL/min/1.73m2 at Visit 1 (before transplantation), 71.66 ± 23.81 mL/min/1.73 m2 at Visit 3 (1 week), 70.54 ± 20.33 mL/min/1.73 m2 at Visit 4 (4 weeks) and 66.76 ± 18.08 mL/min/1.73 m2 at Visit 5 (12 weeks). Renal function (e-GFR) was decreased by 6.74 ± 20.27 mL/min/1.73 m2 with statistically significant difference (p=0.0242) at Visit 5 from Visit 3. Conclusions: Compared with previous literature reports, there was no clinically significant finding in terms of safety and efficacy in this study. And further follow-up evaluation for renal function would be needed because it was not enough follow-up periods to get conclusion.

Clinical characteristics of hospitalized patients with 2019 novel coronavirus disease indicate potential proximal tubular dysfunction.

Clinical characteristics of hospitalized patients with 2019 novel coronavirus disease indicate potential proximal tubular dysfunction.

Identification of compound mutations of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome exhibiting Bartter syndrome-liked phenotypes

BackgroundGitelman syndrome is a rare salt-losing renal tubular disorder associated with mutation of SLC12A3 gene, which encodes the Na-Cl co-transporter (NCCT). Gitelman syndrome is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation. Different SLC12A3 variants may lead to phenotypic variability and severity.MethodsIn this study, we reported the clinical features and genetic analysis of a Chinese pedigree diagnosed with Gitelman syndrome.ResultsThe proband exhibited hypokalaemia, hypomagnesemia, metabolic alkalosis, but hypercalciuria and kidney stone formation. The increased urinary calcium excretion made it confused to Bartter syndrome. The persistent renal potassium wasting resulted in renal tubular lesions, and might affect urinary calcium reabsorption and excretion. Genetic analysis revealed mutations of SLC12A3 gene with c.433C > T (p.Arg145Cys), c.1077C > G (p.Asn359Lys), and c.1666C > T (p.Pro556Ser). Potential alterations of structure and function of NCCT protein due to those genetic variations of SLC12A3 are predicted. Interestingly, one sibling of the proband carried the same mutant sites and exhibited similar clinical features with milder phenotypes of hypokalemia and hypomagnesemia, but hypocalciuria rather than hypercalciuria. Family members with at least one wild type copy of SLC12A3 had normal biochemistry. With administration of spironolactone, potassium chloride and magnesium supplement, the serum potassium and magnesium were maintained within normal ranges.ConclusionsIn this study, we identified compound mutations of SLC12A3 associated with varieties of clinical features. Further efforts are needed to investigate the diversity in clinical manifestations of Gitelman syndrome and its correlation with specific SLC12A3 mutations.

Severe Polyhydramnios with Consistent Fetal Full Bladder: A Novel Sign of Antenatal Bartter's Disease

Bartter's disease, an inherited renal tubular disorder is due to a defect in ion transport across the ascending limb of the loop of Henle leading to failure of the ability of kidneys to concentrate urine and hence polyuria. We present three fetuses of mothers with severe polyhydramnios with normal maternal blood sugar profile, routine Toxoplasma, Rubella, Cytomegalovirus, Herpes (TORCH) serology. The ultrasound showed no structural anomaly in the fetus, but consistent overdistended bladder with severe polyhydramnios was observed without any evidence of obstructive uropathy. The biochemical test on amniotic fluid was suggestive of Bartter's disease in case 1 and borderline in case 2, and next-generation sequencing confirmed a mutation of KCNJ1 associated with Bartter's disease Type II in case 1 and a mutation in SLC21A1 in case 2. Amniotic fluid biochemistry was inconclusive in case 3. A consistent full bladder with severe polyhydramnios with onset around 24 to 25 weeks was a novel finding which was observed due to fetal polyuria and can be used as a clue to investigate cases with severe polyhydramnios with no structural anomaly. Antenatal diagnosis will help in the proper management of child and genetic counseling for the next pregnancy.

SUN-LB133 Analysis of Clinical Characteristics and Gene Mutation in Four Cases of Gitelman Syndrome

Gitelman syndrome is an autosomal recessive renal tubular disorder characterized by renal salt wasting with secondary hyperreninemia and hyperaldosteronism, chronic hypokalemia with renal K wasting and metabolic alkalosis, and hypomagnesemia, and hypocalciuria. GS was found to be caused by mutations in SLC12A3 encoding the thiazide-sensitive sodium chloride cotransporter (NCCT) on the apical membrane of distal convoluted tubule. The prevalence worldwide is estimated at approximately 1:40,000, making it one of the most frequent inherited renal tubular disorders. To date, over 400 mutations scattered throughout SLC12A3 have been identified in GS patients. The majority of patients are compound heterozygous for SLC12A3 mutations, but a significant number of GS patients are found to carry only a single SLC12A3 mutation. The type of the SLC12A3 mutation may be a determinant factor in the severity of GS. The purpose of this study is to analyze clinical characteristics and gene mutation in four cases of GS. Methods: Four patients with closely resembling Gitelman syndrome was selected. Results: Six SLCl2A3 gene mutations were found in these four patients. There were one SLCl2A3 homozygous mutation in case 1 and case 3, and two SLCl2A3 heterozygous mutations in case 2 and case 4, respectively. This six gene mutations include missense mutations, frameshift mutations, and nonsense mutations. Four patients were diagnosed with Gitelman syndrome. Case 4 is the most severe with severe hypokalemia, accompanied by ventricular arrhythmias, which may be related to the presence of two SLC12A3 gene mutations in the patient. Conclusions: Four patients in this study were diagnosed with Gitelman syndrome based on their clinical characteristics and genetic testing results. For patients with hyperreninemia and hyperaldosteronism, chronic hypokalemia with renal K wasting and metabolic alkalosis, and hypomagnesemia, and hypocalciuria need to exclude Gitelman syndrome.Key words: Gitelmen Syndrome, Mutations, SlC12A3 gene

Antihypertensive and renal protective effect of Shunaoxin pill combined with captopril on spontaneous hypertension rats

IntroductionAccording to previous reports, hypertension has become the most common chronic disease in the world. Captopril, an angiotensin-converting enzyme inhibitor, has been widely used for the therapy of arterial hypertension and cardiovascular diseases therapy. Besides, Shunaoxin pill (SNX) as a traditional Chinese prescription showed antihypertensive effect in our previous research. ObjectiveThis study means to investigate whether SNX combining with captopril could show antihypertensive and renal protective effects on spontaneous hypertension rats (SHRs). MethodsSHRs were randomly assigned to four treatment groups, including non-treated group, captopril, SNX, and captopril + SNX-treated groups. Their body weight and systolic blood pressure (SBP) were measured weekly. Histopathological examination was analyzed through Masson staining and hematoxylin and eosin staining. Biochemical analyses, ELISA, and western blot were used to analyze their combining mechanism. ResultsIn this experiment, this combinatorial therapy significantly reduced aortic wall thickness, increased the content of NO, NOS and eNOS, decreased the content of bradykinin and endothelin 1(ET-1), and regulated the levels of TG, TC and HDLC back to normal, which suggested they could induce vasodilation and lower blood pressure. Meanwhile, histological examination alleviated that captopril + SNX remarkably inhibited renal injury, including tubular disorder, inflammatory cell infiltration and fibrosis. They down-regulated the serum levels of BUN and Cr, protein expression of IL-1β, NF-κB, Bax, Cyt c, caspase 3, 8 and 9 in kidney tissues and significantly increased the levels of Bcl-2 in kidney tissues compared with monotherapy group. ConclusionThe combinatorial treatment of SNX and captopril lowered blood pressure through adjusting NO/NOS, ET-1 and dyslipidemia profile. Furthermore, this treatment alleviated the kidney damage via reducing the release of inflammatory factors and the expression of apoptotic markers. Therefore, these results provided a rationale for future clinical use of SNX combined with captopril in antihypertensive and protecting renal functions in hypertension.

A novel compound heterozygous mutation of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome.

Gitelman syndrome (GS) is an autosomal recessive renal tubular disorder characterized by salt wasting and hypokalemia resulting from loss-of-function mutations in the solute carrier family 12A3 (SLC12A3) gene encoding the thiazide-sensitive NaCl cotransporter (NCC). Here, we investigated the clinical manifestations and genetic features of a Chinese pedigree with GS. Next-generation sequencing and Sanger sequencing analysis were performed to define and confirm the SLC12A3 gene mutations of the patient (proband II:1) and this pedigree. Clinical manifestations and biochemical parameters were collected and analyzed. Genetic analysis of the SLC12A3 gene identified two novel mutations in the proband, heterozygous (c.2842delT) and heterozygous (c.1569_1586del) mutation, respectively. Additionally, heterozygous (c.2842delT) mutation in SLC12A3 gene was found in his father and younger brother. The other heterozygous (c.1569_1586del) mutation in SLC12A3 gene was carried by his mother. Two novel mutations may be related to the occurrence of the GS in the pedigree. However, additional studies are particularly required to explore the underlying molecular mechanisms.

Subcellular trafficking of tubular MDM2 implicates in acute kidney injury to chronic kidney disease transition during multiple low-dose cisplatin exposure.

Acute kidney injury (AKI) is the leading cause of renal failure, and quite a few patients will advance to chronic kidney disease (CKD) in the long term. Here, we explore the roles and mechanisms of tubular epithelial cells (TECs) during repeated cisplatin (CP) induced AKI to CKD transition (AKI-CKD). Previously, we reported that murine double minute 2 (MDM2), an E3-ubiquitin ligase, is involved in tubulointerstitial fibrosis. However, whether tubular MDM2 is implicated in AKI-CKD is undefined. Currently, we confirmed that during AKI-CKD, MDM2 shifts from nucleus to cell membrane in TECs both in vivo and in vitro. Whereas regulating MDM2 distribution chemically or genetically has a prominent impact on tubular disorders. And then we investigated the mechanisms of the above findings. First, in the nucleus, repeated CP administration leads to MDM2 reduction with escalated p53 and cell cycle G2/M arrest. On the other hand, multiple CP treatment increases the level of membranous MDM2 with ensuing integrin β8 degradation and TGF-β1 activation. More interestingly, anchoring MDM2 on cell membranes can mimic the reduction of integrin β8 arousing by repeated CP exposure. Collectively, our findings provided the evidence that tubular MDM2 subcellular shuttling is involved in AKI-CKD through p53-G2/M arrest and integrin β8 mediated TGF-β1 activation.

Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis

Distal renal tubular acidosis is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in three genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70% of familial cases of distal renal tubular acidosis. Recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that further monogenic causes of distal renal tubular acidosis remain to be discovered. Panel sequencing and/or whole exome sequencing was performed in a cohort of 17 families with 19 affected individuals with pediatric onset distal renal tubular acidosis. A causative mutation was detected in one of the three "classical" known distal renal tubular acidosis genes in 10 of 17 families. The seven unsolved families were then subjected to candidate whole exome sequencing analysis. Potential disease causing mutations in three genes were detected: ATP6V1C2, which encodes another kidney specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families), previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of the known distal renal tubular acidosis gene SLC4A1. Two of these mutations were assessed for deleteriousness through functional studies. Yeast growth assays for ATP6V1C2 revealed loss-of-function for the patient mutation, strongly supporting ATP6V1C2 as a novel distal renal tubular acidosis gene. Thus, we provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59%) with this disease, identified mutations in ATP6V1C2 as a novel human candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis.

SUN-007 MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE AND MONOCLONAL IMMUNOGLOBULIN RENAL DAMAGE IN MALIGNANT B-CELL DISORDERS: REAL CLINICAL PRACTICE – WHAT IS BEYOND MONOCLONAL IMMUNOGLOBULIN AMYLOIDOSIS?

Monoclonal gammopathy of renal significance (MGRS) merges paraprotein-mediated renal disorders in patients who do not meet criteria for multiple myeloma (MM) and systemic lymphoma (SL). MGRS is driven by monoclonal immunoglobulin (MIg), secreted by small non-malignant B-cell clone. By definition, diagnosis of MGRS requires identification of MIg deposition on kidney biopsy. Spectrum of MGRS, beyond MIg related amyloidosis, includes various types of tubular and glomerular disorders with organized and non-organized MIg or fragments thereof deposition: light chain proximal tubulopathy (LCPT), crystal-storing histiocytosis, fibrillary glomerulonephritis (GN), type I cryoglobulinemic (Cryo) GN, immunotactiod GN, monoclonal immunoglobulin deposition disease (MIDD), proliferative GN with monoclonal Ig deposits (PGNMID), and C3 GN. Membranous nephropathy (MN) and anti-glomerular basement (anti-GBM) GN have also been described. Same lesions may occur during symptomatic B-cell proliferation, however high tumor mass with massive paraprotein precipitation more often results in cast-nephropathy (CN) in MM, or in glomerular intracapillary deposition of MIgM in Waldenström’s macroglobulinemia (WM). We aimed to evaluate the spectrum of MGRS versus MM/SL associated paraprotein-induced renal damage in patients, treated in our unit in 1997-2017. We identified 168 patients with biopsy-proven paraprotein-induced kidney damage, underwent advanced hematologic evaluation. Patients with MIg amyloidosis were excluded from further analysis. Pathology study included light microscopy and immune staining in all cases, and electron microscopy in 19% of cases. Study group included 41 patients, M/F 20/21, median age 61 [30; 76] years. Indications for kidney biopsy were nephrotic syndrome in 6 (14.6%), decline of kidney function in 17 (41.4%), or both in 18 (43.9%) of cases. Clinical diagnosis and pathology are shown in the Table 1. Tabled 1Clinical setting/Pathology patternMGRS 14 (34.1%)MM 20 (48.7%)WM 6 (14.6%)B-cell lymphoma 1 (2.4%)TotalMIDD10818PGNMID213MN22CN77LCPT33CN+LCPT11CN+MIDD22LCPT+MIDD11Anti-GBM GN11Cryo GN11C3 GN112Intracapillary deposition of MIgM44Total14246145 Open table in a new tab Patients with MGRS presented mainly with MIDD with few cases of PGNMID and MN. Patients with MM demonstrated not only CN, but also LCPT and MIDD, and various combinations of these patterns, single cases of PGNMID and anti-GBM GN were also observed in the setting of MM. Patients with WM presented mainly, but not exclusively, with glomerular intracapillary deposition of MIgM, with single cases of Cryo GN and C3 GN. The only case of B-cell lymphoma showed C3 GN. And vice versa, LCDD and PGNMID patterns were found both in MGRS and MM, and only MN was found exclusively in MGRS setting. CN and LCPT or both and in combination with LCDD were characteristic for MM. C3 GN was found in WM and B-cell lymphoma, single cases of anti-GBM GN and Cryo GN were found in MM and WM respectively. We did not find fibrillary and immunotactoid GN in our case series, most likely because of lack of electron microscopy studies. Conditions like LCPT, LCDD, PGNMID, C3 GN and anti-GBM GN, attributed in the literature mostly to MGRS, are also seen in patients with overt malignant B-cell disorders, demanding advanced henatology evaluation. Dual patterns of renal damage are not that rare, reflecting biclonal nature of B-cell proliferation.