Clinical and molecular characteristics of two Italian kindreds with hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome.

PURPOSE: Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome, also known as Barakat syndrome, is a rare autosomal dominant disease characterized by the triad of hypoparathyroidism, deafness, and renal abnormalities. The disorder is caused by the haploinsufficiency of the zinc finger transcription factor GATA3 and exhibits a great clinical variability with an age-dependent penetrance of each feature. We report two unrelated kindreds whose probands were referred to our outpatient clinic for further evaluation of hypoparathyroidism. METHODS: The proband of family 1, a 17-year-old boy, was referred for severe hypocalcemia (5.9 mg/dL) incidentally detected at routine blood tests. Abdomen ultrasound showed bilateral renal cysts. The audiometric evaluation revealed the presence of bilateral moderate hearing loss although the patient could communicate without any problem. Conversely, the proband of family 2, a 19-year-old man, had severe symptomatic hypocalcemia complicated by epileptic seizure at the age of 14 years; his past medical history was remarkable for right nephrectomy at the age of 4 months due to multicystic renal disease and bilateral hearing loss diagnosed at the age of 18 years. RESULTS: Based on clinical, biochemical, and radiologic data, HDR syndrome was suspected and genetic analysis of the GATA3 gene revealed the presence of two pathogenetic variants in exon 3, c.404dupC and c.431dupG, in the proband of family 1 and 2, respectively. CONCLUSION: HDR syndrome is a rare cause of hypoparathyroidism and must be excluded in all patients with apparently idiopathic hypoparathyroidism. A correct diagnosis is of great importance for early detection of other HDR-related features and genetic counseling.

Ferroptosis and secondary nephrosis. / é“æ­»äº¡ä¸Žç»§å‘æ€§è‚¾è„ç— .

Secondary nephrosis is a series of chronic kidney diseases secondary to other underlying diseases, mainly manifesting as structural and functional abnormalities of the kidneys and metabolic disorders. It is one of the important causes of end-stage renal disease, with high morbidity and significant harm. Iron is an essential metal element in human cells, and ferroptosis is a non-traditional form of iron-dependent cell death, and its main mechanisms include iron accumulation, lipid metabolism disorders, abnormal amino acid metabolism, and damage to the antioxidant system. Recently studies have found that ferroptosis is involved in the occurrence and progression of secondary nephrosis, and the mechanism of ferroptosis in different secondary nephrosis vary. Therefore, an in-depth and systematic understanding of the association between ferroptosis and secondary nephrosis, as well as their specific regulatory mechanisms, can provide a theoretical basis for the diagnosis, prevention, treatment, and prognosis assessment of secondary nephrosis, laying the foundation for exploring new clinical therapeutic targets for secondary nephrosis.

Nicorandil protects podocytes via modulation of antioxidative capacity in acute puromycin aminonucleoside-induced nephrosis in rats.

Nephrotic syndrome, characterized by proteinuria and hypoalbuminemia, results from the dysregulation of glomerular podocytes and is a significant cause of end-stage kidney disease. Patients with idiopathic nephrotic syndrome are generally treated with immunosuppressive agents; however, these agents produce various adverse effects. Previously, we reported the renoprotective effects of a stimulator of the mitochondrial ATP-dependent K+ channel (MitKATP), nicorandil, in a remnant kidney model. Nonetheless, the cellular targets of these effects remain unknown. Here, we examined the effect of nicorandil on puromycin aminonucleoside-induced nephrosis (PAN) rats, a well-established model of podocyte injury and human nephrotic syndrome. PAN was induced using a single intraperitoneal injection. Nicorandil was administered orally at 30 mg/kg/day. We found that proteinuria and hypoalbuminemia in PAN rats were significantly ameliorated following nicorandil treatment. Immunostaining and ultrastructural analysis under electron microscopy demonstrated that podocyte injury in PAN rats showed a significant partial attenuation following nicorandil treatment. Nicorandil ameliorated the increase in the oxidative stress markers nitrotyrosine and 8-hydroxy-2-deoxyguanosine in glomeruli. Conversely, nicorandil prevented the decrease in levels of the antioxidant enzyme manganese superoxide dismutase in PAN rats. We found that mitochondrial Ca2+ uniporter levels in glomeruli were higher in PAN rats than in control rats, and this increase was significantly attenuated by nicorandil. We conclude that stimulation of MitKATP by nicorandil reduces proteinuria by attenuating podocyte injury in PAN nephrosis, which restores mitochondrial antioxidative capacity, possibly through mitochondrial Ca2+ uniporter modulation. These data indicate that MitKATP may represent a novel target for podocyte injury and nephrotic syndrome.NEW & NOTEWORTHY Our findings suggest that the mitochondrial Ca2+ uniporter may be an upstream regulator of manganese superoxide dismutase and indicate a biochemical basis for the interaction between the ATP-sensitive K+ channel and Ca2+ signaling. We believe that our study makes a significant contribution to the literature because our results indicate that the ATP-sensitive K+ channel may be a potential therapeutic target for podocyte injury and nephrotic syndrome.

Role of the SLC22A17/lipocalin-2 receptor in renal endocytosis of proteins/metalloproteins: a focus on iron- and cadmium-binding proteins.

The transmembrane protein SLC22A17 [or the neutrophil gelatinase-associated lipocalin/lipocalin-2 (LCN2)/24p3 receptor] is an atypical member of the SLC22 family of organic anion and cation transporters: it does not carry typical substrates of SLC22 transporters but mediates receptor-mediated endocytosis (RME) of LCN2. One important task of the kidney is the prevention of urinary loss of proteins filtered by the glomerulus by bulk reabsorption of multiple ligands via megalin:cubilin:amnionless-mediated endocytosis in the proximal tubule (PT). Accordingly, overflow, glomerular, or PT damage, as in Fanconi syndrome, results in proteinuria. Strikingly, up to 20% of filtered proteins escape the PT under physiological conditions and are reabsorbed by the distal nephron. The renal distal tubule and collecting duct express SLC22A17, which mediates RME of filtered proteins that evade the PT but with limited capacity to prevent proteinuria under pathological conditions. The kidney also prevents excretion of filtered essential and nonessential transition metals, such as iron or cadmium, respectively, that are largely bound to proteins with high affinity, e.g., LCN2, transferrin, or metallothionein, or low affinity, e.g., microglobulins or albumin. Hence, increased uptake of transition metals may cause nephrotoxicity. Here, we assess the literature on SLC22A17 structure, topology, tissue distribution, regulation, and assumed functions, emphasizing renal SLC22A17, which has relevance for physiology, pathology, and nephrotoxicity due to the accumulation of proteins complexed with transition metals, e.g., cadmium or iron. Other putative renal functions of SLC22A17, such as its contribution to osmotic stress adaptation, protection against urinary tract infection, or renal carcinogenesis, are discussed.

ER stress and slit diaphragms: is there a connection?

Galloway-Mowat syndrome is a neurorenal syndrome that has been linked with defective transfer RNA and protein translation caused by variants in the multiprotein complex KEOPS. In the kidney, this syndrome seems to primarily affect the podocytes, but the pathogenesis has remained unclear. In this issue of Kidney International, Krausel et al. use Drosophila nephrocytes to link endoplasmic reticulum stress with defects in the slit diaphragm.

Synergistic role of retinoic acid signaling and Gata3 during primitive choanae formation.

Developmental defects of primitive choanae, an anatomical path to connect the embryonic nasal and oral cavity, result in disorders called choanal atresia (CA), which are associated with many congenital diseases and require immediate clinical intervention after birth. Previous studies revealed that reduced retinoid signaling underlies the etiology of CA. In the present study, by using multiple mouse models which conditionally deleted Rdh10 and Gata3 during embryogenesis, we showed that Gata3 expression is regulated by retinoid signaling during embryonic craniofacial development and plays crucial roles for development of the primitive choanae. Interestingly, Gata3 loss of function is known to cause hypoparathyroidism, sensorineural deafness and renal disease (HDR) syndrome, which exhibits CA as one of the phenotypes in humans. Our model partially phenocopies HDR syndrome with CA, and is thus a useful tool for investigating the molecular and cellular mechanisms of HDR syndrome. We further uncovered critical synergy of Gata3 and retinoid signaling during embryonic development, which will shed light on novel molecular and cellular etiology of congenital defects in primitive choanae formation.

The structural and functional workings of KEOPS.

KEOPS (Kinase, Endopeptidase and Other Proteins of Small size) is a five-subunit protein complex that is highly conserved in eukaryotes and archaea and is essential for the fitness of cells and for animal development. In humans, mutations in KEOPS genes underlie Galloway-Mowat syndrome, which manifests in severe microcephaly and renal dysfunction that lead to childhood death. The Kae1 subunit of KEOPS catalyzes the universal and essential tRNA modification N6-threonylcarbamoyl adenosine (t6A), while the auxiliary subunits Cgi121, the kinase/ATPase Bud32, Pcc1 and Gon7 play a supporting role. Kae1 orthologs are also present in bacteria and mitochondria but function in distinct complexes with proteins that are not related in structure or function to the auxiliary subunits of KEOPS. Over the past 15 years since its discovery, extensive study in the KEOPS field has provided many answers towards understanding the roles that KEOPS plays in cells and in human disease and how KEOPS carries out these functions. In this review, we provide an overview into recent advances in the study of KEOPS and illuminate exciting future directions.

Predicting Modifiers of Genotype-Phenotype Correlations in Craniofacial Development.

Most human birth defects are phenotypically variable even when they share a common genetic basis. Our understanding of the mechanisms of this variation is limited, but they are thought to be due to complex gene-environment interactions. Loss of the transcription factor Gata3 associates with the highly variable human birth defects HDR syndrome and microsomia, and can lead to disruption of the neural crest-derived facial skeleton. We have demonstrated that zebrafish gata3 mutants model the variability seen in humans, with genetic background and candidate pathways modifying the resulting phenotype. In this study, we sought to use an unbiased bioinformatic approach to identify environmental modifiers of gata3 mutant craniofacial phenotypes. The LINCs L1000 dataset identifies chemicals that generate differential gene expression that either positively or negatively correlates with an input gene list. These chemicals are predicted to worsen or lessen the mutant phenotype, respectively. We performed RNA-seq on neural crest cells isolated from zebrafish across control, Gata3 loss-of-function, and Gata3 rescue groups. Differential expression analyses revealed 551 potential targets of gata3. We queried the LINCs database with the 100 most upregulated and 100 most downregulated genes. We tested the top eight available chemicals predicted to worsen the mutant phenotype and the top eight predicted to lessen the phenotype. Of these, we found that vinblastine, a microtubule inhibitor, and clofibric acid, a PPAR-alpha agonist, did indeed worsen the gata3 phenotype. The Topoisomerase II and RNA-pol II inhibitors daunorubicin and triptolide, respectively, lessened the phenotype. GO analysis identified Wnt signaling and RNA polymerase function as being enriched in our RNA-seq data, consistent with the mechanism of action of some of the chemicals. Our study illustrates multiple potential pathways for Gata3 function, and demonstrates a systematic, unbiased process to identify modifiers of genotype-phenotype correlations.

Barakat syndrome.

Barakat syndrome, also known as HDR syndrome, is a clinically heterogenous, autosomal dominant rare genetic disease, which frequency is unknown. It is primarily caused by deletion of chromosome 10p14 or mutation of GATA3 gene, located on chromosome 10. Although this syndrome is phenotypically defined by its triad of HDR: hypoparathyroidism (H), deafness (D), renal disease (R), the literature identifies cases with different components, consisting of HD, DR, HR (1). The syndrome was first described by Amin J. Barakat et al. in 1977 in siblings with hypocalcemia and proteinuria (2). So far, about 180 cases have been reported in the worldwide medical literature (3). In this report we present our own case report of patient with Barakat syndrome with hypoparathyrodism, unilateral deafness and renal impairment.

Functional characterization of a novel TP53RK mutation identified in a family with Galloway-Mowat syndrome.

Galloway-Mowat syndrome (GAMOS) is a very rare condition characterized by early-onset nephrotic syndrome and microcephaly with variable neurologic features. While considerable genetic heterogeneity of GAMOS has been identified, the majority of cases are caused by pathogenic variants in genes encoding the four components of the Kinase, endopeptidase, and other proteins of small size (KEOPS) complex, one of which is TP53RK. Here we describe a 3-year-old male with progressive microcephaly, neurodevelopmental deficits, and glomerular proteinuria. He was found to carry a novel homozygous TP53RK missense variant, c.163C>G (p.Arg55Gly), which was considered as potentially disease-causing. We generated a morpholino tp53rk knockdown model in Xenopus laevis showing that the depletion of endogenous Tp53rk caused abnormal eye and head development. This phenotype could be rescued by the expression of human wildtype TP53RK but not by the c.163C>G mutant nor by another previously described GAMOS-associated mutant c.125G>A (p.Gly42Asp). These findings support the pathogenic role of the novel TP53RK variant.

Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome.

BACKGROUND: Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease. METHODS: Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. In vitro and in vivo studies determined the functional significance of the mutations identified. RESULTS: Three biallelic variants of the transcriptional regulator PRDM15 were detected in six families with proteinuric kidney disease. Four families with a variant in the protein's zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in Xenopus embryos disrupted pronephric development. Human wild-type PRDM15 RNA rescued the disruption, but the three PRDM15 variants did not. Finally, CRISPR-mediated knockout of PRDM15 in human podocytes led to dysregulation of several renal developmental genes. CONCLUSIONS: Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.

[Laparoscopic pyeloplasty combined with ultrasonic lithotripsy via nephroscope for treatment of ureteropelvic junction obstruction with renal calculi].

OBJECTIVE: To investigate the efficacy and safety of laparoscopic pyeloplasty combined with ultrasonic lithotripsy via nephroscope in the treatment of ureteropelvic junction obstruction (UPJO) with renal calculi. METHODS: From June 2016 to January 2022, eight patients including five males and three females underwent laparoscopic pyeloplasty combined with ultrasonic lithotripsy via 19.5F(1F≈0.33 mm) nephroscope in Peking University People' s Hospital. The age ranged from 23-51 years (mean: 40.5 years) and the body mass index (BMI) ranged from 18.8-32.4 kg/m2 (mean 27.0 kg/m2). The lesion located on the left side in all of the eight patients. Two patients had solitary kidney and one patient had horseshoe kidney. Solitary stone was seen in one patient and the other seven patients suffered multiple stones, with two patients had staghorn stones. The largest diameter of stones ranged from 0.6-2.5 cm (mean: 1.5 cm). CT or ultrasound showed that moderate nephrosis was seen in five patients and severe nephrosis was seen in three patients. During surgery, after exposure of renal pelvis and proximal ureter, a small incision of 1.5 cm was performed in the anterior wall of the renal pelvis, and a 19.5F nephroscope was introduced into renal pelvis through laparoscopic trocar and renal pelvis incision. Stones were fragmented and sucked out by 3.3 mm ultrasonic probe placed through nephroscope. After stones were removed, modified laparoscopic pyeloplasty was performed. RESULTS: Surgery was successfully completed in all of the eight patients without conversion to open surgery. The operation time ranged from 160-254 min (mean 213 min) and the time of nephroscopic management time was 25-40 min (mean: 33 min). The hemoglobin was decreased by 3-21 g/L (mean: 10.3 g/L). The stone-free rate was 75% (6/8 cases), stones were incompletely removed in two patients due to abnormal intrarenal structure. The modified Clavien classification system (MCCS) grade ⅢA complication occurred in one patient postoperatively, which was nephrosis due to intrarenal bleeding, and nephrostomy was performed. With the mean follow-up of 30 months (ranged from 2-68 months), there was no evidence of obstruction in all the patients, and one patient underwent percutaneous nephrolithotomy to treat residual calculi. CONCLUSION: Laparoscopic pyeloplasty combined with ultrasonic lithotripsy via 19.5F nephroscope is feasible and safe, and could be a complementary method to treat UPJO and renal calculi.

A patient diagnosed with Galloway-Mowat syndrome presenting with a rod-cone functional anomaly with electronegative dark-adapted ERGs.

PURPOSE: Galloway-Mowat syndrome (GAMOS) is a clinically heterogenous and rare condition classically described as the combination of nephrotic syndrome associated with brain anomaly and delays in development. It was first reported in the literature in 1968 by Galloway W.H and Mowat A.P. Reports of visual anomaly in these patients are generally limited to decreased visual acuity, nystagmus and optic nerve atrophy. To this day, little is known about retinal function in this disease. Therefore, the purpose of this case report is to reveal abnormal retinal function (including light-adapted and dark-adapted retinal function) in a female patient diagnosed with GAMOS due to mutation of the WDR73 gene. METHODS: Complete dilated pediatric ophthalmic examination and ISCEV full field standard light (10 min of light adaptation; background light: 30 cd.m-2; flash intensity: 3.0 cd.sec.m-2) and dark-adapted (20 min of dark adaptation; flash intensities: 0.01, 3.0 and 10.0 cd.sec.m-2) electroretinograms were performed on a 2-year-old female patient diagnosed with GAMOS due to a biallelic mutation in the WDR73 gene. RESULTS: Ophthalmologic evaluation under anesthesia revealed normal appearing anterior segments. Significant bilateral optic nerve pallor was noted. Fundus examination appeared to be abnormal and demonstrated mid-peripheral whitish glistening appearance with possible gliosis. Retinoscopy revealed bilateral high myopia with a refractive error of -8.00 sphere in both eyes. ISCEV standard ERG revealed residual responses under light-adapted condition. Undetectable responses were obtained after 20 min of dark adaptation when using a dim flash (DA 0.01). However, when brighter flashes were used in a dark-adapted condition (DA 3.0 and DA 10.0), the ERGs were detectable, albeit abnormal in amplitudes and of electronegative morphology. CONCLUSIONS: The results obtained showed significant retinal functional deficit affecting both the cone and the rod photoreceptor pathways, along with the inner retina, in a patient diagnosed with GAMOS due to biallelic mutations in the WDR73 gene. Our report is limited to one patient, and additional studies are needed to verify whether retinal functional anomalies, as measured by the full field electroretinogram, present a novel biomarker in all patients affected with GAMOS or only in patients with a mutation in the WDR73 gene. Given the evidence of retinal functional changes presented in this study, it is strongly suggested to include complete ophthalmic examination, retinal imaging, including OCT, and full field ERG testing in patients affected with GAMOS.

Analysis of chronic kidney disease among national hospitalization data with 14 million children.

BACKGROUND: The main purpose was to determine basic epidemiological data on CKD among hospitalized pediatric patients in China. METHODS: Data from pediatric inpatients with CKD hospitalized from June 1, 2013 to May 31, 2017 were extracted from the electronic records of HQMS database, which includes over 14 million inpatients. Codes from the 10th revision of the International Classification of Diseases (ICD-10) were used to search the database. RESULTS: A total of 524 primary diseases of CKD were included in this study. In all, there were 278 231 pediatric inpatients with CKD, which accounted for 1.95 % of the 14 250 594 pediatric inpatients registered in the HQMS database. The number of pediatric inpatients with CKD was 67 498 in 2013, 76 810 in 2014, 81 665 in 2015 and 82 649 in 2016, which accounted for 1.93 %, 1.93 %, 1.99 and 2.09 %, respectively, of the total population of pediatric inpatients. The etiology of CKD was secondary nephrosis in 37.95 % of cases, which ranked first and followed by CAKUT with a percentage of 24.61 %. Glomerular diseases and cystic kidney disease accounted for 21.18 and 5.07 %, respectively. Among all 278 231 patients, 6 581 (2.37 %) had a primary discharge diagnosis of CKD. The renal pathology findings of CKD showed that IgA accounted for 51.17 %. CONCLUSIONS: This study provides a descriptive analysis of the hospitalized population of pediatric CKD patients. Our study provides important, fundamental data for policy making and legislation, registry implementation and the diagnosis, treatment and prevention of CKD in China.

Genetic ablation of SLK exacerbates glomerular injury in adriamycin nephrosis in mice.

Ste20-like kinase SLK is critical for embryonic development and may play an important role in wound healing, muscle homeostasis, cell migration, and tumor growth. Mice with podocyte-specific deletion of SLK show albuminuria and damage to podocytes as they age. The present study addressed the role of SLK in glomerular injury. We induced adriamycin nephrosis in 3- to 4-mo-old control and podocyte SLK knockout (KO) mice. Compared with control, SLK deletion exacerbated albuminuria and loss of podocytes, synaptopodin, and podocalyxin. Glomeruli of adriamycin-treated SLK KO mice showed diffuse increases in the matrix and sclerosis as well as collapse of the actin cytoskeleton. SLK can phosphorylate ezrin. The complex of phospho-ezrin, Na+/H+ exchanger regulatory factor 2, and podocalyxin in the apical domain of the podocyte is a key determinant of normal podocyte architecture. Deletion of SLK reduced glomerular ezrin and ezrin phosphorylation in adriamycin nephrosis. Also, deletion of SLK reduced the colocalization of ezrin and podocalyxin in the glomerulus. Cultured glomerular epithelial cells with KO of SLK showed reduced ezrin phosphorylation and podocalyxin expression as well as reduced F-actin. Thus, SLK deletion leads to podocyte injury as mice age and exacerbates injury in adriamycin nephrosis. The mechanism may at least in part involve ezrin phosphorylation as well as disruption of the cytoskeleton and podocyte apical membrane structure.

Distinct functions of megalin and cubilin receptors in recovery of normal and nephrotic levels of filtered albumin.

Proximal tubule (PT) cells express a single saturable albumin-binding site whose affinity matches the estimated tubular concentration of albumin; however, albumin uptake capacity is greatly increased under nephrotic conditions. Deciphering the individual contributions of megalin and cubilin to the uptake of normal and nephrotic levels of albumin is impossible in vivo, as knockout of megalin in mice globally disrupts PT endocytic uptake. We quantified concentration-dependent albumin uptake in an optimized opossum kidney cell culture model and fit the kinetic profiles to identify albumin-binding affinities and uptake capacities. Mathematical deconvolution fit best to a three-component model that included saturable high- and low-affinity uptake sites for albumin and underlying nonsaturable uptake consistent with passive uptake of albumin in the fluid phase. Knockdown of cubilin or its chaperone amnionless selectively reduced the binding capacity of the high-affinity site, whereas knockdown of megalin impacted the low-affinity site. Knockdown of disabled-2 decreased the capacities of both binding sites. Additionally, knockdown of megalin or disabled-2 profoundly inhibited the uptake of a fluid phase marker, with cubilin knockdown having a more modest effect. We propose a novel model for albumin retrieval along the PT in which cubilin and megalin receptors have different functions in recovering filtered albumin in proximal tubule cells. Cubilin binding to albumin is tuned to capture normally filtered levels of the protein. In contrast, megalin binding to albumin is of lower affinity, and its expression is also essential for enabling the recovery of high concentrations of albumin in the fluid phase.

Osmotic Nephrosis and Acute Kidney Injury Associated With SGLT2 Inhibitor Use: A Case Report.

We report a case of a patient who developed dialysis-requiring acute kidney injury (AKI) after the use of canagliflozin. A 66-year-old man with type 2 diabetes who was recovering from left knee septic arthritis at a rehabilitation facility was admitted with oliguric AKI 5 days after starting treatment with canagliflozin, an inhibitor of sodium/glucose cotransporter 2 (SGLT2). The patient presented with hematuria, non-nephrotic-range proteinuria, and serum creatinine level of 6.8 (baseline, 1.1-1.3) mg/dL. There was no recent use of radiocontrast agents or exposure to other nephrotoxins. The patient subsequently required hemodialysis. Due to recent antibiotic use (ampicillin-sulbactam), acute interstitial nephritis was considered in the differential diagnosis. Kidney biopsy was performed, which showed the presence of osmotic nephropathy. The patient's kidney function returned to baseline after 2 weeks of hemodialysis. This case provides evidence of an association of osmotic nephropathy with the use of canagliflozin and discusses potential mechanisms. We recommend kidney biopsy for cases of severe AKI associated with SGLT2 inhibitors to better understand the relationship of this complication with the use of this class of medications.

Early fulminant BK polyomavirus-associated nephropathy in two kidney transplant patients with low neutralizing antibody titers receiving allografts from the same donor.

BACKGROUND: BK Polyomavirus (BKPyV) causes premature graft failure in 1 to 15% of kidney transplant (KT) recipients. High-level BKPyV-viruria and BKPyV-DNAemia precede polyomavirus-associated nephropathy (PyVAN), and guide clinical management decisions. In most cases, BKPyV appears to come from the donor kidney, but data from biopsy-proven PyVAN cases are lacking. Here, we report the early fulminant course of biopsy-proven PyVAN in two male KT recipients in their sixties, receiving kidneys from the same deceased male donor. CASE PRESENTATIONS: Both recipients received intravenous basiliximab induction, and maintenance therapy consisting of tacrolimus (trough levels 3-7 ng/mL from time of engraftment), mycophenolate mofetil 750 mg bid, and prednisolone. At 4 weeks post-transplant, renal function was satisfactory with serum creatinine concentrations of 106 and 72 µmol/L in recipient #1 and recipient #2, respectively. Plasma BKPyV-DNAemia was first investigated at 5 and 8 weeks post-transplant being 8.58 × 104 and 1.12 × 106 copies/mL in recipient #1 and recipient #2, respectively. Renal function declined and biopsy-proven PyVAN was diagnosed in both recipients at 12 weeks post-transplant. Mycophenolate mofetil levels were reduced from 750 mg to 250 mg bid while tacrolimus levels were kept below 5 ng/mL. Recipient #2 cleared BKPyV-DNAemia at 5.5 months post-transplant, while recipient #1 had persistent BKPyV-DNAemia of 1.07 × 105 copies/mL at the last follow-up 52 weeks post-transplant. DNA sequencing of viral DNA from early plasma samples revealed apparently identical viruses in both recipients, belonging to genotype Ib-2 with archetype non-coding control region. Retrospective serological work-up, demonstrated that the donor had high BKPyV-IgG-virus-like particle ELISA activity and a high BKPyV-genotype I neutralizing antibody titer, whereas both KT recipients only had low neutralizing antibody titers pre-transplantation. By 20 weeks post-transplant, the neutralizing antibody titer had increased by > 1000-fold in both recipients, but only recipient #2 cleared BKPyV-DNAemia. CONCLUSIONS: Low titers of genotype-specific neutralizing antibodies in recipients pre-transplant, may identify patients at high risk for early fulminant donor-derived BKPyV-DNAemia and PyVAN, but development of high neutralizing antibody titers may not be sufficient for clearance.

Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation.

Sphingosine-1-phosphate (S1P) lyase is a vitamin B6-dependent enzyme that degrades sphingosine-1-phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6-dependent enzymes, a finding ascribed largely to the vitamin's chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6-treated patient-derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.

Protein energy-wasting associated with nephrotic syndrome - the comparison of metabolic pattern in severe nephrosis to different stages of chronic kidney disease.

BACKGROUND: Nephrotic syndrome (NS) is associated with a hypercatabolic state expressed as an exacerbated degradation of muscle mass. However, the clinical significance of this phenomenon has not yet been investigated. The aim of the study was to evaluate the nutritional status of patients with severe NS (defined as nephrotic range proteinuria with hypoalbuminemia ≤2.5 g/dL) and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 in comparison to patients in different stages of chronic kidney disease (CKD). METHODS: Twenty men with severe NS (NS group) and 40 men without proteinuria similar in term of serum creatinine (control group) were included into the study. A retrospective cohort of 40 men with CKD stage G4 (PreD group) and 20 haemodialysis men (HD group) were added to the analysis after matching for age, height and weight using propensity score matching. The bioimpedance spectroscopy and biochemical nutritional markers were evaluated. RESULTS: Nephrotic patients had a significantly lower lean tissue mass (LTM; p = 0.035) and index (a quotient of LTM over height squared, LTI; p = 0.068), with an expected deficiency of LTM by 3.2 kg, and LTI by 0.9 kg/m2 when compared to the control group. A significant lean tissue deficit (defined as LTI below the lower limit of the reference range by 1.0 kg/m2) was observed in 12.5% of patients in the control group in comparison to 31.7% with advanced CKD (PreD+HD; p = 0.032) and 50% with NS (p = 0.003). NS group presented with higher phosphorus (p = 0.029), uric acid (p = 0.002) and blood urea (p = 0.049) than the control group. Blood urea was strongly negatively correlated with LTM in NS (r = - 0.64, p = 0.002). Nine nephrotic patients (45%) were identified as hypercatabolic based on severe hyperphosphatemia (> 5.0 mg/dL) and/or hyperuricemia (> 8.0 mg/dL), and were characterized by higher blood urea and lower prealbumin, as well as LTM lower by 5.6 kg than in less catabolic individuals. CONCLUSIONS: In term of lean tissue amount, NS group was more similar to advanced CKD than to the control group. We concluded that specific metabolic pattern with elevated phosphorus, uric acid and blood urea, and lean tissue deficiency may be defined as protein-energy wasting associated with nephrotic syndrome (neph-PEW).