Genetic Markers Among the Israeli Druze Minority Population With End-Stage Kidney Disease.

RATIONALE & OBJECTIVE: Genetic etiologies have been identified among approximately 10% of adults with chronic kidney disease (CKD). However, data are lacking regarding the prevalence of monogenic etiologies especially among members of minority groups. This study characterized the genetic markers among members of an Israeli minority group with end-stage kidney disease (ESKD). STUDY DESIGN: A national-multicenter cross-sectional study of Israeli Druze patients (an Arabic-speaking Near-Eastern transnational population isolate) who are receiving maintenance dialysis for ESKD. All study participants underwent exome sequencing. SETTING & PARTICIPANTS: We recruited 94 adults with ESKD, comprising 97% of the total 97 Druze individuals throughout Israel being treated with dialysis during the study period. PREDICTORS: Demographics and clinical characteristics of kidney disease. OUTCOME: Genetic markers. ANALYTICAL APPROACH: Whole-exome sequencing and the relationship of markers to clinical phenotypes. RESULTS: We identified genetic etiologies in 17 of 94 participants (18%). None had a previous molecular diagnosis. A novel, population-specific, WDR19 homozygous pathogenic variant (p.Cys293Tyr) was the most common genetic finding. Other monogenic etiologies included PKD1, PKD2, type IV collagen mutations, and monogenic forms of noncommunicable diseases. The pre-exome clinical diagnosis corresponded to the final molecular diagnosis in fewer than half of the participants. LIMITATIONS: This study was limited to Druze individuals, so its generalizability may be limited. CONCLUSIONS: Exome sequencing identified a genetic diagnosis in approximately 18% of Druze individuals with ESKD. These results support conducting genetic analyses in minority populations with high rates of CKD and for whom phenotypic disease specificity may be low. PLAIN-LANGUAGE SUMMARY: Chronic kidney disease (CKD) affects many people worldwide and has multiple genetic causes. However, there is limited information on the prevalence of genetic etiologies, especially among minority populations. Our national-multicenter study focused on Israeli Druze patients. Using exome-sequencing, we identified previously undetected genetic causes in nearly 20% of patients, including a new and population-specific WDR19 homozygous pathogenic variant. This mutation has not been previously described; it is extremely rare globally but is common among the Druze, which highlights the importance of studying minority populations with high rates of CKD. Our findings provide insights into the genetic basis of end-stage kidney disease in the Israeli Druze, expand the WDR19 phenotypic spectrum, and emphasize the potential value of genetic testing in such populations.

Acute Kidney Injury and Hair-Straightening Products: A Case Series.

RATIONALE & OBJECTIVE: Keratin-based hair-straightening treatment is a popular hair-styling method. The majority of keratin-based hair-straightening products in Israel contain glycolic acid derivatives, which are considered safe when used topically. Systemic absorption of these products is possible, and anecdotal reports have described kidney toxicity associated with their use. We report a series of cases of severe acute kidney injury (AKI) following use of hair-straightening treatment in Israel during the past several years. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We retrospectively identified 26 patients from 14 medical centers in Israel who experienced severe AKI and reported prior treatment with hair-straightening products in 2019-2022. FINDINGS: The 26 patients described had a median age of 28.5 (range, 14-58) years and experienced severe AKI following a hair-straightening procedure. The most common symptoms at presentation were nausea, vomiting, and abdominal pain. Scalp rash was noted in 10 (38%) patients. Two patients experienced a recurrent episode of AKI following a repeat hair-straightening treatment. Seven patients underwent kidney biopsies, which demonstrated intratubular calcium oxalate deposition in 6 and microcalcification in tubular cells in 1. In all biopsies, signs of acute tubular injury were present, and an interstitial infiltrate was noted in 4 cases. Three patients required temporary dialysis. LIMITATIONS: Retrospective uncontrolled study, small number of kidney biopsies. CONCLUSIONS: This series describes cases of AKI with prior exposure to hair-straightening treatments. Acute oxalate nephropathy was the dominant finding on kidney biopsies, which may be related to absorption of glycolic acid derivatives and their metabolism to oxalate. This case series suggests a potential underrecognized cause of AKI in the young healthy population. Further studies are needed to confirm this association and to assess the extent of this phenomenon as well as its pathogenesis.

Heparanase Increases Podocyte Survival and Autophagic Flux after Adriamycin-Induced Injury.

The kidney glomerular filtration barrier (GFB) is enriched with heparan sulfate (HS) proteoglycans, which contribute to its permselectivity. The endoglycosidase heparanase cleaves HS and hence appears to be involved in the pathogenesis of kidney injury and glomerulonephritis. We have recently reported, nonetheless, that heparanase overexpression preserved glomerular structure and kidney function in an experimental model of Adriamycin-induced nephropathy. To elucidate mechanisms underlying heparanase function in podocytes-key GFB cells, we utilized a human podocyte cell line and transgenic mice overexpressing heparanase. Notably, podocytes overexpressing heparanase (H) demonstrated significantly higher survival rates and viability after exposure to Adriamycin or hydrogen peroxide, compared with mock-infected (V) podocytes. Immunofluorescence staining of kidney cryo-sections and cultured H and V podocytes as well as immunoblotting of proteins extracted from cultured cells, revealed that exposure to toxic injury resulted in a significant increase in autophagic flux in H podocytes, which was reversed by the heparanase inhibitor, Roneparstat (SST0001). Heparanase overexpression was also associated with substantial transcriptional upregulation of autophagy genes BCN1, ATG5, and ATG12, following Adriamycin treatment. Moreover, cleaved caspase-3 was attenuated in H podocytes exposed to Adriamycin, indicating lower apoptotic cell death in H vs. V podocytes. Collectively, these findings suggest that in podocytes, elevated levels of heparanase promote cytoprotection.

Effective elimination of high-dose methotrexate by repeated hemodiafiltration and high-flux hemodialysis in patients with acute kidney injury.

INTRODUCTION: Acute kidney injury (AKI) after high dose methotrexate (HD-MTX) is associated with delayed MTX-excretion and life-threatening toxicity. Glucapridase, the recommended therapy, is expensive and not always available. CASE SERIES: We describe 3 cases (69, 67, 73 years) with diffuse large B-cell lymphoma who developed AKI and early-onset severely delayed MTX elimination after HD-MTX. MTX serum concentrations were 101 and 69 µmol/L at 24 h after administration in two patients and 34 µmol/L at 32 h in the third. MANAGEMENT AND OUTCOME: Since glucarpidase was unavailable, we performed daily high-flux hemodialysis (HF-HD) or online hemodiafiltration (HDF) sessions (median duration, 6 h). The median serum MTX elimination half-life during HDF/HF-HD sessions was similar in all patients (median, 4.4 h; IQR, 3.8-5.3 h), but serum MTX concentrations rebounded after each dialysis by a median of 40% of the trough concentrations. The three patients underwent multiple dialysis sessions, until MTX serum concentrations remained sufficiently low to be neutralized by leucovorin. Only 1 patient developed severe pancytopenia, and renal function normalized in all patients after 3-6 weeks. DISCUSSION: In conclusion, when glucarpidase is unavailable or delayed, early, repeated and prolonged HDF/HF-HD effectively enhance MTX elimination and prevent toxicity in patients with AKI and severely delayed MTX elimination after HD-MTX.

[HEMODIALYSIS: PRESENT INNOVATIONS FOR PATIENTS' FUTURE].

INTRODUCTION: End-stage renal disease (ESRD) is a major cause of morbidity and mortality worldwide. Survival of ESRD patients depends on renal replacement therapies, such as kidney transplantation and dialysis. Due to the shortage of potential kidney donors and patients' comorbidities, dialysis is the major therapeutic option offered to such patients. In this review, recent advances in hemodialysis and hemodiafiltration, and their potential impact on improving patient survival will be discussed.

New Insights into Podocyte Biology in Glomerular Health and Disease.

Podocyte and glomerular research is center stage for the development of improved preventive and therapeutic strategies for chronic progressive kidney diseases. Held April 3-6, 2016, the 11th International Podocyte Conference took place in Haifa and Jerusalem, Israel, where participants from all over the world presented their work on new developments in podocyte research. In this review, we briefly highlight the advances made in characterizing the mechanisms involved in podocyte development, metabolism, acquired injury, and repair, including progress in determining the roles of genetic variants and microRNA in particular, as well as the advances made in diagnostic techniques and therapeutics.

Nephroprotective effect of heparanase in experimental nephrotic syndrome.

BACKGROUND: Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic processes. Recently, an association between heparanase and glomerular injury was suggested. The present study examines the involvement of heparanase in the pathogenesis of Adriamycin-induced nephrotic syndrome (ADR-NS) in a mouse model. METHODS: BALB/c wild-type (wt) mice and heparanase overexpressing transgenic mice (hpa-TG) were tail-vein injected with either Adriamycin (ADR, 10 mg/kg) or vehicle. Albuminuria was investigated at days 0, 7, and 14 thereafter. Mice were sacrificed at day 15, and kidneys were harvested for various analyses: structure and ultrastructure alterations, podocyte proteins expression, and heparanase enzymatic activity. RESULTS: ADR-injected wt mice developed severe albuminuria, while ADR-hpa-TG mice showed only a mild elevation in urinary albumin excretion. In parallel, light microscopy of stained cross sections of kidneys from ADR-injected wt mice, but not hpa-TG mice, showed mild to severe glomerular and tubular damage. Western blot and immunofluorescence analyses revealed significant reduction in nephrin and podocin protein expression in ADR-wt mice, but not in ADR-hpa-TG mice. These results were substantiated by electron-microscopy findings showing massive foot process effacement in injected ADR-wt mice, in contrast to largely preserved integrity of podocyte architecture in ADR-hpa-TG mice. CONCLUSIONS: Our results suggest that heparanase may play a nephroprotective role in ADR-NS, most likely independently of HS degradation. Moreover, hpa-TG mice comprise an invaluable in vivo platform to investigate the interplay between heparanase and glomerular injury.

Impact of hemodialysis on exhaled volatile organic compounds in end-stage renal disease: a pilot study.

AIM: To demonstrate the feasibility of nanomaterial-based sensors for identifying patterns of exhaled volatile organic compound of end-stage renal disease (ESRD) and study the impact of hemodialysis (HD) on these patterns. PATIENTS & METHODS: Exhaled breath samples were collected from a group of 37 volunteers (26 ESRD HD patients; 11 healthy controls); a third of the samples were randomly blinded for determining the sensitivity/specificity of the method. Discriminant function analysis was used to build a model for discriminating ESRD patients and healthy controls (classification accuracy for blind samples: 80%), based on the signals of the nanomaterial sensors. RESULTS & CONCLUSION: The breath pattern of the ESRD patients approached the healthy pattern during the HD treatment, without reaching it completely. Gas chromatography/mass spectrometry identified four volatile organic compounds as potential ESRD biomarkers. Although this pilot study has yielded encouraging results, additional large-scale clinical studies are required to develop a fast, noninvasive breath test for monitoring HD adequacy in real time.

Corin: a new player in the regulation of salt-water balance and blood pressure.

PURPOSE OF REVIEW: Natriuretic peptides play a key role in regulation of blood pressure and volume homeostasis due to their natriuretic/diuretic and vasodilatory actions. The natriuretic and diuretic responses to natriuretic peptides are markedly attenuated in edematous disease states. Our goal is to review the mechanisms underlying this phenomenon, with special emphasis on the role of corin in salt retention and edema formation in heart failure and nephrotic syndrome, and pathogenesis of hypertension. RECENT FINDINGS: Although three decades have passed since the discovery of atrial natriuretic peptide (ANP), major advances in understanding the physiological and pathophysiological role of the natriuretic peptide family in the regulation of sodium (Na) and water balance are still emerging. As well as ANP, the natriuretic peptide family contains at least two other members: brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). Although encoded by different genes, these natriuretic peptides share a high similarity in their chemical structure and biosynthesis pathway. ANP and BNP are produced from proANP and proBNP, respectively, which are converted into the active forms mainly by corin. The latter is a transmembrane serine protease localized to the heart, and to a lesser extent to the kidneys. Recent studies have demonstrated that perturbations in corin activity lead to elevation of the prohormones at the expense of the mature forms, thereby causing the development of salt-sensitive hypertension, preeclampsia, cardiac hypertrophy, and Na and water retention. SUMMARY: Natriuretic peptides are an important endocrine system in the regulation of body fluid balance and blood pressure. Corin mediates an essential step in the cascade of natriuretic peptide biosynthesis and eventually their action. Thus, it is postulated that aberrations in the normal activity of corin may contribute to cardiovascular and renal diseases.

Evaluation of carboplatin dosing in non-small cell lung carcinoma patients using Calvert formula and Cockroft and Gault equation for glomerular filtration rate estimation.

The aim of this study was to evaluate the reliability of the Cockroft and Gault (CG) equation for glomerular filtration rate (GFR) estimation in carboplatin dosing based on the Calvert formula. The records of 117 patients with advanced non-small cell lung carcinoma treated with carboplatin were retrospectively analyzed. Theoretical carboplatin doses derived from the Calvert formula using the CG equation were calculated for each chemotherapy cycle. Fluctuations in the theoretical carboplatin doses were analyzed, and discrepancies between actual carboplatin doses prescribed by the physician and theoretical doses were assessed. It was found that, compared with the first-cycle dose, subsequent theoretical doses were more than 10% higher in 79/320 cycles (24.7%) and more than 10% lower in 53/320 cycles (16.6%; P=0.015). A body mass index greater than or equal to 30 was associated with a tendency for increased CG-estimated GFR during subsequent chemotherapy cycles (P=0.009). Physicians tended to lower the prescribed dose (32.2% of the cycles) by using a higher serum creatinine (Scr) level for dose calculation than was actually measured. We concluded that Calvert formula-derived carboplatin doses fluctuate widely during repeated cycles when actual Scr is used for CG-estimated GFR. The measurement of 24-h creatinine clearance is advised as an alternative in selected patients with reduction in serum creatinine observed during treatments.

Obstructive uropathy caused by retroperitoneal fibrosis presents as a late manifestation of sarcoidosis.

Obstructive uropathy in sarcoidosis can result from retroperitoneal involvement, retroperitoneal fibrosis (RPF), renal stones, or ureteral involvement. We report acute kidney injury (AKI) from obstructive uropathy because of RPF in a female patient, 2 years following the resolution of pulmonary sarcoidosis. We propose that RPF may occur in sarcoidosis even when a lag of years separates the presentations of the illnesses.

Glomerular abundance of nephrin and podocin in experimental nephrotic syndrome: different effects of antiproteinuric therapies.

Nephrotic syndrome (NS) is a clinical state characterized by massive proteinuria, hypoalbuminemia, and eventual edema formation. Although the mechanisms underlying this phenomenon are not yet fully clarified, it is well accepted that nephrin and podocin are involved in the development of proteinuria. The effects of early treatment with various antiproteinuric therapies on proteinuria and glomerular staining of nephrin and podocin in rats with experimental NS have not been previously studied. Proteinuria and glomerular nephrin and podocin immunofluorescence were examined in rat kidneys with adriamycin-induced NS and the effects of antiproteinuric drug therapies during 5 wk with enalapril, losartan, alone or in combination, omapatrilat, and mycophenolate mofetil on these parameters were assessed. Injection of adriamycin caused a significant increase in daily (from 21.8 +/- 1.4 to 983.1 +/- 45.8 mg/day, P < 0.01) and cumulative protein excretion (from negligible values to 22,490 +/- 931 mg, P < 0.001) during 5 wk. Early treatment with enalapril significantly decreased the daily (641.7 +/- 82.4 mg/day, P < 0.0023) and cumulative proteinuria (15,727 +/- 2,204 mg, P < 0.001). A similar effect, although to a lesser extent, was obtained after omapatrilat treatment: cumulative proteinuria was reduced to 18,706 +/- 1,042 mg, P < 0.001. In contrast, losartan treatment did not significantly influence the cumulative proteinuria that remained comparable (20,351 +/- 1,360 mg, P > 0.05) to that observed in untreated NS rats. Unexpectedly, when losartan was given in combination with enalapril, it abolished the beneficial effects of the latter. Pretreatment with mycophenolate mofetil exerted a moderate antiproteinuric effect, which appeared only during the last week of the experimental treatment. Nephrotic rats exhibited severe disruption of slit diaphragm structure as seen by rapid and profound loss of nephrin and podocin. Beneficial effects of enalapril, omapatrilat, and mycophenolate mofetil paralleled the preservation of nephrin, as determined immunohistochemically, and enabled prediction of significant antiproteinuric responses. Enalapril alone or in combination with losartan resulted in significant preservation of podocin. Pretreatment with enalapril, and to a lesser extent omapatrilat, is superior to losartan in reducing proteinuria in NS rats. A combination of ACE inhibitors with ANG II receptor blockers does not provide any advantageous antiproteinuric therapy in these animals. Nephrin loss is an indication of proteinuria in NS and the antiproteinuric effects of ACE inhibitors, vasopeptidase inhibitors, and mycophenolate mofetil attenuate this reduction. Not all the drugs which restore podocin reduce urinary protein in NS.

Differential effects of sera from normotensive and hypertensive pregnant women on Ca(2+) metabolism in normal vasular smooth muscle cells.

The clinical features of preeclampsia have been traditionally ascribed to a generalized vascular endothelial cell dysfunction. The present study investigates the effect of sera from preeclamptic women and normal pregnancy on the metabolism of intracellular Ca(2+) concentration ([Ca(2+)](i)) in normal cultured vascular smooth muscle cells (VSMC). Sera were obtained from normotensive pregnant women (NTP) (n = 17), preeclamptic women (PE) (n = 15), pregnant women with chronic (essential) hypertension (pregnant EHT) (n = 8), non-pregnant women with essential hypertension (non-pregnant EHT) (n = 12), and age-matched non-pregnant normotensive women (NNP) (n = 18). Serum (10%) was applied to both primary cultures of rat aortic smooth muscle cells and to the A-10 vascular muscle cell line. Levels of [Ca(2+)](i) were determined fluorometrically. After a 4-h incubation with serum, basal [Ca(2+)](i) was not significantly altered. However, compared with normal pregnant sera, PE sera markedly reduced hormonally induced Ca(2+) transients. Thus, following acute stimulation of rat VSMC (primary cultures) with 10(-8)M angiotensin II, peak [Ca(2+)](i) responses (% increment over baseline) were 443 +/- 22, 184 +/- 18, 259 +/- 12, 274 +/- 23, and 255 +/- 15% in NTP, PE, pregnant EHT, non-pregnant EHT, and NNP, respectively (P <0.01 PE versus NTP, P <0.05 PE versus NNP and pregnant and non-pregnant EHT). These effects of sera on [Ca(2+)](i) were qualitatively reproduced in platelets obtained from healthy volunteers. Also, depolarization-activated Ca(2+) influx in VSMC was affected by the different sera groups in a manner similar to that seen with hormonally induced [Ca(2+)](i) responses. The altered [Ca(2+)](i) changes by PE sera disappeared 5 wk after delivery. The effect of the different sera groups on hormonally triggered Ca(2+) transients in normal VSMC, as well as the normalization of [Ca(2+)](i) responses after delivery, suggest the presence of a circulating serum factor in PE. Inasmuch as [Ca(2+)](i) is the major determinant of VSMC tone, it is possible that consequent to the attenuation of [Ca(2+)](i) responses, this putative circulating factor counterbalances the intense vasoconstriction in PE.