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.

[KIDNEY DISEASES IN NORTH ISRAEL ACCORDING TO KIDNEY BIOPSIES - BNAI-ZION MEDICAL CENTER 14 YEARS' EXPERIENCE].

INTRODUCTION: Little is known about the prevalence of kidney diseases according to renal biopsy in Israel. Since updated literature worldwide emphasizes changing etiologies of chronic kidney disease, it is crucial to research and define the epidemiology and pathology of kidney disease in Israel. Hereby, we introduce an original review of the prevalence of kidney diseases in our study population, which we believe reflects the prevalence of kidney diseases in the population of Israel. AIMS: To investigate the prevalence of kidney diseases diagnosed by renal biopsy, according to age, gender, race and clinical symptoms. METHODS: A total of 155 kidney biopsies were conducted in the years 2000-2014 in Bnai-Zion Medical Center in Haifa, according to formal accepted indications. Most of the biopsies (65%) were needle aspirations in a retroperitoneal approach, in which 90% were ultrasound guided and the rest computed tomography guided, while the other 35% of biopsies involved laparoscopic approaches. RESULTS: The most common indications for kidney biopsy were nephrotic syndrome, nephritic syndrome and proteinuria (37.4%, 25.8% and 24.5%, respectively). Average glomeruli number per biopsy was 17.5 vs. 82.2 for needle aspiration and laparoscopic approach, respectively (statistically significant). The most common diagnosis was focal segmental glomerulosclerosis (FSGS), followed by chronic glomerulonephritis, IgA nephropathy, lupus nephritis, minimal change disease (MCD), membranous nephropathy and tubulointerstitial disease (20%, 11.5%, 11.5%, 10.1%, 9.5%, 8.1% and 6.1%, respectively). CONCLUSIONS: FSGS was the most common diagnosis in patients presented with nephrotic syndrome or proteinuria, men, and patients above 60 years of age. Patients below 30 years of age were mainly diagnosed with IgA nephropathy. DISCUSSION: In recent years, FSGS is becoming more prevalent compared with other chronic kidney disease especially in the older population. IgA nephropathy is still the most common diagnosis in young patients and in patients presented with hematuria. To the best of our knowledge, no data exists on the prevalence of kidney diseases in Israel, and our study is an important contribution to the epidemiological and clinical knowledge on the subject.

Almost a tragedy: severe methotrexate toxicity in a hemodialysis patient treated for ectopic pregnancy.

BACKGROUND: Methotrexate (MTX), an antimetabolite of folic acid, is the drug of choice for the nonsurgical management of ectopic pregnancy. MTX-related toxicity may include leukopenia, thrombocytopenia, pancytopenia, nausea, vomiting, stomatitis, mucositis, and liver and lung toxicity, depending primarily on the dosage of the drug and patients' renal function. Currently, the use of MTX in hemodialysis patients, even at a low dosage, is controversial, and no clear-cut guidelines are available. CASE REPORT: We report here a rare case of a life-threatening complication characterized by severe pancytopenia and skin and mucosal injury, which developed in a young patient on hemodialysis after oral treatment with MTX for ectopic pregnancy. CONCLUSION: We conclude that even low-dose MTX administration is not to be used in patients with renal insufficiency, and when no other therapeutic options are available we suggest taking several clinical measures to prevent or treat myelosuppression.

Predicting outcomes on head-up tilt based on orthostatic hypotension patterns.

OBJECTIVE: To assess the frequency of different orthostatic hypotension (OH) patterns in patients having supine hypertension with OH ('SHOH') versus patients with OH and normal supine blood pressure ('OH alone'); and to relate OH patterns with outcomes on head-up tilt. METHODS: Consecutive patients with nonspecific dizziness were studied with a 10-min supine, 30-min head-up tilt test. Supine hypertension was diagnosed when supine systolic blood pressure (SBP) was at least 140 mmHg and/or supine diastolic blood pressure was at least 90 mmHg. OH was defined as SBP reduction of at least 20 mmHg within 3 min of tilt. OH patterns were identified corresponding to SBP time-curves during the initial 5 min of tilt: progressive, sustained and transient patterns. RESULTS: Among 400 patients tested, 31 had 'SHOH' and 39 had 'OH alone'. Frequencies of OH patterns were similar in both groups. The progressive OH pattern predicted symptomatic hypotension, leading to early tilt termination in all 'SHOH' and 88% of 'OH alone' patients. In comparison, tilt was early terminated in 33-48% of patients with sustained OH, transient OH and without OH. Early tilt termination was unrelated to age, gender, magnitude of supine SBP, pulse pressure and nadir SBP within 5 min tilt. CONCLUSIONS: Five minutes of postural challenge permitted assessing OH patterns. Outcome on protracted tilt was related to OH patterns, the worse outcome being likened to progressive OH, both in patients with 'SHOH' and in patients with 'OH alone'. Future studies will show whether OH patterns may serve as guidance for blood pressure therapy in selected patients.

Pulse transit time by R-wave-gated infrared photoplethysmography: review of the literature and personal experience.

OBJECTIVE: Pulse transit time (PTT) is the time it takes a pulse wave to travel between two arterial sites. A rela tively short PTT is observed with high blood pressure (BP), aging, arteriosclerosis and diabetes mellitus. Most methods used for measuring the PTT are cumbersome and expensive. In contrast, the interval between the peak of the R-wave on the electrocardiogram and the onset of the corresponding pulse in the finger pad measured by photoplethysmography can be easily measured. We review herein the literature and impart the experience at our institution on clinical applications of R-wave-gated photo-plethysmography (RWPP) as measurement of PTT. METHODS: The MEDLINE data base on clinical applications of RWPP was reviewed. In addition, studies performed in the author's institution are presented. RESULTS: When used as a surrogate for beat-to-beat BP monitoring, RWPP did not meet the level of accuracy required for medical practice (two studies). RWPP produced accurate and reproducible signals when utilized as a surrogate for intra-thoracic pressure changes in obstructive sleep apnea, as well as BP arousals which accompany central sleep apnea (five studies). In estimation of arterial stiffness, RWPP was unsatisfactory (one study). In assessment of cardiovascular reactivity, abnormal values of RWPP were noted in autonomic failure (one study), while disease-specific reactivity patterns were identified utilizing a method involving RWPP (two studies). CONCLUSIONS: In clinical practice, sleep-apnea may be accurately monitored by RWPP. RWPP seems to reflect autonomic influences and may be particularly well-suited for the study of vascular reactivity. Thus, further descriptions of disease-specific cardiovascular reactivity patterns may be possible with techniques based on RWPP. Other clinical uses of RWPP are investigational.

Early detection of hepatic encephalopathy by recording visual evoked potential (VEP).

The visual evoked potential (VEP) record in response to a pattern stimulus is a non invasive and reliable method of detecting central and peripheral nerve system abnormalities. VEP recording have been used in animals with fulminant hepatic failure, and also in-patients with hepatic encephalopathy and acute severe hepatitis. Our aims were: a. to evaluate the potency of PVEP in assessing hepatic encephalopathy. b. to find the rate of pathologic PVEP in patients with advanced liver cirrhosis. VEP was recorded in 14 chronic liver cirrhotic patients (6 alcoholic, 6 HCV-related, 2 cryptogenic) and 14 controls. Patients with any neurologic abnormalities were excluded from the study. All patients were subjected to the Mental State Score (MSS) test, and venous blood ammonia was measured on the same day of VEP recording. In 10/14 (71%) patients some VEP recording abnormality was detected. In the cirrhotic patients, P100 latency was significantly longer (P < 0.05) than in controls. Low amplitude was observed in 8 patients compared to controls. Marked increase of N75 (3 patients) and marked increase of N145 (2 patients) were observed. Mean blood ammonia and MSS score were normal in all patients. No correlation was found between both MSS score and blood ammonia levels and the P100 delay. Five out of 10 patients with pathologic VEP developed hepatic encephalpathy during a follow-up of one year, compared to one out of 4 patients with no pathology on VEP recording. VEP recording may be a valuable tool in assessing patients with early hepatic encephalopathy and in predicting encephalopathy.