A multidisciplinary nephrogenetic referral clinic for children and adults-diagnostic achievements and insights.

BACKGROUND: Genetic kidney diseases contribute a significant portion of kidney diseases in children and young adults. Nephrogenetics is a rapidly evolving subspecialty; however, in the clinical setting, increased use of genetic testing poses implementation challenges. Consequently, we established a national nephrogenetics clinic to apply a multidisciplinary model. METHODS: Patients were referred from different pediatric or adult nephrology units across the country if their primary nephrologist suspected an undiagnosed genetic kidney disease. We determined the diagnostic rate and observed the effect of diagnosis on medical care. We also discuss the requirements of a nephrogenetics clinic in terms of logistics, recommended indications for referral, and building a multidisciplinary team. RESULTS: Over 24 months, genetic evaluation was completed for a total of 74 unrelated probands, with an age range of 10 days to 72 years. The most common phenotypes included congenital anomalies of the kidneys and urinary tract, nephrotic syndrome or unexplained proteinuria, nephrocalcinosis/nephrolithiasis, tubulopathies, and unexplained kidney failure. Over 80% of patients were referred due to clinical suspicion of an undetermined underlying genetic diagnosis. A molecular diagnosis was reached in 42/74 probands, yielding a diagnostic rate of 57%. Of these, over 71% of diagnoses were made via next generation sequencing (gene panel or exome sequencing). CONCLUSIONS: We identified a substantial fraction of genetic kidney etiologies among previously undiagnosed individuals which influenced subsequent clinical management. Our results support that nephrogenetics, a rapidly evolving field, may benefit from well-defined multidisciplinary co-management administered by a designated team of nephrologist, geneticist, and bioinformatician. A higher resolution version of the Graphical abstract is available as Supplementary information.

The effect of poly (ADP-ribose) polymerase inhibition on aminoglycoside-induced acute tubular necrosis in rats.

INTRODUCTION: Aminoglycosides (AG) cause nephrotoxicity in 10 - 20% of patients. One of the mechanisms is by generating reactive oxygen species (ROS), leading to DNA destruction and activation of poly(ADPribose) polymerase (PARP) causing necrotic tubular cell death. PARP inhibition on gentamicin-induced nephrotoxicity was studied. METHODS: 19 female Wistar-Kyoto rats divided into 3 groups: control (3 rats receiving no treatment); gentamicin-treated group (8 rats); and 8 rats treated with gentamicin combined with 3-aminobenzamide (3 AB). Kidney functions, protein, and gentamicin levels as well as urinary trypsin inhibitory activity (TIA) were measured. Tissue microscopic examination and immunohistochemical study for proliferative cell nuclear antigen (PCNA) were determined. The effect of PARP inhibitor on the bactericidal activity of gentamicin was also assessed. RESULTS: The following results were statistically significant: urea (mg/dL) 39.9 ± 5.86, 88.3 ± 50.3, and 48.5 ± 12.7 (p = 0.048); serum creatinine (mg/dL): 0.6 ± 0.26, 1.05 ± 0.7, 0.6 ± 0.06 (p = 0.043); proteinuria (mg/24-hours): 7.27 ± 3.65, 41.2 ± 18.1, and 17.6 ± 13.9 (p = 0.050); the number of tubular macronuclei (per 10 mm2): 18.33 ± 16.07, 218 ± 101.8, 41.7 ± 36.2 (p = 0.012); the number of dilated tubes (per 10 mm2): 61.67 ± 12.58, 276.3 ± 112.7, 140.0 ± 90.9 (p = 0.04); and the number of PCNA positive nuclei (per 10 mm2): 223.3 ± 95.69, 3,585 ± 2,215.3, 626.7 ± 236.9 (p = 0.034) in the control, gentamicin, and gentamicin+3AB-treated groups, respectively. The following biochemical and histologic parameters were also examined, however, they showed no statistically significant difference: TIA (p = 0.055), mitoses (p = 0.14), mononuclear infiltrate (p = 0.188), and intratubular cast formation (p = 0.084). No effect on bactericidal activity was observed. CONCLUSION: This study illustrates that PARP inhibitor significantly attenuates gentamicin-induced nephrotoxicity in rats with no effect on the bactericidal activity.

Effect of atorvastatin on IgA nephropathy in the rat.

BACKGROUND: IgA nephropathy (IgAN) is the most common chronic glomerulonephritis in humans and is a major cause of end-stage kidney disease worldwide. There is no agreement on the exact underlying mechanism or therapeutic intervention for this disorder. Mesangial proliferation typifies the renal histopathology in IgAN. Statin drugs, as prenylationinhibitors, have been shown to have an antiproliferative effect on renal mesangial cells and to reduce IgAN-associated glomerulusclerosis and proteinuria. The aim of this study is to examine the effect of atorvastatin on kidney function, proteinuria and kidney histology changes in IgANinduced rats. METHODS: IgAN was induced in Wistar-Kyoto rats by bovine γ-globulin (BGG). Four groups of rats were treated in metabolic cages: 1) control; 2) atorvastatin (2 mg/kg body weight/day through nasogastric tube) - treated rats; 3) IgAN-rats; 4) IgAN-rats treated with atorvastatin. Urine volume, urine protein excretion, blood urea and creatinine concentrations in addition to creatinine clearance were examined every 14 days, throughout the duration of the study (56 days). All kidneys from sacrificed rats were examined for histology including glomerular cell nuclei count and immunofluorescence. RESULTS: There were no differences in blood creatinine concentrations between the groups. Creatinine clearance was lower on the 42nd day and proteinuria was higher on Days 14, 42 and 56, in rats in Group 3 compared to all others; additionally, histology examination revealed a higher glomerular cell nuclei count in this group. Immunofluorescence was equally positive for IgA in mesangial cells in the kidneys from rats of Groups 2, 3 and 4. CONCLUSIONS: Atorvastatin attenuates kidney-function impairment, proteinuria and mesangial cell proliferation in BGG model of IgANinduced rats.

Medication apprehension and compliance among dialysis patients--a comprehensive guidance attitude.

BACKGROUND: Compliance with treatment regimens is a continuing challenge for chronic dialysis patients and their medical caregivers. Poor patient adherence to prescribed medications can adversely affect treatment outcome. STUDY DESIGN: In this pre- versus post-intervention study, 89 chronic dialysis patients [75 hemodialysis (HD), 14 continuous ambulatory peritoneal dialysis (CAPD); mean age 62.7 +/- 12.39 years, 34 females] responded to a written questionnaire designed to assess knowledge about and compliance with 5 groups of prescribed medications: metabolic drugs, antihypertensives, cardiac-supporting agents, peptic disease therapy and hematological replacement therapy. Mode of intake, storage, means of supply and source of information for each class of drug were also assessed. Patients then received both oral and written instructions regarding their prescribed medications (intervention). This information was repeated 3 months later. Six months after the intervention, patients were re-administered the questionnaires. Response to the questionnaires and laboratory data were compared prior to and following the intervention. RESULTS: Overall, compliance with prescribed medications significantly improved following the intervention, from 89 to 95.7%, p = 0.0007. This relative improvement was greater in HD than CAPD patients (27 vs. 2%, p < 0.0001). Improvement in compliance was associated with lower initial scores, fewer years of education, and longer dialysis vintage. Compared to baseline values, post-intervention blood hemoglobin, hematocrit, mean corpuscular volume, ferritin and Ca levels were significantly improved. CONCLUSIONS: Dialysis patients appear to benefit from receiving comprehensive guidance about medications, in terms of compliance with medications and blood chemistry and hematology measures.

A randomized controlled clinical trial comparing the efficacy of dead sea mineral-enriched body lotion versus two types of placebo in the treatment of cutaneous dryness, itching, peeling and tightness in hemodialysis patients (EDIT).

BACKGROUND/AIMS: The present study was designed to investigate the short-term safety and efficacy of topical application with body lotion enriched with minerals from the Dead Sea versus 2 different placebo treatments in reducing symptoms of uremic pruritus. METHODS: In this single-center, randomized, double placebo-controlled clinical trial, 78 hemodialysis patients with self-reported uremic pruritus were randomized to twice-daily topical treatment with body lotion enriched with minerals from the Dead Sea (DS) or to each of 2 types of placebo: (1) lotion with no Dead Sea minerals but otherwise identical to DS (P1) or (2) lotion with no active ingredients (P2). Symptoms of uremic pruritus (itching, dryness, peeling, tightness) were evaluated at baseline and 2 weeks (14 days) after treatment intervention using a 5-point Likert scale. RESULTS: Following treatment, significant differences in symptom severity scores between DS and P1 and, separately, between group DS and P2, were not detected. Additionally, when DS was compared to the combined placebo groups (P1 and P2 together), significant post-treatment differences in symptom severity scores were not observed. Symptoms were less severe post-treatment regardless of treatment assignment. CONCLUSIONS: DS was not superior to either of the placebo treatments in the symptomatic relief of uremic pruritus.

Familial pure proximal renal tubular acidosis--a clinical and genetic study.

BACKGROUND: Inherited proximal renal tubular acidosis (pRTA) is commonly associated with more generalized proximal tubular dysfunctions and occasionally with other organ system defects. Inherited combined pRTA and distal RTA with osteopetrosis and pure pRTA associated with ocular abnormalities, a rare disease which has been recently described. Only one family with pure isolated pRTA has been reported so far and the genetic cause for this disease is unknown. Objectives. We report a unique family with isolated pRTA. The aim of the project was to define the phenotype and to try to find the gene defect causing the disease. METHODS: Clinical and metabolic evaluation of all family members was performed and a family pedigree was constructed. DNA was extracted from blood samples of affected and unaffected family members. We amplified by PCR and sequenced the coding areas and splice-sites of the genes that contribute to HCO(-)(3) reclamation in the proximal tubule. The genes studied were as follows: CA II, CA IV, CA XIV, NCB1, Na(+)/H(+) exchanger (NHE)-3, NHE-8, the regulatory proteins of NHE3, NHRF1 and NHRF2 and the Cl(-)/HCO(-)(3) exchanger, SLC26A6. RESULTS: The father and all four children had RTA with blood HCO(-)(3) levels of 11-14 meq/l and urine pH of 5.3-5.4. Increased HCO(-)(3) fractional excretion after bicarbonate loading to 40-60% confirmed the diagnosis pRTA. No other tubular dysfunction was found, and no organ system dysfunction was detected, besides short stature. No mutation was found in all candidate genes studied. CONCLUSIONS: We presented a second family in the literature with familial isolated pure pRTA. The mode of inheritance is compatible with an autosomal dominant disease. Because of the small size of the family, wide genome search was not applicable and the gene candidate approach was chosen. Nine important candidate genes were extensively studied but the molecular basis of the disease was not yet found and genotyping nine important gene candidates were negative.

Antihypertensive effect of low calcium dialysis.

BACKGROUND: During maintenance hemodialysis acute elevation in serum calcium is common. Low calcium dialysis is advocated as a therapy for prevention of dialysis-induced hypercalcemia. Approximately 16% of our chronic hemodialysis patients experience elevated arterial blood pressure during the hemodialysis session, becoming hypertensive by the end of the treatment. All these patients exhibited post-dialysis hypercalcemia. OBJECTIVES: To investigate the effect of low calcium dialysis on post-dialysis hypertension in view of an evident link between serum calcium and blood pressure in both normal renal function and chronic renal failure patients. METHODS: We evaluated 19 chronic hemodialysis patients in whom both post-dialysis hypertension and PDHCa were observed. We investigated changes in serum total calcium, ionized calcium, intact parathormone levels and arterial blood pressure in response to 4 weeks low calcium dialysis as a treatment for PDHCa. RESULTS: When PDHT patients were treated with low calcium dialysis, post-dialysis blood pressure was significantly decreased compared to pre-dialysis values (155.3 +/- 9.7/82.2 +/- 7.9 mmHg pre-dialysis vs. 134.1 +/- 20.8/80 +/- 8.6 mmHg post-dialysis, P = 0.001). Additionally, post-dialysis blood pressure was significantly lower than post-dialysis blood pressure prior to the low calcium dialysis treatment (176.1 +/- 15/86 +/- 10.8 mmHg post-standard dialysis, 134.1 +/- 20.8/80 +/- 8.6 mmHg after low calcium dialysis, P = 0.001). A decline in post-dialysis serum calcium (2.34 +/- 0.2 vs. 2.86 +/- 0.12 mmol/L, P= 0.04) and ionized calcium (1.17 +/- 0.12 vs. 1.3 +/- 0.06 mmol/L, P = 0.03) compared to pre-dialysis levels was also achieved by this treatment, with no significant changes in iPTH levels. CONCLUSIONS: These data suggest a role for low calcium dialysis in treating acute serum calcium elevation and post-dialysis hypertension in patients receiving maintenance hemodialysis.

Neonates with extra-renal pelvis: the first 2 years.

Extra-renal pelvis (ERpel) is a common ultrasonographic finding among neonates who have undergone recurrent ultrasound examinations for a better definition of prenatal renal pelvic dilatation. This study tries to determine whether or not ERpel has important prognostic implications. Seventy-nine neonates (17 female) were examined. All had a diagnosis of prenatal renal pelvis dilatation, which was shown by postnatal ultrasound to be ERpel. Sixty ERpel neonates were examined 1.5 months to 2.5 months after the ultrasound (US) diagnosis by both Tc-99m diethylene triamine penta-acetic acid (DPTA) dynamic renal scanning and (99m)Tc-pertechnetate direct cystography. Clinical assessment, urine cultures and renal ultrasound follow-up were maintained for 2 years. The proportion of urinary tract infections (UTIs) in patients with ERpel was compared with that of the total neonatal and infantile population with normal US scans in the region of our hospital. Associated minor congenital malformations were found in 12 of 79 neonates (15.2%). Four had a family history of ERpel. Among 60 neonates who underwent renal scanning, 36 (60%) were found to have urinary retention in the collecting system. Another nine (15%) had vesico-ureteral (VU) reflux, of which seven had urinary retention. Fifteen (25%) showed normal isotope imaging. Urinary tract infection was diagnosed in 16 ERpel neonates in whom only one exhibited VU reflux (grade 2). The incidence of neonatal UTI in the ERpel group was more than that of either neonatal or infantile UTI in those with normal US scans in the local population (20.2% vs 1.2% and 4.3%, respectively). Fifty-three infants completed a 2-year follow-up. Repeat renal ultrasonography indicated that one infant (1.8%) had developed bilateral hydronephrosis, 12 (22.6%) had unchanged findings, 18 (40%) showed an improvement (decrease of ERpel width or resolution in one side) and, in 22 (41.5%) infants, the condition had resolved. No clinical or kidney function deterioration was observed. Seven patients (13.2%) each had one episode of UTI during the 2-year follow-up period; none of them had VU reflux. Neonatal ERpel is more frequent in male infants. It is associated with greater rates of minor congenital malformations, VU reflux and UTI than in the general population of the same ages. The increased UTI incidence is not attributed to VU reflux.