Severe Impairment Of Renal Function Research Articles

Partial nephrectomy preserves renal function without increasing the risk of complications compared with radical nephrectomy for renal cell carcinomas of stages pT2-3a.

To compare the operative and functional result of partial and radical nephrectomy in renal cell carcinomas of stages pT2-3a. Consecutive patients with renal cell carcinoma of stages pT2-3a, cN0 and cM0, who underwent partial or radical nephrectomy between January 2005 and October 2019 at a tertiary care center were included. Data were collected retrospectively. End-points included severe postoperative complications (Clavien-Dindo classification ≥3), acute and chronic renal function impairment, and overall survival. Uni- and multivariable outcome analyses were based on logistic regression. A total of 158 patients were included (110 radical nephrectomy and 48 partial nephrectomy). Over time, partial nephrectomy was increasingly used. A RENAL score ≥10 was the only independent predictor influencing the surgical approach (radical nephrectomy vs partial nephrectomy, odds ratio 8.62, 95% confidence interval 3.32-22.37, P<0.001). No significant differences in complications for radical nephrectomy versus partial nephrectomy were found (12.7% vs 8.3%, P=0.424). Renal function was better preserved in the partial nephrectomy group (the latest chronic kidney disease stage ≥3: radical nephrectomy 73% vs partial nephrectomy 41%, P=0.005). The surgical approach was a significant factor for chronic kidney disease (odds ratio 51.07, 95% confidence interval 3.57-730.59, P=0.004). Overall survival did not significantly differ between radical nephrectomy and partial nephrectomy (mean overall survival 85.86months, 95% confidence interval 3.83-78.36 vs 81.28months, 95% confidence interval 4.59-72.29, P=0.702). In selected patients, partial nephrectomy can be used in large or locally advanced renal cell carcinoma. Compared with radical nephrectomy, it allows better preservation of renal function without harboring an increased risk of severe postoperative complications.

P0204PREVALENCE AND PREDICTIVE FACTORS OF BIOPSY-PROVEN NEPHROPATHY RELATED TO MONOCLONAL GAMMOPATHY

Abstract Background and Aims The prevalence of monoclonal gammopathy (MG) and kidney disease increases with age. When a patient present with both conditions, it is often necessary to perform a kidney biopsy in order to rule out a Monoclonal Immunoglobulin-Related Nephropathy (MIRN) that may require a specific therapy that targets either an overt hematological malignancy or a MG or Renal Significance (MGRS). The aim of our study was to identify factors that predict the presence of MIRN in this setting. Method This retrospective monocentric study included all patients who underwent a kidney biopsy between 2007 and 2018 with concurrent presence of GM, as defined by positive serum immuno-electrophoresis and/or Bence-Jones proteinuria. Results 328 patients were included, representing 11.8% of all kidney biopsies performed in our center during this period. Indication of biopsy was renal failure (eGFR &amp;lt;60ml/min/1.73m) in 77.4% of cases and/or proteinuria (urine protein-to-creatinine ratio &amp;gt;0.5g/g) in 75.9% of them. Median (IQR) serum creatinine was 155 μmol/L (111-233), eGFR 37.5 (22-56) ml/min/1.73m, serum albumin 29.5 (24-35) g/l. Median age was 67 (57/75), the M/F ratio was 198/130, diabetes mellitus was present in 21.3% of cases, hypertension in 53.1%. Kidney biopsy revealed that nephropathy was related to MG in 91/328 patients (27.7%). Myeloma cast nephropathy and AL amyloidosis were the most common histopathological subtypes (36 and 34% respectively), followed by monoclonal immunoglobulin deposition disease (15%) and cryoglobulinemic glomerulonephritis (8%). Patients with MIRN had more severe renal function impairment with median (IQR) serum creatinine of 176 (119-307) vs 149 (108-216) μmol/l (p=0.003) and heavier proteinuria, 3.9 (2.2-8.2) vs 2.0 (0.9-5.2) g/g (p&amp;lt; 0.001), when compared to non-MIRN patients. Hematological malignancy was diagnosed in 83 cases (25,3%) (Multiple Myeloma in 62, non-Hodgkin Lymphoma in 6, Waldenström Macroglobulinemia in 6, Chronic Lymphoid Leukemia in 6, Plasmocytoma in 3). Among them, MIRN was diagnosed in 51 (61%) cases but tumoral lympho-plasmocytic infiltration was observed in 9 (11%) cases. In this subgroup of patients, no laboratory test could predict the presence of a specific nephropathy. Among patients with no hematological malignancy (n=245), MIRN was diagnosed in 40 cases (16%) to confirm MGRS diagnosis. The markers that were most commonly associated with the presence of MGRS were positive Bence-Jones proteinuria (OR 4.7; 95%CI 2.2-10.3; p&amp;lt; 0.001), abnormal serum Free Light Chain (FLC) ratio (OR 4.2; 95%CI 1.7-10.7; p&amp;lt; 0.001), and serum electrophoresis spike &amp;gt;1.5 g/l (OR 5.9; 95%CI 2.6-13.5; p&amp;lt; 0.001). However, none of those markers had sufficient power to formally predict the result of the biopsy, as positive (PPV) or negative (NPV) predictive values were 36/41/45 % and 89/86/88 % respectively. Conclusion Almost one-third of patients with MG and kidney disease referred to our Department have biopsy-proven related nephropathy. Although negativity of Bence-Jones proteinuria and a normal serum FLC ratio are frequently associated with the absence of MGRS, kidney biopsy, beyond its diagnostic and prognostic interest, remains the most discriminating test.

Association between renal function impairment and multivessel involvement in patients with acute ST-elevation myocardial infarction.

The aim of this study was to evaluate the association between acute ST-elevation myocardial infarction (STEMI) involving multivessel and the severity of renal function impairment. We reviewed medical records of patients with acute STEMI admitted to a regional teaching hospital in southern Taiwan between March 1999 and October 2013. A total of 1215 patients who underwent coronary angiography were included. Multiple logistic regression analysis showed that multivessel involvement (at least two) with significant stenosis was significantly associated with stage 4 chronic kidney disease (adjusted odds ratio [aOR]=2.14, 95% confidence interval [CI]=1.09–4.20) and stage 5 chronic kidney disease (aOR=2.35, 95% CI=1.13–4.89), adjusting for age, sex, type 2 diabetes mellitus, hyperlipidemia, and systolic blood pressure at admission in patients with acute STEMI. In addition, multivessel total occlusion was significantly associated with stage 4 chronic kidney disease (aOR=3.68, 95% CI=1.27–10.70) and stage 5 chronic kidney disease (aOR=3.43, 95% CI=1.08–10.82), adjusting for heart rate at admission and systolic blood pressure at admission in patients with acute STEMI. In conclusion, severe renal function impairment was significantly associated with multivessel significant stenosis and multivessel total occlusion in patients with acute STEMI.

Clinical efficacy of AngioJet™ mechanical thrombectomy for the treatment of acute lower extremity arterial embolism and thrombosis

PURPOSE: This study aimed to evaluate the clinical efficacy of mechanical thrombectomy using the AngioJet™ System for the treatment of lower extremity acute arterial embolism and thrombosis.METHODS: A total of twenty patients who had acute arterial embolism and thrombosis of the lower extremity were recruited. All patients were treated using the AngioJet mechanical thrombectomy system. Clinical data of the patients were retrospectively collected. The clinical efficacy of thrombectomy was analyzed.RESULTS: Eighteen (90%) of the twenty patients successfully completed the mechanical thrombectomy using the AngioJet system. The mean time for hospital stay and operation was 4.2 ± 1.4 days and 1.31 ± 0.41 h, respectively. The average doses of urokinase and heparin during operation were 358,000 ± 123,000 U and 45.10 ± 8.30 mg, respectively. Two patients received a complementary treatment of incision for removing the thrombus. Two patients received catheter-directed thrombolysis (CDT) after the mechanical thrombectomy. Five patients received bare-metal stent implantation after balloon expansion. According to the Cooley standard, ten patients were in excellent conditions, six in good conditions, two in fair conditions, and two in poor conditions. No severe bleeding or renal function impairment was observed.CONCLUSION: The AngioJet mechanical thrombectomy system is safe and effective. Combined with the use of CDT and stent implantation, the AngioJet system could lead to quick recoveries of the perfusion of the lower extremity and improve the limb salvage rates, exhibiting excellent clinical values.

Analysis of Metformin Effects on Bone Marrow Fibrosis and Disease Progression in Primary Myelofibrosis Patients: Preliminary Results of an Open Label Phase II Trial (FIBROMET)

Background: Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) characterized by increased myeloid proliferation and associated with mutations that induce tyrosine-kinase activation mainly via JAK-STAT pathway, culminating in extensive bone marrow (BM) fibrosis in the course of disease progression. In contrast to the monoclonal origin of hematopoietic cells, fibroblasts proliferation is polyclonal, and mediators involved in fibrosis, neoangiogenesis and osteosclerosis seem to be involved in disease progression. Metformin (MTF) is a biguanide that exerts selective antineoplastic activity in a variety of malignancies, through its action on nutrients privation and hypoxia, leading to apoptosis. In JAK2-mutated cell lines, MTF reduced cell viability, proliferation and clonogenicity, while in Jak2V617F knock-in-induced mice, MTF reduced Ba/F3 JAK2V617F tumor burden and splenomegaly. These data suggest that MTF could have a therapeutic effect in PMF patients. Aims: To conduct an open label phase II study to evaluate MTF effects on BM fibrosis, inflammation mediators, JAK-STAT pathway activation and disease progression in PMF patients. Methods: PMF non-diabetic adults were eligible. Subjects with severe renal function impairment were not included. Patients received MTF (Glifage XR®) in rising doses until a maximum of 2500mg PO daily, according to tolerance. Primary endpoint was BM fibrosis reversion. Secondary endpoints included reduction of inflammation and downregulation of the JAK-STAT pathway. Clinical data was systematically compiled. Blood and BM samples were collected at the time points: pretreatment (0), 3 mo and 6 mo. Collagen was evaluated in BM biopsy specimens by Masson's trichrome stain: three representative areas from each slide were analyzed and the collagen/sample area was quantified using Image J software; the mean percentage of each slide was used for statistics. IL-6, IL-8 and TNF-α levels were analyzed in BM samples using multiplex assay. Phosphorylation status of intracellular proteins STAT3 and STAT5 was analyzed by flow cytometry and the percentage of cells was recorded using FlowJo software. In order to evaluate gene modulation following MTF exposure, samples at time points 0 and 6 mo were analyzed by PCR array for insulin signaling genes (PAHS-030Z, Qiagen). Genes with ±1.5 fold-change in both directions were selected for validation. For each experiment, statistical analysis was performed and a p value &amp;lt;0.05 was considered statistically significant. Results were expressed as medians (min-max). This trial was approved by the Institutional and National Review Board; written informed consent was obtained from all subjects. Results: 11 patients (aged 40-84y) were included. Two subjects had early treatment discontinuation due to non-related causes. The median exposure to MTF was 10 mo (5-11) and the median dose was 2000mg/day (1500-2500mg). The most frequent adverse event was diarrhea (n=3). No life threatening event occurred. A reduction in BM collagen area percentage was observed comparing pretreatment biopsies (26.9% (14.8-53.1%)) versus 3 months (3.8% (2.3-4.0%), p=0.062) and versus 6 months of MTF use (0.84% (0.12-17.1%), p=0.125), however, this result was not statistically significant probably due to the low number of patients analyzed (n=5). IL-6, IL-8 and TNF-α levels did not differ between time points. Flow cytometry analysis demonstrated a trend in STAT3 phosphorylation decrease when comparing pretreatment samples versus 6 months of MTF use, though this result was not statistically significant (p=0.06). Mean fluorescence intensity for pSTAT3 was: pretreatment 10.53 ± 5.75, 3 mo 7.34 ± 2.4, 6 mo 5.41 ± 1.14; and for pSTAT5: pretreatment 14.03 ± 7.41; 3 mo 10.71 ± 7.74; 6 mo 6.03 ± 1.41. PCR array for insulin signaling genes showed 21 genes downregulated after 6 months of MTF treatment, including genes previously associated with MPN phenotype: INS (0 and 6 mo treatment fold-decrease: 0.18), NOS2 (0.24), VEGFA (0.34), LEP (0.34), IGFBP1 (0.38) and IRS2 (0.62). Conclusions: In this study, metformin showed to be a safe and well-tolerated drug. Our preliminary results demonstrated a trend in BM collagen reduction in PMF patients following metformin treatment. Downregulation of important genes associated with MPN phenotype was also noted. The trial is ongoing and these results will be validated at other time points for all subjects. Disclosures Pagnano: Abbvie: Consultancy; Pint Pharma: Consultancy; Sandoz: Consultancy.

Comparison between three different equations for the estimation of glomerular filtration rate in predicting mortality after coronary artery bypass

BackgroundThis study was undertaken to compare the accuracy of chronic kidney disease-epidemiology collaboration (eGFRCKD-EPI) to modification of diet in renal disease (eGFRMDRD) and the Cockcroft-Gault formulas of Creatinine clearance (CCG) equations in predicting post coronary artery bypass grafting (CABG) mortality.MethodsData from 4408 patients who underwent isolated CABG over a 11-year period were retrieved from one institutional database. Discriminatory power was assessed using the c-index and comparison between the scores’ performance was performed with DeLong, bootstrap, and Venkatraman methods. Calibration was evaluated with calibration curves and associated statistics.ResultsThe discriminatory power was higher in eGFRCKD-EPI than eGFRMDRD and CCG (Area under Curve [AUC]:0.77, 0.55 and 0.52, respectively). Furthermore, eGFRCKD-EPI performed worse in patients with an eGFR ≤29 ml/min/1.73m2 (AUC: 0.53) while it was not influenced by higher eGFRs, age, and body size. In contrast, the MDRD equation was accurate only in women (calibration statistics p = 0.72), elderly patients (p = 0.53) and subjects with severe impairment of renal function (p = 0.06) whereas CCG was not significantly biased only in patients between 40 and 59 years (p = 0.6) and with eGFR 45–59 ml/min/1.73m2 (p = 0.32) or ≥ 60 ml/min/1.73m2 (p = 0.48).ConclusionsIn general, CKD-EPI gives the best prediction of death after CABG with unsatisfactory accuracy and calibration only in patients with severe kidney disease. In contrast, the CG and MDRD equations were inaccurate in a clinically significant proportion of patients.

Coptisine ameliorates renal injury in diabetic rats through the activation of Nrf2 signaling pathway.

The present study has been designed and carried out to evaluate the potential of coptisine on diabetic nephropathy. Diabetes was induced in SD rats through one single intraperitoneal injection of streptozotocin (65mg/kg) method, and then diabetic rats were orally administered with 25mg/kg/day coptisine or 50mg/kg/day coptisine for 8weeks. Severe impairment of renal function in rats with diabetes was observed as indicated by increased urine protein excretion, kidney hypertrophy index, serum creatinine level, and blood urea nitrogen level. Oxidative stress damage was observed as indicated by increased levels of reactive oxygen species, malondialdehyde, and decreased levels of glutathione, superoxide dismutase, and catalase. However, these alterations in kidneys of rats with diabetes were alleviated by administration of coptisine. Furthermore, the expression levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and its targeted antioxidative genes heme oxygenase 1 and NADPH quinone oxidoreductase 1 in the diabetic kidneys were significantly increased after coptisine treatment. These results suggested that coptisine ameliorated oxidative renal injury in diabetic rats, and the possible mechanisms for the renoprotective effects of coptisine may be related to activation of the Nrf2 signaling pathway.

MON-302 ADMINISTRATION OF DAPAGLIFLOZIN IN TYPE 2 DIABETES MELLITUS PATIENTS WITH CHRONIC KIDNEY DISEASE: A SYSTEMATIC REVIEW

The increasing number of diabetes mellitus has led to an increase in the incidence of chronic kidney disease (CKD). Roughly, a third of all patients with diabetes mellitus also develop CKD as the disease progresses. Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, is the latest agent used in type 2 diabetes mellitus patients. The drug lower blood sugar levels by prevent glucose reabsorption in the proximal renal tubule. Inhibition of sodium reabsorption, on the other hand, manifested as an acute reduction in glomerular filtration rate (GFR) and albuminuria. This systematic review aims to analyze the clinical impact of dapagliflozin uses in type 2 diabetes patients with CKD. Interventional studies related to dapaglifozin administration in type 2 diabetes mellitus patients with chronic kidney disease were reviewed systematically. Inaugural literature searching was finished in four scientific databases (PubMed, EbscoHost, ProQuest, and Cochrane) using specific medical subheading (MeSH) terms and filters. Articles screened and selected by three authors independently to prevent bias. Studies that were relevant included to be further reviewed using tools provided by Centre for Evidence-based Medicine (CEBM). Two related articles were included in the review. Dapagliflozin was administered in a total of 441 type 2 diabetes mellitus patients with stages 3a-4 CKD. Study period ranged between 24-weeks to 104-weeks. Investigation reveals dapagliflozin considered as safe and effective in moderate renal impairment. However, the capacity of the drug to lower blood glucose levels tend to decrease in severe impaired renal function. This review draws to the conclusion that dapagliflozin administration may not improve glycemic index in diabetes mellitus patients with severe chronic kidney disease.

Evaluation of renal dysfunction using texture analysis based on DWI, BOLD, and susceptibility-weighted imaging.

To explore the value of texture analysis based on diffusion-weighted imaging (DWI), blood oxygen level-dependent MRI (BOLD), and susceptibility-weighted imaging (SWI) in evaluating renal dysfunction. Seventy-two patients (mean age 53.72 ± 13.46years) underwent MRI consisting of DWI, BOLD, and SWI. According to their estimated glomerular filtration rate (eGFR), the patients were classified into either severe renal function impairment (sRI, eGFR < 30mL/min/1.73m2), non-severe renal function impairment (non-sRI, eGFR ≥ 30mL/min/1.73m2, and < 80mL/min/1.73m2), or control (CG, eGFR ≥ 80mL/min/1.73m2) groups. Thirteen texture features were extracted and then were analyzed to select the most valuable for discerning the three groups with each imaging method. A ROC curve was performed to compare the capacities of the features to differentiate non-sRI from sRI or CG. Six features proved to be the most valuable for assessing renal dysfunction: 0.25QuantileDWI, 0.5QuantileDWI, HomogeneityDWI, EntropyBOLD, SkewnessSWI, and CorrelationSWI. Three features derived from DWI (0.25QuantileDWI, 0.5QuantileDWI, and HomogeneityDWI) were smaller in sRI than in non-sRI; EntropyBOLD and CorrelationSWI were smaller in non-sRI than in CG (p < 0.05). 0.25QuantileDWI, 0.5QuantileDWI, and HomogeneityDWI showed similar capacities for differentiating sRI from non-sRI. Similarly, EntropyBOLD and CorrelationSWI showed equal capacities for differentiating non-sRI from CG. Texture analysis based on DWI, BOLD, and SWI can assist in assessing renal dysfunction, and texture features based on BOLD and SWI may be suitable for assessing renal dysfunction during early stages. • Texture analysis based on MRI techniques allowed for assessing renal dysfunction. • Texture features based on BOLD and SWI, but not DWI, may be suitable for assessing renal function impairment during early stages. • SWI exhibited a similar capacity to BOLD for assessing renal dysfunction.

The safety of empagliflozin plus metformin for the treatment of type 2 diabetes

ABSTRACTIntroduction: Metformin is the first-line glucose-lowering medication in type 2 diabetes mellitus (T2DM), but it generally requires soon or later the addition of a second-line therapy, among which a sodium-glucose cotransporter type 2 (SGLT-2) inhibitor, to reach and maintain adequate glucose control.Areas covered: This narrative review provides an analysis of both efficacy and safety of a dual therapy combining metformin and empagliflozin, a SGLT-2 inhibitor that has proven its’ potential to reduce major cardiovascular (CV) events, mortality, and renal outcomes in patients with T2DM and established CV disease. Pharmacokinetic studies showed the absence of drug–drug interactions and demonstrate bioequivalence between fixed-dose combination (FDC) and individual tablets of empagliflozin and metformin. Focus will be put on the use of this dual therapy in special populations.Expert opinion: The addition of empagliflozin to metformin therapy improves glucose control, with a minimal risk of hypoglycemia, while reducing body weight and arterial blood pressure. EMPA-REG OUTCOME showed that this combined therapy may be used in patients with established CV disease or heart failure. However, caution may be required in fragile elderly patients and in patients with severe impaired renal function. Further post-marketing surveillance is recommended to demonstrate long-term safety. FDC may improve adherence.

Hantavirus Infections with Renal Involvement do not Result in Chronic Renal Disease or End-stage Renal Failure

Rodent-borne hantavirus infections are one of the most important causes worldwide of acute kidney injury in previously healthy, mostly young adults, but remain still heavily underestimated as such by the global nephrological community. Despite of a sometimes severe impairment of renal function, often accompanied by massive proteinuria, this acute zoonotic affection has, after survival, an excellent renal and general prognosis on short and on long term. However, this fact remains contradicted by repeated and unproven statements of the opposite in literature. Indeed, with the advent of early hantavirus research in the ‘80’s, speculations rose as to the potential of this novel agent to cause chronic renal disease, and even end-stage renal failure, since the bulk of pathogenic hantaviruses has the human kidney as main target organ. In several sections of this review, the authors try to dismantle point by point these unjustified assumptions. Finally, they show that in two recent Finnish retrospective studies on a local form of hantaviral acute kidney injury, nor the degree of acute renal impairment, nor the degree of acute but transient proteinuria, had any negative impact on the good renal outcome. These two studies, including the most important cohort numbers so far for the two specific questions, confirm an increasing series of case-reports or clinical overviews of hantavirus infections, all showing a good renal prognosis. The generally somber prognosis for acute kidney injury during hospitalization, as expressed in numerous publications based on Kidney Disease: Improving Global Outcomes (KDIGO), should be reviewed for the peculiar case of hantavirus infections.

Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities.

Progressive chronic kidney diseases (CKDs) are on the rise worldwide. However, the sequence of events resulting in CKD progression remain poorly understood. Animal models of CKD exploring these issues are confounded by systemic toxicities or surgical interventions to acutely induce kidney injury. Here we report the generation of a CKD mouse model through the inducible podocyte-specific ablation of an essential endogenous molecule, the chromatin structure regulator CCCTC-binding factor (CTCF), which leads to rapid podocyte loss (iCTCFpod-/-). As a consequence, iCTCFpod-/- mice develop severe progressive albuminuria, hyperlipidemia, hypoalbuminemia, and impairment of renal function, and die within 8-10 weeks. CKD progression in iCTCFpod-/- mice leads to high serum phosphate and elevations in fibroblast growth factor 23 (FGF23) and parathyroid hormone that rapidly cause bone mineralization defects, increased bone resorption, and bone loss. Dissection of the timeline leading to glomerular pathology in this CKD model led to the surprising observation that podocyte ablation and the resulting glomerular filter destruction is sufficient to drive progressive CKD and osteodystrophy in the absence of interstitial fibrosis. This work introduces an animal model with significant advantages for the study of CKD progression, and it highlights the need for podocyte-protective strategies for future kidney therapeutics.

Implantablecardioverter-defibrillator in the elderly: Predictors of appropriate interventions and mortality at 12-month follow-up.

The effectiveness of implantable cardioverter-defibrillator (ICD) in the elderly is uncertain, given their competing risk of nonarrhythmic death. Guidelines state that an ICD should be implanted if the expectation of survival is at least 1 year. However, survival is not easy to predict in elderly patients with severe cardiac disease. To assess 12-month survival after ICD implantation in patients aged ≥75 years, to identify predictors of 12-month mortality, and to evaluate the incidence of ICD therapy during follow-up. We retrospectively analyzed all clinical, instrumental, and survival data of patients ≥75 years old who received an ICD in our center from 2000 to 2013. We included 127 patients (mean age 78 years). ICD was implanted for primary prevention in 61%. The 12-month survival rate was 87.4%. At both univariate and multivariate analyses, left ventricular ejection fraction (EF) ≤ 25%, and moderate to severe impaired renal function (IRF) independently predicted 12-month mortality that was as high as 45.5% in patients with both risk factors. During a median follow-up of 38 months, 30 patients (23.6%) received ≥1 appropriate ICD interventions, but only 3.1% of shocks occurred during the first year, and none in the subgroup of patients with EF ≤ 25% and IRF. Twelve-month survival in elderly patients after ICD implantation is good and the indication for ICD should not be based on age alone. However, the subgroup with EF ≤ 25% and IRF showed a high 12-month nonarrhythmic mortality and did not benefit from ICD implantation.

Prenatal detection of megacystis: not always an adverse prognostic factor. Experience in 25 consecutive cases in a tertiary referral center, with complete neonatal outcome and follow-up

Megacystis is a condition of abnormal enlarged fetal bladder for gestational age, which is usually associated with urological malformations that may constitute a life-threatening condition for the baby. The purpose of this study was to assess the prognostic and etiological criteria of fetal megacystis and to describe the neonatal outcome in a large series collected in a single tertiary center. A retrospective observational study was conducted between 2008 and 2012. We reviewed all consecutive cases of fetal megacystis diagnosed during routine ultrasound (US) screening. The following data were collected and analyzed: maternal age, gestational age at diagnosis, prenatal ultrasonographic details of the urinary system, extra-urinary ultrasonographic anomalies, fetal karyotype, pregnancy outcome, postnatal diagnosis, and medical/surgical follow-up. Of the 25 fetuses included in this study, 76% were males. The mean gestational age (GA) at diagnosis was 23.1±7.5 weeks (range 12-34), among them only four (16%) were diagnosed during the first trimester. Associated urological malformations were detected in 92% (n=23) of the cases, while other malformations were detected in 36% (n=9). Oligohydramnios or anyhydramnios were observed in 52% (n=13) of the cases. Twelve (48%) fetuses were considered as having poor prognosis for renal function. Vesicocentesis with or without vesico-amniotic infusion were performed in 28% (n=7) of the cases. Pregnancy outcome was surprisingly good, with only one case of prenatal death and survival rate of 96% (n=24) of liveborn babies. Posterior urethral valve (PUV) (n=9, 36%) was the most common etiology of the fetal megacystis, followed by persistent urogenital sinus (n=2, 8%), Prune belly syndrome (n=2, 8%) and bilateral vescico-ureteral reflux (VUR) (n=2, 8%). Surgical or endoscopic procedures were performed in 75% (n=18) of the cases. Six (24%) newborns presented with moderate/severe respiratory distress that requested invasive assisted ventilation. Three cases (n=3, 12%) of perinatal death were observed due to severe impaired renal function. After a median follow-up of 29 months renal function was good in 79% (n=19) of the cases. Fetal megacystis may underline a wide range of associated pathologies with the highest prevalence of urinary malformation. Optimal counseling of the involved parents requires a multidisciplinary approach to allow the best management during the pregnancy and the perinatal period. Despite the high risk of renal failure, lung hypoplasia, and severe associated anomalies, the outcome of fetuses with megacystis could be improved thanks to an appropriate perinatal diagnosis and neonatal management.

Expanding the therapeutic options for renal involvement in lupus: eculizumab, available evidence.

In this study, we aimed to systematically review available literature on the efficacy of eculizumab for the treatment of renal involvement in patients with systemic lupus erythematosus (SLE). We conducted a literature search developed a priori, to identify articles reporting clinical experience with the use of eculizumab in SLE patients, focusing on renal involvement. The search strategy was applied to Ovid MEDLINE, EMBASE, In-Process and Other Non-Indexed Citation, Cochrane Central Register of Controlled Trials and Scopus from 2006 to present. Abstracts from EULAR and ACR congresses were also screened. We included six publications describing the renal outcome in SLE patients receiving eculizumab. Five out of six cases described the occurrence of thrombotic microangiopathy (TMA) in renal biopsies of patients with known SLE; three cases with biopsy-proven lupus nephritis (LN) and two patients with SLE-related antiphospholipid syndrome without histologic evidence of LN. One study reported the outcome of a patient with severe refractory LN successfully treated with eculizumab. All patients, regardless of the presence of concomitant LN, presented with severe hypocomplementemia and renal function impairment. All patients showed a sustained improvement of renal function and normalization of complement parameters after treatment with eculizumab[median follow-up 9 months (1-17)]. Despite the limitations of the currently available evidence, existing data are promising and provide preliminary support for the use of eculizumab in selected cases of SLE with renal involvement, especially in the presence of TMA, or in patients with refractory LN.

Eculizumab in secondary atypical haemolytic uraemic syndrome.

Background. Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab. Methods. We identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 109/L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration. Results. Twenty-nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses. Conclusion. Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing condition.

Renal function on admission affects both treatment strategy and long-term outcomes of patients with myocardial infarction (from the Polish Registry of Acute Coronary Syndromes).

Impairment of renal function (IRF) is an independent risk factor of myocardial infarction (MI). The aim of study was to determine if the presence of IRF affects the choice of treatment strategy in patients with MI, and if long-term mortality rates are influenced by the use of an invasive strategy in patients with MI according to the grade of IRF. Data from the PL-ACS Registry of 22,431 patients hospitalised for MI during 2007-2008 with an available estimated glomerular filtration rate (eGFR) with 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula were included. Patients were stratified based on eGFR: ≥ 90 (normal); 60-89 (mild IRF); 30-59 (moderate IRF); 15-29 (severe IRF); and < 15 mL/min/1.73 m² (end-stage IRF). After adjustment, each increase in IRF grade reduced the likelihood of percutaneous coronary intervention by 19% (odds ratio [OR] 0.81; 95% confidence interval [CI] 0.78-0.85; p < 0.001). A higher IRF grade was independently associated with mortality (OR 2.01; 95% CI 1.86-2.18; p < 0.001) and major bleeding (OR 1.42; 95% CI 1.22-1.66; p < 0.001) during hospitalisation, and mortality at 12 (hazard ratio [HR] 1.55; 95% CI 1.49-1.62; p < 0.001) and 36 months (HR 1.50; 95% CI 1.45-1.55; p < 0.001). Invasive treatment was independently associated with improved 12-month prognosis in non-ST-segment elevation MI (NSTEMI) patients with mild-to-severe IRF and in ST-elevation MI (STEMI) patients at all IRF grades. Invasive procedures were less frequent with worsening renal dysfunction. Invasive treatment was associ-ated with improved 12-month prognosis in STEMI patients regardless of renal function and in NSTEMI patients with eGFR ≥ 15 mL/min/1.73 m².

Effect of varying degrees of renal impairment on the pharmacokinetics and tolerability of taspoglutide.

To evaluate single-dose pharmacokinetics and tolerability of taspoglutide in people with varying degrees of renal impairment and matched healthy participants. Participants in the present study were people with mild renal impairment (n = 10), moderate impairment (n = 10), severe impairment (n = 9), and a matched healthy control group (n = 10). Participants received a single subcutaneous injection of taspoglutide (10 mg) on day 1. Plasma and urine drug concentration, antibody formation, vital signs, ECGs and routine laboratory variables were measured frequently and adverse events (AEs) were monitored for 9 weeks. Taspoglutide exposure was higher among participants with moderate and severe renal impairment compared with participants with normal renal function. Mean AUClast was 13% and 38% higher in participants with moderate and severe renal impairment, respectively compared with participants with normal renal function. Likewise, mean peak plasma concentration (Cmax ) was 57% and 93% higher in participants with moderate and severe renal function impairment, respectively, compared with participants with normal renal function. Linear regression analyses showed a statistically significant inverse relationship between taspoglutide exposure parameters (AUC and Cmax ) and creatinine clearance. Higher incidences of gastrointestinal (GI) AEs were reported in participants with severe renal impairment. Renal impairment altered the pharmacokinetics of taspoglutide. The degree of renal impairment was associated with an increased exposure to taspoglutide and an increased risk of GI AEs.

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis induced by compound heterozygous mutation of CLDN16: a case report and literature review

Objective To investigate the clinical features and disease-causing mutations of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis. Methods In February 2016, a 24 year old female patient with left kidney stone and nephrocalcinosis in bilateral kidneys was admitted to our hospital. One month prior to this admission, she had been treated by PCNL to remove the most part of left kidney stone in other hospital. After admission, She was found hypomagnesaemia (serum magnesium 0.65 mmol/L) and hypercalciuria (24h urine calcium 364.0 mg) but with normal renal function (serum creatinine 101.5μmol/L). And the remained part of left kidney stone was removed by flexible ureteroscope. As she was considered probably with an autosomal recessive FHHNC, an analysis of CLDN16 and CLDN19 gene mutations was performed using her and her parents' peripheral white blood cells. Results Mutation analysis revealed this patient had two heterozygous mutations in the CLDN16. One is an one-base deletion mutation in the 123th codon in exon 2: 368delA. The other is a missense mutation in the 139th codon in exon 2: 416C→T which resulted in an amino acid change Ala139Val. Her parents respectively had one of each heterozygous mutation. In the six months follow-up, an oral administration with hydrochlorothiazide, potassium citrate, and calcium magesium supplements significantly reduced her hypomagnesaemia (serum magnesium 1.0 mmol/L) and hypercalciuria (24-h urine calcium 156.0 mg), and no stone recurrence and aggravation of nephrocalcinosis and renal dysfunction occurred. Conclusions We diagnosed a patient with FHHNC who had a novel compound heterozygous mutation of CLDN16. This rare disease should be suspected if there are three constant clinical features of hypomagnesaemia, hypercalciuria and nephrocalcinosis, and verified with CLDN16 and CLDN19 gene test. Currently the option for treatment of FHHNC is symptomatic treatment until severe deterioration of renal function. The hydrochlorothiazide, potassium citrate, and calcium magesium supplements may have considerable effects on hypomagnesaemia and hypercalciuria. Key words: Hypomagnesaemia; Hypercalciuria; Nephrocalcinosis; CLDN16 gene; Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis

Lucerastat, an iminosugar for substrate reduction therapy: pharmacokinetics, tolerability, and safety in subjects with mild, moderate, and severe renal function impairment

Lucerastat, an inhibitor of glucosylceramide synthase, has the potential for substrate reduction therapy in glycosphingolipid storage disorders such as Fabry disease. In pharmacokinetic studies in rats, dogs, and healthy subjects, the main route of elimination was renal. The pharmacokinetics, tolerability, and safety of lucerastat were evaluated in subjects with mild (group A), moderate (group B), and severe (group C) renal impairment. Group D included healthy subjects. Thirty-two subjects (8 per group) were included in this single-center, open-label study and received a single oral dose of 1000 mg lucerastat in groups A and B and 500 mg in groups C and D. The degree of renal impairment of the subjects was based on estimated glomerular filtration rate. Plasma lucerastat concentrations (dose-corrected) were higher in groups B and C compared to group D. The elimination phase half-life was slower in groups B (9.6 hours) and C (16.1 hours) compared to group D (7.0 hours). Increased exposure to lucerastat was observed in subjects from groups B and C with ratio of geometric means (90%CI) of 1.60 (1.29, 1.98) for group B vs D and 3.17 (2.76, 3.65) for group C vs D. There were no clinically relevant abnormalities in vital signs, 12-lead electrocardiograms, and clinical laboratory values. Four nonserious adverse events were reported by 4 subjects (1 in group A, 3 in group D). Lucerastat was well tolerated in all dose groups. Dose adjustment is warranted in subjects with moderate and severe renal impairment.