1-year mortality following contrast-induced nephropathy

Objective: The aim of this study was to determine the 1-year mortality risk subsequent to Contrast-Induced Nephropathy (CIN) following CECT imaging, relative to other well-recognized predictors of mortality. Methods: We followed a prospective, consecutive cohort of ambulatory patients who received intravenous contrast for CECT for the outcome of death from any cause within 1 year. In a multivariate analysis, we compared CIN with other predictors of mortality: active malignancy, coronary artery disease (CAD), congestive heart failure (CHF) and age ≥70 years. Anticipating that terminal cancers would account for the majority of deaths in this population, we also analyzed the subset of patients without an active malignancy at the time of enrollment. Results: We followed 633 patients and 46 died (7%, 95%CI: 5-9%) within 1 year. The incidence of CIN was 11% (95%CI: 8-14%). Active malignancy (HR 9.2, 95%CI: 5.1-16.8), CIN (HR 2.4, 95%CI: 1.3-4.6), CHF (HR 2.1, 95%CI: 1.0-4.2), CAD (HR 2.2, 95%CI: 1.0-5.5) and age ≥70 years (HR 1.8, 95%CI: 1.0-3.8) were significant predictors of all-cause mortality. Among patients without active malignancies, the mortality rate was 4% (25/580, 95%CI: 3-6%) and CIN (HR 4.0, 95%CI: 1.7-9.6) and age ≥70 years (HR 3.7, 95%CI: 1.4-9.7) were significantly associated with death, whereas CAD (HR 2.5, 95%CI: 0.8-7.7) and CHF (HR 1.8, 95%CI: 0.6-5.3) were not. Conclusions: The development of CIN following CECT is associated with an increased likelihood of death at 1 year among patients with and without active malignancies, comparable to CAD, CHF and advanced age

Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel

Andrew S Bomback1, James A Tumlin2, Joel Baranski3, James E Bourdeau4, Anatole Besarab5, Alice S Appel1, Jai Radhakrishnan1, Gerald B Appel11Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY, USA; 2Department of Internal Medicine, Division of Nephrology, University of Tennessee College of Medicine in Chattanooga, Chattanooga, TN, USA; 3Balboa Nephrology Medical Group, San Diego, CA, USA; 4Nephrology Specialists of Oklahoma, Tulsa, OK, USA; 5Department of Medicine, Division of Nephrology and Hypertension, Henry Ford Health System, Detroit, MI, USAPurpose: A synthetic adrenocorticotropin (ACTH) analog has shown efficacy in Europe as primary and secondary therapy for nephrotic syndrome, but there is no published experience using the natural, highly purified ACTH gel formulation, available in the United States, for nephrotic syndrome. We therefore investigated the use of ACTH gel for nephrotic syndrome in the United States.Patients and methods: Twenty-one patients with nephrotic syndrome treated with ACTH gel outside of research settings in the United States, with initiation of therapy by December 31, 2009, allowing a minimum 6 months follow-up. We defined complete remission as stable renal function with proteinuria falling to <500 mg/day, and partial remission as stable renal function with >50% reduction in proteinuria from 500 to 3500 mg/day.Results: Twenty-one patients with nephrotic syndrome were treated: 11 with idiopathic membranous nephropathy (iMN), 4 with membranoproliferative glomerulonephritis (MPGN), 1 with focal segmental glomerulosclerosis (FSGS), 1 with minimal change disease (MCD), 1 with immunoglobulin A (IgA) nephropathy, 1 with class V systemic lupus erythematosus (SLE) glomerulonephritis, 1 with monoclonal diffuse proliferative glomerulonephritis, and 1 with unbiopsied nephrotic syndrome. ACTH was used as primary therapy for 3 patients; the remaining patients had previously failed a mean 2.3 immunosuppressive regimens. Eleven patients achieved a complete or partial remission, with 4 (19%) in complete remission. Of the 11 patients who achieved remission, 9 had iMN, 1 had FSGS, and 1 had IgA nephropathy. Of the 11 patients with iMN, 3 (27%) achieved complete remission and 6 (55%) achieved partial remission despite having previously failed a mean 2.4 therapies. Five patients reported steroid-like adverse effects, but there were no severe infections. The limitations were retrospective data analysis with short-term follow-up.Conclusion: ACTH gel may be a viable treatment option for resistant nephrotic syndrome due to membranous nephropathy. Short-term data suggest that remission rates may approach 80%.Keywords: nephrotic syndrome, membranous nephropathy, chronic kidney diseas

Development and Standardization of a Furosemide Stress Test to Predict the Severity of Acute Kidney Injury

Introduction: In the setting of early acute kidney injury (AKI), no test has been shown to definitively predict the progression to more severe stages. Methods: We investigated the ability of a furosemide stress test (FST) (one-time dose of 1.0 or 1.5 mg/kg depending on prior furosemide-exposure) to predict the development of AKIN Stage-III in 2 cohorts of critically ill subjects with early AKI. Cohort 1 was a retrospective cohort who received a FST in the setting of AKI in critically ill patients as part of Southern AKI Network. Cohort 2 was a prospective multicenter group of critically ill patients who received their FST in the setting of early AKI. Results: We studied 77 subjects; 23 from cohort 1 and 54 from cohort 2; 25 (32.4%) met the primary endpoint of progression to AKIN-III. Subjects with progressive AKI had significantly lower urine output following FST in each of the first 6 hours (p\u3c0.001). The area under the receiver operator characteristic curves for the total urine output over the first 2 hours following FST to predict progression to AKIN-III was 0.87 (p = 0.001). The ideal-cutoff for predicting AKI progression during the first 2 hours following FST was a urine volume of less than 200mls(100ml/hr) with a sensitivity of 87.1% and specificity 84.1%.Conclusions: The FST in subjects with early AKI serves as a novel assessment of tubular function with robust predictive capacity to identify those patients with severe and progressive AKI. Future studies to validate these findings are warranted. © 2013 Chawla et al. licensee BioMed Central Ltd

A phase 2, double-blind, placebo-controlled, randomized study of fresolimumab in patients with steroid-resistant primary focal segmental glomerulosclerosis

Introduction: Steroid-resistant focal segmental glomerulosclerosis (SR-FSGS) is a common glomerulopathy associated with nephrotic range proteinuria. Treatment goals are reduction in proteinuria, which can delay end-stage renal disease. Methods: Patients with SR-FSGS were enrolled in a randomized, double-blind placebo-controlled trial of fresolimumab, a monoclonal anti transforming growth factor b antibody, at 1 mg/kg or 4 mg/kg for 112 days, followed double-blind for 252 days (NCT01665391). The primary efficacy endpoint was the percentage of patients achieving partial (50% reduction) or complete (< 300 mg/g Cr) remission of proteinuria. Results: Of 36 enrolled patients, 10, 14, and 12 patients received placebo, fresolimumab 1 mg/kg, and fresolimumab 4 mg/kg, respectively. The baseline estimated glomerular filtration rate (eGFR) and urinary protein/creatinine ratio were 63 ml/min/1.73 m2 and 6190 mg/g, respectively. The study was closed before reaching its target of 88 randomized patients. None of the prespecified efficacy endpoints for proteinuria reduction were achieved; however, at day 112, the mean percent change in urinary protein/creatinine ratio (a secondary efficacy endpoint) was –18.5% (P ¼ 0.008), þ10.5% (P ¼ 0.52), and þ9.0% (P ¼ 0.91) in patients treated with fresolimumab 1 mg/kg, fresolimumab 4 mg/kg, and placebo, respectively. There was a nonsignificant trend toward greater estimated glomerular filtration rate decline in the placebo group compared to either of the fresolimumab-treated arms up to day 252. Discussion: The study was underpowered and did not meet the primary or secondary endpoints. However, fresolimumab was well tolerated and is appropriate for continued evaluation in larger studies with adequate power

Angiotensin II for the Treatment of Vasodilatory Shock

BACKGROUND Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODS We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 mu g of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTS A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P = 0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P = 0.12). CONCLUSIONS Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843.)Peer reviewe

Development of a Kemp\u27s Ridley Sea Turtle Stock Assessment Model

We developed a Kemp’s ridley (Lepidochelys kempii) stock assessment model to evaluate the relative contributions of conservation efforts and other factors toward this critically endangered species’ recovery. The Kemp’s ridley demographic model developed by the Turtle Expert Working Group (TEWG) in 1998 and 2000 and updated for the binational recovery plan in 2011 was modified for use as our base model. The TEWG model uses indices of the annual reproductive population (number of nests) and hatchling recruitment to predict future annual numbers of nests on the basis of a series of assumptions regarding age and maturity, remigration interval, sex ratios, nests per female, juvenile mortality, and a putative ‘‘turtle excluder device effect’’ multiplier starting in 1990. This multiplier was necessary to fit the number of nests observed in 1990 and later. We added the effects of shrimping effort directly, modified by habitat weightings, as a proxy for all sources of anthropogenic mortality. Additional data included in our model were incremental growth of Kemp’s ridleys marked and recaptured in the Gulf of Mexico, and the length frequency of stranded Kemp’s ridleys. We also added a 2010 mortality factor that was necessary to fit the number of nests for 2010 and later (2011 and 2012). Last, we used an empirical basis for estimating natural mortality, on the basis of a Lorenzen mortality curve and growth estimates. Although our model generated reasonable estimates of annual total turtle deaths attributable to shrimp trawling, as well as additional deaths due to undetermined anthropogenic causes in 2010, we were unable to provide a clear explanation for the observed increase in the number of stranded Kemp’s ridleys in recent years, and subsequent disruption of the species’ exponential growth since the 2009 nesting season. Our consensus is that expanded data collection at the nesting beaches is needed and of high priority, and that 2015 be targeted for the next stock assessment to evaluate the 2010 event using more recent nesting and in-water data

Randomized trial on the effect of an oral spleen tyrosine kinase inhibitor in the treatment of IgA nephropathy

Introduction We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells. Methods This study was a double-blind, randomised, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomised to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors (RASi). The primary end point was reduction of proteinuria. Secondary endpoints included change from baseline in eGFR and kidney histology. Results While we could not detect significant reduction in proteinuria with fostamatinib overall, in a pre-determined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27% and 36% in the placebo, fostamatinib 100 mg and 150 mg groups respectively) in patients with baseline urinary protein to creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well tolerated. Side effects included diarrhea, hypertension and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (-1.5 v 1.7 SYK+ cells/glomerulus in the placebo group, p<0.05). Conclusions There was a trend towards reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)

The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death

Safety and Efficacy of Combination ACTHar Gel and Tacrolimus in Treatment-Resistant Focal Segmental Glomerulosclerosis and Membranous Glomerulopathy

H.P. ACTHar gel is a preparation of melanocortin peptides that has been used to treat resistant forms of nephrotic syndrome. To determine whether combination therapy with ACTHar gel and tacrolimus reduces proteinuria and stabilizes renal function, we conducted a prospective, open-label trial in patients with treatment-resistant membranous glomerulopathy (MGN) and focal segmental glomerulosclerosis (FSGS). Methods: Nine patients with treatment-resistant MGN and 13 with treatment-resistant FSGS received subcutaneous ACTHar gel for 6 months. Patients with no response or a partial response to ACTHar gel alone received an additional 6 months of therapy with combination ACTHar gel and oral tacrolimus. The study endpoint was the percentage of patients achieving a complete or partial remission after 6 months of combination therapy. Results: Among patients with MGN, treatment with ACTHar gel alone achieved a partial remission in 44% and no response in 56% of patients. No patient achieved a complete response with ACTHar gel therapy alone. An additional 6 months of combination therapy with ACTHar gel and tacrolimus resulted in partial and complete response rates of 25% and 75%, respectively. Among patients with FSGS, ACTHar gel therapy alone resulted in complete and partial response rate of 7.7% and 62.0%. Combination therapy increased complete response rates to 17% and partial responses to 66%. Proteinuria (urinary protein-to-creatinine ratio) was significantly reduced in both patients with MGN and those with FSGS after 6 months of ACTHar gel alone and was further reduced among the patients with MGN with the addition of tacrolimus. There were no significant changes in estimated glomerular filtration rate during the treatment phase or long-term follow-up. Discussion: Combination therapy with ACTHar gel and tacrolimus was well tolerated by patients with treatment-resistant MGN and FSGS and significantly reduced proteinuria and improved clinical response rates compared with ACTHar gel alone

Randomized clinical trial of the iron-based phosphate binder PA21 in hemodialysis patients

BACKGROUND AND OBJECTIVES: A dose-finding study was undertaken to investigate the efficacy of PA21, a novel polynuclear iron(III)-oxyhydroxide phosphate binder. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a randomized, active-controlled, multicenter, open-label study at 50 clinical sites in Europe and the United States, hemodialysis patients were randomized to PA21 at dosages of 1.25, 5.0, 7.5, 10.0, or 12.5 g/d or sevelamer-HCl 4.8 g/d for 6 weeks. The primary efficacy endpoint was the change in serum phosphorus concentration from baseline. RESULTS: There were 154 participants who were randomized and received the study drug. All groups except PA21 1.25 g/d showed a significant decrease in serum phosphorus. Mean decreases in serum phosphorus in PA21 10 g/d and 12.5 g/d were -2.00±1.71 mg/dl and -1.69±1.81 mg/dl, respectively. A similar decrease to sevelamer-HCl (-1.06±1.35 mg/dl) was seen with PA21 5.0 g/d (-1.08±2.12 mg/dl) and 7.5 g/d (-1.25±1.21 mg/d). Overall, 60.9% of participants randomized to PA21 and 57.7% randomized to sevelamer-HCl reported ≥1 adverse event. The most frequent adverse events were hypophosphatemia (18.0%) and discolored feces (11.7%) for the pooled PA21 dose groups, and diarrhea, hypophosphatemia, and hypotension (each 11.5%) for sevelamer-HCl. Discontinuation due to adverse events occurred at a similar rate in PA21-treated (21.1%) and sevelamer-HCl-treated (23.1%) participants. CONCLUSIONS: PA21 5-12.5 g/d significantly reduces serum phosphorus in hemodialysis patients. The 5 g/d and 7.5 g/d dosages showed similar efficacy to 4.8 g/d of sevelamer-HCl. The adverse events rate was similar for PA21 and sevelamer-HCl