Usefulness of alirocumab and evolocumab for the treatment of patients with diabetic dyslipidemia.

In 2015, the US Food and Drug Administration (FDA) approved the anti-proprotein convertase subtilsin/kexin type 9 (PCSK9) monoclonal antibodies, alirocumab and evolocumab, to treat patients with hypercholesterolemia and mixed dyslipidemia. Since then, considerable attention has been paid to the use of these monoclonal antibodies for the treatment of diabetic dyslipidemia with a goal of reducing the risk for cardiovascular disease. Recently, consensus statements on the clinical use of PCSK9 inhibitors in patients with type 2 diabetes mellitus, who are unable to achieve the goal of low-density lipoprotein cholesterol (<70 mg/dL or <1.8 mmol/L), have been published by panels of experts in Greece, Europe (European Society of Cardiology and European Atherosclerosis Society Task Force), and the United States (American College of Cardiology Consensus Committee). On December 1, 2017, the FDA approved evolocumab to prevent heart attack, stroke, and coronary revascularization. In this article, we review recent advances concerning the pathophysiology of diabetic dyslipidemia, the physiology of PCSK9, the mechanisms of action of PCSK9 inhibitors, clinical trials examining PCSK9 inhibitors in type 2 diabetes, and perspectives of nonstatin therapy in the treatment of diabetic dyslipidemia.

Cardiovascular outcomes in diabetic kidney disease: insights from recent clinical trials.

The prevalence of type 2 diabetes is catalyzing a pandemic in kidney disease, with ensuing cardiovascular complications. The effort to identify antidiabetic agents capable of promoting benefits that go beyond the bounds of glucose control has produced remarkable outcomes in recent cardiovascular outcomes trials in patients with type 2 diabetes mellitus, many of whom have diabetic kidney disease. Two novel antidiabetic drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), improve cardiovascular outcomes in different ways, with SGLT2is reducing the risk of heart failure and cardiovascular death and GLP-1 RAs being associated with reduced risk of myocardial infarction and cardiovascular death. Further mechanistic studies and additional cardiovascular outcome trials are ongoing and are expected to determine whether these benefits are a result of class effect, as well as to delineate optimum timing for intervention and population target.

ApoCIII as a Cardiovascular Risk Factor and Modulation by the Novel Lipid-Lowering Agent Volanesorsen.

PURPOSE OF REVIEW: Apolipoprotein CIII (ApoCIII) is now recognized as a key regulator in severe hypertriglyceridemia, chylomicronemia, and conditions of triglyceride-rich lipoprotein (TRL) remnant excess due to its inhibition of lipoprotein lipase (LPL) and hepatic lipase, leading to decreased hepatic reuptake of TRLs, as well as enhanced synthesis and secretion of VLDL from the liver. ApoCIII gain-of-function mutations are associated with atherosclerosis and coronary heart disease (CHD), and contribute to the development of cardiometabolic syndrome, hypertriglyceridemia, and type 2 diabetes mellitus. Conversely, loss-of-function mutations in ApoCIII are associated with lower levels of plasma triglycerides (TG), attenuation of vascular inflammatory processes such as monocyte adhesion and endothelial dysfunction, and potentially, a reduction in the incidence and progression of atherosclerosis and cardioprotection. RECENT FINDINGS: Evidence is now emerging that volanesorsen, a second-generation antisense oligonucleotide drug targeting ApoCIII messenger RNA resulting in decreases in TG in patients with familial chylomicronemia syndrome, severe hypertriglyceridemia, and metabolic dyslipidemia with type 2 diabetes giving support to the hypothesis that ApoCIII is a powerful inhibitor of LPL, and when reduced, endogenous clearance of TRLs can result in substantial reductions in TG levels. Discovery of the ApoCIII inhibitor volanesorsen opens a new era of lipid-lowering drugs for reduction in TG and potentially for reduction in LDL-C. Herein, this review will provide an update on the pathophysiology of ApoCIII-linked atherosclerosis and the development of the first drug to target ApoCIII, volanesorsen, as a promising lipid-lowering agent.

Rhabdomyolysis-induced acute kidney injury in a cancer patient exposed to denosumab and abiraterone: a case report.

BACKGROUND: Denosumab and abiraterone were approved by the United States Food and Drug Administration in 2011 for the treatment of metastatic castration-resistant prostate cancer. Neither denosumab nor abiraterone is known to cause rhabdomyolysis. CASE PRESENTATION: A 76-year-old Caucasian man with metastatic prostate cancer presented with non-oliguric severe acute kidney injury (AKI) 3 weeks after receiving simultaneous therapy with denosumab and abiraterone. The patient had been on statin therapy for more than 1 year with no recent dose adjustments. His physical exam was unremarkable. Blood work on admission revealed hyperkalemia, mild metabolic acidosis, hypocalcemia, and elevated creatine kinase (CK) at 44,476 IU/L. Kidney biopsy confirmed the diagnosis of rhabdomyolysis-induced AKI. The patient responded well to intravenous isotonic fluids and discontinuation of denosumab, abiraterone, and rosuvastatin, with normalization of CK and recovery of kidney function. CONCLUSION: We report the first case of biopsy-proven rhabdomyolysis-induced AKI in a cancer patient acutely exposed to denosumab and abiraterone. Whether one of these drugs individually, or the combination, was the bona fide culprit of muscle breakdown is unknown. Nonetheless, our report is hypothesis-generating for further investigations on the effect of these drugs on muscle cells.

Comparative analysis of pediatric and adult visceral leishmaniasis in Brazil.

BACKGROUND: The aim of this study was to compare clinical manifestations, laboratory data, morbidity and mortality between adults and children with visceral leishmaniasis, with a focus on kidney function. METHODS: This was a retrospective cohort study with 432 patients with visceral leishmaniasis diagnosed at 1 center in the northeast of Brazil. Patients were divided into 2 groups according to age (>21 years and ≤ 21 years old). RESULTS: The time between onset of symptoms and beginning of treatment was longer in adults (89.5 versus 48.5 days, P < 0.001); signs and symptoms were similar in both groups. Failure of treatment with glucantime was more common in adults (17.6% versus 8.8%, P = 0.008). Acute kidney injury was observed in 160 patients (37.0%), and it was more severe in adults. Risk factors for acute kidney injury in adults were hypokalemia, leukopenia, chills and amphotericin B use. In children, secondary infections were found to increase the risk for acute kidney injury. Overall mortality was 8.8%, and it was significantly higher in adults (12.6% versus 4.1%, P = 0.002). CONCLUSIONS: The adult population had more severe laboratory abnormalities and a worse prognosis, possibly due to delay in diagnosis. Acute kidney injury is prevalent in both groups, and it is usually more severe in adults.

Acute kidney injury in children with visceral leishmaniasis.

BACKGROUND: There is no comprehensive study about renal function in children with visceral leishmaniasis (VL). The aim of this study was to investigate the incidence of acute kidney injury (AKI) in children with VL using pRIFLE classification and to determine the risk factors for AKI. METHODS: A retrospective cohort study was conducted with 146 patients younger than 14 years of age with VL diagnosis in one center located at the northeast of Brazil from December 2003 to 2010. AKI was evaluated by pediatric Risk, Injury, Failure, Loss, End-stage kidney disease (pRIFLE) criteria. RESULTS: The mean age was 5 ± 4.0 years (range, 5 months to 14 years), and 53.4% were males. AKI was observed in 67 patients (45.9%). The distribution according to the pRIFLE criteria was as follows: risk 45 (67.2%), injury 21 (31.3%), and failure 1 (1.5%). Patients in the AKI group were significantly younger (P < 0.001) and had jaundice (P = 0.028) and secondary infections (P = 0.001) more often than non-AKI patients. The AKI group had a significantly lower serum sodium (P = 0.03), potassium (P = 0.009), serum albumin (P = 0.001), and elevated serum globulins (P = 0.04), and a more prolonged prothrombin time (P = 0.001) at admission. Independent risk factors for AKI were: secondary infections (OR: 3.65, 95% CI: 1.426-9.358, P = 0.007), serum albumin decrement (OR: 1.672, 95% CI: 1.065-2.114, P = 0.019 per each 1 mg dL(-1) serum albumin decrement), and high serum globulin (OR: 1.35, 95% CI: 1.031-1.779, P = 0.029 per each 1 mg dL(-1) serum globulin increment). CONCLUSIONS: AKI is a frequent complication in children with VL. The risk factors for AKI were secondary infections, high serum globulin and low serum albumin.

Visceral leishmaniasis in children: a cohort of 120 patients in a metropolitan city of Brazil.

There are few studies regarding the clinical presentation of visceral leishmaniasis (VL) in children. The aim of this study was to investigate the clinical manifestations, major complications and causes of death in children with VL. A retrospective study was performed with pediatric patients (< or = 14 years old) with a diagnosis of VL in Fortaleza, state of Ceara, in Northeast Brazil. A total of 120 patients were included. The mean age was 5 +/- 3.9 years, and 53.4% were male. The main clinical manifestations at admission were: fever (94.2%), splenomegaly (94.2%), hepatomegaly (82.5%), anorexia (55%), malaise (47.5%), cough (41.6%), abdominal pain (27.5%), vomiting (25.5%), and diarrhea (16.6%). Acute kidney injury was found in 25% of the patients. The main complication during hospital stay was pulmonary infection, found in 27.5% (n = 33), leading to sepsis in 3 cases. Glucantime was the drug of choice in 90% (n = 108) of the cases, amphotericin B in 7.5% (n = 9) and AmBisome in 2.5% (n = 3). Death occurred in 4 cases (3.3%) due to sepsis (3 cases) and hemorrhagic complications (1 case). Visceral leishmaniasis is a frequent infection among children in our region. The main complications were pulmonary infection and acute kidney injury related to antiparasitic therapy, along with sepsis and hemorrhage.

Renal dysfunction in leprosy: a historical cohort of 923 patients in Brazil.

We investigated the factors associated with renal dysfunction in leprosy patients from Brazil. We report on a historical cohort of leprosy patients followed in two hospitals in Fortaleza City in northeastern Brazil. The factors associated with renal dysfunction were investigated. A total of 923 patients were included, with a mean age of 41.5 ± 19.1 years, and 53.3% were male. Renal dysfunction was found in 35 cases (3.8%). Proteinuria was found in 4.8% of cases, haematuria in 6.8% and leukocyturia in 10.4%. Factors associated with renal dysfunction by multivariate analysis were: reaction episode (odds ratio [OR] = 3.9, P = 0.03), multibacillary classification (OR = 3.5, P = 0.02) and advanced age (OR = 1.04, P = 0.01). Four patients (0.4%) died. Leprosy is associated with renal dysfunction, especially in older patients and those presenting with reaction episode and multibacillary classification.

Renal function improvement with pentavalent antimonial agents in patients with visceral leishmaniasis.

BACKGROUND: The aim of this study is to investigate tubular and glomerular function after visceral leishmaniasis (VL) treatment with pentavalent antimonials. METHODS: This is a prospective study including 14 patients with VL diagnosis treated with pentavalent antimonials. Urine acidification and concentration tests were performed. Estimated glomerular filtration rate (eGFR), fractional excretion of sodium (FE(Na)) and potassium (FE(K)) and free water clearance (C(H2O)) were measured to assess glomerular and tubular function. RESULTS: The VL group had a significantly lower FE(K), serum sodium and plasma osmolality (P(osm)). No significant differences were found regarding proteinuria, eGFR, FE(Na) or C(H2O). Patients in the VL group had lower urinary osmolality (U(osm)) before DDAVP use when compared to the control group, as well as a lower U/P(osm). The urinary pH before and after CaCl(2) load was higher in the VL group. CONCLUSION: This study shows evidence of reversal of some tubular dysfunction in VL, but other dysfunctions may persist, especially urinary acidification capacity.

Risk factors for acute kidney injury in visceral leishmaniasis (Kala-Azar).

The aim of this study was to investigate the factors associated with acute kidney injury (AKI) in patients with visceral leishmaniasis (VL). The study patients had a diagnosis of VL and were admitted to a tertiary hospital. A multivariate analysis was performed to analyze the risk factors for AKI. A total of 224 patients were included. The mean age was 36 +/- 15 years. AKI was observed in 33.9% of cases. Risk factors associated with AKI were male gender (odds ratio [OR] = 2.2; P = 0.03), advanced age (OR = 1.05; P < 0.001), and jaundice (OR = 2.9; P = 0.002). There was an association between amphotericin B use and AKI (OR = 18.4; P < 0.0001), whereas glucantime use was associated with lower incidence of AKI compared with amphotericin B use (OR = 0.05; P < 0.0001). Mortality was 13.3%, and it was higher in AKI patients (30.2%). Therefore, factors associated with AKI were male gender, advanced age, and jaundice. Amphotericin B was an important cause of AKI in VL.

Acute kidney injury after trauma: Prevalence, clinical characteristics and RIFLE classification.

BACKGROUND: Acute kidney injury (AKI) is an uncommon but serious complication after trauma. The objective of this study was to evaluate the prevalence, clinical characteristics and outcome of AKI after trauma. PATIENTS AND METHODS: This was a retrospective study performed from January 2006 to January 2008 in an emergency specialized hospital in Fortaleza city, northeast of Brazil. All patients with AKI admitted in the study period were included. Prevalence of AKI, clinical characteristics and outcome were investigated. RESULTS: Of the 129 patients admitted to the intensive care unit (ICU), 52 had AKI. The mean age was 30.1 ± 19.2 years, and 79.8% were males. The main causes of AKI were sepsis in 27 cases (52%) and hypotension in 18 (34%). Oliguria was observed in 33 cases (63%). Dialysis was required for 19 patients (36.5%). Independent risk factors associated with AKI were abdominal trauma [odds ratio (OR) = 3.66, P = 0.027] and use of furosemide (OR = 4.10, P = 0.026). Patients were classified according to RIFLE criteria as Risk in 12 cases (23%), Injury in 13 (25%), Failure in 24 (46%), Loss in 1 (2%) and End-stage in 2 (4%). Overall in-hospital mortality was 95.3%. The main cause of death was sepsis (24%). Mortality was 100% among patients with AKI. CONCLUSIONS: AKI is a fatal complication after trauma, which presented with a high mortality in the studied population. A better comprehension of factors associated with death in trauma-associated AKI is important, and more effective measures of prevention and treatment of AKI in this population are urgently needed.