The Incidence of Primary vs Secondary Focal Segmental Glomerulosclerosis: A Clinicopathologic Study

Objectives

To describe the change in the incidence rates of primary and secondary focal segmental glomerulosclerosis (FSGS) from 1994 through 2013 in Olmsted County, Minnesota, and to identify the clinical and biopsy characteristics that distinguish primary from secondary FSGS.

Mechanism of adrenocortical toxicity induced by quinocetone and its bidesoxy-quinocetone metabolite in porcine adrenocortical cells in vitro

Quinocetone (QCT) is a new feeding antibacterial agent in the QdNOs family. The mechanism of its adrenal toxicity is far from clear. This study was conducted to estimate the adrenal cell damage induced by QCT and its bidesoxy-quinocetone (B-QCT) metabolite and to further investigate their mechanisms. Following doses of QCT increasing from 5 to 50 μM, cell apoptosis and necrosis, mitochondrial dysfunction and redox imbalance were observed in porcine adrenocortical cells. The mRNA levels of the six components of intermediary enzymes and the adrenal renin-angiotensin-aldosterone system (RAAS) displayed a dysregulation induced by QCT, indicating that QCT might influence aldosterone secretion not only through the upstream of the production but also through the downstream of the adrenal RAAS pathway. In contrast, B-QCT had few toxic effects on the cell apoptosis, mitochondrial dysfunction and redox imbalance. Moreover, LCMS-IT-TOF analysis showed that no desoxy metabolites of QCT were found in either cell lysate or supernatant samples. In conclusion, we reported on the cytotoxicity in porcine adrenocortical cells exposed to QCT via oxidative stress, which raised awareness that its toxic effects resulted from N→O groups, and its toxic mechanism might involve the interference of the steroid hormone biosynthesis pathway.     

Developmental programing of thirst and sodium appetite

Thirst and sodium appetite are the sensations responsible for the motivated behaviors of water and salt intake, respectively, and both are essential responses for the maintenance of hydromineral homeostasis in animals. These sensations and their related behaviors develop very early in the postnatal period in animals. Many studies have demonstrated several pre- and postnatal stimuli that are responsible for the developmental programing of thirst and sodium appetite and, consequently, the pattern of water and salt intake in adulthood in need-free or need-induced conditions. The literature systematically reports the involvement of dietary changes, hydromineral and cardiovascular challenges, renin–angiotensin system and steroid hormone disturbances, and lifestyle in these developmental factors. Therefore, this review will address how pre- and postnatal challenges can program lifelong thirst and sodium appetite in animals and humans, as well as which neuroendocrine substrates are involved. In addition, the possible epigenetic molecular mechanisms responsible for the developmental programing of drinking behavior, the clinical implications of hydromineral disturbances during pre- and postnatal periods, and the developmental origins of adult hydromineral behavior will be discussed.     

COVID-19 and the heart: An update for clinicians

SARS-CoV-2, the cause of the COVID-19 pandemic has significantly impacted cardiovascular healthcare. Patients with pre-existing cardiovascular disease are at higher risk of morbidity and mortality. The virus may affect the heart directly and indirectly with clinical syndromes of acute myocardial injury, myocarditis, acute coronary syndromes, heart failure, arrhythmias, and venous thromboembolism. Some therapeutics under investigation for COVID-19 may also have adverse cardiac effects. The involvement of the RAAS system in viral entry makes it pertinent to consider the effects of medications that modulate the system. Comprehensive knowledge of peculiar cardiovascular manifestations of COVID-19 and the role of RAAS in the prognosis of COVID-19 disease is needed for optimal patient management.     

Pathophysiologic mechanisms in diabetic kidney disease: A focus on current and future therapeutic targets

Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease around the globe and is one of the main complications in patients with type 1 and 2 diabetes. The standard treatment for DKD is drugs controlling hyperglycemia and high blood pressure. Renin angiotensin aldosterone system blockade and sodium glucose cotransporter 2 (SGLT2) inhibition have yielded promising results in DKD, but many diabetic patients on such treatments nevertheless continue to develop DKD, leading to kidney failure and cardiovascular comorbidities. New therapeutic options are urgently required. We review here the promising therapeutic avenues based on insights into the mechanisms of DKD that have recently emerged, including mineralocorticoid receptor antagonists, SGLT2 inhibitors, glucagon-like peptide-1 receptor agonist, endothelin receptor A inhibition, anti-inflammatory agents, autophagy activators and epigenetic remodelling. The involvement of several molecular mechanisms in DKD pathogenesis, together with the genetic and epigenetic variability of this condition, makes it difficult to target this heterogeneous patient population with a single drug. Personalized medicine, taking into account the genetic and mechanistic variability, may therefore improve renal and cardiovascular protection in diabetic patients with DKD.     

Arterial hypertension and thyroid disorders: what is important to know in clinical practice?

This review describes the pathogenic mechanisms of blood pressure (BP) regulation and long-term control in thyroid disorders. Variations from the euthyroid status affect virtually all physiological systems but the effects on the cardiovascular system are particularly pronounced. Thyroid disorders induce several hemodynamic changes leading to elevated BP as a consequence of their interaction with endothelial function, vascular reactivity, renal hemodynamic and renin-angiotensin system. However, in thyroid disorders, the regulation of BP and the development and maintenance of variable forms of arterial hypertension (HT) are different. Hyperthyroidism results in an increased endothelium-dependent responsiveness secondary to the shear stress induced by the hyperdynamic circulation, and contributes to reduce vascular resistance. Conversely, hypothyroidism is accompanied by a marked decrease in sensitivity to sympathetic agonists with an increase of peripheral vascular resistance and arterial stiffness. Furthermore in animal models, hypothyroidism reduces the endothelium-dependent and nitric oxide-dependent vasodilatation. HT due to thyroid disorders is usually reversible with achievement of euthyroidism, but in some cases pharmacological treatment for BP control is required. In hyperthyroidism, β-blockers are the first-choice treatment to control BP but when they are contraindicated or not tolerated, ACE-inhibitors or calcium-channel blockers (CCB) are recommended. Hypothyroidism is a typical low rennin HT form showing a better antihypertensive response to CCB and diuretics; indeed in hypothyroidism a low-sodium diet seems further to improve BP control. Randomized clinical trials to compare the efficacy on BP control of the antihypertensive treatment in thyroid disorders are needed.     

RAAS Inhibitors in the Cardiovascular Continuum: What is Still Missing?

Recently, clinical trials evaluating cardiovascular outcomes with antihypertensive drugs that target the renin-angiotensin-aldosterone system have been dramatically increasing in size. The CONSENSUS trial in 1987 enrolled 253 patients, while Val-HeFT in 1999 enrolled 5,010 patients; indeed, the Val-HeFT subgroup of patients not receiving angiotensin-converting enzyme inhibitors was bigger than the whole CONSENSUS trial even though the 366 patients were only 7% of the total trial population. More recent and ongoing cardiovascular trials have even greater patient numbers with 14,703 patients enrolled in VALIANT, 15,314 in VALUE, 23,400 in ONTARGET and 33,357 in ALLHAT. Part of the reason is that in modern trials, patients in the control group are already receiving optimal therapy. Therefore, in order to be adequately powered to detect any benefit of new drugs, trials must recruit thousands of patients. This expanding trend cannot continue forever because of time and economic constraints and as a result, trials are shifting their design to include composite and surrogate endpoints. In addition, more predefined substudies are being carried out to analyze possible benefits in specific patient populations such as those with type 2 diabetes or renal impairment. Modern trials are also placing more emphasis on protection as a long-term strategy to control cardiovascular risks. Examples of these points, particularly regarding the size of modern cardiovascular trials to have the power to show protective effects, are illustrated by Val-HeFT, LIFE, ELITE II, VALIANT, VALUE, CHARM and NAVIGATOR.     

Treatments with losartan or enalapril are equally sensitive to deterioration in renal function from cyclooxygenase inhibition

BACKGROUND: The beneficial effects of angiotensin converting enzyme (ACE)-inhibitors are in part mediated through the inhibition of the degradation of the vasodilator bradykinin. The bradykinin effect is counteracted by cyclooxygenase-inhibitors. Angiotensin receptor blockers (ARBs) do not affect bradykinin. AIMS: To test the hypothesis that renal counteraction from a cyclooxygenase-inhibitor, diclofenac, is different in subjects treated with an ACE-inhibitor, enalapril compared with an ARB, losartan. METHODS: Twelve elderly, healthy, slightly over-hydrated subjects received diclofenac orally after pre-treatment with a diuretic, bendroflumethiazide, and enalapril or bendroflumethiazide and losartan, in a double-blind cross-over fashion, with a wash-out period of at least 1 week. RESULTS: Diclofenac reduced GFR significantly from 81(64-98) ml/min at first observations after dose for enalapril to 29(16-42) and from 76(64-88) after losartan to 35(24-46). There was no significant difference between enalapril and losartan in GFR. Diclofenac induced decreases in urine flow, excretion rates and clearances of sodium, osmolality clearance and free water clearance, irrespective of treatment with enalapril or losartan. However, serum potassium and handling of potassium were significantly lower after losartan-treatment. CONCLUSION: The negative renal effects of diclofenac administration in subjects with activation of the renin-angiotensin system and enalapril treatment are the same in subjects with activation of the renin-angiotensin system and losartan treatment.     

ACS合并AHF患者治疗中RAAS抑制剂对CI-AKI发病的影响

目的 探讨肾素血管紧张素醛固酮系统（RAAS）抑制剂在急性冠状动脉综合征（ACS）合并急性心力衰竭（AHF）患者经皮冠状动脉介入术（PCI）中对比剂致急性肾损伤（CI-AKI）中的作用。方法 回顾性分析成功行PCI手术ACS合并AHF患者504例,并于术后24～48 h内复查肾功能。分别按照有无CI-AKI及有无应用RAAS抑制剂进行分组,对比相关观察指标,并将差异有统计学意义的观察指标进行Logistics回归分析。结果 504例患者中144例（28.6%）患者发生CI-AKI。CI-AKI组RAAS抑制剂使用比例、高血压、糖尿病患病率与非CI-AKI组比较,差异有统计学意义（P?<0.05）。CI-AKI组反映心脏功能超声指标LVEF、LVEDD、PAP、NT-proBNP、hs-CRP及Hcy水平与非CI-AKI组比较,差异有统计学意义（P?<0.05）。将上述指标引入Logistic回归分析发现,应用RAAS抑制剂对CI-AKI影响消失。而高血压、NT-proBNP、Hcy、hs-CRP、LVEF、PAP仍为心力衰竭患者CI-AKI发生高危因素。结论 对ACS合并AHF患者需行PCI治疗患者,常规应用RAAS抑制剂并不增加CI-AKI发生风险。     

肾素血管紧张素系统对糖尿病早期肾脏病变的预防作用

糖尿病肾病临床上表现为尿白蛋白排泄率上升,同时常伴有高血压和视网膜病变。糖尿病肾病一般首先表现为白蛋白尿,然后出现肾小球率过滤降低,最终会导致终末期肾功能衰竭而危及生命。在1型糖尿病和2型糖尿病中糖尿病肾病的发病率约为30%～35%并有家庭聚集的倾向。糖尿病肾脏病变能显著增加心血管疾病的发病率并与早期的微量蛋白尿有关。近年来,肾素血管紧张素醛固酮系统已经被用于治疗和预防糖尿病肾病。现在研究证实大多数糖尿病和肾脏疾病患者在进展为肾功能衰竭前已经死于心血管疾病。这篇综述中列举了很多研究,但我们认为现在仍然缺乏肾素血管紧张素醛固酮系统(RAAS)抑制剂显著预防糖尿病肾病进展的证据,需要更多的研究证实。然而,RAAS抑制剂控制血压及其他多因素的控制(血糖、血脂等)已被批准用于慢性糖尿病肾病的二级预防和治疗。