Mineralocorticoid Receptor Antagonists in the Treatment of Diabetic Kidney Disease: Their Application in the Era of SGLT2 Inhibitors and GLP-1 Receptor Agonists.

PURPOSE OF REVIEW: This review focuses on new clinical data involving a novel class of drugs, nonsteroidal mineralocorticoid receptor antagonists (NS-MRAs), specifically, finerenone and its effects on cardiovascular and diabetic kidney disease outcomes. RECENT FINDINGS: NS-MRAs are a novel class of agents for treating diabetic kidney disease (DKD). While they are chemically and pharmacologically distinct from steroidal MRAs (spironolactone, eplerenone), they effectively inhibit the MR receptor differently. Inhibition of MR receptor activation reduces inflammatory and profibrotic pathways involving the cardiorenal/vascular systems. Small diabetic kidney disease (DKD) clinical studies demonstrate that steroidal MRAs reduce albuminuria relative to placebo, although hyperkalemia is a major adverse event that has precluded large outcome trials. The NS-MRA, finerenone, demonstrated slowed progression of DKD and reduction of cardiovascular death primarily driven by reduced heart failure incidence in two separate randomized controlled clinical trials (FIDELIO and FIGARO). Use of NS-MRAs, therefore, provides a third "pillar of therapy" to reduce cardiorenal events added to blockers of the renin-angiotensin system and SGLT2 inhibitors. If the pending outcome trial, FLOW, is positive, potentially, GLP1-RAs may also be part of this "pillar" structure.

Hypertension in the elderly: recent developments and insights.

PURPOSE OF REVIEW: This article will summarize the effects of more intensive blood pressure (BP) control on cardiovascular, cognitive, and renal outcomes among elderly (age ≥75 years) individuals at high risk for cardiovascular events. Subsets of patients who may not benefit and obstacles to implementation will be addressed. The authors' insights will conclude the review. RECENT FINDINGS: A burst of new research regarding the effects of lower BP targets on cardiovascular, cognitive, and renal endpoints among the elderly has been published. Achieved values of 123 mmHg systolic in those without diabetes or prior stroke revealed striking declines in all-cause mortality, heart failure, and stroke. Although there was no benefit on the incidence of dementia, mild cognitive impairment was reduced. A trend towards modest declines in renal function and higher adverse event rates with normalization of BP were noted. Whether those with poor functional status or diastolic hypotension realize comparable gains remains unknown. SUMMARY: Intensive BP control (systolic goal 120-130 mmHg systolic) results in lower rates of all-cause mortality and major adverse cardiac events. Elderly individuals with a good functional status and no history of diabetes or stroke are suitable candidates.

Blood Pressure Lowering and Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2is): More Than Osmotic Diuresis.

PURPOSE OF REVIEW: This is an update of data regarding changes in blood pressure using sodium-glucose co-transporter 2 inhibitors (SGLT2i) for the treatment of diabetes. The mechanism of blood pressure lowering by SGLT2i was thought to be due to their osmotic diuretic effects. New data, however, has emerged from meta-analyses and studies of people with impaired kidney function demonstrating similar or greater magnitudes of blood pressure reduction in the absence of significant glycosuria. Potential additional mechanisms are proposed and reviewed. RECENT FINDINGS: Two separate meta-analyses in over 10,000 participants combined demonstrate an average of 4/2 mmHg reduction in blood pressure by SGLT2i. This includes consistency between measurements of in-office and ambulatory blood pressure monitoring. This reduction extends to decreases in nocturnal blood pressure of 2.6 mmHg systolic pressure. These reductions in blood pressure by SGLT2i are also present when added to ongoing treatment with ACE inhibitors or ARBs. In one study, dapagliflozin, when added to a regimen of a renin-angiotensin-aldosterone system (RAAS) antagonist and a diuretic, further lowered in-office systolic pressure by 2.4 mmHg. In contrast, when prescribed to those on a RAAS antagonist plus a calcium channel blocker or RAAS antagonist plus a beta blocker, systolic pressure decreased 5.4 mmHg. Lastly, post hoc analyses of major cardiovascular outcome trials across the spectrum of estimated glomerular filtration rates from 30 to 80 ml/min/1.73 m2 demonstrated similar magnitudes of BP reduction in spite of far less reduction in glucosuria among those with advanced kidney disease. Moreover, recent data implicate the potential for increased ketones associated with SGLT2i contributing to blood pressure lowering in advanced-stage kidney disease. SGLT2i are well established to lower blood pressure. Their mechanism appears to be multifactorial and has a hemodynamic as well as metabolic component contributing to this reduction.

Management of Hypertension in Diabetic Nephropathy: How Low Should We Go?

Hypertension is a frequent comorbidity often following the development of diabetic nephropathy among individuals with type 1 diabetes and affecting most patients with type 2 diabetes at the time of diagnosis. Multiple prospective randomized placebo-controlled trials demonstrate that tight blood pressure control among patients with diabetic nephropathy reduces the rates of macrovascular and microvascular complications. While randomized trials exist and support a blood pressure goal of <140/90 mm Hg for patients with nondiabetic kidney disease, there are no prospective data regarding a specific blood pressure goal on progression of diabetic nephropathy. Retrospective data analyses from trials show a linear relationship between either baseline or achieved study blood pressure and progression of nephropathy. Very high albuminuria is a hallmark of diabetic nephropathy with reductions by either angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blocker (ARB) monotherapy associated with slowed nephropathy progression. However, combination antihypertensive therapy, while decreasing proteinuria, augments the risk of hyperkalemia, hypotension, and kidney dysfunction. Given the lack of trial data for a BP goal among patients with diabetic nephropathy, prospective trials are needed to define the optimal blood pressure necessary to preserve kidney function. At present, guideline blood pressure goals of less than 140/90 mm Hg and the use of ACEi or ARB therapy for those with more than 300 mg of albuminuria are mandated.

The Kidney in Hypertension.

Hypertension is the second most common cause of chronic kidney disease (CKD) and is a potentiator of kidney failure when accompanying disease. CKD is a common cause of resistant hypertension. Nephropathy progression has dramatically slowed over the past 3 decades from an average of 8 to between 2-3 mL/min per year regardless of diabetes status. The incidence of very high albuminuria as well as progression from high albuminuria very high albuminuria has substantially decreased over the past 3 decades. This improvement relates to better blood pressure control using agents that slow nephropathy as well as better glycemic and cholesterol control.

Two cases of spontaneous remission of non-parasitic chyluria.

OBJECTIVES: Chyluria is a medical condition with presence of chyle in urine. The disease is most prevalent in South East Asian countries mostly caused by parasitic (Wuchereria bancrofti) infections. Our objective was to investigate the spontaneous remission of non-parasitic chyluria. DESIGN AND METHODS: The spontaneous remission of non-parasitic chyluria cases were worked up with diagnostic investigations, clinical assessment and studied in detail with respect to their natural evolution. RESULTS: We present two patients who were evaluated in the nephrology clinic with symptoms of milky urine and painless hematuria. Midnight blood smear was negative for filarial parasites. Urine culture was without mycobacteria. Urine cytology and IgG western blot for cysticercus were negative. Imaging for a lymphatic leak by lymphoscintigraphy was unrevealing. Chyluria resolved spontaneously in both patients. CONCLUSIONS: In our cases, radiologic visualization via lymphoscintigraphy was unrevealing. The patients were managed conservatively and fortunately underwent spontaneous remission marked by the disappearance of chyluria within several months of her initial diagnosis. In our opinion this spontaneous remission could be due to unrevealed lymphatico-renal fistula collapse or sclerosis of lymphatics caused by contrast media.

Hypercalcemia of malignancy and new treatment options.

Hypercalcemia of malignancy affects up to one in five cancer patients during the course of their disease. It is associated with both liquid malignancies, commonly multiple myeloma, leukemia, and non-Hodgkins lymphoma and solid cancers, particularly breast and renal carcinomas as well as squamous cell carcinomas of any organ. The clinical manifestations of hypercalcemia are generally constitutional in nature and not specific to the inciting malignancy. Such physical manifestations can range from malaise to lethargy and confusion. Constipation and anorexia are common. Acute kidney injury is likely the most frequently encountered manifestation of end organ damage. Symptomatology is closely linked to both the absolute elevation of serum calcium levels and the rapidity of calcium rise. The majority of cases are humoral in etiology and related to parathyroid hormone-related protein (PTHrP). Approximately 20% of cases are the result of direct bone metastasis with extra-renal 1,25-dihydroxyvitamin D (calcitriol) and ectopic parathyroid hormone production likely accounting for less than 1% of cases. The diagnosis of hypercalcemia of malignancy is confirmed either by an elevated PTHrP or by an evidence of bone metastasis in the appropriate clinical setting. Treatment is predicated on the patient's symptoms and absolute serum calcium level. Interventions are aimed at lowering the serum calcium concentration by inhibiting bone resorption and increasing urinary calcium excretion, the former accomplished via bisphosphonate therapy and the latter with aggressive hydration. Novel therapies for refractory disease include denosumab, a monoclonal antibody against the receptor activator of nuclear factor κB ligand, and the calcimimetic cinacalcet. Finally, anti-PTHrP antibodies have been successfully deployed in animal models of disease. Despite the efficacy of the above therapies, hypercalcemia of malignancy portends an ominous prognosis, indicating advanced and often refractory cancer with survival on the order of months.