Background Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1811744

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

The essential metals for humans: a brief overview

In rats with streptozotocln-induced diabetes an increase in arterial blood pressure was observed as early as the first week after the drug was injected. Blood pressure reached maximal values around the fourth week and remained stable for a long period of follow-up. The responsiveness of these rats to the three major vasopressor hormones, angiotensin II, norepinephrine, and vasopressin, was decreased in the early phase of diabetes and returned to normal in the late phase. Acute treatment at the third, sixth, and twelfth weeks with blockers of these vasopressor hormones resulted in a significant fall in blood pressure at the third week with captopril and at the twelfth week with propranolol plus phentolamine. No significant fall was observed when a specific vasopressin inhibitor was administered. Good control of the blood pressure was obtained when these rats were treated chronically with captopril or prazosin, and partial control was achieved when they were fed a low salt diet. An attenuation in arterial blood pressure levels was observed hi rats with two-kidney, one clip hypertension when diabetes was induced by streptozotocin. Plasma creatinlne levels hi diabetic rats were significantly higher than those in control rats only in the sixth and twelfth weeks. Electron microscopy revealed some minor glomerular lesions only at the twelfth week. (Hypertension 11 [Suppl I]: I-14-I-18, 1988)

Diabetes mellitus and hypertension

Skeletal complications caused by osteoporosis or bone metastases are associated with considerable pain, increased mortality, and reduced quality of life. Furthermore, such events place a burden on health care resources. Agents that prevent bone resorption, such as bisphosphonates or denosumab, can reduce the risk of skeletal-related events and are widely used in patients with osteoporosis or bone metastases of cancer. Medication-related osteonecrosis of the jaw (MRONJ) is a rare, but potentially serious, adverse event associated with high cumulative doses of bisphosphonates or denosumab. However, MRONJ can be treated, and the likelihood of the development of this condition can be reduced through prophylactic dental care and the maintenance of good oral hygiene. Dentists, as part of a multiprofessional team, have a critical role in preventing MRONJ. This review describes the incidence and pathophysiology of MRONJ and provides guidance for dental practitioners with regard to the screening, prophylactic treatment, diagnosis, and management of patients with this condition.

Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment

Therapeutics and clinical risk management

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.

/pdf/hypercalcemia-of-malignancy-and-new-treatment-options-4i2c7mtal1.pdf

Hypercalcemia of malignancy and new treatment options

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. 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.

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

The Kidney in Hypertension.

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.

/pdf/management-of-hypertension-in-diabetic-nephropathy-how-low-2lrtnrcx1c.pdf

Hillel Sternlicht

Papers

Hypercalcemia of malignancy and new treatment options

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

The Kidney in Hypertension.

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

Spironolactone for resistant hypertension—hard to resist?