Lipid Toxicity in the Cardiovascular-Kidney-Metabolic Syndrome (CKMS).

Recent studies of Cardiovascular-Kidney-Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized LDL, and lipoproteins (a, b) are toxic to kidney and heart function. Energy production for renal proximal tubule resorption of critical fuels and electrolytes is required for homeostasis. Cardiac energy for ventricular contraction/relaxation is preferentially supplied by long chain fatty acids. Metabolism of long chain fatty acids is accomplished within the cardiomyocyte cytoplasm and mitochondria by means of the glycolytic, tricarboxylic acid, and electron transport cycles. Toxic lipids and excessive lipid concentrations may inhibit cardiac function. Cardiac contraction requires calcium movement from the sarcoplasmic reticulum from a high to a low concentration at relatively low energy cost. Cardiac relaxation involves calcium return to the sarcoplasmic reticulum from a lower to a higher concentration and requires more energy consumption. Diastolic cardiac dysfunction occurs when cardiomyocyte energy conversion is inadequate. Diastolic dysfunction from diminished ATP availability occurs in the presence of inadequate blood pressure, glycemia, or lipid control and may lead to heart failure. Similar disruption of renal proximal tubular resorption of fuels/electrolytes has been found to be associated with phospholipid (sphingolipid) accumulation. Elevated concentrations of tissue oxidized low-density lipoprotein cholesterols are associated with loss of filtration efficiency at the level of the renal glomerular podocyte. Macroscopically excessive deposits of epicardial and intra-nephric adipose are associated with vascular pathology, fibrosis, and inhibition of essential functions in both heart and kidney. Chronic triglyceride accumulation is associated with fibrosis of the liver, cardiac and renal structures. Successful liver, kidney, or cardiac allograft of these vital organs does not eliminate the risk of lipid toxicity. Lipid lowering therapy may assist in protecting vital organ function before and after allograft transplantation.

Hyperglycemia and Hyperlipidemia with Kidney or Liver Transplantation: A Review.

Although solid organ transplantation in persons with diabetes mellitus is often associated with hyperglycemia, the risk of hyperlipidemia in all organ transplant recipients is often underestimated. The diagnosis of diabetes often predates transplantation; however, in a moderate percentage of allograft recipients, perioperative hyperglycemia occurs triggered by antirejection regimens. Post-transplant prescription of glucocorticoids, calcineurin inhibitors and mTOR inhibitors are associated with increased lipid concentrations. The existence of diabetes mellitus prior to or following a liver transplant is associated with shorter times of useful allograft function. A cycle involving Smad, TGF beta, m-TOR and toll-like receptors has been identified in the contribution of rejection and aging of allografts. Glucocorticoids (prednisone) and calcineurin inhibitors (cyclosporine and tacrolimus) induce hyperglycemia associated with insulin resistance. Azathioprine, mycophenolate and prednisone are associated with lipogenesis. mTOR inhibitors (rapamycin) are used to decrease doses of atherogenic agents used for immunosuppression. Post-transplant medication management must balance immune suppression and glucose and lipid control. Concerns regarding rejection often override those relative to systemic and organ vascular aging and survival. This review focuses attention on the underlying mechanism of relationships between glycemia/lipidemia control, transplant rejection and graft aging.

Gated Calcium Ion Channel and Mutation Mechanisms in Multidrug-Resistant Tuberculosis.

A wide spectrum of Gram-positive/Gram-negative bacteria has been found resistant to a wide spectrum of antibiotics in the United States of America during the past decade. Drug-resistant tuberculosis is not yet a major threat in North/South America, Europe, and the Middle East. However, the migration of populations in times of drought, famine, and hostilities may increase the global reach of this ancient pathogen. Given an increased spread from China and India to African countries, drug-resistant Mycobacterium tuberculosis has become an emerging topic of concern for Europe and North America. Due to the dangers associated with the spread of pathogens among different populations, the World Health Organization continues to expand healthcare advisories for therapeutic approaches for both stationary and migrating populations. As much of the literature focuses on endemic to pandemic viruses, we remain concerned that other treatable communicable diseases may be ignored. One such disease is multidrug-resistant tuberculosis. We focus on molecular mechanisms that this pathogen relies upon for the development of multidrug resistance via gene mutation and the evolutionary development of new enzyme and calcium channels.

The Diabetic Cardiorenal Nexus.

The end-stage of the clinical combination of heart failure and kidney disease has become known as cardiorenal syndrome. Adverse consequences related to diabetes, hyperlipidemia, obesity, hypertension and renal impairment on cardiovascular function, morbidity and mortality are well known. Guidelines for the treatment of these risk factors have led to the improved prognosis of patients with coronary artery disease and reduced ejection fraction. Heart failure hospital admissions and readmission often occur, however, in the presence of metabolic, renal dysfunction and relatively preserved systolic function. In this domain, few advances have been described. Diabetes, kidney and cardiac dysfunction act synergistically to magnify healthcare costs. Current therapy relies on improving hemodynamic factors destructive to both the heart and kidney. We consider that additional hemodynamic solutions may be limited without the use of animal models focusing on the cardiomyocyte, nephron and extracellular matrices. We review herein potential common pathophysiologic targets for treatment to prevent and ameliorate this syndrome.

SGLT-2 inhibitors may be targeting higher risk patients with diabetes possibly justifying higher cost: Single center repeated cross-sectional analysis.

INTRODUCTION: We studied the use of all hypoglycemic agents in periods before and after introduction of SGLT-2 inhibitors in the USA by repeated cross sectional analysis to initially assess improvement in HbA1c control among patients with type 2 diabetes and hypertension. We sought to identify changes in glucose management related to the availability of the SGLT-2 inhibiting agents. We hypothesized that patients transitioned to SGLT-2 inhibitor-based therapy represented a higher risk group that derived benefits in terms of Hba1c control. METHODS: Deidentified records of patients seen at least twice during the relevant time periods at Joslin Clinic between January 1, 2010 and December 31, 2012 and/or between January 1, 2014 and December 31, 2016 were examined. Records required all of the following: demographic information of gender, age, height, weight, BMI, HbA1c, eGFR, blood pressure, smoking status and completed medication lists. RESULTS: 10,191 patients met criteria for analysis, 7769 seen in period 1 and 6576 in period 2. 4625 patients were seen in both periods. The group of patients defined by SGLT-2 use had significantly higher BMI and HbA1c. Notable shifts in medication use were observed as SGLT-2 use increased from none to 14%. Increased use (all p < 0.001) of GLP-1 agents (16.0 to 23.8%), insulin (56.1 to 60.5%) and statins (78.4 to 81.5%) and statistically significant decreases (all p < 0.001) in use of biguanides (69.5 to 66.3%) and sulfonylurea compounds (44.7 to 39.4%), thiazolidinediones (13.6 to 3.4%) and diuretics (32.4 to 28.9%) were observed. Statistically significant decreases (all p < 0.001) of HbA1c (7.9 to 7.8%), BMI (32.5 to 32.1), eGFR (80.6 to 77.5 ml/min) and increased systolic blood pressure (130 to 132 mm Hg) were documented. CONCLUSIONS: In the absence of glycemia treatment resistance or clinical heart failure SGLT-2 inhibitor use may not be cost effective. Enthusiasm for use of SGLT-2 inhibition should be based upon long-term cardiorenal protection rather than short-term glycemia control given limited impact upon HbA1c levels in our tertiary care type 2 diabetes population.

Variations in glucose/C-peptide ratio in patients with type 2 diabetes associated with renal function.

INTRODUCTION: Accurate dosing of medications for glycemic control is a challenge for clinicians in diabetic patients with kidney disease. Diminishing glomerular filtration rates are associated with decreased renal clearance of insulin and increased prevalence of hypoglycemic episodes. Measurement of glucose/C peptide ratios may be useful to guide dosing in those patients who receive powerful insulin secretogogues as glomerular function decreases with age and disease. METHODS: In order to determine the relationship between glucose, C-peptide and renal function, we reviewed the records of patients with type 2 diabetes followed in our kidney hypertension clinic who met the following criteria: age 35-90 years, requirement of medications to control glycemia, at least 4 simultaneous measurements of C peptide, HbA1c, creatinine and blood glucose. RESULTS: 87 patients (67 males, 20 females), ages 67.1 ±â€¯10.6 years, BMI 32.5 ±â€¯5.2, A1c 8.2 ±â€¯1.2%, eGFR 73 ±â€¯27.2 ml/min, had glucose/C-peptide ratios 60.7 ±â€¯46.4. 59% of the total group were taking insulin secretogogues. Patients were divided into groups based upon mean eGFR and use or absence of insulin secretogogues. Glucose C-peptide ratios were lowest in the quartile of patients with the lowest eGFR (<50 ml/min). CONCLUSION: Diminished renal function and advanced age are associated with the lowest glucose/C-peptide ratios, independent of achieved glycemic control. With similar use of secretogogues, glucose/C-peptide ratio were lower when eGFR was ≤49 ml/min compared to >50-80 ml/min. Use of secretogogues was associated with decreased glucose/C-peptide levels. In patients with reduced renal function (eGFR < 50 ml/min), use of insulin secretogogues may be associated with lower glucose/C-peptide ratios associated with higher risks for hypoglycemic reactions.

Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease.

AIMS: Metformin could have benefits on cardiovascular disease and kidney disease progression but is often withheld from individuals with diabetes and chronic kidney disease (CKD) because of a concern that it may increase the risk of lactic acidosis. MATERIALS AND METHODS: All-cause mortality, cardiovascular death, cardiovascular events (death, hospitalization for heart failure, myocardial infarction, stroke or myocardial ischemia), end stage renal disease (ESRD) and the kidney disease composite (ESRD or death) were compared in metformin users and non-users with diabetes and CKD enrolled in the Trial to Reduce Cardiovascular Events with Aranesp (darbepoeitin-alfa) Therapy (TREAT) (NCT00093015). Outcomes were compared after propensity matching of users and non-users and in multivariable proportional hazards models. RESULTS: There were 591 individuals who used metformin at baseline and 3447 non-users. Among propensity-matched users, the crude incidence rate for mortality, cardiovascular mortality, cardiovascular events and the combined endpoint was lower in metformin users than in non-users, but ESRD was marginally higher (4.0% vs 3.6%). Metformin use was independently associated with a reduced risk of all-cause mortality (HR, 0.49; 95% CI, 0.36-0.69), cardiovascular death (HR, 0.49; 95% CI, 0.32-0.74), the cardiovascular composite (HR, 0.67, 95% CI, 0.51-0.88) and the kidney disease composite (HR, 0.77; 95% CI, 0.61-0.98). Associations with ESRD (HR, 1.01; 95% CI, 0.65-1.55) were not significant. Results were qualitatively similar in adjusted analyses of the full population. Two cases of lactic acidosis were observed. CONCLUSIONS: Metformin may be safer for use in CKD than previously considered and may lower the risk of death and cardiovascular events in individuals with stage 3 CKD.

Effects of Smoking on Solid Organ Transplantation Outcomes.

Tobacco smoking is the leading preventable cause of death worldwide. Both donor and recipient smoking have been shown to increase graft loss and mortality in solid organ transplant recipients in many studies. Only in lung transplants is smoking a universal contraindication to transplantation. Transplant centers implement different policies regarding smoking recipients and allografts from smoking donors. Due to scarcity of available allografts, the risks of smoking have to be weighed against the risks of a longer transplant waitlist period. Although transplant centers implement different strategies to encourage smoking cessation pre- and post-transplant, not many studies have been published that validate the efficacy of smoking cessation interventions in this vulnerable population. This article summarizes the results of studies investigating prevalence, impact on outcomes, and cessationinterventions for smoking in the transplant population. We report herein a review of the elevated risks of infection, malignancy, graft loss, cardiovascular events, and mortality in solid organ transplant populations.

Diabetes and the solid organ transplant recipient.

Solid organ transplant candidates undergo very strict screening for cardiovascular risk. Such screening has permitted significant decreases in cardiovascular morbidity and mortality over the ensuing decades of follow up. Long term follow-up has enabled us to identify an increasing incidence of pulmonary and urinary tract infections with or without sepsis as competing factors of morbidity and mortality. Indeed, all-cause mortality may now be dominated by infection-related endpoints. No population of transplant recipients is more naturally susceptible to infection as a diabetic subset, now submitted to immunosuppression. The current review details infection risk for kidney, liver, heart, and lung allograft recipients. A specific feature of this report emphasizes the enhanced risk for bacterial and fungal infection found in diabetic allograft recipients on immunosuppression therapy. The risk of repeated prescription of antibiotics in terms of evolutions of resistant strains of infectious pathogens is emphasized.

Calcium Ion Channels: Roles in Infection and Sepsis Mechanisms of Calcium Channel Blocker Benefits in Immunocompromised Patients at Risk for Infection.

Immunosuppression may occur for a number of reasons related to an individual's frailty, debility, disease or from therapeutic iatrogenic intervention or misadventure. A large percentage of morbidity and mortality in immunodeficient populations is related to an inadequate response to infectious agents with slow response to antibiotics, enhancements of antibiotic resistance in populations, and markedly increased prevalence of acute inflammatory response, septic and infection related death. Given known relationships between intracellular calcium ion concentrations and cytotoxicity and cellular death, we looked at currently available data linking blockade of calcium ion channels and potential decrease in expression of sepsis among immunosuppressed patients. Notable are relationships between calcium, calcium channel, vitamin D mechanisms associated with sepsis and demonstration of antibiotic-resistant pathogens that may utilize channels sensitive to calcium channel blocker. We note that sepsis shock syndrome represents loss of regulation of inflammatory response to infection and that vitamin D, parathyroid hormone, fibroblast growth factor, and klotho interact with sepsis defense mechanisms in which movement of calcium and phosphorus are part of the process. Given these observations we consider that further investigation of the effect of relatively inexpensive calcium channel blockade agents of infections in immunosuppressed populations might be worthwhile.