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.

Kidney Mentoring and Assessment Program for Students: a guide for engaging medical students in nephrology.

BACKGROUND: The American Society of Nephrology's (ASN) Workforce Committee created a unique program called the Kidney Mentoring and Awareness Program for Students to engage medical students in the fight against kidney diseases and interest them in careers in nephrology. METHODS: The program provided a framework and 2 years of funding to three medical schools to organize and carry out health screenings in underserved areas of their communities as well as a structure for student mentoring by the practicing nephrologists. RESULTS: The Workforce Committee identified three medical schools (Emory University, Atlanta, GA; Indiana University, Indianapolis, IN and University of Louisville, Louisville, KY) and engaged faculty at each school to serve as advisors. The ASN committed funding to the groups for 2 years, after which the groups became self-sufficient. Three nephrologists participated in each chapter, building on existing relationships with community groups to identify sites and carry out kidney screening events. CONCLUSIONS: We report here the experience of those chapters and a blueprint for other schools interested in setting up a similarly structured program to interest students in nephrology while working with community groups to spread awareness of the major underlying causes of kidney disease.

Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan.

Early detection and accurate monitoring of chronic kidney disease (CKD) could improve care and retard progression to end-stage renal disease. Here, using untargeted metabolomics in 2155 participants including patients with stage 1-5 CKD and healthy controls, we identify five metabolites, including 5-methoxytryptophan (5-MTP), whose levels strongly correlate with clinical markers of kidney disease. 5-MTP levels decrease with progression of CKD, and in mouse kidneys after unilateral ureteral obstruction (UUO). Treatment with 5-MTP ameliorates renal interstitial fibrosis, inhibits IκB/NF-κB signaling, and enhances Keap1/Nrf2 signaling in mice with UUO or ischemia/reperfusion injury, as well as in cultured human kidney cells. Overexpression of tryptophan hydroxylase-1 (TPH-1), an enzyme involved in 5-MTP synthesis, reduces renal injury by attenuating renal inflammation and fibrosis, whereas TPH-1 deficiency exacerbates renal injury and fibrosis by activating NF-κB and inhibiting Nrf2 pathways. Together, our results suggest that TPH-1 may serve as a target in the treatment of CKD.

Changes in treatment of hyperglycemia in a hypertensive type 2 diabetes population as renal function declines.

BACKGROUND: Cardiovascular complications associated with expensive noninsulin agents for type 2 diabetes are the focus of concern in light of the risk of kidney dysfunction with aging. Head-to-head comparisons are unavailable to guide the choice of new drugs for hyperglycemia in patients with type 2 diabetes, decreased estimated glomerular filtration rate (eGFR) and increased cardiovascular risk. A first approach would be to document current medication choices. METHODS: All prescriptions for 10 151 patients (5623 males/4528 females) with both type 2 diabetes and hypertension seen two or more times during a 5-year period (2007-12) at Joslin Diabetes Center were evaluated. {mean age 64 years [interquartile range (IQR) 64-65)], body mass index 31 kg/m2 (IQR 30-32) and mean eGFR 78 mL/min/1.73 m2 (IQR 78, 78)}. RESULTS: Insulin was used in >60% of patients, metformin in 50% and sulfonylurea derivatives in 25%. Dipeptidyl peptidase 4 (DPP4) and acarbose class drugs were prescribed in 10% of patients, GLP-1 in 8% and other classes [including thiazolidinediones (TZD)] in <5%. Patients were grouped into four drug Categories none, 447 (4%); insulin only, 3836 (38%); other than insulin, 2910 (29%) and insulin combinations, 2955 (29%). Common combinations included insulin/metformin [n = 2493 (25%)], insulin/sulfonylureas [706 (7%)], metformin/sulfonylureas [2017 (20%)], metformin/GLP1 [949 ( 9%)], metformin/DPP4 [895 (9%)] and metformin/TZD [500 (5%)]. Insulin use increased to 70% from 35% as eGFR dropped to <30 mL/min/1.73 m2; use of insulin combined with other drugs dropped to 12% from 31% and the use of other drugs alone without insulin dropped similarly to 12% from 30%. CONCLUSIONS: Reduced renal function was associated with increased use of insulin and decreased use of other anti-diabetic agents in a statistically significant progression. BMI and gender did not influence medication choice.

Putting the "No" in Non Nocere: Surgery, Anesthesia, and a Patient's Right to Withdraw Consent.

[Full article available at http://rimed.org/rimedicaljournal-2017-10.asp].

Sodium-glucose cotransporter-2 inhibition and acidosis in patients with type 2 diabetes: a review of US FDA data and possible conclusions.

OBJECTIVE: To evaluate whether adverse event reports to the US Food and Drug Administration on incidents of ketoacidosis from use of sodium glucose cotransport inhibitors (SGLT2 inhibitors) provide insight into ways this new class of drugs is being prescribed with other antihyperglycemic agents; to examine possible mechanisms to explain ketoacidosis. DESIGN AND METHODS: Reports of adverse events concerned to SGLT2 inhibitors, namely, empagliflozin, dapagliflozin, and canagliflozin were obtained under the Freedom of Information Act for 5 years ending in August 31, 2015. The data were evaluated for incidents of ketoacidosis by looking for keywords such as diabetic ketoacidosis, ketoacidosis, lactic acidosis, acidosis, and metabolic acidosis. Results were tabulated individually for empagliflozin (n=260 adverse event reports), dapagliflozin (n=520), and canagliflozin (n=2159). Adverse events were categorized according to age, gender, and insulin use. RESULTS: There were 46, 144, and 450 reports of ketoacidosis concerned with the use of empagliflozin, dapagliflozin, and canagliflozin, respectively. The use of SGLT2 inhibitors was not strictly limited to patients with type 2 diabetes but was cut across categories of insulin use, including a total of 172 cases of SGLT2-related ketoacidosis in individuals above the age of 40 who were not on insulin. CONCLUSION: Further studies should focus to detect pleiotropic effects of SGLT2 inhibitors, particularly with other oral antihyperglycemic drugs or insulin. A review of the literature suggests that patients with type 2 diabetes with low C-peptide level may be at increased risk of ketoacidosis, particularly if they are on statins and diuretics due to hypokalemia and impaired release of insulin. More studies are warranted to further clarify these mechanisms.

Immunosuppression in the failing and failed transplant kidney: optimizing outcomes.

There is little data to guide clinicians on the optimal management of immunosuppression in patients whose kidney transplant has failed and who have returned to dialysis. Nor is there robust data on whether to perform a transplant nephrectomy. Finally, management of late stage chronic kidney disease, including deciding on dialysis initiation, modality and access planning, must occur simultaneously with efforts aimed at preserving the failing kidney and residual renal function for as long as possible. In this article, we will review the evidence on these topics and suggest areas for improvement.

Developments in extracorporeal therapy for the poisoned patient.

The modern use of extracorporeal therapies to treat poisoning and drug overdoses dates back to the early 20th century and has evolved along with their use as treatment for acute kidney injury or as maintenance therapy in advanced kidney disease. As our understanding of drug pharmacokinetics and membrane materials has increased, the technologies of extracorporeal therapy and their applications have become more sophisticated. Despite that, there is little robust evidence to guide clinicians on the optimal use of extracorporeal therapy in treating poisoning beyond case reports and series. New efforts are underway to remedy that: the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) is an international effort on the part of nephrologists, pharmacists and toxicologists to review the available data and formulate evidence-based guidelines on how to use extracorporeal techniques to treat poisoning and improve patient outcomes. Meanwhile, new techniques and membranes are under development. This review will summarize those key scientific and technologic developments, the efforts to optimize their use and new directions in research.

Immunosuppression after renal allograft failure: a survey of US practices.

BACKGROUND: Little data exist to guide the management of immunosuppression after renal graft failure. More aggressive tapering of immunosuppressive medications may reduce the risk of infection, but may increase the risk of rejection and sensitization. METHODS: To document current practices in the US, we emailed a questionnaire to medical and surgical transplant directors as identified by the United Network for Organ Sharing (UNOS). RESULTS: Emails were sent to 221 programs, of which 93 (42.1%) responded. About 24.7% of respondents reported adjusting immunosuppression according to a standard protocol; 75.3% said practices are physician dependent. The majority said that 80 or 100% of patients are off all immunosuppression one yr after returning to dialysis. The most important factors cited in deciding whether to stop immunosuppression were plans to retransplant (40.2%) and signs and symptoms of rejection (37.0%). When asked which immunosuppressive medications are continued indefinitely, 21.5% responded prednisone and 71.0% said none. Respondents most commonly said they performed graft nephrectomy only if there are signs and symptoms of rejection (47.3%) or if signs and symptoms of rejection fail to respond to steroids (34.4%). CONCLUSIONS: In the absence of good data to guide decisions on immunosuppression in patients with failed allografts, practices in the US vary greatly. More data are needed to determine which policies lead to the best outcomes.

Do biologic markers predict cardiovascular end points in diabetic end-stage renal disease? A prospective longitudinal study.

BACKGROUND: Diabetic patients on hemodialysis are at high risk of death from cardiovascular disease, and research has suggested that various biologic markers of inflammation, oxidative stress and hemostasis may give added value to clinical information for predicting cardiovascular event (CVE)-free survival. This information could be particularly important in evaluating this population for renal transplant, given the scarcity of organs. We hypothesized that in diabetic patients undergoing renal replacement therapy (RRT) these biologic markers would prove useful in predicting event-free follow-up in a prospective study. METHODS: One hundred and fifty diabetic (76 type 1, 74 type 2) and 27 non-diabetic stable RRT patients were followed for 0.04-13.69 years for CVE (myocardial infarction, coronary arterial intervention, peripheral arterial bypass or amputation, cerebrovascular accident or carotid artery intervention), cardiac and all-cause mortality. Measured biologic markers of inflammation included the following: Il-6, C reactive protein, fibrinogen; of hemostasis: fibrinogen, plasminogen activator inhibitor (PAI), fibrinolytic activity, von Willebrand factor VII (vWF), platelet-selectin, viscosity and of oxidative stress: advanced glycated end products and antibody to oxidized low-density lipoprotein. For each, upper versus lower tertiles were compared for duration of event-free follow-up. RESULTS: Cardiovascular events prior to study entry occurred in 51.3% of DM1, 54.0% of DM2 and 25.9% of DM0 patients. Subsequent cardiovascular events were noted in 31.6% of DM1, 45.9% of DM2 and 11.1% of DM0 patients. All mean levels of biologic markers at baseline were abnormal (P < 0.05). CONCLUSIONS: In this RRT population, all biologic marker levels except PAI did not improve clinical prediction of events.

Minimal-change renal disease and Graves' disease: a case report and literature review.

OBJECTIVE: To describe a possible association between Graves' disease and nephrotic syndrome secondary to minimal change renal disease and to review the literature related to renal diseases in patients with Graves' disease. METHODS: The clinical, laboratory, and renal biopsy findings in a patient with Graves' disease and minimal change renal disease are discussed. In addition, the pertinent English-language literature published from 1966 to 2009, determined by means of a MEDLINE search, is reviewed. RESULTS: A 63-year-old man who was admitted to the hospital with nephrotic syndrome. Patient had a history of Graves' disease for last 2 years with associated ophthalmopathy. He had been treated with methimazole and low low-dose steroids (prednisone 5 mg daily). Examination revealed generalized oedemaedema and exophthalmoses. Laboratory tests showed 6.62 g/day of proteinuria. Antinuclear antibodies, anti-glomerular basement membrane antibodies, antineutrophil cytoplasmic antibody (ANCA), serum complement levels, cryoglobulin, hepatitis screen and serum and urine protein electrophoreses were normal. A kidney biopsy revealed features consistent with minimal change disease on light, immunofluorescence, and electron microscopy. The patient had an excellent clinical and laboratory response after treatment with steroids and near total thyroidectomy. CONCLUSIONS: To the best of our knowledge, this is the fourth report of the occurrence of minimal change disease in a patient with Graves' disease in the absence of any other immunologic disorder known to be associated with minimal change renal disease.