Faculty Bibliography

Objective: Renal transplant is associated with substantial survival advantage in patients with end-stage renal disease. However, little is known about the outcomes of renal transplant recipients (RTRs) after endovascular abdominal aortic aneurysm repair (EVAR). This study aimed to study the effect of renal transplant on perioperative outcomes and long-term survival after elective infrarenal EVAR.
Method(s): The Vascular Quality Initiative database was queried for all patients undergoing elective EVAR from 2003 to 2021. Functioning RTRs were compared with non-renal transplant recipients without a diagnosis of end-stage renal disease (non-RTRs). The outcomes included 30-day mortality, acute kidney injury (AKI), new renal failure requiring renal replacement therapy (RRT), endoleak, aortic-related reintervention, major adverse cardiac events, and 5-year survival. A logistic regression analysis was used to assess the association between RTRs and perioperative outcomes.
Result(s): Of 60,522 patients undergoing elective EVAR, 180 (0.3%) were RTRs. RTRs were younger (median, 71 years vs 74.5 years; P <.001), with higher incidence of hypertension (92% vs 84%; P =.004) and diabetes (29% vs 21%; P =.005). RTRs had higher median preoperative serum creatinine (1.3 mg/dL vs 1.0 mg/dL; P <.001) and lower estimated glomerular filtration rate (51.6 mL/min vs 69.4 mL/min; P <.001). There was no difference in the abdominal aortic aneurysm diameter and incidence of concurrent iliac aneurysms. Procedurally, RTRs were more likely to undergo general anesthesia with lower amount of contrast used (median, 68.6 mL vs 94.8 ml; P <.001) and higher crystalloid infusion (median, 1700 mL vs 1500 mL; P =.039), but no difference was observed in the incidence of open conversion, endoleak, operative time, and blood loss. Postoperatively, RTRs experienced a higher rate of AKI (9.4% vs 2.7%; P <.001), but the need for new RRT was similar (1.1% vs 0.4%; P =.15). There was no difference in the rates of postoperative mortality, aortic-related reintervention, and major adverse cardiac events. After adjustment for potential confounders, RTRs remained associated with increased odds of postoperative AKI (odds ratio, 3.33; 95% confidence interval, 1.93-5.76; P <.001) but had no association with other postoperative complications. A subgroup analysis identified that diabetes (odds ratio, 4.21; 95% confidence interval, 1.17-15.14; P =.02) is associated with increased odds of postoperative AKI among RTRs. At 5 years, the overall survival rates were similar (83.4% vs 80%; log-rank P =.235).
Conclusion(s): Among patients undergoing elective infrarenal EVAR, RTRs were independently associated with increased odds of postoperative AKI, without increased postoperative renal failure requiring RRT, mortality, endoleak, aortic-related reintervention, or major adverse cardiac events. Furthermore, 5-year survival was similar. As such, while EVAR may confer comparable benefits and technical success perioperatively, RTRs should have aggressive and maximally optimized renal protection to mitigate the risk of postoperative AKI. Keywords: End-stage renal disease, Endovascular abdominal aortic aneurysm, Multi-institutional study, Renal transplant, Renal transplant recipient, Vascular Quality Initiative database
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OBJECTIVE:Diabetes among individuals with low BMI (<19 kg/m2) has been recognized for >60 years as a prevalent entity in low- and middle-income countries (LMICs) and was formally classified as "malnutrition-related diabetes mellitus" by the World Health Organization (WHO) in 1985. Since the WHO withdrew this category in 1999, our objective was to define the metabolic characteristics of these individuals to establish that this is a distinct form of diabetes. RESEARCH DESIGN AND METHODS/METHODS:State-of-the-art metabolic studies were used to characterize Indian individuals with "low BMI diabetes" (LD) in whom all known forms of diabetes were excluded by immunogenetic analysis. They were compared with demographically matched groups: a group with type 1 diabetes (T1D), a group with type 2 diabetes (T2D), and a group without diabetes. Insulin secretion was assessed by C-peptide deconvolution. Hepatic and peripheral insulin sensitivity were analyzed with stepped hyperinsulinemic-euglycemic pancreatic clamp studies. Hepatic and myocellular lipid contents were assessed with 1H-nuclear magnetic resonance spectroscopy. RESULTS:The total insulin secretory response was lower in the LD group in comparison with the lean group without diabetes and the T2D group. Endogenous glucose production was significantly lower in the LD group than the T2D group (mean ± SEM 0.50 ± 0.1 vs. 0.84 ± 0.1 mg/kg · min, respectively; P < 0.05). Glucose uptake was significantly higher in the LD group in comparison with the T2D group (10.1 ± 0.7 vs. 4.2 ± 0.5 mg/kg · min; P < 0.001). Visceral adipose tissue and hepatocellular lipids were significantly lower in LD than in T2D. CONCLUSIONS:These studies are the first to demonstrate that LD individuals in LMICs have a unique metabolic profile, suggesting that this is a distinct entity that warrants further investigation.

BACKGROUND:Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. METHODS:To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 μg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. RESULTS:Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006).Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. CONCLUSIONS:Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual's susceptibility to developing HAAF.

Purpose of study Since vitamin D (25(OH)D) has anti-inflammatory and anti-fibrotic effects, expression of its receptor in adipocytes and macrophages suggests that 25(OH)D signaling could mediate paracrine effects within adipose tissue and improve insulin resistance. We assessed the effects of vitamin D on adipose tissue inflammation and fibrosis, and on systemic insulin resistance. Methods used We performed a randomized, double-blinded placebo-controlled trial to examine the effects of repleting vitamin D levels to >30 ng/ml in 25(OH)D-deficient (<20 ng/ ml), insulin resistant, obese humans (n=19). Insulin sensitivity was assessed with stepped euglycemic hyperinsulinemic clamps before (1st visit) and after administration of vitamin D or placebo (2nd visit). Adipose tissue fibrosis and inflammation were quantified in subcutaneous abdominal adipose tissue. To determine whether vitamin D's effects are mediated through adipocytes, we performed hyperinsulinemic clamps and adipose tissue analysis in an adipocyte-specific vitamin D receptor knockout (VDR KO) mouse model. Summary of results 25(OH)D repletion was associated with reductions in adipose tissue gene expression of inflammatory (0.6-0.7-fold decreased expression of TNF-alpha, IL-6, iNOS, PAI- 1) and pro-fibrotic (0.4-0.8-fold decreased expression of TGFbeta1, HiF1alpha, Collagen I, V, VI and MMP7) factors, decreased collagen VI immunofluorescence (p=0.02) and improved hepatic insulin sensitivity in humans, with suppression of endogenous glucose production(EGP)(p=0.03)(figure 1a). Compared to wild type (WT), adipose-specific VDR KO mice exhibited increased adipose tissue expression of several pro-inflammatory (Tnf-alpha, iNos, Pai-1, Mcp-1, F4/80; 4-10 fold) and pro-fibrotic genes (Tgf-beta1, Collagen VI, Tsp1; 2-4 fold) in concert with hepatic insulin resistance (p=0.021)(figure 1b). There were no changes in glucose uptake in either humans or mice. Conclusions These complementary human and rodent studies establish a beneficial role of vitamin D to improve hepatic insulin resistance, likely by restraining adipose tissue inflammation and fibrosis. Thus, normalizing 25(OH)Dlevels could have metabolic benefits in targeted individuals. (Figure Presented)

Introduction: Hypercalcemia is a rare finding in tuberculosis (TB). The prevalence varies from 2% to 48%. Elevation of 1,25(OH)2D is characteristic in hypercalcemia due to granulomatous disorders such as TB, but this has not been a consistent finding. We present a case of hypercalcemia due to TB with a normal 1,25(OH)2D. Case Presentation: A 35 year-old woman with newly diagnosed HIV was admitted for treatment of multidrug resistant granulomatous TB present in lungs, pleura and genitourinary tract. One week after admission, increase in serum calcium was noted with a peak at 14.2mg/dL. Further work-up showed normal 1,25(OH)2D 55pg/mL, 25(OH)D 17ng/mL, PTH 6.7pg/mL, 24h urine calcium 256 mg/24h, and normal PTHrP, thyroid function tests, serum and urine protein electrophoresis, morning cortisol and serum creatinine. Physical exam was remarkable for dry skin and mucosa, and reduced breath sounds in lung fields. Intravenous hydration was started, but the serum calcium continued to increase. At this point, prednisone 20 mg daily was started. Serum calcium has decreased to less than 11mg/dl and 1,25(OH)2D to 41 pg/mL after two weeks of therapy. Discussion: Classic laboratory findings in hypercalcemia due to granulomatous diseases are suppressed PTH, elevated 1,25(OH)2D and normal 25(OH)D. The reason behind increased 1,25(OH)2D levels in TB is the generation of cathelicidins to potentiate macrophage killing of Mycobacterium tuberculosis. Lymphocytes, monocytes, and macrophages outside of the granuloma, as well as pulmonary alveolar macrophages (PAMs) within the granuloma, drive the metabolism of 25(OH)D to 1,25(OH)2D via PAM 25(OH)D3-1 alpha hydroxylase. However, Sullivan et al (1987) highlighted four cases of active TB with low 1,25(OH)2D. Parker et al (1984) and Ryzen et al (1985), reported a case of coccidioidomycosis and leprosy respectively, both with low 1,25(OH)2D. Falk et al (2007) described a case of sarcoidosis with normal levels of 1,25(OH)2D. There are potential causes of inappropriately normal 1,25(OH)2D. One possibility is an inappropriately low baseline 1,25(OH)2D with an increase to normal values when the disease is active. A second potential cause is rifampin or isoniazid induced hypocalcitriolemia. A third possibility is a decrease in Vitamin D Binding Protein (

Although intensive glycemic control improves outcomes in type 1 diabetes mellitus, iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as Hypoglycemia-Associated Autonomic Failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, twelve healthy, non-diabetic subjects (7M, age 32.3 +/- 2.2 yr, BMI 25.1 +/- 1.0 kg/m2) participated in two study protocols in random order over two consecutive days. On day 1 subjects received two 120-minute infusions of either saline (SAL) or morphine (MOR, 0.1mug/kg/min), separated by a 120-minute break (all euglycemic). On day 2 subjects underwent stepped hypoglycemic clamps (nadir 60mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced a approximately 30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF's development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM.

Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related death in the United States. Since it is usually diagnosed at an advanced stage, its prognosis remains poor. The initial presentation varies according to the tumor location. The most common presenting signs are weight loss, jaundice, and pain. Several epidemiological, clinical, and experimental studies over the past 2 decades have shown that long-standing diabetes is a modest risk factor for pancreatic cancer. However, new-onset diabetes has also been observed to be an early manifestation of pancreatic cancer. We report 2 cases where worsening glycemic control led to the diagnosis of pancreatic cancer.

The challenges of achieving optimal glycemic control in type 2 diabetes highlight the need for new therapies. Inappropriately elevated endogenous glucose production (EGP) is the main source of hyperglycemia in type 2 diabetes. Because activation of central ATP-sensitive potassium (KATP) channels suppresses EGP in nondiabetic rodents and humans, this study examined whether type 2 diabetic humans and rodents retain central regulation of EGP. The KATP channel activator diazoxide was administered in a randomized, placebo-controlled crossover design to eight type 2 diabetic subjects and seven age- and BMI-matched healthy control subjects. Comprehensive measures of glucose turnover and insulin sensitivity were performed during euglycemic pancreatic clamp studies following diazoxide and placebo administration. Complementary rodent clamp studies were performed in Zucker Diabetic Fatty rats. In type 2 diabetic subjects, extrapancreatic KATP channel activation with diazoxide under fixed hormonal conditions failed to suppress EGP, whereas matched control subjects demonstrated a 27% reduction in EGP (P = 0.002) with diazoxide. Diazoxide also failed to suppress EGP in diabetic rats. These results suggest that suppression of EGP by central KATP channel activation may be lost in type 2 diabetes. Restoration of central regulation of glucose metabolism could be a promising therapeutic target to reduce hyperglycemia in type 2 diabetes.