Connie M. Rhee

Association Between Iodinated Contrast Media Exposure and Incident Hyperthyroidism and Hypothyroidism

BACKGROUND Sudden exposure to high iodide levels may cause thyroid dysfunction. Despite compelling biological plausibility and clinical implication, the association between iodinated contrast media exposure and incident hyperthyroidism and hypothyroidism has not been rigorously studied. METHODS We performed a nested case-control study of patients treated between January 1, 1990, and June 30, 2010, who did not have preexisting hyperthyroidism or hypothyroidism. In parallel analyses, incident hyperthyroid or hypothyroid cases were defined by a change in thyrotropin level from normal (at baseline) to low or high (follow-up measurement). Euthyroid controls were selected using an incidence density sampling approach and were matched to cases on the basis of age, sex, race/ethnicity, estimated glomerular filtration rate, follow-up thyrotropin measurement date, and interval between baseline and the follow-up thyrotropin measurement date. Iodinated contrast media exposure was assessed using claims data for contrast-enhanced computed tomography or cardiac catheterization. RESULTS In total, 178 and 213 incident hyperthyroid and hypothyroid cases, respectively, were matched to 655 and 779 euthyroid controls, respectively. Iodinated contrast media exposure was associated with incident hyperthyroidism (odds ratio [OR], 1.98; 95% CI, 1.08-3.60), but a statistically significant association with incident hypothyroidism was not observed (OR, 1.58; 95% CI, 0.95-2.62). In prespecified secondary analysis, iodinated contrast media exposure was associated with incident overt hyperthyroidism (follow-up thyrotropin level ≤ 0.1 mIU/L; OR, 2.50; 95% CI, 1.06-5.93) and with incident overt hypothyroidism (follow-up thyrotropin level >10 mIU/L; OR, 3.05; 95% CI, 1.07-8.72). CONCLUSION Iodinated contrast media exposure is associated with subsequent development of incident hyperthyroidism and incident overt hypothyroidism.

CONVERSION OF INTRAVENOUS INSULIN INFUSIONS TO SUBCUTANEOUSLY ADMINISTERED INSULIN GLARGINE IN PATIENTS WITH HYPERGLYCEMIA

OBJECTIVE To determine the optimal dose of insulin glargine needed to maintain glycemic control in patients undergoing conversion from intravenous regular insulin infusions to a subcutaneous insulin regimen. METHODS Seventy-five hospitalized patients receiving continuous insulin infusions were randomized to receive 40%, 60%, or 80% of their total daily insulin requirement, calculated from the rate during the final 6 hours of the infusion, as insulin glargine at the time of conversion to a subcutaneous regimen. Prandial insulin aspart was added to the subcutaneous regimen when patients began oral intake, and the dosage was left to clinical judgment. Capillary blood glucose monitoring (CBGM) was performed before every meal and at bedtime. All CBGM values for the 24-hour period after conversion were collected. RESULTS Three hundred ninety-two CBGM values were recorded and analyzed. The mean for all CBGM values during the 24-hour period after conversion to the subcutaneous insulin regimen was 151.9 +/- 42.5 mg/dL in the 40% group, 164.0 +/- 41.6 mg/dL in the 60% group, and 153.2 +/- 66.2 mg/dL in the 80% group (P = 0.66). The percentage of CBGM values in the predefined study target range (80 to 140 mg/dL) was 43.2%, 34.8%, and 48% in the 40%, 60%, and 80% groups, respectively (P = 0.09). Secondary analysis with use of a glycemic target of 80 to 150 mg/dL and removal of outliers resulted in CBGM values within that range in 58.7%, 44.4%, and 67.6% for the 40%, 60%, and 80% groups, respectively (overall, P = 0.001; 40% group versus the 60% group, P = 0.03; 60% group versus the 80% group, P = 0.0004; and 40% group versus the 80% group, P = 0.18). CONCLUSION Conversion from continuous insulin infusion to subcutaneously administered insulin glargine at a dose equal to 80% of the total daily insulin requirements resulted in the highest percentage of CBGM values in the glycemic target range of 80 to 150 mg/dL within the first 24 hours after regimen conversion in comparison with conversion at 40% and 60%, albeit the difference between the 40% and 80% groups was not statistically significant.

INPATIENT MANAGEMENT OF HYPERGLYCEMIA: THE NORTHWESTERN EXPERIENCE

OBJECTIVE To describe a novel method of safe and effective intensive management of inpatient hyperglycemia with use of cost-effective protocols directed by a glucose management service (GMS). METHODS An intravenous insulin protocol was designed to achieve a glycemic target of 80 to 110 mg/dL. When stable inpatients were transferred from the intravenous protocol to a subcutaneous insulin protocol, which consisted of basal long-acting and prandial and supplemental rapid-acting insulins, the blood glucose target was 80 to 150 mg/dL. Glucose levels were reviewed by the GMS at least daily for protocol adjustments, when necessary. RESULTS The intravenous insulin protocol was used in 276 patients, and 4,058 capillary blood glucose levels were recorded. Glycemic target levels (80 to 110 mg/dL) were achieved, on average, 10.6 +/- 5.2 hours after initiation of insulin drip therapy. The mean capillary blood glucose level during the study interval was 135.3 +/- 49.9 mg/dL. Hypoglycemia (< or = 60 mg/dL) was recorded in 1.5% of glucose values, and hyperglycemia (> or = 400 mg/dL) was recorded in only 0.06%. The subcutaneous insulin protocol was used in 922 patients, and 18,067 capillary glucose levels were documented. The mean blood glucose level was 145.6 +/- 55.8 mg/dL during the study period. The blood glucose target of 80 to 150 mg/dL was achieved in 58.6%, whereas 74.3% of glycemic values were in the clinically acceptable range (80 to 180 mg/dL). Hypoglycemia (< or = 60 mg/dL) occurred in 1.3% of capillary blood glucose values, and hyperglycemia (> or = 400 mg/dL) occurred in 0.4% of values. CONCLUSION Validated protocols dedicated to the achievement of strict glycemic goals were implemented by a GMS and resulted in substantial improvements in glycemic control on the surgical inpatient services, with a reduced frequency of hypoglycemia. The protocols and the GMS have been well received by the inpatient nursing and surgical staff members, and all of this has been done in a cost-effective manner.

Incremental Hemodialysis, Residual Kidney Function, and Mortality Risk in Incident Dialysis Patients: A Cohort Study

BACKGROUND Maintenance hemodialysis is typically prescribed thrice weekly irrespective of a patients residual kidney function (RKF). We hypothesized that a less frequent schedule at hemodialysis therapy initiation is associated with greater preservation of RKF without compromising survival among patients with substantial RKF. STUDY DESIGN A longitudinal cohort. SETTING & PARTICIPANTS 23,645 patients who initiated maintenance hemodialysis therapy in a large dialysis organization in the United States (January 2007 to December 2010), had available RKF data during the first 91 days (or quarter) of dialysis, and survived the first year. PREDICTOR Incremental (routine twice weekly for >6 continuous weeks during the first 91 days upon transition to dialysis) versus conventional (thrice weekly) hemodialysis regimens during the same time. OUTCOMES Changes in renal urea clearance and urine volume during 1 year after the first quarter and survival after the first year. RESULTS Among 23,645 included patients, 51% had substantial renal urea clearance (≥3.0mL/min/1.73m(2)) at baseline. Compared with 8,068 patients with conventional hemodialysis regimens matched based on baseline renal urea clearance, urine volume, age, sex, diabetes, and central venous catheter use, 351 patients with incremental regimens exhibited 16% (95% CI, 5%-28%) and 15% (95% CI, 2%-30%) more preserved renal urea clearance and urine volume at the second quarter, respectively, which persisted across the following quarters. Incremental regimens showed higher mortality risk in patients with inadequate baseline renal urea clearance (≤3.0mL/min/1.73m(2); HR, 1.61; 95% CI, 1.07-2.44), but not in those with higher baseline renal urea clearance (HR, 0.99; 95% CI, 0.76-1.28). Results were similar in a subgroup defined by baseline urine volume of 600mL/d. LIMITATIONS Potential selection bias and wide CIs. CONCLUSIONS Among incident hemodialysis patients with substantial RKF, incremental hemodialysis may be a safe treatment regimen and is associated with greater preservation of RKF, whereas higher mortality is observed after the first year of dialysis in those with the lowest RKF. Clinical trials are needed to examine the safety and effectiveness of twice-weekly hemodialysis.

Why cachexia kills: examining the causality of poor outcomes in wasting conditions

Weight loss is the hallmark of any progressive acute or chronic disease state. In its extreme form of significant lean body mass (including skeletal muscle) and fat loss, it is referred to as cachexia. It has been known for millennia that muscle and fat wasting leads to poor outcomes including death. On one hand, conditions and risk factors that lead to cachexia and inadequate nutrition may independently lead to increased mortality. Additionaly, cachexia per se, withdrawal of nutritional support in progressive cachexia, and advanced age may lead to death via cachexia-specific pathways. Despite the strong and consistent association of cachexia with mortality, no unifying mechanism has yet been suggested as to why wasting conditions are associated with an exceptionally high mortality risk. Hence, the causality of the cachexia–death association, even though it is biologically plausible, is widely unknown. This century-long uncertainty may have played a role as to why the field of cachexia treatment development has not shown major advances over the past decades. We suggest that cachexia-associated relative thrombocytosis and platelet activation may play a causal role in cachexia-related death, while other mechanisms may also contribute including arrhythmia-associated sudden deaths, endocrine disorders such as hypothyroidism, and immune system compromise leading to infectious events and deaths. Multidimensional research including examining biologically plausible models is urgently needed to investigate the causality of the cachexia–death association.

A comparative effectiveness research study of the change in blood pressure during hemodialysis treatment and survival

It is not clear to what extent changes in blood pressure (BP) during hemodialysis affect or predict survival. Studying comparative outcomes of BP changes during hemodialysis can have major clinical implications including the impact on management strategies in hemodialysis patients. Here we undertook a retrospective cohort study of 113,255 hemodialysis patients over a 5 year period to evaluate an association between change in BP during hemodialysis and mortality. The change in BP was defined as post- minus pre-hemodialysis BP and mean of BP change values during the hemodialysis session was used as a mortality predictor. The patients averaged 61 years old and consisted of 45% women, 32% African-Americans and 58% diabetics. Over a median follow-up of 2.2 years, a total of 53,461 (47.2%) all-cause and 21,548 (25.7%) cardiovascular deaths occurred. In fully adjusted Cox regression model with restricted cubic splines, there was a U-shaped association between change systolic BP and all-cause mortality. Post-dialytic drops in systolic BP between −30 to 0 mmHg were associated with greater survival, but large decreases of systolic BP (more than −30 mmHg) and any increase in systolic BP (over 0 mmHg) were related to increased mortality. Peak survival was found at a change in systolic BP of −14 mmHg. The U-shaped association was also found for cardiovascular mortality. Thus, modest declines in BP after hemodialysis are associated with the greatest survival, whereas any rise or large decline in BP is associated with worsened survival.

Residual Kidney Function Decline and Mortality in Incident Hemodialysis Patients

In patients with ESRD, residual kidney function (RKF) contributes to achievement of adequate solute clearance. However, few studies have examined RKF in patients on hemodialysis. In a longitudinal cohort of 6538 patients who started maintenance hemodialysis over a 4-year period (January 2007 through December 2010) and had available renal urea clearance (CLurea) data at baseline and 1 year after hemodialysis initiation, we examined the association of annual change in renal CLurea rate with subsequent survival. The median (interquartile range) baseline value and mean±SD annual change of CLurea were 3.3 (1.9-5.0) and -1.1±2.8 ml/min per 1.73 m2, respectively. Greater CLurea rate 1 year after hemodialysis initiation associated with better survival. Furthermore, we found a gradient association between loss of RKF and all-cause mortality: changes in CLurea rate of -6.0 and +3.0 ml/min per 1.73 m2 per year associated with case mix-adjusted hazard ratios (95% confidence intervals) of 2.00 (1.55 to 2.59) and 0. 61 (0.50 to 0.74), respectively (reference: -1.5 ml/min per 1.73 m2 per year). These associations remained robust against adjustment for laboratory variables and ultrafiltration rate and were consistent across strata of baseline CLurea, age, sex, race, diabetes status, presence of congestive heart failure, and hemoglobin, serum albumin, and serum phosphorus levels. Sensitivity analyses using urine volume as another index of RKF yielded consistent associations. In conclusion, RKF decline during the first year of dialysis has a graded association with all-cause mortality among incident hemodialysis patients. The clinical benefits of RKF preservation strategies on mortality should be determined.

Updates on the Management of Diabetes in Dialysis Patients

Diabetes mellitus is the leading cause of end‐stage renal disease (ESRD) in the U.S. and many countries globally. The role of improved glycemic control in ameliorating the exceedingly high mortality risk of diabetic dialysis patients is unclear. The treatment of diabetes in ESRD patients is challenging, given changes in glucose homeostasis, the unclear accuracy of glycemic control metrics, and the altered pharmacokinetics of glucose‐lowering drugs by kidney dysfunction, the uremic milieu, and dialysis therapy. Up to one‐third of diabetic dialysis patients may experience spontaneous resolution of hyperglycemia with hemoglobin A1c (HbA1c) levels <6%, a phenomenon known as “Burnt‐Out Diabetes,” which remains with unclear biologic plausibility and undetermined clinical implications. Conventional methods of glycemic control assessment are confounded by the laboratory abnormalities and comorbidities associated with ESRD. Similar to more recent approaches in the general population, there is concern that glucose normalization may be harmful in ESRD patients. There is uncertainty surrounding the optimal glycemic target in this population, although recent epidemiologic data suggest that HbA1c ranges of 6% to 8%, as well as 7% to 9%, are associated with increased survival rates among diabetic dialysis patients. Lastly, many glucose‐lowering drugs and their active metabolites are renally metabolized and excreted, and hence, require dose adjustment or avoidance in dialysis patients.

Association of Body Mass Index with Clinical Outcomes in Non-Dialysis-Dependent Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Background: Previous studies have not shown a consistent link between body mass index (BMI) and outcomes such as mortality and kidney disease progression in non-dialysis-dependent chronic kidney disease (CKD) patients. Therefore, we aimed to complete a systematic review and meta-analysis study on this subject. Methods: We searched MEDLINE, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane Central Register of Controlled Trials (CENTRAL), and screened 7,123 retrieved studies for inclusion. Two investigators independently selected the studies using predefined criteria and assessed each studys quality using the Newcastle-Ottawa quality assessment scale. We meta-analyzed the results based on the BMI classification system by the WHO. Results: We included 10 studies (with a total sample size of 484,906) in the systematic review and 4 studies in the meta-analyses. The study results were generally heterogeneous. However, following reanalysis of the largest reported study and our meta-analyses, we observed that in stage 3-5 CKD, being underweight was associated with a higher risk of death while being overweight or obese class I was associated with a lower risk of death; however, obesity classes II and III were not associated with risk of death. In addition, reanalysis of the largest available study showed that a higher BMI was associated with an incrementally higher risk of kidney disease progression; however, this association was attenuated in our pooled results. For earlier stages of CKD, we could not complete meta-analyses as the studies were sparse and had heterogeneous BMI classifications and/or referent BMI groups. Conclusion: Among the group of patients with stage 3-5 CKD, we found a differential association between obesity classes I-III and mortality compared to the general population, indicating an obesity paradox in the CKD population.

Subclinical Hypothyroidism and Survival: The Effects of Heart Failure and Race

CONTEXT Studies examining the association between subclinical hypothyroidism and mortality have yielded conflicting results. Emerging data suggest these associations may depend upon underlying congestive heart failure (CHF) and/or race, but this has not been empirically determined. OBJECTIVE Our objective was to examine the association between subclinical hypothyroidism and hypothyroidism overall with mortality according to pre-existing CHF and race. DESIGN AND PARTICIPANTS We examined the associations of subclinical hypothyroidism (TSH higher than assay upper limit of normal; total T4 within reference) and hypothyroidism overall (TSH higher than assay upper limit of normal; total T4 below lower limit of normal or within reference) with all-cause mortality among Third National Health and Nutrition Examination Survey participants stratified by CHF and race using multivariable Cox models. To confirm whether differences between strata were statistically significant, we tested for interaction on the basis of CHF (separately) and race by likelihood ratio testing. RESULTS There were 14 130 (95.0%) euthyroid controls and 749 (5.0%) participants with hypothyroidism, 691 (4.6%) of whom had subclinical disease. Subclinical hypothyroidism vs euthyroidism was associated with greater mortality in those with CHF but not in those without: adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) = 1.44 (1.01-2.06) and 0.97 (0.85-1.11), respectively (P interaction = .03). Similar findings were observed for hypothyroidism overall. Hypothyroidism overall vs euthyroidism was associated with greater mortality in Black participants (HR = 1.44 [95% CI = 1.03-2.03]) but not in non-Blacks (HR = 0.95 [95% CI = 0.83-1.08]) (P interaction = .03). CONCLUSION Among participants with CHF, subclinical hypothyroidism and hypothyroidism overall are associated with greater death risk. Additional studies are needed to confirm findings and explore possible mechanisms for the differential hypothyroidism-mortality association across race.