Massive adrenocortical carcinoma presenting as peripheral edema: a case report.

BACKGROUND: Adrenocortical carcinoma is a rare, but potentially lethal, malignancy that is usually detected as an incidental finding on abdominal imaging studies or owing to hormonal complications. This report recounts an unusual presentation with leg edema due to compression of the inferior vena cava. The dearth of proven effective treatment is also addressed. CASE PRESENTATION: A 65-year-old White male physician presented with severe, bilateral pitting edema that extended from the toes to the thighs. It progressed over several months. He also experienced paroxysmal dyspnea. Evaluation of cardiac, hepatic, and renal function failed to determine a cause. Computed tomography revealed a tumor above the right kidney, with compression of the intrahepatic inferior vena cava and upstream distension. Serum cortisol and dehydroepiandrosterone sulfate concentrations were elevated, 24-hour urinary cortisol level was elevated, and serum adrenocorticotropic hormone and testosterone concentrations were suppressed. A 27-cm tumor, the right lobe of the liver, the right kidney, and 26 lymph nodes were resected. Histological study confirmed the diagnosis of adrenocortical carcinoma. Ki67 proliferation index was 26.7% (worse prognosis associated with index > 10%). Lymph nodes were negative for malignancy, but a separate 2.7-cm tumor was found near the renal hilum. Adjuvant mitotane chemotherapy was prescribed. Serum testosterone concentration returned to normal. High-dose hydrocortisone administration was needed because of adrenal suppression and CYP 3A4 induction by mitotane. CONCLUSION: Imaging of the abdomen and pelvis should be conducted in cases of unexplained leg edema. In this case, a large adrenal cancer compressed the vena cava. Iron deficiency followed resection of the large tumor. Advanced stages of adrenocortical carcinoma are associated with poor prognosis. Mitotane chemotherapy is a standard but unproven adjuvant treatment that is associated with many complications, and its induction of hepatic CYP 3A4 enzymes necessitates adjustment of other medications.

Resistance to Erythropoiesis-Stimulating Agents among Patients on Hemodialysis Is Typically Transient.

INTRODUCTION: This study examines factors associated with erythropoiesis-stimulating agent (ESA) hyporesponsiveness, the duration of ESA hyporesponsiveness, the frequency of new episodes, and variation across countries. METHODS: We used international Dialysis Outcomes and Practice Patterns Study data from 2015 to 2018 (N = 26,656) to investigate changes in ESA Resistance Index (ERI), calculated as epoetin dose divided by [hemoglobin × body weight] in patients on hemodialysis. We illustrated the proportion of patients who moved to other ERI quintiles over 12 months, and we studied the incidence and duration of ESA resistance. We examined case-mix factors associated with quintiles of ERI. RESULTS: Most patients migrated out of their original ERI quintile within 4 months. Only 22% of patients in the top quintile of ERI at baseline (4.4% of all patients) remained in the top quintile during all 12 months of follow-up. A total of 42% of patients manifested an upper-quintile ERI during at least 1 month. Median duration of a new episode of ESA resistance was 2 months. Catheter hemoaccess, elevated C-reactive protein, lower transferrin saturation, lower serum albumin concentration, and recent hospitalization occurred more frequently among patients in the highest ERI quintile at baseline. ERI values were highest in the USA, Italy, and Mideastern nations and lowest in Russia and Japan. DISCUSSION/CONCLUSION: It is a misconception to envision a sizable, fixed segment of the population with permanent resistance to ESA - resistance fluctuates frequently. The implications of these findings for prescription of ESAs and of hypoxia-inducible factor-prolyl hydroxylase inhibitors are discussed.

Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality.

Intravenous (IV) iron is required for optimal management of anemia in the majority of hemodialysis (HD) patients. While IV iron prescription has increased over time, the best dosing strategy is unknown and any effect of IV iron on survival is unclear. Here we used adjusted Cox regression to analyze associations between IV iron dose and clinical outcomes in 32,435 HD patients in 12 countries from 2002 to 2011 in the Dialysis Outcomes and Practice Patterns Study. The primary exposure was total prescribed IV iron dose over the first 4 months in the study, expressed as an average dose/month. Compared with 100-199 mg/month (the most common dose range), case-mix-adjusted mortality was similar for the 0, 1-99, and 200-299 mg/month categories but significantly higher for the 300-399 mg/month (HR of 1.13, 95% CI of 1.00-1.27) and 400 mg/month or more (HR of 1.18, 95% CI of 1.07-1.30) groups. Convergent validity was proved by an instrumental variable analysis, using HD facility as the instrument, and by an analysis expressing IV iron dose/kg body weight. Associations with cause-specific mortality (cardiovascular, infectious, and other) were generally similar to those for all-cause mortality. The hospitalization risk was elevated among patients receiving 300 mg/month or more compared with 100-199 mg/month (HR of 1.12, 95% CI of 1.07-1.18). In light of these associations, a well-powered clinical trial to evaluate the safety of different IV iron-dosing strategies in HD patients is urgently needed.

Variation in intravenous iron use internationally and over time: the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: To examine patterns of intravenous (IV) iron use across 12 countries from 1999 to 2011. METHODS: Trends in iron use are described among 32 192 hemodialysis (HD) patients in the Dialysis Outcomes and Practice Patterns Study. Adjusted associations of IV iron dose with serum ferritin and transferrin saturation (TSAT) values were also studied. RESULTS: IV iron was administered to 50% of patients over 4 months in 1999, increasing to 71% during 2009-11, with increasing use in most countries. Among patients receiving IV iron, the mean monthly dose increased from 232 ± 167 to 281 ± 211 mg. Most countries used 3 to 4 doses/month, but Canada used about 2 doses/month, Italy increased from 3 to almost 6 doses/month and Germany used 5 to 6 doses/month. The USA and most European countries predominantly used iron sucrose and sodium ferric gluconate. A significant use of iron dextran was limited to Canada and France; iron polymaltose was used in Australia and New Zealand; and Japan used ferric oxide saccharate, chondroitin polysulfate iron complex and cideferron. Ferritin values rose in most countries: 22% of patients had ≥ 800 ng/mL in the recent years of study. TSAT levels increased to a lesser degree over time. Japan had much lower IV iron dosing and ferritin levels, but similar TSAT levels. In adjusted analyses, serum ferritin and TSAT levels increased signifcantly by 14 ng/mL and 0.16%, respectively, for every 100 mg/month higher mean monthly iron dose. CONCLUSIONS: IV iron prescription patterns varied between countries and changed over time from 1999 to 2011. IV iron use and dose increased in most countries, with notable increases in ferritin but not TSAT levels. With rising cumulative IV iron doses, studies of the effects of changing IV iron dosing and other anemia management practices on clinical outcomes should be a high priority.

Naturally occurring higher hemoglobin concentration does not increase mortality among hemodialysis patients.

A small percentage of hemodialysis patients maintain higher hemoglobin concentrations without transfusion or erythropoietic therapy. Because uncertainty exists regarding the effects of higher hemoglobin concentration on mortality and quality of life among hemodialysis patients, studying this group of patients with sufficient endogenous erythropoietin may provide additional insights. The prospective, observational Dialysis Outcomes and Practice Patterns Study provides an opportunity to investigate this group. Among 29,796 patients in 12 nations, 545 (1.8%) maintained hemoglobin concentrations >12 g/dl for 4 months without erythropoietic support. This subset tended to be male, to have a longer duration of end-stage renal disease, and to not dialyze via a catheter. Cystic disease as the underlying cause of renal failure was over-represented in this group but was present in only 25%. Lung disease, smoking, and cardiovascular disease were associated with increased likelihood of naturally higher hemoglobin concentration. Quality-of-life scores were not higher among this subset compared with the other patients. Unadjusted mortality risk for patients with hemoglobin >12 g/dl and no erythropoietic therapy was lower than for the other patients, but after thorough adjustment for case mix, there was no difference between groups (relative risk, 0.98; 95% CI 0.80 to 1.19). These data show that naturally occurring hemoglobin concentration >12 g/dl does not associate with increased mortality among hemodialysis patients.

Hemodialysis vascular access training and practices are key to improved access outcomes.

Recognizing that autologous arteriovenous fistula use was associated with improved outcomes in hemodialysis patients, the 1997 Dialysis Outcomes Quality Initiative (DOQI) vascular access practice guidelines from the National Kidney Foundation stressed fistulas as the optimal means of dialysis vascular access. In the United States, this emphasis has continued with the Fistula First Breakthrough Initiative. Much of the data supporting fistulas for dialysis access are derived from longitudinal cohorts, including the Dialysis Outcomes and Practice Patterns Study (DOPPS), dialysis provider databases, and other sources. This article reviews major findings from these data sources, focusing on specific practices and characteristics associated with greater arteriovenous fistula use in dialysis facilities worldwide. Important and often overlooked characteristics that are discussed in detail include specific preferences of dialysis staff regarding access type and the emphasis placed on fistula primacy and the number of fistulas created during surgical training. For example, in the DOPPS, the risk of initial fistula failure was 34% lower when fistulas were placed by surgeons who had created at least 25 fistulas during training (P = 0.002). It is imperative that dialysis clinicians advocate actively for specific dialysis access types on behalf of individual patients. Vascular surgery teaching programs must supervise adequate numbers of fistula procedures for every trainee.

The burden of amputation among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Hemodialysis patients are at increased risk of amputation, particularly those with diabetes. Limited data exist about the prevalence, incidence, risk factors for, and sequelae of amputation in hemodialysis patients. STUDY DESIGN: A prospective observational study of hemodialysis practices and outcomes. SETTING & PARTICIPANTS: Data from 29,838 patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) from 1996 to 2004 were analyzed. PREDICTOR/FACTOR: Demographic factors, comorbid conditions, laboratory values, years since end-stage renal disease onset, and currently prescribed medications at study enrollment. OUTCOME: Prior amputation at study enrollment by using logistic regression and amputation during follow-up by using Cox models. Amputation was ascertained from medical record review. RESULTS: There was a high prevalence (6%) and incidence (2.0 events/100 patient-years at risk) of amputation in hemodialysis patients; patients with diabetes had a more than 9 times greater incidence of new amputation. Wide variations among countries were observed in risk of amputation, with the lowest prevalence in Japan and the highest in Belgium, France, and Germany. Traditional cardiovascular risk factors, such as age, peripheral vascular disease, and smoking were predictive of amputation, as were such risk factors related to hemodialysis as altered mineral metabolism and years of hemodialysis therapy. In patients with diabetes, greater relative risks of amputation were observed in men, smokers, and those with other diabetic complications, anemia, and malnutrition. The relative risk of mortality after amputation was 1.54 (95% confidence interval, 1.41 to 1.68; P < 0.001) with a mean survival of 2.0 versus 3.8 years. LIMITATIONS: The database does not differentiate between types of amputations; some amputations may have concerned the upper limbs and could have been linked to ischemia related to vascular access. CONCLUSIONS: Amputation in hemodialysis patients is a very frequent event, particularly in patients with diabetes, and is associated with both traditional cardiovascular risk factors and factors linked to kidney failure treated by hemodialysis. Interventional trials are needed to reduce the burden of amputation.

Enhanced training in vascular access creation predicts arteriovenous fistula placement and patency in hemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study.

OBJECTIVE: To investigate whether intensity of surgical training influences type of vascular access placed and fistula survival. SUMMARY BACKGROUND DATA: Wide variations in fistula placement and survival occur internationally. Underlying explanations are not well understood. METHODS: Prospective data from 12 countries in the Dialysis Outcomes and Practice Patterns Study were analyzed; outcomes of interest were type of vascular access in use (fistula vs. graft) in hemodialysis patients at study entry and time from placement until primary and secondary access failures, as predicted by surgical training. Logistic and Cox regression models were adjusted for patient characteristics and time on hemodialysis. RESULTS: During training, US surgeons created fewer fistulae (US mean = 16 vs. 39-426 in other countries) and noted less emphasis on vascular access placement compared with surgeons elsewhere. Significant predictors of fistula versus graft placement in hemodialysis patients included number of fistulae placed during training (adjusted odds ratio [AOR] = 2.2 for fistula placement, per 2 times greater number of fistulae placed during training, P < 0.0001) and degree of emphasis on vascular access creation during training (AOR = 2.4 for fistula placement, for much-to-extreme emphasis vs. no emphasis, P = 0.0008). Risk of primary fistula failure was 34% lower (relative risk = 0.66, P = 0.002) when placed by surgeons who created > or = 25 (vs. < 25) fistulae during training. CONCLUSIONS: Surgical training is key to both fistula placement and survival, yet US surgical programs seem to place less emphasis on fistula creation than those in other countries. Enhancing surgical training in fistula creation would help meet targets of the Fistula First Initiative.

Mortality among hemodialysis patients in Europe, Japan, and the United States: case-mix effects.

BACKGROUND: The Dialysis Outcomes and Practice Patterns Study is well suited to identify case-mix effects, given its extensive data set. The data set was used to examine the influence of case-mix variables on mortality and the extent to which these variables account for differences in mortality across regions, as well as the prevalence and incidence of hepatitis B and hepatitis C. METHODS: Demographic and comorbid disease features were determined for 8,615 patients internationally; mortality was recorded for this cohort, plus replacement patients (total n = 16,720), from 1996 to 2002. Mortality was associated with increasing age, nonblack race, coronary artery disease, congestive heart failure, other cardiac disease, diabetes mellitus, peripheral vascular disease, cerebrovascular disease, absence of hypertension, lung disease, cancer, human immunodeficiency virus infection, gastrointestinal bleeding, neurologic disease, psychiatric disease, cellulitis/gangrene, hepatitis C, and smoking. RESULTS: US patients were slightly older than those in Europe or Japan and had the highest prevalence of diabetes, coronary artery disease, congestive heart failure, peripheral vascular disease, and cerebrovascular disease. CONCLUSION: Upon adjusting for case-mix to assess mortality across facilities, it was found that regional differences in mortality (highest in the United States and lowest in Japan) and differences across facilities within nations remain after such corrections. It is likely that practice patterns account for some of this variation. Prevalence of hepatitis B virus (HBV) across facilities increased as the number of dialyzing patients per facility increased; risk of HBV seroconversion decreased among facilities using protocols for treatment of patients with HBV infection. Greater employment of staff with at least 2 years of formal nursing training was associated with lower prevalence of hepatitis C virus infection and lower seroconversion risk.

Mortality and hospitalization in haemodialysis patients in five European countries: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Mortality and hospitalization rates are reported for nationally representative random samples of haemodialysis patients treated at randomly selected dialysis facilities in five European countries participating in the Dialysis Outcomes and Practice Pattern Study (DOPPS) (France, Germany, Italy, Spain and the UK). RESULTS: In the UK, 28.1% of haemodialysis patients received prior peritoneal dialysis treatment compared with 4.2-8.3% in other countries. Kidney transplantation rates ranged from 3.3 (per 100 patient years) in Italy to 11.6 in Spain. The relative risk (RR) of mortality, adjusted for age, sex and diabetes status was significantly higher in the UK (RR = 1.39, P = 0.02) compared with Italy (reference) and increased in association with age (RR = 1.60 for every 10 years older, P <0.001), diabetes as cause of end-stage renal disease (ESRD) (RR = 1.55, P < 0.001), male patients <65 years (RR = 1.29, P = 0.02) and peritoneal dialysis in the 12 months prior to starting haemodialysis (RR = 1.72, P = 0.06). Hospitalization for cardiovascular disease was highest in France and Germany (0.40 and 0.43 hospitalizations per patient year, respectively) and lowest in the UK (0.19), although cardiovascular comorbidity was similar in the UK and France. Hospitalization rates for vascular access-related infection ranged from 0.01 hospitalizations per patient year in Italy to 0.08 in the UK, consistent with the higher dialysis catheter use in the UK (25%) vs Italy (5%). Hospitalization risk was significantly higher in France than in other Euro-DOPPS countries and was significantly (P < 0.05) associated with prior peritoneal dialysis therapy, peripheral vascular disease, gastrointestinal bleeding in the prior 12 months, diabetes, cancer, cardiac disease, psychiatric disease and recent onset of ESRD (within 30 days of study entry). CONCLUSIONS: The large differences in haemodialysis practice and outcomes in the Euro-DOPPS countries suggest opportunities for improvement in patient care.

Vascular access use in Europe and the United States: results from the DOPPS.

BACKGROUND: A direct broad-based comparison of vascular access use and survival in Europe (EUR) and the United States (US) has not been performed previously. Case series reports suggest that vascular access practices differ substantially in the US and EUR. We report on a representative study (DOPPS) which has used the same data collection protocol for> 6400 hemodialysis (HD) patients to compare vascular access use at 145 US dialysis units and 101 units in five EUR countries (France, Germany, Italy, Spain, and the United Kingdom). METHODS: Logistic analysis evaluated factors associated with native arteriovenous fistula (AVF) versus graft use or permanent access versus catheter use for prevalent and incident HD patients. Times to failure for AVF and graft were analyzed using Cox proportional hazards regression. RESULTS: AVF was used by 80% of EUR and 24% of US prevalent patients, and was significantly associated with younger age, male gender, lower body mass index, non-diabetic status, lack of peripheral vascular disease, and no angina. After adjusting for these factors, AVF versus graft use was still much higher in EUR than US (AOR=21, P < 0.0001). AVF use within facilities varied from 0 to 87% (median 21%) in the US, and 39 to 100% (median 83%) in EUR. For patients who were new to HD, access use was: 66% AVF in EUR versus 15% in US (AOR=39, P < 0.0001), 31% catheters in EUR vs. 60% in US, and 2% grafts in EUR vs. 24% in US. In addition, 25% of EUR and 46% of US incident patients did not have a permanent access placed prior to starting HD. In EUR, 84% of new HD patients had seen a nephrologist for> 30 days prior to ESRD compared with 74% in the US (P < 0.0001); pre-ESRD care was associated with increased odds of AVF versus graft use (AOR=1.9, P=0.01). New HD patients had a 1.8-fold greater odds (P=0.002) of starting HD with a permanent access if a facility's typical time from referral to access placement was < or =2 weeks. AVF use when compared to grafts was substantially lower (AOR=0.61, P=0.04) when surgery trainees assisted or performed access placements. When used as a patient's first access, AVF survival was superior to grafts regarding time to first failure (RR=0.53, P=0.0002), and AVF survival was longer in EUR compared with the US (RR=0.49, P=0.0005). AVF and grafts each displayed better survival if used when initiating HD compared with being used after patients began dialysis with a catheter. CONCLUSION: Large differences in vascular access use exist between EUR and the US, even after adjustment for patient characteristics. The results strongly suggest that a facility's preferences and approaches to vascular access practice are major determinants of vascular access use.

Pharmacologic and cytokine treatment of commonly encountered anemias.

Anemia has multiple etiologies: it may be caused by nutritional deficiencies or congenital abnormalities, or it may be associated with a number of conditions, such as chronic kidney disease, cancer, or human immunodeficiency virus (HIV) infection. Anemia is associated with an increase in morbidity and mortality in patients with endstage renal disease, cancer, or HIV infection. Each case of anemia is different, with different causes, clinical consequences, and treatment strategies. Identifying the most appropriate treatment requires an understanding of the etiology of the anemia and investigation of the nature of the causative medical condition. In some cases, such as anemia associated with chronic kidney disease, treatment is well defined and consists of administration of erythropoiesis-stimulating agents, accompanied by iron supplementation where appropriate. In other instances, such as megaloblastic anemia, which may be caused by vitamin or folate deficiency, vitamin supplementation alone may be a clinically appropriate treatment. This article gives an overview of the etiologies and current therapies of the most commonly encountered types of anemia, highlighting both the diverse nature of the condition, and the equally diverse pharmacologic and supportive treatment approaches.