Stephen M. Sozio

Steroid avoidance in liver transplantation: meta-analysis and meta-regression of randomized trials.

Steroid use after liver transplantation (LT) has been associated with diabetes, hypertension, hyperlipidemia, obesity, and hepatitis C (HCV) recurrence. We performed meta‐analysis and meta‐regression of 30 publications representing 19 randomized trials that compared steroid‐free with steroid‐based immunosuppression (IS). There were no differences in death, graft loss, and infection. Steroid‐free recipients demonstrated a trend toward reduced hypertension [relative risk (RR) 0.84, P = 0.08], and statistically significant decreases in cholesterol (standard mean difference −0.41, P < 0.001) and cytomegalovirus (RR 0.52, P = 0.001). In studies where steroids were replaced by another IS agent, the risks of diabetes (RR 0.29, P < 0.001), rejection (RR 0.68, P = 0.03), and severe rejection (RR 0.37, P = 0.001) were markedly lower in steroid‐free arms. In studies in which steroids were not replaced, rejection rates were higher in steroid‐free arms (RR 1.31, P = 0.02) and reduction of diabetes was attenuated (RR 0.74, P = 0.2). HCV recurrence was lower with steroid avoidance and, although no individual trial reached statistical significance, meta‐analysis demonstrated this important effect (RR 0.90, P = 0.03). However, we emphasize the heterogeneity of trials performed to date and, as such, do not recommend basing clinical guidelines on our conclusions. We believe that a large, multicenter trial will better define the role of steroid‐free regimens in LT. Liver Transpl 14:512–525, 2008.

Cerebrovascular disease incidence, characteristics, and outcomes in patients initiating dialysis: the choices for healthy outcomes in caring for ESRD (CHOICE) study.

BACKGROUND Stroke is the third most common cause of cardiovascular disease death in patients on dialysis therapy; however, characteristics of cerebrovascular disease, including clinical subtypes and subsequent consequences, have not been well described. STUDY DESIGN Prospective national cohort study, the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study. SETTINGS & PARTICIPANTS 1,041 incident dialysis patients treated in 81 clinics enrolled from October 1995 to July 1998, followed up until December 31, 2004. PREDICTOR Time from dialysis therapy initiation. OUTCOMES & MEASUREMENTS Cerebrovascular disease events were defined as nonfatal (hospitalized stroke and carotid endarterectomy) and fatal (stroke death) events after dialysis therapy initiation. Stroke subtypes were classified by using standardized criteria from the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) system. The incidence of cerebrovascular event subtypes was analyzed by using time-to-event analyses accounting for competing risk of death. Clinical outcomes after stroke were abstracted from medical records. RESULTS 165 participants experienced a cerebrovascular event with an overall incidence of 4.9 events/100 person-years. Ischemic stroke was the most common (76% of all 200 events), with cardioembolism subtype accounting for 28% of the 95 abstracted ischemic events. Median time from onset of symptoms to first stroke evaluation was 8.5 hours (25th and 75th percentiles, 1 and 42), with only 56% of patients successfully escaping death, nursing home, or skilled nursing facility. LIMITATIONS Relatively small sample size limits power to determine risk factors. CONCLUSIONS Cerebrovascular disease is common in dialysis patients, is identified late, and carries a significant risk of morbidity and mortality. Stroke etiologic subtypes on dialysis therapy are multifactorial, suggesting risk factors may change the longer one has end-stage renal disease. Additional studies are needed to address the poor prognosis through prevention, early identification, and treatment.

Combined Prednisone and Mycophenolate Mofetil Treatment for Retroperitoneal Fibrosis: A Case Series

BACKGROUND Small case series suggest that a combination of mycophenolate mofetil and prednisone may be an effective treatment for patients with retroperitoneal fibrosis. OBJECTIVE To describe the outcomes of adults with retroperitoneal fibrosis who received a combination of prednisone and mycophenolate mofetil. DESIGN Prospective case series of patients followed between 1 April 2005 and 1 July 2009. SETTING Single tertiary care facility. PATIENTS 28 patients with retroperitoneal fibrosis. INTERVENTION Prednisone, 40 mg/d, tapered over 6 months, and mycophenolate mofetil, 1000 mg twice daily, for a mean of 24.3 months. MEASUREMENTS Clinical course, laboratory assessment, and measurement of periaortic mass. Mean follow-up was 1012 days, and no patients were lost to follow-up. RESULTS Systemic symptoms resolved in all patients; 89% had a 25% or greater reduction in periaortic mass. Elevated erythrocyte sedimentation rate and serum creatinine level and decreased hemoglobin level normalized in all patients. Disease recurred in 2 of 28 patients. LIMITATION This was a small case series. CONCLUSION Combined prednisone and mycophenolate mofetil therapy is a potentially effective treatment for retroperitoneal fibrosis that warrants evaluation in randomized trials. PRIMARY FUNDING SOURCE None.

Management of Renal Masses and Localized Renal Cancer: Systematic Review and Meta-Analysis

PURPOSE Several options exist for management of clinically localized renal masses suspicious for cancer, including active surveillance, thermal ablation and radical or partial nephrectomy. We summarize evidence on effectiveness and comparative effectiveness of these treatment approaches for patients with a renal mass suspicious for localized renal cell carcinoma. MATERIALS AND METHODS We searched MEDLINE®, Embase® and the Cochrane Central Register of Controlled Trials from January 1, 1997 through May 1, 2015. Paired investigators independently screened articles to identify controlled studies of management options or cohort studies of active surveillance, abstracted data sequentially and assessed risk of bias independently. Strength of evidence was graded by comparisons. RESULTS The search identified 107 studies (majority T1, no active surveillance or thermal ablation stratified outcomes of T2 tumors). Cancer specific survival was excellent among all management strategies (median 5-year survival 95%). Local recurrence-free survival was inferior for thermal ablation with 1 treatment but reached equivalence to other modalities after multiple treatments. Overall survival rates were similar among management strategies and varied with age and comorbidity. End-stage renal disease rates were low for all strategies (0.4% to 2.8%). Radical nephrectomy was associated with the largest decrease in estimated glomerular filtration rate and highest incidence of chronic kidney disease. Thermal ablation offered the most favorable perioperative outcomes. Partial nephrectomy showed the highest rates of urological complications but overall rates of minor/major complications were similar among interventions. Strength of evidence was moderate, low and insufficient for 11, 22 and 30 domains, respectively. CONCLUSIONS Comparative studies demonstrated similar cancer specific survival across management strategies, with some differences in renal functional outcomes, perioperative outcomes and postoperative harms that should be considered when choosing a management strategy.

Frailty and Cognitive Function in Incident Hemodialysis Patients

BACKGROUND AND OBJECTIVES Patients of all ages undergoing hemodialysis (HD) have a high prevalence of cognitive impairment and worse cognitive function than healthy controls, and those with dementia are at high risk of death. Frailty has been associated with poor cognitive function in older adults without kidney disease. We hypothesized that frailty might also be associated with poor cognitive function in adults of all ages undergoing HD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS At HD initiation, 324 adults enrolled (November 2008 to July 2012) in a longitudinal cohort study (Predictors of Arrhythmic and Cardiovascular Risk in ESRD) were classified into three groups (frail, intermediately frail, and nonfrail) based on the Fried frailty phenotype. Global cognitive function (3MS) and speed/attention (Trail Making Tests A and B [TMTA and TMTB, respectively]) were assessed at cohort entry and 1-year follow-up. Associations between frailty and cognitive function (at cohort entry and 1-year follow-up) were evaluated in adjusted (for sex, age, race, body mass index, education, depression and comorbidity at baseline) linear (3MS, TMTA) and Tobit (TMTB) regression models. RESULTS At cohort entry, the mean age was 54.8 years (SD 13.3), 56.5% were men, and 72.8% were black. The prevalence of frailty and intermediate frailty were 34.0% and 37.7%, respectively. The mean 3MS was 89.8 (SD 7.6), TMTA was 55.4 (SD 29), and TMTB was 161 (SD 83). Frailty was independently associated with lower cognitive function at cohort entry for all three measures (3MS: -2.4 points; 95% confidence interval [95% CI], -4.2 to -0.5; P=0.01; TMTA: 12.1 seconds; 95% CI, 4.7 to 19.4; P<0.001; and TMTB: 33.2 seconds; 95% CI, 9.9 to 56.4; P=0.01; all tests for trend, P<0.001) and with worse 3MS at 1-year follow-up (-2.8 points; 95% CI, -5.4 to -0.2; P=0.03). CONCLUSIONS In adult incident HD patients, frailty is associated with worse cognitive function, particularly global cognitive function (3MS).

Diagnostic Accuracy and Risks of Biopsy in the Diagnosis of a Renal Mass Suspicious for Localized Renal Cell Carcinoma: Systematic Review of the Literature

PURPOSE Clinical practice varies widely on the diagnostic role of biopsy for clinically localized renal masses suspicious for renal cell carcinoma. Therefore, we performed a systematic review of the available literature to quantify the accuracy and rate of adverse events of renal mass biopsy. MATERIALS AND METHODS MEDLINE®, Embase® and the Cochrane databases were searched (January 1997 to May 2015) for relevant studies. The systematic review process established by the Agency for Healthcare Research and Quality was followed. Nondiagnostic biopsies were excluded from diagnostic accuracy calculations. RESULTS A total of 20 studies with 2,979 patients and 3,113 biopsies were included in the study. The overall nondiagnostic rate was 14.1% with 90.4% of those undergoing surgery found to have malignancy. Repeat biopsy led to diagnosis in 80% of patients. The false-positive rate was low (4.0%), histological and renal cell carcinoma subtype concordance was substantial, and Fuhrman upgrading notable (16%) from low grade (1 to 2) to high grade (3 to 4). Core biopsy was highly sensitive (97.5%, CI 96.5-98.5) and specific (96.2%, CI 90.7-100) when a diagnostic result was obtained, but most patients (∼80%) did not undergo surgery after a benign biopsy. Among patients undergoing extirpation 36.7% with a negative biopsy had malignant disease on surgical pathology (negative predictive value 63.3%, CI 52.4-74.2). Direct complications included hematoma (4.9%), clinically significant pain (1.2%), gross hematuria (1.0%), pneumothorax (0.6%) and hemorrhage (0.4%). CONCLUSIONS Diagnostic accuracy was generally high for biopsy of localized renal masses with a low complication rate, but the nondiagnostic rate and negative predictive value were concerning. Renal mass sampling should be used judiciously as further research will determine its true clinical utility.

Serum Fructosamine and Glycated Albumin and Risk of Mortality and Clinical Outcomes in Hemodialysis Patients

OBJECTIVE Assays for serum total glycated proteins (fructosamine) and the more specific glycated albumin may be useful indicators of hyperglycemia in dialysis patients, either as substitutes or adjuncts to standard markers such as hemoglobin A1c, as they are not affected by erythrocyte turnover. However, their relationship with long-term outcomes in dialysis patients is not well described. RESEARCH DESIGN AND METHODS We measured fructosamine and glycated albumin in baseline samples from 503 incident hemodialysis participants of a national prospective cohort study, with enrollment from 1995–1998 and median follow-up of 3.5 years. Outcomes were all-cause and cardiovascular disease (CVD) mortality and morbidity (first CVD event and first sepsis hospitalization) analyzed using Cox regression adjusted for demographic and clinical characteristics, and comorbidities. RESULTS Mean age was 58 years, 64% were white, 54% were male, and 57% had diabetes. There were 354 deaths (159 from CVD), 302 CVD events, and 118 sepsis hospitalizations over follow-up. Both fructosamine and glycated albumin were associated with all-cause mortality; adjusted HR per doubling of the biomarker was 1.96 (95% CI 1.38–2.79) for fructosamine and 1.40 (1.09–1.80) for glycated albumin. Both markers were also associated with CVD mortality [fructosamine 2.13 (1.28–3.54); glycated albumin 1.55 (1.09–2.21)]. Higher values of both markers were associated with trends toward a higher risk of hospitalization with sepsis [fructosamine 1.75 (1.01–3.02); glycated albumin 1.39 (0.94–2.06)]. CONCLUSIONS Serum fructosamine and glycated albumin are risk factors for mortality and morbidity in hemodialysis patients.

Plant Protein Intake is Associated With Fibroblast Growth Factor 23 and Serum Bicarbonate Levels in Patients With Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort Study

BACKGROUND Protein from plant, as opposed to animal, sources may be preferred in chronic kidney disease (CKD) because of the lower bioavailability of phosphate and lower nonvolatile acid load. STUDY DESIGN Observational cross-sectional study. SETTING AND PARTICIPANTS A total of 2,938 participants with CKD and information on their dietary intake at the baseline visit in the Chronic Renal Insufficiency Cohort Study. PREDICTORS Percentage of total protein intake from plant sources (percent plant protein) was determined by scoring individual food items using the National Cancer Institute Diet History Questionnaire (DHQ). OUTCOMES Metabolic parameters, including serum phosphate, bicarbonate (HCO₃), potassium, and albumin, plasma fibroblast growth factor 23 (FGF-23), and parathyroid hormone (PTH), and hemoglobin levels. MEASUREMENTS We modeled the association between percent plant protein and metabolic parameters using linear regression. Models were adjusted for age, sex, race, diabetes status, body mass index, estimated glomerular filtration rate, income, smoking status, total energy intake, total protein intake, 24-hour urinary sodium concentration, use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and use of diuretics. RESULTS Higher percent plant protein was associated with lower FGF-23 (P = .05) and higher HCO₃ (P = .01) levels, but not with serum phosphate or parathyroid hormone concentrations (P = .9 and P = .5, respectively). Higher percent plant protein was not associated with higher serum potassium (P = .2), lower serum albumin (P = .2), or lower hemoglobin (P = .3) levels. The associations of percent plant protein with FGF-23 and HCO₃ levels did not differ by diabetes status, sex, race, CKD stage (2/3 vs. 4/5), or total protein intake (≤0.8 g/kg/day vs. >0.8 g/kg/day; P-interaction >.10 for each). LIMITATIONS This is a cross-sectional study; determination of percent plant protein using the Diet History Questionnaire has not been validated. CONCLUSIONS Consumption of a higher percentage of protein from plant sources may lower FGF-23 and raise HCO₃ levels in patients with CKD.

Inflammation and the Paradox of Racial Differences in Dialysis Survival

African Americans experience a higher mortality rate and an excess burden of ESRD compared with Caucasians in the general population, but among those treated with dialysis, African Americans typically survive longer than Caucasians. We examined whether differences in inflammation may explain this paradox. We prospectively followed a national cohort of incident dialysis patients in 81 clinics for a median of 3 years (range 4 months to 9.5 years). Among 554 Caucasians and 262 African Americans, we did not detect a significant difference in median CRP between African Americans and Caucasians (3.4 versus 3.9 mg/L). Mortality was significantly lower for African Americans versus Caucasians (34% versus 56% at 5 years); the relative hazard was 0.7 (95% CI, 0.5 to 0.9) after adjusting for age, gender, dialysis modality, smoking, body mass index, diabetes, BP, cholesterol, cardiovascular disease, congestive heart failure, comorbid disease, hemoglobin, albumin, CRP, and IL-6. However, the risk varied by CRP tertile: the relative hazards for African Americans compared with Caucasians were 1.0 (95% CI, 0.7 to 1.4), 0.7 (95% CI, 0.4 to 1.3), and 0.5 (95% CI, 0.3 to 0.8) in the lowest, middle, and highest tertiles, respectively. We obtained similar results when we accounted for transplantation as a competing event, and we examined mortality across tertiles of IL-6. In summary, racial differences in survival among dialysis patients are not present at low levels of inflammation but are large at higher levels. Differences in inflammation may explain, in part, the racial paradox of ESRD survival.

Central Pulse Pressure in Chronic Kidney Disease: A Chronic Renal Insufficiency Cohort Ancillary Study

Central pulse pressure (PP) can be noninvasively derived using the radial artery tonometric methods. Knowledge of central pressure profiles has predicted cardiovascular morbidity and mortality in several populations of patients, particularly those with known coronary artery disease and those receiving dialysis. Few data exist characterizing central pressure profiles in patients with mild-moderate chronic kidney disease who are not on dialysis. We measured central PP cross-sectionally in 2531 participants in the Chronic Renal Insufficiency Cohort Study to determine correlates of the magnitude of central PP in the setting of chronic kidney disease. Tertiles of central PP were <36 mm Hg, 36 to 51 mm Hg, and >51 mm Hg with an overall mean (±SD) of 46±19 mm Hg. Multivariable regression identified the following independent correlates of central PP: age, sex, diabetes mellitus, heart rate (negatively correlated), glycosylated hemoglobin, hemoglobin, glucose, and parathyroid hormone parathyroid hormone concentrations. Additional adjustment for brachial mean arterial pressure and brachial PP showed associations for age, sex, diabetes mellitus, weight, and heart rate. Discrete intervals of brachial PP stratification showed substantial overlap within the associated central PP values. The large size of this unique chronic kidney disease cohort provides an ideal situation to study the role of brachial and central pressure measurements in kidney disease progression and cardiovascular disease incidence.