Change Over Time in Pre-End-Stage Renal Disease 24-Hour Urine Creatinine as Muscle Mass Surrogate and Post-End-Stage Renal Disease Mortality.

OBJECTIVE: Loss of muscle mass and sarcopenia are common in chronic kidney disease (CKD) and end-stage renal disease (ESRD), and sarcopenia can worsen insidiously in patients with advancing CKD. The temporal dynamics of sarcopenia in patients with progressive loss of kidney function, and its association with future outcomes, is unclear. METHODS: In a contemporary national cohort of incident ESRD US veterans, we selected 661 patients who had at least 2 24-hour urine creatinine (24hrUC) measurements, a surrogate of muscle mass, performed during the 3-year prelude period prior to ESRD transition. We estimated 24hrUC slopes in mixed effects models. To assess the temporal dynamics of pre-ESRD changes in 24hrUC and its association with changing eGFR, we separately fitted in mixed effects models a penalized spline regression of 24hrUC on time and on eGFR. We examined the association of 24hrUC slopes with postdialysis all-cause mortality using Cox models adjusted for confounders. RESULTS: The mean slope of 24hrUC versus time was -78 mg/year (95% confidence interval: -102 to -54), with a steeper decline noted in the last year prior to ESRD. More severe decreases in 24hrUC were associated with higher all-cause mortality: a 100 mg/year decrease in 24hrUC was associated with a multivariable adjusted death hazard ratio of 1.41 (95% confidence interval: 1.00-1.98, P = .05). CONCLUSION: Patients with advanced CKD lose a substantial proportion of their muscle mass each year during pre-ESRD prelude. Loss of muscle mass accelerates near ESRD transition, and more loss of muscle mass is associated with higher mortality after ESRD transition.

The use of neurobiological evidence in sentencing mitigation.

Neurobiological evidence has grown increasingly relevant in U.S. criminal proceedings, particularly during sentencing. Neuroimaging, such as functional Magnetic Resonance Imaging and Positron Emission Tomography scans, may be introduced by defense counsel to demonstrate brain abnormalities to argue for more lenient sentencing. This practice is common for penalty mitigation in cases eligible for capital punishment. This article reviews the history of the use of neuroscience in criminal cases from the early 20th Century to present, noting pertinent legal and ethical considerations for the use of such evidence. The authors review important empirical research conducted in recent years regarding the use of neurobiological evidence in legal proceedings (such as mock-juror studies) and guidance from the federal sentencing guidelines and the American Bar Association. The discussion also notes relevant case law in which neuroimaging, behavioral genetics, or other neurobiological data were introduced in criminal proceedings, particularly precedent-setting U.S. Supreme Court cases.

A Survey of Forensic Psychiatry Fellowship Program Directors on Selecting Fellowship Applicants.

In the 2019-2020 academic year, there were 48 accredited forensic psychiatry fellowship programs in the United States. Programs vary in application requirements and timeline. There are no published objective data on factors that fellowship program directors (PDs) use when selecting fellows. We created an electronic survey that was emailed to PDs via a list from the Association of Directors of Forensic Psychiatry Fellowships. The survey was open November 6, 2019 to December 31, 2019. Twenty-five PDs participated from programs ranging in size from one to six positions, receiving zero to 30 applications. The most important factors when selecting a candidate to interview were "perceived commitment to specialty" and "perceived interest in your program." The most important factors when offering a position were "interpersonal skills" and "interactions during interview." The least important factors in both categories were USMLE/COMLEX scores and honor society membership(s). "Lack of a set timeline" during the application process was the most frequently cited difficulty (via multiple choice) during the application and interview process. Our study is the first to provide quantitative data regarding factors that forensic psychiatry fellowship PDs use to evaluate applicants in decisions regarding offering interviews and positions.

Systemic Inflammatory Response Syndrome Secondary to Nitrofurantoin.

Nitrofurantoin is considered optimal treatment for acute uncomplicated cystitis by the Infectious Diseases Society of America and is being increasingly recommended due to microbial resistance to sulfamethoxazole/trimethoprim and various fluoroquinolone antibiotics. Adverse effects of nitrofurantoin are generally considered mild, with gastrointestinal complaints being the most common. However, there have been isolated case reports describing a more severe systemic inflammatory response syndrome-like reaction, which leads to diagnostic challenges and treatment complications. We report the case of a patient with repeat episodes of systemic inflammatory response syndrome secondary to nitrofurantoin, which was initially attributed to recurrent urinary tract infections.

Effects of Intensive Blood Pressure Control in Patients with and without Albuminuria: Post Hoc Analyses from SPRINT.

BACKGROUND AND OBJECTIVES: It is unclear whether the presence of albuminuria modifies the effects of intensive systolic BP control on risk of eGFR decline, cardiovascular events, or mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Systolic Blood Pressure Intervention Trial randomized nondiabetic adults ≥50 years of age at high cardiovascular risk to a systolic BP target of <120 or <140 mm Hg, measured by automated office BP. We compared the absolute risk differences and hazard ratios of ≥40% eGFR decline, the Systolic Blood Pressure Intervention Trial primary cardiovascular composite outcome, and all-cause death in those with or without baseline albuminuria (urine albumin-creatinine ratio ≥30 mg/g). RESULTS: Over a median follow-up of 3.1 years, 69 of 1723 (4%) participants with baseline albuminuria developed ≥40% eGFR decline compared with 61 of 7162 (1%) participants without albuminuria. Incidence rates of ≥40% eGFR decline were higher in participants with albuminuria (intensive, 1.74 per 100 person-years; standard, 1.17 per 100 person-years) than in participants without albuminuria (intensive, 0.48 per 100 person-years; standard, 0.11 per 100 person-years). Although effects of intensive BP lowering on ≥40% eGFR decline varied by albuminuria on the relative scale (hazard ratio, 1.48; 95% confidence interval, 0.91 to 2.39 for albumin-creatinine ratio ≥30 mg/g; hazard ratio, 4.55; 95% confidence interval, 2.37 to 8.75 for albumin-creatinine ratio <30 mg/g; P value for interaction <0.001), the absolute increase in ≥40% eGFR decline did not differ by baseline albuminuria (incidence difference, 0.38 events per 100 person-years for albumin-creatinine ratio ≥30 mg/g; incidence difference, 0.58 events per 100 person-years for albumin-creatinine ratio <30 mg/g; P value for interaction =0.60). Albuminuria did not significantly modify the beneficial effects of intensive systolic BP lowering on cardiovascular events or mortality evaluated on relative or absolute scales. CONCLUSIONS: Albuminuria did not modify the absolute benefits and risks of intensive systolic BP lowering.

Resolution of IgA and C3 immune deposits in Staphylococcus infection-associated glomerulonephritis in a kidney transplant recipient
.

Staphylococcus infection-associated glomerulonephritis (SAGN) is characterized by the presence of IgA and C3 as the predominant components present in the glomerular immune deposits. Glomerulonephritis frequently resolves after effective treatment of the staphylococcal infection. However, there have been few studies of repeat kidney biopsy after resolution of glomerulonephritis. We present a combined kidney-pancreas transplant patient who developed SAGN due to Staphylococcus aureus bacteremia from an old infected arteriovenous (AV) graft, which occurred after a long period of stable allograft function. Clinical improvement occurred following surgical debridement and appropriate antibiotics with subsequent clearance of bacteremia. However, 3 weeks later he presented with severe acute kidney injury related to rapidly progressive glomerulonephritis. Renal allograft biopsy revealed immune complex glomerulonephritis with predominance of IgA and C3 in subendothelial and mesangial deposits, consistent with SAGN. There was no evidence for recurrent staphylococcal infection. High-dose steroid therapy was followed by resolution of hematuria and improvement in allograft function with gradual return of serum creatinine concentration to near baseline levels. However, 1 year after the diagnosis of SAGN, he developed gradually worsening allograft function with persistent proteinuria. Repeat allograft biopsy showed sclerosing glomerular changes and extensive interstitial fibrosis and tubular atrophy. There was complete resolution of proliferative changes, and IgA and C3 deposits were no longer detectable. Despite transient allograft function stabilization, the patient progressed to end-stage renal disease (ESRD), and maintenance hemodialysis was reinitiated 2.5 years after the diagnosis of SAGN. Pancreatic allograft function remained normal.

Longer Predialysis ACEi/ARB Utilization Is Associated With Reduced Postdialysis Mortality.

BACKGROUND: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) improve predialysis outcomes; however, ACEi/ARB are underused in patients transitioning to dialysis. We examined the association of different patterns of predialysis ACEi/ARB use with postdialysis survival and whether potentially modifiable adverse events are associated with lower predialysis ACEi/ARB use. METHODS: This was a historic cohort study of 34,676 US veterans with, and 10,690 without, ACEi/ARB exposure in the 3-year predialysis period who subsequently transitioned to dialysis between 2007 and 2014. Associations of different patterns of predialysis ACEi/ARB use with postdialysis all-cause mortality and with predialysis acute kidney injury and hyperkalemia events were examined using multivariable adjusted regression analyses. RESULTS: The mean age of the cohort was 70 years, 98% were males and 27% were African Americans. Compared to ACEi/ARB nonuse, continuous ACEi/ARB use was associated with lower postdialysis all-cause mortality (adjusted hazard ratio [aHR]; 95% confidence interval [95% CI] 0.87; 0.83-0.92). In analyses modeling the duration of predialysis ACEi/ARB use, ACEi/ARB use of 50%-74% and ≥75% were associated with lower mortality compared to nonuse (adjusted hazard ratio, 95% confidence interval 0.96, 0.92-0.99 and 0.91; 0.88-0.94, respectively), whereas no increase in postdialysis survival was observed with shorter predialysis ACEi/ARB use. Predialysis acute kidney injury was associated with shorter duration (<50%) of ACEi/ARB use and hyperkalemia was associated with interrupted and ACEi/ARB use of <75%. CONCLUSIONS: Longer predialysis ACEi/ARB exposure was associated with lower postdialysis mortality. Prospective studies are needed to evaluate the benefits of strategies enabling uninterrupted predialysis ACEi/ARB use.

Resolution of syphilis-related rapidly progressive glomerulonephritis with penicillin therapy: Case report
.

Renal manifestations of syphilis are variable, with membranous nephropathy being the most commonly described lesion. Rapidly progressive glomerulonephritis (RPGN) is rare and there is only one case report in the literature describing syphilis-associated crescentic glomerulonephritis. We report a rare case of RPGN secondary to latent syphilis, which resolved with penicillin treatment in the absence of immunosuppressive therapy. A 28-year-old Black male with a history of HIV was evaluated for severe acute kidney injury, nephrotic-range proteinuria, and active urine sediment. Serologies for glomerulonephritis were negative. Rapid plasma reagin and treponema pallidum particle agglutination assay were reactive, confirming syphilis diagnosis. Kidney biopsy revealed focal and segmental necrotizing and crescentic lesion. Patient received weekly benzathine penicillin (PCN) for 3 weeks, and renal function improved to baseline. This dramatic improvement happened with PCN alone, a finding which has not been previously reported. We recommend that syphilis be considered in the differential diagnosis of all patients with proteinuria or suspected glomerulonephritis.

Adjudicative Competence and the Criminalization of Intellectual Disability.

Wood and colleagues effectively argue that Title II of the Americans with Disabilities Act applies to securing accommodations for persons with intellectual/disability disorder so that such persons can meaningfully participate in the criminal adjudicative process. This invited commentary further discusses the challenges in identifying, assisting, and fully accommodating persons with intellectual/disability disorder in the criminal justice system. It also highlights ongoing problems with stereotypes within this population, which may affect the outcome of criminal proceedings. This commentary argues that persons with intellectual/disability disorder will likely continue to be treated unequally in the criminal justice system until better supports, treatments, and services are provided in community settings because treatment and placement options are often closely linked with case disposition.

The SPRINT trial suggests that markers of tubule cell function in the urine associate with risk of subsequent acute kidney injury while injury markers elevate after the injury.

Urine markers can quantify tubular function including reabsorption (α-1 microglobulin [α1m]) and ß-2-microglobulin [ß2m]) and protein synthesis (uromodulin). Individuals with tubular dysfunction may be less able to compensate to insults than those without, despite similar estimated glomerular filtration rate (eGFR) and albuminuria. Among Systolic Blood Pressure Intervention Trial (SPRINT) participants with an eGFR under 60 ml/min/1.73m2, we measured urine markers of tubular function and injury (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], interleukin-18 [IL-18], monocyte chemoattractant protein-1, and chitinase-3-like protein [YKL-40]) at baseline. Cox models evaluated associations with subsequent acute kidney injury (AKI) risk, adjusting for clinical risk factors, baseline eGFR and albuminuria, and the tubular function and injury markers. In a random subset, we remeasured biomarkers after four years, and compared changes in biomarkers in those with and without intervening AKI. Among 2351 participants, 184 experienced AKI during 3.8 years mean follow-up. Lower uromodulin (hazard ratio per two-fold higher (0.68, 95% confidence interval [0.56, 0.83]) and higher α1m (1.20; [1.01, 1.44]) were associated with subsequent AKI, independent of eGFR and albuminuria. None of the five injury markers were associated with eventual AKI. In the random subset of 947 patients with repeated measurements, the 59 patients with intervening AKI versus without had longitudinal increases in urine NGAL, IL-19, and YKL-40 and only 1 marker of tubule function (α1m). Thus, joint evaluation of tubule function and injury provided novel insights to factors predisposing to AKI, and responses to kidney injury.

Markers of kidney tubule function and risk of cardiovascular disease events and mortality in the SPRINT trial.

AIMS: Biomarkers of kidney tubule injury, inflammation and fibrosis have been studied extensively and established as risk markers of adverse kidney and cardiovascular disease (CVD) outcomes. However, associations of markers of kidney tubular function with adverse clinical events have not been well studied, especially in persons with chronic kidney disease (CKD). METHODS AND RESULTS: Using a sample of 2377 persons with CKD at the baseline Systolic Blood Pressure Intervention Trial (SPRINT) visit, we evaluated the association of three urine tubular function markers, alpha-1 microglobulin (α1m), beta-2 microglobulin (ß2m), and uromodulin, with a composite CVD endpoint (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes) and mortality using Cox proportional hazards regression, adjusted for baseline estimated glomerular filtration rate (eGFR), albuminuria, and CVD risk factors. In unadjusted analysis, over a median follow-up of 3.8 years, α1m and ß2m had positive associations with composite CVD events and mortality, whereas uromodulin had an inverse association with risk for both outcomes. In multivariable analysis including eGFR and albuminuria, a two-fold higher baseline concentration of α1m was associated with higher risk of CVD [hazard ratio (HR) 1.25; 95% confidence interval (CI): 1.10-1.45] and mortality (HR 1.25; 95% CI: 1.10-1.46), whereas ß2m had no association with either outcome. A two-fold higher uromodulin concentration was associated with lower CVD risk (HR 0.79; 95% CI: 0.68-0.90) but not mortality (HR 0.86; 95% CI: 0.73-1.01) after adjusting for similar confounders. CONCLUSION: Among non-diabetic persons with CKD, biomarkers of tubular function are associated with CVD events and mortality independent of glomerular function and albuminuria.

Acute esophageal necrosis (black esophagus) complicating calcific uremic arteriolopathy
.

The current case report describes a chronic hemodialysis patient presenting with painful penile ulceration that was clinically and histologically proven to be related to calcific uremic arteriolopathy. The patient subsequently developed severe upper gastrointestinal bleeding that was both endoscopically and histologically shown to be due to acute esophageal necrosis (AEN), also known as necrotizing esophagitis and "black esophagus". AEN is a rare condition characterized by diffuse necrosis of the esophageal mucosa. The condition is diagnosed endoscopically with demonstration of circumferential mucosal necrosis involving the distal esophagus that can extend proximally. Mortality rates for both calcific uremic ateriolopathy and acute esophageal necrosis are high. Management of both conditions is reviewed. The patient recovered from the acute illness, but expired 6 months later due to progressive failure to thrive. To our knowledge, AEN has not previously been described secondary to calcific uremic arteriolopathy.
.

PTH, FGF23, and Intensive Blood Pressure Lowering in Chronic Kidney Disease Participants in SPRINT.

BACKGROUND AND OBJECTIVES: The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive BP lowering reduced the risk of cardiovascular disease, but increased eGFR decline. Serum parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) concentrations are elevated in CKD and are associated with cardiovascular disease. We evaluated whether intact PTH or intact FGF23 concentrations modify the effects of intensive BP control on cardiovascular events, heart failure, and all-cause mortality in SPRINT participants with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We measured PTH and FGF23 in 2486 SPRINT participants with eGFR<60 ml/min per 1.73 m2 at baseline. Cox models were used to evaluate whether serum PTH and FGF23 concentrations were associated with cardiovascular events, heart failure, and all-cause mortality, and whether PTH and FGF23 modified the effects of intensive BP control. RESULTS: The mean age of this subcohort was 73 years, 60% were men, and mean eGFR was 46±11 ml/min per 1.73 m2. Median PTH was 48 (interquartile range [IQR], 35-67) pg/ml and FGF23 was 66 (IQR, 52-88) pg/ml. There were 261 composite cardiovascular events, 102 heart failure events, and 179 deaths within the subcohort. The adjusted hazard ratio (HR) per doubling of PTH concentration for cardiovascular events, heart failure, and all-cause mortality were 1.29 (95% confidence interval [95% CI], 1.06 to 1.57), 1.32 (95% CI, 0.96 to 1.83), and 1.04 (95% CI, 0.82 to 1.31), respectively. There were significant interactions between PTH and BP arm for both the cardiovascular (P-interaction=0.01) and heart failure (P-interaction=0.004) end points. Participants with a PTH above the median experienced attenuated benefits of intensive BP control on cardiovascular events (adjusted HR, 1.02; 95% CI, 0.72 to 1.42) compared with participants with a PTH below the median (adjusted HR, 0.67; 95% CI, 0.45 to 1.00). FGF23 was not independently associated with any outcome and did not modify the effects of the intervention. CONCLUSIONS: SPRINT participants with CKD and a high serum PTH received less cardiovascular protection from intensive BP therapy than participants with a lower serum PTH.

AAPL Practice Resource for the Forensic Psychiatric Evaluation of Competence to Stand Trial.

Full Document: Wall BW, Ash P, Keram E, et al: AAPL Practice Resource for the Forensic Psychiatric Evaluation of Competence to Stand Trial Update 2018. Journal of the American Academy of Psychiatry and the Law Online Supplement 2018, 46 (3). Available at: http://www.jaapl.org/content/46/3_Supplement.

Changes With Lanthanum Carbonate, Calcium Acetate, and Phosphorus Restriction in CKD: A Randomized Controlled Trial.

INTRODUCTION: Abnormal phosphorus homeostasis develops early in chronic kidney disease (CKD). It is unclear if its correction results in improved clinical outcomes in non-dialysis dependent CKD. METHODS: We conducted a randomized controlled, parallel design clinical trial in 120 patients with estimated glomerular filtration rate 15 to 59 ml/min per 1.73 m2 and abnormal phosphorus homeostasis (serum phosphorus >4.6 mg/dl, parathyroid hormone [PTH] >70 pg/ml or tubular reabsorption of phosphorus [TRP] <80%). Patients were randomized to open-label lanthanum carbonate versus calcium acetate versus dietary intervention over 1 year. The co-primary outcomes were month 12 (vs. baseline) biochemical (serum phosphorus, TRP, PTH, calcium, bone-specific alkaline phosphatase [bALP], and fibroblast growth factor 23 [FGF23]) and vascular parameters (coronary artery calcium score, pulse wave velocity, and endothelial dysfunction) in all patients. Secondary outcomes were between-treatment differences in change for each parameter between month 12 and baseline. All analyses were intention to treat. RESULTS: Baseline characteristics were similar in the 3 groups. A total of 107 patients (89%) completed 12 months of follow-up. Differences were not significant at month 12 (vs. baseline) for any of the outcomes except bALP (median [25th, 75th] percentile at month 12 versus baseline: 13.8 [10.6, 17.6] vs. 15.8 [12.1, 21.1], P < .001) and FGF23 (132 [99, 216] vs. 133 [86, 189], P = .002). Changes for all outcomes were similar in the 3 arms except for PTH, which was suppressed more effectively by calcium acetate (P < .001). CONCLUSION: A 1-year intervention to limit phosphorus absorption using dietary restriction or 2 different phosphorus binders resulted in decreased bALP suggesting improved bone turnover, but no other significant changes in biochemical or vascular parameters in patients with CKD stage 3/4. (ClinicalTrials.gov: NCT01357317).

Recurrent Pyroglutamic Acidosis Related to Therapeutic Acetaminophen.

Pyroglutamic acid, an intermediate in glutathione metabolism, can lead to elevated anion gap metabolic acidosis as rare complication of acetaminophen therapy in adults. Acquired pyroglutamic acidosis has been observed primarily in settings associated with glutathione deficiency. Risk factors for glutathione deficiency include critical illness, chronic liver or kidney disease, advanced age, female gender, alcohol abuse, malnutrition, pregnancy, antiepileptic drugs, and chronic acetaminophen use. Diagnosis of pyroglutamic acidosis requires both the exclusion of common etiologies of increased anion gap metabolic acidosis and a high index of suspicion. Treatment involves discontinuation of acetaminophen, supportive care, and addressing risk factors for glutathione deficiency. The current report describes an ambulatory patient with multiple risk factors for glutathione deficiency, who developed recurrent pyroglutamic acidosis due to acetaminophen use with therapeutic blood levels of acetaminophen.