Benjamin J. Lee

PRENATAL EXPOSURE TO THALIDOMIDE, ALTERED VASCULOGENESIS, AND CNS MALFORMATIONS

Malformations of cortical development (MCD) result from abnormal neuronal positioning during corticogenesis. MCD are believed to be the morphological and perhaps physiological bases of several neurological diseases, spanning from mental retardation to autism and epilepsy. In view of the fact that during development, an appropriate blood supply is necessary to drive organogenesis in other organs, we hypothesized that vasculogenesis plays an important role in brain development and that E15 exposure in rats to the angiogenesis inhibitor thalidomide would cause postnatal MCD. Our results demonstrate that thalidomide inhibits angiogenesis in vitro at concentrations that result in significant morphological alterations in cortical and hippocampal regions of rats prenatally exposed to this vasculotoxin. Abnormal neuronal development was associated with vascular malformations and a leaky blood-brain barrier. Protein extravasation and uptake of fluorescent albumin by neurons, but not glia, was commonly associated with abnormal cortical development. Neuronal hyperexcitability was also a hallmark of these abnormal cortical regions. Our results suggest that prenatal vasculogenesis is required to support normal neuronal migration and maturation. Altering this process leads to failure of normal cerebrovascular development and may have a profound implication for CNS maturation.

Association of the Small GTPase Rheb with the NMDA Receptor Subunit NR3A

The NMDAR subunit NR3A is most highly expressed during the second postnatal week, when synaptogenesis reaches peak levels. Genetic ablation or overexpression of the NR3A subunit negatively interferes with the maturation of cortical synapses and leads to changes in the shape and number of dendritic spines, the density of which is increased in NR3A knock-out mice and decreased in NR3A-overexpressing transgenic mice. Alterations in spine density have been linked to dysregulation of mTOR signaling and synaptic protein translation. Using a yeast two-hybrid system, we identified the mTOR-activating GTPase Rheb as an interacting protein of the NMDAR subunit NR3A. We confirmed the interaction in mammalian cells by expressing recombinant Rheb and NR3A and showed that Rheb and NR3A could be co-immunoprecipitated from synaptic plasma membranes from the developing rat brain. These data suggest that NR3A sequesters synaptic Rheb and might thus function as a break of the mTOR-dependent synaptic translation of protein.

Physical therapy–induced rhabdomyolysis and acute kidney injury associated with reduced activity of muscle lactate dehydrogenase A

History of the Present Illness One week prior to the presentation, the patient underwent her first session of physical therapy for muscle weakness at the recommendation of her primary care physician. She had exercised all extremities for approximately an hour, followed by whirlpool for 30 minutes. At the end of the session, she began to experience whole-body pain and weakness. Her symptoms worsened over the ensuing several days. She took narcotics for the pain and developed nausea, decreased appetite, and constipation. On day 5 following physical therapy, she was admitted to a local hospital where evaluation revealed stable vital signs, but marked creatine kinase (CK) elevation (22,000 IU/liter), leukocytosis (white blood cell [WBC] count of 18.3 10 cells/ml), and lactic acidosis (lactate of 3.49 mmoles/liter). Her serum creatinine level was 1.0 mg/dl, and a chest radiograph showed bibasilar atelectasis versus infiltrates. She was started on empiric antimicrobials for possible pneumonia. Despite the treatment, her condition failed to improve. Two days later, she was transferred to our institution for further evaluation and management.

Pre-admission proteinuria impacts risk of non-recovery after dialysis-requiring acute kidney injury

Renal recovery after dialysis-requiring acute kidney injury (AKI-D) is an important clinical and patient-centered outcome. Here we examined whether the pre-admission proteinuria level independently influences risk for non-recovery after AKI-D in a community-based population. All adult members of Kaiser Permanente Northern California who experienced AKI-D between January 1, 2009 and September 30, 2015 were included. Pre-admission proteinuria levels were determined by dipstick up to four years before the AKI-D hospitalization and the outcome was renal recovery (survival and dialysis-independence four weeks and more) at 90 days after initiation of renal replacement therapy. We used multivariable logistic regression to adjust for baseline estimated glomerular filtration rate (eGFR), age, sex, ethnicity, short-term predicted risk of death, comorbidities, and medication use. Among 5,347 adults with AKI-D, the mean age was 66 years, 59% were men, and 50% were white. Compared with negative/trace proteinuria, the adjusted odds ratios for non-recovery (continued dialysis-dependence or death) were 1.47 (95% confidence interval 1.19-1.82) for 1+xa0proteinuria and 1.92 (1.54-2.38) for 2+ or more proteinuria. Among survivors, the crude probability of recovery ranged from 83% for negative/trace proteinuria with baseline eGFR over 60 mL/min/1.73m2 to 25% for 2+ or more proteinuria with eGFR 15-29 mL/min/1.73m2. Thus, the pre-AKI-D level of proteinuria is a graded, independent risk factor for non-recovery and helps to improve short-term risk stratification for patients with AKI-D.

Non-recovery from dialysis-requiring acute kidney injury and short-term mortality and cardiovascular risk: a cohort study.

BackgroundThe high mortality and cardiovascular disease (CVD) burden in patients with end-stage renal disease (ESRD) is well-documented. Recent literature suggests that acute kidney injury is also associated with CVD. It is unknown whether patients with incident ESRD due to dialysis-requiring acute kidney injury (AKI-D) are at higher short-term risk for death and CVD events, compared with incident ESRD patients without preceding AKI-D. Few studies have examined the impact of recovery from AKI-D on subsequent CVD risk.MethodsIn this retrospective cohort study, we evaluated adult members of Kaiser Permanente Northern California who initiated dialysis from January 2009 to September 2015. Preceding AKI-D and subsequent outcomes of death and CVD events (acute coronary syndrome, heart failure, ischemic stroke or transient ischemic attack) were identified from electronic health records. We performed multivariable Cox regression models adjusting for demographics, comorbidities, medication use, and laboratory results.ResultsCompared to incident ESRD patients who experienced AKI-D (nu2009=u20091865), patients with ESRD not due to AKI-D (nu2009=u20093772) had significantly lower adjusted rates of death (adjusted hazard ratio [aHR] 0.56, 95% CI: 0.47–0.67) and heart failure hospitalization (aHR 0.45, 0.30–0.70). Compared to AKI-D patients who did not recover and progressed to ESRD, AKI-D patients who recovered (nu2009=u20091347) had a 30% lower adjusted relative rate of death (aHR 0.70, 0.55–0.88).ConclusionsPatients who transition to ESRD via AKI-D are a high-risk subgroup that may benefit from aggressive monitoring and medical management, particularly for heart failure. Recovery from AKI-D is independently associated with lower short-term mortality.

Refining the Policy for Timing of Kidney Transplant Waitlist Qualification

Background Earlier qualification for the kidney transplant waitlist expedites transplant and is therefore associated with improved outcomes. U.S. Organ Procurement and Transplantation Network policies state that “measured or calculated creatinine clearance or glomerular filtration rate less than or equal to 20 mL/min” triggers waitlist time accrual. The choice of qualification method is somewhat arbitrary, and the policy implies that decline in renal function is monotonic. Methods (1) We used survival analysis to quantify temporal differences in waitlist qualification by applying 3 kidney-function-estimating equations (Cockcroft-Gault, Modification of Diet in Renal Disease study, Chronic Kidney Disease Epidemiology Collaboration) to serial creatinine measurements from 3 patient cohorts: 1 of waitlisted patients at a major U.S. academic center and 2 national, multicenter cohorts of chronic kidney disease patients (African American Study of Kidney Disease and Hypertension, Modification of Diet in Renal Disease). (2) Survival analysis assessed whether requiring patients to demonstrate persistently reduced renal function on 2 occasions at least 90 days apart would meaningfully change qualification order. Results On average, time to waitlist qualification would be delayed on the order of 1 to 2 years by using calculated creatinine clearance (per the Cockcroft-Gault equation). Compared with current policy, requiring demonstration of persistently reduced renal function delayed qualification by 0.6 to 2.1 years and caused 40% to 50% of patients to switch the order in which they qualify by 6 months or more. Conclusions The kidney transplantation policies should be revised, such that timing of waitlist qualification is more standardized. We suggest that mention of using calculated creatinine clearance be dropped from the Organ Procurement and Transplantation Network policy wording and the units to quantify kidney function be changed to mL/min per 1.73 m2. Some consideration should be given to whether requiring persistently reduced renal function would better identify patients most likely to benefit from earlier waitlist qualification.

Acute kidney injury is important in the hospital and afterward

Acute kidney injury (AKI) is a major contributor to morbidity and mortality in hospitalized patients across the world.1 Affecting up to 20% of all admissions (depending on which definition of AKI is used),2 AKI is the most common reason for new-inpatient nephrology consultation. Recent data suggest that AKI incidence has risen rapidly, by up to 10% per year.3,4 AKI is associated with a variety of serious shortand longterm complications. Approximately 33% to 60% of critically ill patients who develop dialysis-requiring AKI do not survive to hospital discharge, and mortality associated with dialysis-requiring AKI is greater than that associated with other serious conditions such as myocardial infarction or acute respiratory distress syndrome.5 Even relatively mild AKI in the acute inpatient setting appears to be an independent risk factor for mortality.6 For several decades, many physicians believed that AKI was a self-limited process followed by complete recovery of renal function to pre-AKI levels among survivors. (Numerous trainees have been taught some variant of the old adage: “If the patients survive, so will their kidneys.”) But studies linking AKI with the development of new-onset chronic kidney disease (CKD) or the accelerated progression of pre-existing CKD have changed this view.7 One important reason the long-term impact of AKI hasn’t been appreciated is that, traditionally, clinical studies of AKI examined inhospital outcomes such as short-term mortality and resource usage and did not consider what transpired months to years after discharge. More recently, epidemiologic studies linking inpatient events with outpatient outcomes have filled this knowledge gap.8 Contemporary animal models of AKI have shed light on potential mechanisms of maladaptive repair after AKI, characterized by fibrosis, vascular rarefaction, tubular loss, glomerulosclerosis, and chronic interstitial inflammation, all of which result in renal function decline. So over the last decade there has been a paradigm shift in how we think about AKI and CKD. Rather than distinct entities, AKI and CKD are now viewed as interconnected syndromes since AKI is a risk factor for CKD progression and CKD is a risk factor for new episodes of AKI.9 Two studies published in this issue of the Journal of Hospital Medicine augment our understanding of AKI and its clinical impact in hospitalized patients. Analyzing data from the National Inpatient Sample, Silver et al.10 found that hospitalizations that include AKI are substantially costlier and associated with longer lengths of stay than hospitalizations without AKI. The authors also highlight that the additional economic costs of AKI exceeded those of many other higher-profile yet less-common acute medical conditions, such as myocardial infarction and gastrointestinal bleeding. These results re-emphasize the important economic burden of AKI at a national level and expand on prior literature by confirming findings previously limited to single-center and regional studies. Better defining the impact AKI has on our healthcare system could help ensure that adequate resources are invested to combat AKI. The second study, by Rutter et al.,11 found that among hospitalized patients with normal baseline renal function, use of vancomycin in combination with piperacillin-tazobactam is associated with a higher incidence of AKI after antibiotic exposure than use of either agent as monotherapy. This association persisted even after adjusting for potential confounders such as underlying comorbidities, exposure to nephrotoxic agents, documented hypotension, and baseline renal impairment. This study adds to a growing body of literature that suggests synergistic nephrotoxicity between vancomycin and piperacillin-tazobactam. It underscores that any medical intervention—even treatments typically envisioned as non-hazardous and frequently life-saving—involve inherent risks and should prompt the medical community to promote proper antimicrobial stewardship. Whether such exposures to vancomycin or beta-lactam derivatives cause AKI via direct tubular damage, interstitial nephritis, or some other novel mechanism remains to be elucidated. Better delineation of the contemporary causes of AKI, including increased antibiotic exposure, is the first step toward identifying ways to reduce AKI incidence. Both of these papers serve to highlight the clinical importance of AKI among hospitalized patients. Their findings re-emphasize the need for vigilance in detecting AKI and intervening early to achieve the best clinical outcomes. Given recent understanding that survivors of AKI are at greater risk for more rapid loss of renal function long after hospital discharge, one goal the US Department of Health and Human Services put forth for Healthy People 2020 is to “increase the proportion of hospital patients who incurred AKI who have follow-up renal evaluation in 6 months post-discharge” (10% improvement targeted).12 Transitions of care after hospitalizations complicated by AKI require special attention to ensure that patients’ needs are optimally *Address for correspondence and reprint requests: Benjamin J. Lee, MD, Division of Nephrology, University of California San Francisco, 533 Parnassus Avenue, U404, San Francisco, CA 94143; Telephone: 415-476-1812; Fax: 415476-3381; E-mail: bjlee@ucsf.edu