Comparison of Two Waves of COVID-19 in Critically Ill Patients: A Retrospective Observational Study.

Background: The SARS-CoV-2 virus caused the global COVID-19 pandemic, with waxing and waning course. This study was conducted to compare outcomes in the first two waves, in mechanically ventilated patients. Methods: This retrospective observational study included all mechanically ventilated COVID-19 patients above 18 years of age, between March 2020 and January 2021. Patients were grouped into first wave from March 2020 to July 2020, and second wave from August 2020 to January 2021. Outcome measures were mortality, the development of acute kidney injury (AKI), and need for renal replacement therapy (RRT). Univariate and multivariate cox regression analysis were used to delineate risk factors for the outcome measures. Results: A total of 426 patients, 285 in the first wave and 185 in the second wave, were included. The incidence of AKI was significantly lower in the second wave (72% vs. 63%; p=0.04). There was no significant difference in mortality (70% vs. 63%; p=0.16) and need for RRT (36% vs. 30%; p=0.1). Risk factors for mortality were increasing age and AKI in both waves, and chronic kidney disease (CKD) (adj. HR 1.7; 95% CI 1.02-2.68; p=0.04) in the second wave. Risk factors for AKI were CKD in both the waves, while it was diabetes (adj. HR 1.4; 95% CI 1.02-1.95; p=0.04) and increasing age in the first wave. Remdesivir (adj. HR 0.5; 95% CI 0.3-0.7; p < 0.01) decreased the risk of AKI, and convalescent plasma (adj. HR 0.5; 95% CI 0.3-0.9; p=0.02) decreased the risk of mortality in the first wave, however, such benefit was not observed in the second wave. Conclusions: Our study shows a decrease in the incidence of AKI in critically ill patients, however, the reason for this decrease is still unknown. Studies comparing the waves of the pandemic would not only help in understanding disease evolution but also to develop tailored management strategies.

Novel methods of predicting ionized calcium status from routine data in critical care: External validation in MIMIC-III.

BACKGROUND: Low ionized calcium (ICa) is prevalent and prognostic in critical care, but poorly detected by either total calcium (TCa) or albumin-corrected TCa (cTCa). We recently derived models of ICa (Pred-ICa) and low ICa (ProbHYPO) in critical care that adjust TCa for binding to albumin and small anions-represented by the anion gap's components. On internal validation, they outperformed cTCa in diagnosing low ICa. Two other new anion gap-based models of ICa, derived in renal patients, have not been validated. This study tested the external validity of these 4 new models in the Medical Information Mart for Intensive Care III (MIMIC-III) database. METHODS: We identified 4105 patients in MIMIC-III with ICa measured on an arterial blood gas panel within 20 min of chemistry panel measurements of TCa, albumin, sodium, chloride, and total carbon dioxide. The 4 models and cTCa were assessed by their diagnostic discrimination for low ICa (<1.10 mmol/l) and high ICa (>1.32 mmol/l), and by the agreement between predicted and observed values. RESULTS: Pred-ICa and ProbHYPO had the best discrimination and agreement. CONCLUSIONS: Pred-ICa and ProbHYPO were externally validated in MIMIC-III. They can help clinicians efficiently decide when to order direct ICa testing in critical care.

Predicting ionized hypocalcemia: External validation of an ionized calcium prediction model in patients with COVID-19 and renal failure.

BACKGROUND: Ionized hypocalcemia is common in critically ill patients with COVID-19 and is associated with adverse outcomes. We previously developed a linear model that estimates ionized calcium (ICa) by adjusting total calcium (TCa) for the three components of the anion gap and albumin. On internal validation, it outperformed the popular method that corrects TCa for albumin alone (cTCa) in diagnosing low ICa. In this study, we sought to externally validate our ICa model in hospitalized COVID-19 positive patients. METHODS: We retrospectively studied all 200 patients with COVID-19 who were admitted to the State University of New York Downstate Medical Center between March 11th and April 30th 2020 and referred to the nephrology service for renal failure, and who had ICa measured on a venous blood gas within 25 min of a comprehensive metabolic panel. We compared the performance of the ICa model and cTCa in diagnosing low ICa by ROC analysis, and also examined the accuracy of the absolute values predicted by the two methods relative to measured ICa. RESULTS: On ROC analysis, the ICa model was better than cTCa (area under ROC curve: 0.872 [0.025] vs. 0.835 [0.028]; p = 0.045). The ICa model estimated ICa accurately, but the cTCa method seemed to overcorrect TCa, as a substantial number of patients with clearly normal cTCa values had low ICa. CONCLUSIONS: In an external validation cohort, the ICa model estimated ICa accurately and was better than cTCa in the diagnosis of low ICa. This finding can be useful in guiding direct ICa testing.

Clotting of Hemodialysis Access in Patients with COVID-19 in an Inner-City Hospital.

BACKGROUND: An increased incidence of thrombotic complications in patients with coronavirus disease 2019 (COVID-19) has been reported. Severe acute kidney injury (AKI) is one of the major clinical manifestations of COVID-19 with the need for renal replacement therapy. It was observed that hemodialysis (HD) accesses tended to thrombose more often in the COVID-19 population than in non-COVID-19 patients. We hypothesize that the hypercoagulable state of COVID-19 is associated with higher incidence of access clotting. METHOD: In this retrospective single-centered study at Kings County Hospital in New York City, 1,075 patients with COVID-19 were screened, and 174 patients who received HD from January 3, 2021 to May 15, 2020 were enrolled to examine the risk factors of dialysis access clotting in patients with COVID-19. RESULTS: Of the 174 patients, 109 (63%) were COVID-19 positive. 39 (22.6%) patients had dialysis access clotting at least once during their hospitalization, and they had significantly higher body mass index (BMI) (p = 0.001), higher rates of COVID-19 (p = 0.015), AKI (p < 0.001), higher platelet counts (p = 0.029), higher lactate dehydrogenase levels (p = 0.009), and lower albumin levels (p = 0.001) than those without access malfunctions. Low albumin levels (p = 0.008), AKI (p = 0.008), and high BMI (p = 0.018) were risk factors associated with HD access clotting among COVID-19 patients. CONCLUSION: Patients with COVID-19 who receive HD for AKI with high BMI are at a higher risk of clotting their HD access.

The Implication of Dropping Race from the MDRD Equation to Estimate GFR in an African American-Only Cohort.

The widely used Modification of Diet in Renal Disease (MDRD) formula adapts a 1.212 multiplier for individuals who are identified as African Americans (AAs) or Blacks, which leads to a higher GFR estimation. As it stands, AAs have a lower prevalence of chronic kidney disease (CKD) but higher incidence of end-stage renal disease (ESRD) compared with Whites. Many hypotheses have been postulated to explain this paradox, but the imprecision of the GFR estimation with race-adaptation could be contributory. We performed a single-center, longitudinal, retrospective study on a cohort of outpatient AA patients using the MDRD and MDRDrace removed and CKD-EPI and CKD-EPIrace removed and their progression to CKD G5 (eGFR <15 ml/min/1.73 m2). 327 patients were analyzed. Median follow-up was 88.1 months (interquartile range, 34.4-129.1). When race was removed from MDRD, 39.9% of patients in CKD G1/2 were reclassified to CKD G3a, 72.6% of patients in CKD G3a would be reclassified to CKD G3b, and 54.1% and 36.4% of patients would be reclassified from CKD 3b to CKD G4 and CKD G4 to CKD G5, respectively (p < 0.0001). Comparing the CKD-EPI formula against the MDRD in our cohort, we found that 8.2%, 18.8%, and 11.4% of patients were reclassified from CKD G1/2 to CKD G3a, CKD G3a to G3b, and CKD G3b to CKD G4 respectively. Overall median time to progression to CKD G5 was 137.4 (131.9-142.8) months in patients who were not reclassified and 133.6 (127.6-139.6) months for patients who were reclassified by MDRDrace removed(p < 0.288). Concerns of inequitable access to healthcare have elicited calls to review race-corrected eGFR equations. A substantial number of individuals would have their CKD stage reclassified should have the MDRDrace removed equation be adopted en masse on an AA-only population. The discrepancy is highest at the 45-59 and >60 ml/min/1.72 min2 ranges. This will have tremendous impact on our center's approach to pharmacological dosing, referral system, best practices, and outcome surveillance. Comprehensive review of the current "race-corrected" eGFR will require a multifaceted approach and adjunctive use of noncreatinine-based approach.

Opioids and Acute Kidney Injury.

Opioid use and misuse in the United States has been at epidemic proportions and is predicted to increase further in the setting of the Coronavirus disease 19 pandemic. Acute kidney injury is a condition associated with significant morbidity and increased mortality. We review the literature on the effect of opioids on kidney function and critically examine the association between opioid use and acute kidney injury and identify at-risk populations in whom opioids should be used with caution. We also discuss the role of biomarkers in elucidating this condition and propose preventive measures, novel therapeutic options, and research directions.

Association of Physical Function and Survival in Older-Adult Renal Transplant Recipients.

There is an increase in older-adult renal transplant recipients in United States. The objective of this study was to assess the association between physical function (PF) and patient survival in renal transplant recipients who are aged 65 years or older. Using United Network for Organ Sharing (UNOS) data from 2007 to 2016, renal transplant recipients aged 65 years or older were included. Multivariable Cox regression was used to assess associations between survival and functional status adjusted for age, sex, race, donor quality, diabetes, and dialysis vintage. The study identified 26,721 patients. Patient survival was significantly higher in recipients who needed no assistance and lowest in patients in need of total assistance (P < .0001). In deceased donor (DD) transplants, the relative risk for mortality was 2.06 (1.74-2.43) for total assistance and 1.17 (1.08-1.28) for moderate assistance compared to no assistance (P < .0001). In living donor (LD) transplants, the relative risk of mortality was 1.38 (0.78-2.42) for patients needing total assistance and 1.37 (1.14-1.65) for patients needing moderate assistance compared to patients who did not need assistance (0.003). PF is an independent predictor of post-transplant mortality. Assessment of older potential renal transplant recipients should include assessment and standardization of functional status to counsel about post-transplant survival.

Predicting Ionized Hypocalcemia in Critical Care: An Improved Method Based on the Anion Gap.

BACKGROUND: Low ionized calcium (ICa) is prevalent in critical care patients. It is poorly detected by the popular indirect method, which corrects serum total calcium (TCa) for change in albumin. That correction (cTCa) ignores any concomitant change in the anion-complexed fraction of TCa. We tested whether the diagnosis of low ICa can be improved by further correcting for calcium complexation, represented by the anion gap (AG) or its components-sodium, chloride, and total carbon dioxide (tCO2). METHODS: We retrospectively studied all patients in our intensive care units between 2009 and 2011 with ICa measured on arterial (n = 310) or venous (n = 462) gas panels within 19 min of a comprehensive chemistry panel. Logistic models to predict low ICa and linear models to estimate ICa were derived in the arterial group and validated in the venous group, using either AG (AG model) or its components (Ion model) as predictors, adjusted for TCa and albumin. RESULTS: AG and its set of components were each highly significant independent predictors of low ICa. On validation, the logistic Ion model was better than the logistic AG model (ROC curve area ± SE: 0.92 ± 0.02 vs 0.89 ± 0.02; P = 0.008), which, in turn, was far better than cTCa (0.81 ± 0.03; P = 0.0006); the hypocalcemia rates predicted by the models showed good fit with the observed rates. Linear estimates of ICa were too imprecise for clinical use. CONCLUSIONS: The adjustment of TCa for AG or for sodium, chloride, and tCO2 markedly improves the diagnosis of low ICa. This finding may be useful in guiding ICa testing.

Utilization of peritoneal dialysis in the United States: Reasons for underutilization, specifically in New York State and the boroughs of New York City.

Peritoneal dialysis (PD) is currently underutilized in the United States (US), even within resource-rich neighborhoods. We analyzed data from US Renal Data Service to determine PD utilization within the US, New York State (NYS), selected boroughs within New York City (NYC), and Boston, Massachusetts. We then compared the odds of selecting PD with hemodialysis (HD) and analyzed how diabetes mellitus status, age >65 years, gender, and race influenced PD utilization between 2010 and 2016. We then compared a high-volume PD center (HVC) with a low-volume PD center (LVC). The odds of starting PD vs HD were as follows: Brooklyn 0.30 (0.25-0.36; <0.0001), Bronx 0.56 (0.47-0.67; <0.0001), Queens 0.66 (0.54-0.80; <0.0001), and Manhattan 0.61 (0.52-0.71; <0.0001). In 2016, the odds of starting PD compared with the rest of the US were as follows: Brooklyn 0.14 (0.08-0.22; <0.0001), Bronx 0.39 (0.27-0.56; <0.0001), Queens 0.32 (0.23-0.45; <0.0001), Manhattan 0.54 (0.36-0.79; 0.002), and Boston 0.89 (0.58-1.4; 0.624). Analysis of influencing factors showed that only age >65 significantly (<0.0001) influenced PD modality selection in Brooklyn and Boston. Differences between HVC and LVC in terms of modality transition, peritonitis rate, or provider:patient ratio were not statistically significant. Factors that influence PD utilization in urban neighborhoods are discussed and remediation measures are proposed.

Intestinal dialysis for conservative management of Uremia.

PURPOSE OF REVIEW: Renal replacement therapies, such as hemodialysis are invasive and impose significant financial burden as well as burden on quality of life. Conservative and 'gentler' forms of renal replacement therapy for the frail and palliative care patient is an unmet medical need. RECENT FINDINGS: The treatment of uremia using the gut as a substitute for the kidney has been proposed but is not practiced widely because of proven lack of long-term mortality benefit coupled with complications like edema and hyperchloremia. Mounting evidence showed that endotoxins from gastrointestinal tract are a major source of chronic inflammation in chronic kidney disease (CKD). The high load of nitrogenous waste elimination through the bowel could potentially serve as an alternative modality to remove uremic wastes especially in people who opt for conservative management for end-stage renal disease with some recent studies in Iran and China showing promising benefits in uremia. SUMMARY: In this review, we will discuss the history, recent evidence and potential of these therapies and their implications in CKD for conservative and easy management of uremia.

Atypical Causes of Urinary Tract Obstruction.

Acute kidney injury due to urinary tract obstruction invariably suggests lower urinary tract obstruction or bilateral ureteric obstruction since obstruction of a single kidney while the contralateral kidney is normal and not obstructed would not cause a perceptible rise in creatinine. Assuming a total body volume of 42 L, 70 kg male that generates approximately 1400 mg of creatinine daily (20 mg/kg/day) who has complete urinary tract obstruction would experience a 3.33 mg/dL per day increase in serum creatinine. Thus, for an individual who had prior normal renal function and who presents with a creatinine of 30 mg/dL, one could surmise that the obstructive pathology had lasted at least 10 days. However, the rise in serum creatinine is a poor marker of renal injury and subsequent prognosis. Urinary tract obstruction leading to AKI can be due to a variety of causes, and its management is tailored to the underlying etiology. This case series describes the varied clinical course of four patients at our center who experienced AKI from atypical causes of obstructive uropathy. Current and future diagnostic modalities and caveats in the treatment of this disease entity are also discussed.

Trends and outcomes in dual kidney transplantation- A narrative review.

Dual kidney transplantation (DKT) is a viable option to increase the donor pool and improve access equity to kidney transplantation. Dual kidneys are procured from carefully selected marginal donors that are not generally acceptable to most transplant centers. This is a narrative review of literature focusing on donor kidney allocation systems and selection of the ideal recipient for DKT. We also discussed surgical approaches for DKTs as well as patient and allograft outcomes. We found that most studies to date showed that DKTs has similar graft survival and delayed graft function rates when compared to single kidney transplants (SKTs). DKT is technically feasible with outcomes that are comparable to expanded criteria donor kidneys (ECD); and has substantial potential in expanding the donor pool. For allograft survival, most studies with strict allocation criteria showed that graft survival was similar in DKT as compared to SKT - ECD transplants.. Our review may encourage transplant centers to review their policies for donor and recipient selection leading to increase in DKT.

Try to Remember: Interplay between Memory and Substance Use Disorder.

Memories associated with substance use disorders, or substance-associated cues increase the likelihood of craving and relapse during abstinence. There is a growing consensus that manipulation of synaptic plasticity may reduce the strength of substance abuse-related memories. On the biological front, there are new insights that suggest memories associated with substance use disorder may follow unique neurobiological pathways that render them more accessible to pharmacological intervention. In parallel to this, research in neurochemistry has identified several potential candidate molecules that could influence the formation and maintenance of long-term memory. Drugs that target these molecules (blebbistatin, isradipine and zeta inhibitory peptide) have shown promise at the preclinical stage. In this review, we shall provide an overview of the evolving understanding on the biochemical mechanisms involved in memory formation and expound on the premise that substance use disorder is a learning disorder.

Apolipoprotein L1 and kidney transplantation.

PURPOSE OF REVIEW: Consistent associations between variants of the apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy have been reported in individuals of African descent. Donor APOL1 genotype has also been linked to shorter renal allograft survival. This review summarizes recent advances in understanding the biology of APOL1 and their implications to kidney donors and recipients. RECENT FINDINGS: Approximately 12-13% of African Americans have two renal risk APOL1 variants but most do not develop kidney disease. Although the exact mechanisms linking APOL1 genotype to renal injury are not known, evidence from new experimental models suggests APOL1 mutations may accelerate age-related podocyte loss. Recent epidemiological studies indicate potential kidney donors with high-risk APOL1 variants have increased risk of chronic kidney disease (CKD) and donors with high-risk APOL1 variants have lower estimated glomerular filtration rate (eGFR) than those with low-risk variants. The absolute risk of CKD in otherwise healthy individuals carrying high-risk APOL1 mutations is likely low. SUMMARY: Recent studies suggest high-risk APOL1 mutations in kidney donors are linked to shorter graft survival and lower postdonation eGFR. APOL1 genotyping may be used as one of many factors that contribute to assessment of the risk of postdonation CKD and informed decision making.

Ethanol-Induced Changes in PKCε: From Cell to Behavior.

The long-term binge intake of ethanol causes neuroadaptive changes that lead to drinkers requiring higher amounts of ethanol to experience its effects. This neuroadaptation can be partly attributed to the modulation of numerous neurotransmitter receptors by the various protein kinases C (PKCs). PKCs are enzymes that control cellular activities by regulating other proteins via phosphorylation. Among the various isoforms of PKC, PKCε is the most implicated in ethanol-induced biochemical and behavioral changes. Ethanol exposure causes changes to PKCε expression and localization in various brain regions that mediate addiction-favoring plasticity. Ethanol works in conjunction with numerous upstream kinases and second messenger activators to affect cellular PKCε expression. Chauffeur proteins, such as receptors for activated C kinase (RACKs), cause the translocation of PKCε to aberrant sites and mediate ethanol-induced changes. In this article, we aim to review the following: the general structure and function of PKCε, ethanol-induced changes in PKCε expression, the regulation of ethanol-induced PKCε activities in DAG-dependent and DAG-independent environments, the mechanisms underlying PKCε-RACKε translocation in the presence of ethanol, and the existing literature on the role of PKCε in ethanol-induced neurobehavioral changes, with the goal of creating a working model upon which further research can build.

Alcohol Addiction- Metabotropic Glutamate Receptor Subtype 5 and its Ligands: How They All Come Together?

In the past decade, many studies have highlighted the role of metabotropic glutamate receptor subtype 5 (mGlu5) modulators in attenuating alcohol-related biological effects such as alcohol consumption, alcohol-seeking and relapse-like behaviors. Taken together, these findings suggest that pharmacological agents acting at mGlu5 could be promising tools in curbing inebriation. mGlu5s are present abundantly in brain regions known to be involved in emotion regulation, motivation and drug administration. On a cellular level, they are primarily located at the postsynaptic part of the neuron where the receptor is functionally linked to various downstream proteins that are involved in cell signaling and gene transcription that mediate the alcohol-induced neuroplasticity. As well, the discovery of a functional link between mGlu5 and a specific isozyme, Protein Kinase C epsilon (PKCε) in mediating the attenuating effects of selective negative allosteric modulators of mGlu5 such as methyl- 6(phenylethynyl)pyridine (MPEP) and 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) has sparked interesting speculations. In this article, we shall review the following: the effects of acute and chronic alcohol intake on mGlu5 signaling; the effects of mGlu5 ligands on alcohol-related neurobehavioral changes that are currently being studied both at pre-clinical and clinical stages; and the mechanisms underlying the pharmacological effects of these drugs.

Consolidation radiotherapy for advanced-stage aggressive B-cell non-Hodgkin lymphoma: A systematic review and meta-analysis.

Patients with advanced aggressive B-cell non-Hodgkin lymphomas (NHL) are usually treated with rituximab in combination with chemotherapy. However, disease relapse rates are high. Radiotherapy (RT) has been shown to be efficacious in treating early-stage NHL but its role in advanced stage diseases is unclear. We performed a systematic review of randomized controlled trials (RCTs) comparing chemotherapy with RT to chemotherapy alone in patients with newly diagnosed advanced aggressive NHL. We searched online databases and pooled similar outcome estimates. For time-to-event outcomes, we estimated hazard ratios (HR) for overall survival (OS) and event-free survival (EFS) using the fixed-effect model. Two RCTs involving 254 patients met inclusion criteria. The trials were single-centre RCTs with follow-up period of five and ten years. Both trials were conducted in the pre-rituximab era. Patients treated with consolidation RT had better OS (HR for mortality 0.61; 95 % CI 0.38 to 0.97) and EFS (HR for mortality 0.67; 95 % CI 0.46 to 0.98) compared to those who received no RT. There was an apparent benefit of RT on local control (OR 0.09; 95 % CI 0.04 to 0.20); although this was estimated as a dichotomous rather than time-to-event outcome. Limited evidence shows benefits of consolidation RT in advanced aggressive NHL. However, we were not able to estimate the effect size with confidence due to small number of trials and sample size. We cannot recommend routine consolidation RT in advanced aggressive NHL. More RCTs with the inclusion of rituximab and PET-CT monitoring are needed.