Diuretic combinations in critically ill patients with respiratory failure: A systematic review and meta-analysis.

BACKGROUND: In patients with respiratory failure, loop diuretics remain the cornerstone of the treatment to maintain fluid balance, but resistance is common. AIM: To determine the efficacy and safety of common diuretic combinations in critically ill patients with respiratory failure. METHODS: We searched MEDLINE, Embase, Cochrane Library and PROSPERO for studies reporting the effects of a combination of a loop diuretic with another class of diuretic. A meta-analysis using mean differences (MD) with 95% confidence interval (CI) was performed for the 24-h fluid balance (primary outcome) and the 24-h urine output, while descriptive statistics were used for safety events. RESULTS: Nine studies totalling 440 patients from a total of 6510 citations were included. When compared to loop diuretics alone, the addition of a second diuretic is associated with an improved negative fluid balance at 24 h [MD: -1.06 L (95%CI: -1.46; -0.65)], driven by the combination of a thiazide plus furosemide [MD: -1.25 L (95%CI: -1.68; -0.82)], while no difference was observed with the combination of a loop-diuretic plus acetazolamide [MD: -0.40 L (95%CI: -0.96; 0.16)] or spironolactone [MD: -0.65 L (95%CI: -1.66; 0.36)]. Heterogeneity was high and the report of clinical and safety endpoints varied across studies. CONCLUSION: Based on limited evidence, the addition of a second diuretic to a loop diuretic may promote diuresis and negative fluid balance in patients with respiratory failure, but only when using a thiazide. Further larger trials to evaluate the safety and efficacy of such interventions in patients with respiratory failure are required.

Subphenotypes in acute kidney injury: a narrative review.

Acute kidney injury (AKI) is a frequently encountered syndrome especially among the critically ill. Current diagnosis of AKI is based on acute deterioration of kidney function, indicated by an increase in creatinine and/or reduced urine output. However, this syndromic definition encompasses a wide variety of distinct clinical features, varying pathophysiology, etiology and risk factors, and finally very different short- and long-term outcomes. Lumping all AKI together may conceal unique pathophysiologic processes specific to certain AKI populations, and discovering these AKI subphenotypes might help to develop targeted therapies tackling unique pathophysiological processes. In this review, we discuss the concept of AKI subphenotypes, current knowledge regarding both clinical and biomarker-driven subphenotypes, interplay with AKI subphenotypes and other ICU syndromes, and potential future and clinical implications.

Urinary biomarkers predict progression and adverse outcomes of acute kidney injury in critical illness.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized patients and is associated with high morbidity and mortality. The Dublin Acute Biomarker Group Evaluation study is a prospective cohort study of critically ill patients (n = 717). We hypothesized that novel urinary biomarkers would predict progression of AKI and associated outcomes. METHODS: The primary (diagnostic) analysis assessed the ability of biomarkers levels at the time of early Stage 1 or 2 AKI to predict progression to higher AKI stage, renal replacement therapy (RRT) or death within 7 days of intensive care unit admission. In the secondary (prognostic) analysis, we investigated the association between biomarker levels and RRT or death within 30 days. RESULTS: In total, 186 patients had an AKI within 7 days of admission. In the primary (diagnostic) analysis, 8 of the 14 biomarkers were independently associated with progression. The best predictors were cystatin C [adjusted odds ratio (aOR) 5.2; 95% confidence interval (CI) 1.3-23.6], interleukin-18 (IL-18; aOR 5.1; 95% CI 1.8-15.7), albumin (aOR 4.9; 95% CI 1.5-18.3) and neutrophil gelatinase-associated lipocalin (NGAL; aOR 4.6; 95% CI 1.4-17.9). Receiver-operating characteristics and net reclassification index analyses similarly demonstrated improved prediction by these biomarkers. In the secondary (prognostic) analysis of Stages 1-3 AKI cases, IL-18, NGAL, albumin and monocyte chemotactic protein-1 were also independently associated with RRT or death within 30 days. CONCLUSIONS: Among 14 novel urinary biomarkers assessed, cystatin C, IL-18, albumin and NGAL were the best predictors of Stages 1-2 AKI progression. These biomarkers, after further validation, may have utility to inform diagnostic and prognostic assessment and guide management of AKI in critically ill patients.

The furosemide stress test: current use and future potential.

Loop diuretics are among the most widely used drugs worldwide and are commonly employed in the management of complications associated with acute kidney injury (AKI), namely volume overload and electrolyte management. The use of loop diuretics in critically ill patients with AKI is paramount to preventing or treating pulmonary edema. The naturetic response to a loop diuretic is based on its unique renal pharmacology. Our review article summarizes the pharmacology of furosemide in the intact nephron and discusses how this response might be altered by the presence of AKI. We discuss the increasing body of literature on the latest clinical utility of furosemide namely, it's challenge test, known as the furosemide stress test which has highlighted a new and novel role for furosemide over the past number of years. This test assists with the identification of AKI subjects at higher risk of AKI progression and the need for renal replacement therapy. The stress test can also predict cessation of continuous renal replacement therapy in patients with established AKI. On the basis of the evidence presented in this review, we propose future potential studies of furosemide in AKI.

Higher Prevalence of Concurrent Thrombocytopenia in Patients Receiving Continuous Renal Replacement Therapy in the Cardiac Intensive Care Unit.

INTRODUCTION: Thrombocytopenia (TCP) is a common finding in patients receiving continuous renal replacement therapy (CRRT). OBJECTIVE: The purpose of this study was to assess the nature of TCP in patients receiving CRRT. METHODS: This is a single-center case-control observational study of 795 patients involving over 166,950 h of delivered CRRT at Johns Hopkins Hospital. Concurrent TCP in patients receiving CRRT was defined as a decrease in platelet count of ≥50% any time within 72 h of initiation of CRRT with strict exclusion criteria. RESULTS: There was a higher incidence of TCP in the cardiac intensive care unit (CICU) (22.5%) compared to medical ICU (MICU) (13.1%). Using logistic regression, the odds of developing concurrent TCP in patients receiving CRRT was 2.46 (95% CI 1.32-3.57, p < 0.05) times higher in the CICU compared with the MICU. There was no difference in the incidence of severe or profound TCP or timing of acute TCP between the CICU and MICU. CONCLUSION: Safe delivery of dialysis care in the ICU is paramount and creating awareness of potential risks such as concurrent TCP in patients receiving CRRT should be part of this care.

Onconephrology: The intersections between the kidney and cancer.

Onconephrology is a new subspecialty of nephrology that recognizes the important intersections of kidney disease with cancer. This intersection takes many forms and includes drug-induced nephrotoxicity, electrolyte disorders, paraneoplastic glomerulonephritis, and the interactions of chronic kidney disease with cancer. Data clearly demonstrate that, when patients with cancer develop acute or chronic kidney disease, outcomes are inferior, and the promise of curative therapeutic regimens is lessened. This highlights the imperative for collaborative care between oncologists and nephrologists in recognizing and treating kidney disease in patients with cancer. In response to this need, specific training programs in onconephrology as well as dedicated onconephrology clinics have appeared. This comprehensive review covers many of the critical topics in onconephrology, with a focus on acute kidney injury, chronic kidney disease, drug-induced nephrotoxicity, kidney disease in stem cell transplantation, and electrolyte disorders in patients with cancer.

The impact of donor urine chemical toxicology analysis on outcomes of kidney transplantation.

BACKGROUND: Acceptance of organs from acute chemical intoxicated donors remains controversial and outcomes are insufficiently explored. METHODS: This is a single-center retrospective cohort analysis of 484 patients undergoing deceased donor kidney transplantation (DDKT). We assessed the association of positive urine drug screen before transplantation with cohort statistics, delayed graft function (DGF), and graft outcomes at 2 years. Multiple logistical regression (MLR) analysis was used to assess the odds ratio for DGF. RESULTS: Of 484 random DDKTs performed at our institution between January 2010 and October 2015, 280 deceased kidney donors were current drug users. Mean age was 35.4 (15) years, 39% male, 61% were African Americans, and 38.2% had more than one test positive. The main chemical toxins detectable in donor urine were alcohol, heroin, opioid/methadone, cocaine, marijuana, benzodiazepines, methamphetamine, ecstasy, and LSD. Single and multiple urine chemical toxicology of kidney donors did not have a significant effect on KT outcomes of DGF and graft failure during a median follow-up (P for odds ratios > 0.05). CONCLUSIONS: The use of deceased donor kidney grafts from donors with positive urine chemical toxicology may be a worthwhile method of increasing the availability of scarce donor kidney organs as such exposure to illicit drug(s) is not associated with major adverse transplant outcomes.

Eosinophilia and risk of incident end stage kidney disease.

BACKGROUND: Eosinophils in kidney disease are poorly understood and are often incidental findings on kidney biopsy. Eosinophilia in blood and renal biopsy tissue is associated with a host of immune and non-immune kidney diseases. The significance of eosinophilia in renal diseases has not been well addressed. We evaluated the presence of peripheral eosinophilia (> 4% of blood leukocytes) with biopsy tissue eosinophilia and their association with end-stage-kidney-disease (ESKD). METHODS: A nested case-control (2:1) of patients who underwent kidney biopsies at Johns Hopkins Hospital and Medical University of South Carolina from 2004 to 2018 were included in the study. From the 616 eligible patients, 178 patients were identified through the registry of kidney biopsies as 18 years or older without missing biopsy reports or hematology results. Controls (n = 154) had no ESKD at the time of case (n = 24) designation and were assembled using incident density sampling and matched on age and sex. The association of peripheral eosinophilia (> 4% of peripheral blood leukocytes) with the risk of progression to ESKD was evaluated using conditional logistic model after adjusting for clinical demographics. RESULTS: Among 178 patients, 65 (37%) had peripheral eosinophilia and 113 (63%) had no eosinophilia. Compared to patients without eosinophilia, patients with peripheral eosinophilia were notably male and had a higher serum creatinine at the time of their biopsy. Peripheral eosinophilia was associated with higher risk of ESKD (OR 15.9 [1.9, 134.7]) adjusted for patient demographics including hypertension, proteinuria and eGFR at the time of kidney biopsy. Peripheral eosinophilia had a significant linear association with kidney tissue eosinophils, 22 (standard deviation [SD] 20) per high power field (hpf) in 4-10% peripheral eosinophilia, 19 (SD 18) per hpf in ≥10% eosinophilia and 3 (SD 7) per hpf in no eosinophilia (P <  0.001). CONCLUSIONS: Peripheral eosinophilia is an independent predictor of tissue eosinophilia and subsequent progression to ESKD. Peripheral eosinophilia may be an early biomarker for underlying inflammation and disease, but further studies to investigate this clinical association are warranted.

Achieving Osmotic Stability in the Context of Critical Illness and Acute Kidney Injury During Continuous Renal Replacement Therapy.

The concept of osmotic stability during renal replacement therapy has received limited attention thus far. We report an illustrative case of a previously healthy 22 year old male presenting after prolonged ventricular fibrillation with 75 minutes of resuscitative efforts before regaining spontaneous perfusing rhythm. Central nervous system protecting hypothermia protocol and veno-arterious (VA) extracorporeal membrane oxygenator (ECMO) therapy were initiated at hospital admission due to refractory hypoxemia. Cardiovascular imaging procedures described global hypokinesis. Due to the combination of anuria, mixed acidosis and hemodynamic instability, we started continuous renal replacement therapy (CRRT) in continuous veno-venous hemodiafiltration functionality with added hypertonic saline solution (HTS) protocol, calculated to stabilize his serum sodium between 148 and 150 mEq/L. Serum osmolality also ranged between 321 and 317 mOsm/kg thereafter. Course was complicated by an acute right leg ischemia distal to VA ECMO cannula placement, requiring salvage therapy with cryoamputation. Vasoactive medication requirement and hemodynamics improved after the addition of intravenous (IV) hydrocortisone. Brain magnetic resonance imaging (MRI) 22 days post-arrest showed signals of limited hypoxic injury. He left the hospital in stable condition with limited neurologic sequelae. Therefore, the use of HTS during CRRT is a viable way to address potential or manifest cerebral edema and reduce the degree of cerebral injury.

GFR Measurement and Chemotherapy Dosing in Patients with Kidney Disease and Cancer.

Chemotherapeutic agents require precise dosing to ensure optimal efficacy and minimize complications. For those agents that are removed from the body by the kidney, accurate knowledge of GFR is critical. In addition, GFR needs to be determined rapidly, easily, and, if possible, with little additional cost. The ability to easily measure GFR also allows for rapid detection of nephrotoxicity. Current methodologies include direct clearance measurement of an indicator substance or estimation of creatinine clearance or GFR through regression equations that use a serum marker, such as creatinine or cystatin C. These methodologies all have shortfalls and limitations, some of which are specific to the patient with cancer. Newer methodologies that directly measure GFR are in clinical trials and offer the ability to rapidly and noninvasively provide accurate estimates of drug clearance as well as detection of nephrotoxicity. These methods offer the opportunity to refine drug dosing and improve outcomes.

Biomarker Predictors of Adverse Acute Kidney Injury Outcomes in Critically Ill Patients: The Dublin Acute Biomarker Group Evaluation Study.

BACKGROUND: The Dublin Acute Biomarker Group Evaluation (DAMAGE) Study is a prospective 2-center observational study investigating the utility of urinary biomarker combinations for the diagnostic and prognostic assessment of acute kidney injury (AKI) in a heterogeneous adult intensive care unit (ICU) population. The objective of this study is to evaluate whether serial urinary biomarker measurements, in combination with a simple clinical model, could improve biomarker performance in the diagnostic prediction of severe AKI and clinical outcomes such as death and need for renal replacement therapy (RRT). METHODS: Urine was collected daily from patients admitted to the ICU, for a total of 7 post-admission days. Urine biomarker concentrations (neutrophil gelatinase-associated lipocalin [NGAL], α-glutathione S-transferase [GST], π-GST, kidney injury molecule-1 [KIM-1], liver-type fatty acid-binding protein [L-FABP], Cystatin C, creatinine, and albumin) were measured. Urine biomarkers were combined with a clinical prediction of AKI model, to determine ability to predict AKI (any stage, within 2 days or 7 days of ICU admission), or a -30-day composite clinical outcome (RRT - or death). RESULTS: A total of 257 (38%) patients developed AKI within 7 days of ICU admission. Of those who developed AKI, 106 (41%) patients met stage 3 AKI within 7 days of ICU admission and 208 patients of the entire study cohort (31%) met the composite clinical endpoint of in-hospital mortality or RRT within 30 days of ICU admission. The addition of urinary NGAL/albumin to the clinical model modestly improved the prediction of AKI, in particular severe stage 3 AKI (area under the curve [AUC] of 0.9 from 0.87, p = 0.369) and the prediction of 30-day RRT or death (AUC 0.83 from 0.79, p = 0.139). CONCLUSION: A clinical model incorporating severity of illness, patient demographics, and chronic illness with currently available clinical biomarkers of renal function was strongly predictive of development of AKI and associated clinical outcomes in a heterogeneous adult ICU population. The addition of urinary NGAL/albumin to this simple clinical model improved the prediction of severe AKI, need for RRT and death, but not at a statistically or clinically significant level, when compared to the clinical model alone.

Association of HIV Suppression With Kidney Disease Progression Among HIV-Positive African Americans With Biopsy-Proven Classic FSGS.

BACKGROUND: In the era of combined antiretroviral therapy, classic focal segmental glomerulosclerosis (FSGS) is the most common histopathological finding in African American HIV-positive patients with kidney disease. We sought to determine whether HIV suppression is associated with lower risk of progression to end-stage renal disease (ESRD) among HIV-positive African Americans with biopsy-confirmed classic FSGS. METHODS: HIV-positive African Americans who underwent kidney biopsies at a single tertiary hospital between January 1996 and June 2011 were confirmed as having classic FSGS by the presence of segmental glomerulosclerosis without features of HIV-associated nephropathy. Multivariable Cox proportional hazards models were used to examine the independent association of viral suppression (HIV-RNA < 400 copies per milliliter at biopsy) with time to progression to ESRD. RESULTS: Of the 55 HIV-positive African Americans with classic FSGS, 26 had suppressed viral loads at the time of biopsy. Compared to viremic patients, those who were virally suppressed had a significantly higher mean CD4 cell count (452 vs. 260 cell/mm, respectively; P = 0.02) and median estimated glomerular filtration rate (53.5 vs 35.5 mL/min/1.73 m, respectively; P = 0.002). Adjusting for sex and baseline CD4 cell count, estimated glomerular filtration rate, and proteinuria, those with HIV-RNA levels <400 copies per milliliter at baseline had a 75% lower risk of progressing to ESRD (hazard ratio = 0.25; 95% CI: 0.07 to 0.88) during a median follow-up time of 2.70 years (interquartile range: 0.80-5.15 years). CONCLUSIONS: HIV suppression is associated with significantly lower risk of progression to ESRD among HIV-infected African Americans with classic FSGS, supporting the potential role of combined antiretroviral therapy for this histopathology in addition to HIV-associated nephropathy among HIV-positive individuals.

HIV-associated nephropathy: links, risks and management.

Despite the decreased incidence of human immunodeficiency virus (HIV)-associated nephropathy due to the widespread use of combined active antiretroviral therapy, it remains one of the leading causes of end-stage renal disease (ESRD) in HIV-1 seropositive patients. Patients usually present with low CD4 count, high viral load and heavy proteinuria, with the pathologic findings of collapsing focal segmental glomerulosclerosis. Increased susceptibility exists in individuals with African descent, largely due to polymorphism in APOL1 gene. Other clinical risk factors include high viral load and low CD4 count. Advanced kidney disease and nephrotic range proteinuria have been associated with progression to ESRD. Improvement in kidney function has been observed after initiation of combined active antiretroviral therapy. Other treatment options, when clinically indicated, are inhibition of the renin-angiotensin system and corticosteroids. Further routine management approaches for patients with chronic kidney disease should be implemented. In patients with progression to ESRD, kidney transplant should be pursued, provided that viral load control is adequate. Screening for the presence of kidney disease upon detection of HIV-1 seropositivity in high-risk populations is recommended.

Pharmacotherapy and treatment options for HIV-associated nephropathy.

INTRODUCTION: Human immunodeficiency virus (HIV) remains a worldwide disease with significant mortality and morbidity. There are a multitude of HIV-related kidney diseases including HIV-associated nephropathy (HIVAN) most prominently. The risk of developing HIVAN increases with decreasing CD4 count, higher viral load, and based on genetic factors. The mortality rate for those with HIVAN-end stage renal disease (ESRD) remains 2.5-3 times higher than ESRD patients without HIVAN. AREAS COVERED: The epidemiology of HIVAN, particularly risk assessment, will be explored in this review. Further, the pathogenesis of HIVAN, from viral-specific renal expression to the role of genetics as well as characteristic renal pathology will be described. Diagnosis and management of HIVAN will be addressed, with an emphasis on various treatment strategies including medication, dialysis, and kidney transplantation. EXPERT OPINION: HIVAN is associated with a high risk for progression to ESRD and increased mortality. The backbone of HIVAN therapy remains combined anti-retroviral therapy (cART), while adjunctive therapies including RAAS blockade and prednisone, should be considered. In those who progress to ESRD, dialysis remains the mainstay of management, though increasing evidence has demonstrated that kidney transplantation can be effective in those with controlled HIV disease.

The prognostic value of the furosemide stress test in predicting delayed graft function following deceased donor kidney transplantation.

OBJECTIVES AND METHODS: The Furosemide Stress Test (FST) is a novel dynamic assessment of tubular function that has been shown in preliminary studies to predict patients who will progress to advanced stage acute kidney injury, including those who receive renal replacement therapy (RRT). The aim of this study is to investigate if the urinary response to a single intraoperative dose of intravenous furosemide predicts delayed graft function (DGF) in patients undergoing deceased donor kidney transplant. RESULTS: On an adjusted multiple logistic regression, a single 100 mg dose of intraoperative furosemide after the anastomosis of the renal vessels (FST) predicted the need for RRT at 2 and 6 h post kidney transplantation (KT). Recipient urinary output was measured at 2 and 6 h post furosemide administration. In receiver-operating characteristic (ROC) analysis, the FST predicted DGF with an area-under-the curve of 0.85 at an optimal urinary output cut-off of <600 mls at 6 h with a sensitivity of and a specificity of 83% and 74%, respectively. CONCLUSIONS: The FST is a predictor of DGF post kidney transplant and has the potential to identify patients requiring RRT early after KT.

Tenofovir alafenamide nephrotoxicity in an HIV-positive patient: A case report.

RATIONALE: Tenofovir alafenamide (TAF) is novel prodrug of Tenofovir, a nucleotide reverse transcriptase inhibitor. TAF is less nephrotoxic than its predecessor prodrug, tenofovir disoproxil fumarate (TDF). Tenofovir causes mitochondrial dysfunction and tubular injury when there is elevated accumulation in proximal tubule cells. TAF's unique pharmacokinetic profile enables provision of lower required doses for antiviral efficacy. Lower concentrations reach renal tubules minimizing intracellular accumulation and mitochondrial damage. TAF has not been associated with the histologic markers of tenofovir-associated nephrotoxicity that are seen with TDF, such as dysmorphic mitochondria in proximal tubule cells. Here, we report a patient with dysmorphic mitochondria on kidney biopsy after initiating therapy with TAF. LESSONS: This case suggests that at risk individuals may experience tubular mitochondrial injury from lower concentrations of tenofovir with TAF.

Hyperuricemia after orthotopic liver transplantation: divergent associations with progression of renal disease, incident end-stage renal disease, and mortality.

BACKGROUND: Although hyperuricemia is common after orthotopic liver transplantation (OLT), its relationship to mortality, progressive kidney disease, or the development of end stage renal disease (ESRD) is not well-described. METHODS: Data from 304 patients undergoing OLT between 1996 and 2010 were used to assess the association of mean serum uric acid (UA) level in the 3-months post-OLT with mortality, doubling of creatinine, and ESRD incidence. Post-OLT survival to event outcomes according to UA level and eGFR was assessed using the Kaplan Meier method and multivariate Cox proportional hazards models. RESULTS: Mean UA level among the 204 patients with an eGFR level ≥60 ml/min/1.73 m2 was 6.4 mg/dl compared to 7.9 mg/dl among the 100 patients with eGFR <60 (p < 0.0001). During a median of 4.6 years of follow-up, mortality rate, doubling of creatinine, and ESRD incidence were 48.9, 278.2, and 20.7 per 1000 person-years, respectively. In the first 5 years of follow-up, elevated UA was associated with mortality (Hazard Ratio, HR = 1.7; p = 0.045). However, among those with eGFR ≥ 60, UA level did not predict mortality (HR = 1.0; p = 0.95), and among those with eGFR < 60, elevated UA was a strong predictor of mortality (HR = 3.7[1.1, 12.0]; p = 0.03). UA was not associated with ESRD, but was associated with doubling of creatinine among diabetics (HR = 2.2[1.1, 4.3]; p = 0.025). CONCLUSION: In this post-OLT cohort, hyperuricemia independently predicted mortality, particularly among patients with eGFR < 60, and predicted doubling of creatinine among diabetics.