Effect of Loop Diuretics on the Fractional Excretion of Urea in Decompensated Heart Failure.

BACKGROUND: Fractional excretion of urea (FEUrea) is often used to understand the etiology of acute kidney injury (AKI) in patients receiving diuretics. Although FEUrea demonstrates diagnostic superiority over fractional excretion of sodium (FENa), clinicians often assume FEUrea is not affected by diuretics. OBJECTIVE: To assess the intravenous loop diuretic effect on FEUrea. METHODS: We analyzed a prospective cohort (n=297) hospitalized with hypervolemic heart failure at Yale New Haven Hospital System. FENa and FEUrea were calculated at baseline and serially after diuretics. The change in FEUrea at peak diuresis was compared with the pre-diuretic baseline. RESULTS: Mean baseline FEUrea was 35.2% ± 10.5% and increased by a mean 5.6% ± 10.5% following 80 mg (40-160 mg) of furosemide equivalents (P < .001). The magnitude of change in FEUrea was clinically important as the distribution of change in FEUrea was similar to the overall distribution of baseline FEUrea. Change in FEUrea was related to the diuretic response (r = 0.61, P < .001), with a larger FEUrea increase in diuretic responders (8.8%, interquartile range [IQR]: 1.8-16.9) than non-responders (1.2%, IQR: -3.2 to 5.5; P < .001). Diuretic administration reclassified 27% of patients between low and high FEUrea groups across a 35% threshold. Neither change in FEUrea nor percentage reclassified out of a low FEUrea category differed between patients with and without AKI (P > .63 for both). CONCLUSIONS: FEUrea is meaningfully affected by loop diuretics. The degree of change in FEUrea is highly variable between patients and commonly of a magnitude that could reclassify across categories of FEUrea.

The Changing Face of Human Immunodeficiency Virus-Mediated Kidney Disease.

In nearly 40 years since human immunodeficiency virus (HIV) first emerged, much has changed. Our understanding of the pathogenesis of HIV infection and its effect on the cells within each kidney compartment has progressed, and the natural history of the disease has been transformed. What was once an acutely fatal illness is now a chronic disease managed with oral medications. This change is largely due to the advent of antiretroviral drugs, which have dramatically altered the prognosis and progression of HIV infection. However, the success of antiretroviral therapy has brought with it new challenges for the nephrologist caring for patients with HIV/acquired immune deficiency syndrome, including antiretroviral therapy-induced nephrotoxicity, development of non-HIV chronic kidney disease, and rising incidence of immune-mediated kidney injury. In this review, we discuss the pathogenesis of HIV infection and how it causes pathologic changes in the kidney, review the nephrotoxic effects of select antiretroviral medications, and touch upon other causes of kidney injury in HIV cases, including mechanisms of acute kidney injury, HIV-related immune complex glomerular disease, and thrombotic microangiopathy.

The nephrotoxicity of new immunotherapies.

Introduction: Advanced cancers that did not respond to chemotherapy were once a death sentence, but now there are newer therapies utilizing the patient's own immune system to fight cancer that are proving effective in chemotherapy-refractory malignancies. However, this success against cancer cells may be accompanied by immune-related adverse events that can affect the kidneys. Areas covered: Using Medline and Scopus, we compiled all publications through February 2019 that pertained to immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor T-cells (CAR T-cells).  The focus of this review is the discussion of these new cancer therapies, with attention to the reported kidney-related adverse effects.. Expert opinion: Autoimmunity is repressed by molecular pathways that inhibit T-cell activation against selected antigens. These self-protective mechanisms have been appropriated by tumor cells as a means of evading immune detection and destruction. New immunotherapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy incite an aggressive immune response directed against tumor cells. This unrestrained activation of the immune system may result in kidney injury via multiple mechanisms.

Serum and Urine Albumin and Response to Loop Diuretics in Heart Failure.

BACKGROUND AND OBJECTIVES: Diuretic resistance can limit successful decongestion of patients with heart failure. Because loop diuretics tightly bind albumin, low serum albumin and high urine albumin can theoretically limit diuretic delivery to the site of action. However, it is unknown if this represents a clinically relevant mechanism of diuretic resistance in human heart failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 208 outpatients with heart failure at the Yale Transitional Care Center undergoing diuretic treatment were studied. Blood and urine chemistries were collected at baseline and 1.5 hours postdiuretic administration. Urine diuretic levels were normalized to urine creatinine and adjusted for diuretic dose administered, and diuretic efficiency was calculated as sodium output per doubling of the loop diuretic dose. Findings were validated in an inpatient heart failure cohort (n=60). RESULTS: Serum albumin levels in the outpatient cohort ranged from 2.4 to 4.9 g/dl, with a median of 3.7 g/dl (interquartile range, 3.5-4.1). Serum albumin had no association with urinary diuretic delivery (r=-0.05; P=0.52), but higher levels weakly correlated with better diuretic efficiency (r=0.17; P=0.02). However, serum albumin inversely correlated with systemic inflammation as assessed by plasma IL-6 (r=-0.35; P<0.001), and controlling for IL-6 eliminated the diuretic efficiency-serum albumin association (r=0.12; P=0.12). In the inpatient cohort, there was no association between serum albumin and urinary diuretic excretion (r=0.15; P=0.32) or diuretic efficiency (r=-0.16; P=0.25). In the outpatient cohort, 39% of patients had microalbuminuria, and 18% had macroalbuminuria. There was no correlation between albuminuria and diuretic efficiency after adjusting for kidney function (r=-0.02; P=0.89). Results were similar in the inpatient cohort. CONCLUSIONS: Serum albumin levels were not associated with urinary diuretic excretion, and urinary albumin levels were not associated with diuretic efficiency.

Cardiorenal complications of immune checkpoint inhibitors.

The development of immune checkpoint inhibitors (ICIs) has driven a revolutionary change in cancer treatment. Although traditional chemotherapeutic agents remain the first-line option for most cancers, targeted immune therapies are emerging as standard treatments for advanced-stage cancers. These agents target cell surface checkpoint proteins to stimulate the recognition and destruction of cancer cells by the immune system. Clinical studies have demonstrated these immunotherapeutics to elicit favourable antitumour responses in a variety of chemotherapy-refractory malignancies. However, use of these agents can also induce immune-related adverse events (irAEs) in off-target organs, including the heart and kidney. The most common manifestations of heart and kidney damage are myocarditis and acute interstitial nephritis, respectively, but other manifestations have been reported and, although rare, these off-target effects can be life threatening. Available data suggest that ICIs induce their off-target effects through several mechanisms, including direct binding to cell surface proteins expressed in healthy tissue, activation of T cells that cross-react with off-target tissues, generation of autoantibodies or by increasing levels of pro-inflammatory cytokines. Greater understanding of the adverse effects of cancer immunotherapies and the underlying mechanisms will facilitate the development of biomarkers to identify at-risk patients and approaches to prevent these irAEs.

Reduced Cardiac Index Is Not the Dominant Driver of Renal Dysfunction in Heart Failure.

BACKGROUND: It is widely believed that a reduced cardiac index (CI) is a significant contributor to renal dysfunction in patients with heart failure (HF). However, recent data have challenged this paradigm. OBJECTIVES: This study sought to determine the relationship between CI and renal function in a multicenter population of HF patients undergoing pulmonary artery catheterization (PAC). METHODS: Patients undergoing PAC in either the randomized or registry portions of the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial were included (n = 575). We evaluated associations between CI and renal function across multiple subgroups and assessed for nonlinear, threshold, and longitudinal relationships. RESULTS: There was a weak but significant inverse correlation between CI and estimated glomerular filtration rate (eGFR), such that higher CI was paradoxically associated with worse eGFR (r = -0.12; p = 0.02). CI was not associated with blood urea nitrogen (BUN) or the BUN to creatinine ratio. Similarly, no associations were observed between CI and better renal function across multiple subgroups defined by indications for PAC or hemodynamic, laboratory, or demographic parameters. A nonlinear or threshold effect could not be identified. In patients with serial assessments of renal function and CI, we were unable to find within-subject associations between change in CI and eGFR using linear mixed modeling. Neither CI nor change in CI was lower in patients developing worsening renal function (p ≥ 0.28). CONCLUSIONS: These results reinforce evidence that reduced CI is not the primary driver for renal dysfunction in patients hospitalized for HF, irrespective of the degree of CI impairment or patient subgroup analyzed.

Early postoperative results in stapedectomy.

OBJECTIVE: To measure early audiometric changes after primary stapedotomy. STUDY DESIGN: Case series with chart review. SETTING: Academic inner-city hospitals. SUBJECTS AND METHODS: Consecutive patients operated on by the first author were included (only 1 ear in cases of bilateral surgery), and their audiometric results were reviewed. Data were analyzed from 45 ears. Air and bone audiometric measures were analyzed from 5 days post operation and 6 months post operation. Threshold shifts were quantified at 5 days and 6 months post operation. RESULTS: Overall results for the group were good, with 91% of patients achieving an air-bone gap less than or equal to 10 dB by 6 months post operation. Threshold shifts in at least 1 frequency were common at 5 days (62% of patients), but less so at 6 months (36%). Patients with shifts did not have worse overall outcomes at 6 months than those with no shifts. No difference in results was observed for the 2 prostheses used in this series. CONCLUSION: Early audiometric results after stapedectomy commonly reveal worsened bone conduction (postoperative threshold shifts), which may reflect cochlear trauma, but do not lead to poorer outcomes as measured by conventional methods.