Significance Statement To combat both untoward effects of nephrotoxicity and ototoxicity in cisplatin-treated patients, two potential therapeutic oral anticancer drugs AZD5438 and dabrafenib, a phase-2 clinical trial protein kinase CDK2 inhibitor and an US Food and Drug Administration–approved drug BRAF inhibitor, respectively, were tested in an established mouse AKI model. Both drugs have previously been shown to protect significantly against cisplatin-induced hearing loss in mice. Each drug ameliorated cisplatin-induced increases in the serum biomarkers BUN, creatinine, and neutrophil gelatinase-associated lipocalin. Drugs also improved renal histopathology and inflammation, mitigated cell death by pyroptosis and necroptosis, and significantly enhanced overall survival of cisplatin-treated mice. Background Cisplatin is an effective chemotherapy agent for a wide variety of solid tumors, but its use is dose-limited by serious side effects, including AKI and hearing loss. There are no US Food and Drug Administration–approved drugs to treat both side effects. Recently, two anticancer oral drugs, AZD5438 and dabrafenib, were identified as protective against cisplatin-induced hearing loss in mice. We hypothesize that similar cell stress and death pathways are activated in kidney and inner ear cells when exposed to cisplatin and tested whether these drugs alleviate cisplatin-induced AKI. Methods The HK-2 cell line and adult FVB mice were used to measure the protection from cisplatin-induced cell death and AKI by these drugs. Serum markers of kidney injury, BUN, creatinine, and neutrophil gelatinase-associated lipocalin as well as histology of kidneys were analyzed. The levels of markers of kidney cell death, including necroptosis and pyroptosis, pERK, and proliferating cell nuclear antigen, were also examined by Western blotting and immunofluorescence. In addition, CDK2 knockout (KO) mice were used to confirm AZD5438 protective effect is through CDK2 inhibition. Results The drugs reduced cisplatin-induced cell death in the HK-2 cell line and attenuated cisplatin-induced AKI in mice. The drugs reduced serum kidney injury markers, inhibited cell death, and reduced the levels of pERK and proliferating cell nuclear antigen, all of which correlated with prolonged animal survival. CDK2 KO mice were resistant to cisplatin-induced AKI, and AZD5438 conferred no additional protection in the KO mice. Conclusions Cisplatin-induced damage to the inner ear and kidneys shares similar cellular beneficial responses to AZD5438 and dabrafenib, highlighting the potential therapeutic use of these agents to treat both cisplatin-mediated kidney damage and hearing loss.

Introduction: The ACC/AHA hypertension guidelines recommended chlorthalidone (CTD) over hydrochlorothiazide (HCTZ) due to its longer half-life and proven reduction in major adverse cardiovascular events. The mechanism of the potential benefit of CTD compared to HCTZ has not been established. Unlike other thiazide diuretics, studies suggest that CTD may affect platelet aggregation, gene transcription, angiogenesis, and vascular permeability. We aimed to compare the antiplatelet effects of CTD versus HCTZ. Methods: We conducted a prospective, double-blind, randomized, three-way crossover study comparing the antiplatelet effects of CTD, HCTZ, and aspirin (ASA) in healthy volunteers ≥ 19 years of age. ASA was included in the study as a known control for inhibition of platelet aggregation. Whole blood aggregometry was used to assess the impact of treatments on platelet activation and aggregation. Results: Of the 40 subjects, 34 (85%) completed the 3-way crossover comparison. Six subjects were excluded due to non-compliance and adverse effects. Compared to ASA, both CTD and HCTZ had no antiplatelet effects (Table 1). There was no statistically significant difference between CTD and HCTZ in terms of platelet function. Conclusions: Although recent studies showed increased cardiovascular benefit with CTD compared to HCTZ, CTD and HCTZ do not have antiplatelet effects. Larger studies are needed to confirm our findings.

Chlorthalidone (CTD) may be superior to hydrochlorothiazide (HCTZ) in the reduction of adverse cardiovascular events in hypertensive patients. The mechanism of the potential benefit of CTD could be related to antiplatelet effects. The objective of this study was to determine if CTD or HCTZ have antiplatelet effects. This study was a prospective, double-blind, randomized, three-way crossover comparison evaluating the antiplatelet effects of CTD, HCTZ, and aspirin (ASA) in healthy volunteers. The effects of these treatments on platelet activation and aggregation were assessed using a well-established method with five standard platelet agonists. Thirty-four patients completed the three-way crossover comparing pre- and post-treatment changes in platelet activation and aggregation studies. There were statistically significant antiplatelet effects with ASA but not with CTD or HCTZ. Hypokalemia occurred in 0 (0%), 10 (30%), and 6 (18%) of the ASA, CTD, and HCTZ patients, respectively. The results of our study suggest that the benefits of CTD and HCTZ in reducing adverse cardiovascular events in patients with hypertension is not a result of an antiplatelet effect. In our study, hypokalemia with CTD was more prevalent than that reported in a large outcome trial in patients with hypertension. The clinical relevance of this finding is uncertain.

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: Fluid balance and fluid management are complex issues affected by multiple patient variables. Positive net fluid balance has been correlated with increased mortality in sepsis. This study evaluated net fluid balance in patients with a diagnosis of sepsis at an academic medical center. METHODS: This study was approved by the Creighton University Institutional Review Board. We retrospectively reviewed the charts of 574 patients with sepsis who required >48 hours of ICU care in 2019. The primary outcome was mortality: secondary endpoints included SOFA score, ICU length of stay, site of infection, comorbidities, vasopressor use, and fluid balance at 24 hours, 72 hours, 7 days in the ICU, and cumulative fluid balance at ICU discharge. RESULTS: 199 patients met our inclusion criteria and were further analyzed; 51 (25.6%) died. Increased age (OR=1.28 for each 10-year increase, 95% CI: 1.01 to 1.62; P=0.042), increased SOFA scores (OR=1.26, 95% CI: 1.12 to 1.42; p<0.001), and pneumonia (OR=3.74, 95% CI: 1.63 to 8.60, P=0.002) were independent predictors of increased mortality. A higher net fluid balance at ICU discharge was associated with a statistically significant increase in mortality (OR=1.03 for each 500 mL increase, 95% CI: >1.00 to 1.05; P=0.022). Pneumonia was the source of sepsis in most patients (n=52, 26%). The relationship between fluid balance and mortality did not differ between pneumonia and non-pneumonia patients. CONCLUSIONS: The present retrospective analysis suggests that in patients diagnosed with sepsis a lower net fluid balance is associated with decreased mortality. Younger age and lower severity of illness were correlated with decreased mortality among patients with sepsis. CLINICAL IMPLICATIONS: Our study affirms that a thoughtful approach to fluid resuscitation should be utilized in septic critically ill patients, which may include judicious fluid administration and diuretic strategies to further improve patient outcomes. In addition, the relationship between pneumonia and fluid balance may warrant a more in-depth investigation. DISCLOSURES: No relevant relationships by Sarah Aurit, source=Web Response No relevant relationships by Khalid Bashir, source=Web Response No relevant relationships by Daniel Hilleman, source=Web Response No relevant relationships by Mark Malesker, source=Web Response No relevant relationships by Lee Morrow, source=Web Response No relevant relationships by Robert Plambeck, source=Web Response No relevant relationships by Abaigeal Tarpey, source=Web Response

Acute kidney injury (AKI), formerly known as acute renal failure (ARF), denotes a sudden and often reversible reduction in kidney function, as measured by glomerular filtration rate (GFR). There is no clear definition of AKI. Several different criteria have been used in research studies, such as RIFLE, AKIN (Acute Kidney Injury Network), or KDIGO (Kidney Disease: Improving Global Outcomes) criteria. However, KDIGO is the most recent and most commonly used. According to KDIGO, AKI is the presence of any of the following: Increase in serum creatinine by 0.3 mg/dL or more (26.5 micromoles/L or more) within 48 hours Increase in serum creatinine to 1.5 times or more baseline, within the prior 7 days Urine volume less than 0.5 mL/kg/h for at least 6 hours

Allergic interstitial nephritis (AIN) is the most common form of acute interstitial nephritis. It is most often caused by exposure to a drug. AIN is often associated with an acute decline in renal function and may be associated with permanent renal insufficiency. The hallmark pathologic finding of AIN is a marked inflammatory infiltrate of the renal interstitium. The classic clinical picture of AIN (i.e., fever, rash, eosinophilia) was well-described with the use of methicillin, which caused AIN in approximately 17% of cases. Identification and discontinuation of the offending medication have been the mainstays of treatment, with conflicting evidence regarding the benefit of steroid treatment.

[Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis] (AAV) is an autoimmune disease characterized by systemic vascular inflammation. We present a case of a 76-year-old man who presented with shortness of breath, fatigue, and weakness. He was eventually diagnosed with hydralazine-induced ANCA-associated renal limited glomerulonephritis. The presentation of this case was unique for a few reasons; the patient showed an initial improvement in kidney function, was non-oliguric, and had no systemic signs of vasculitis. This led to the patient being discharged prematurely with the diagnosis of acute tubular necrosis. We discuss educational features of this case and warn future clinicians about the possibility of waxing and waning renal function in these patients, as well as the importance of having a higher index of suspicion for glomerulonephritis in patients who take hydralazine.

A 63-year-old woman with a past medical history of invasive ductal carcinoma of the breast, status post lumpectomy and chemoradiation, 15 cm left inguinal-femoral enlarged lymph node consistent with high-grade serous carcinoma of the ovary and 4.7 cm right adnexal mass underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and lymph node dissection with cystoscopy and bilateral ureteral catheter placement. There was no intraoperative complication. After surgery, patient's urine output decreased, and she developed acute kidney injury (AKI). Initially, it was thought that her reduced output might be due to surgery/anesthesia. She also developed arm and leg weakness raising suspicion for stroke. The neurological workup was unremarkable for any acute abnormality. Her creatinine kinase (CK) level was >20,000 u/l consistent with rhabdomyolysis. She was hydrated aggressively and required hemodialysis due to hyperkalemia. During the hospital course, her kidney function improved, and rhabdomyolysis resolved, and she did not require dialysis after discharge.

It's been estimated that half of all symptomatic kidney stones could be prevented with proper diagnosis and prophylactic treatment of underlying chemical nephrolithiasis risk factors. Preventive medical evaluation and treatment of stone disease are underutilized, inconsistent, and generally inadequate. Additionally, quality of life scores are dramatically lowered in nephrolithiasis patients, even in those with asymptomatic stones.Direct and indirect costs are estimated at over $10 billion yearly, and this is predicted to exceed $15 billion by 2030. This is due to the increasing incidence of stone disease in part from the rise in other associated disorders that contribute to nephrolithiasis, such as diabetes and obesity, together with general population growth and global warming. Low urinary citrate excretion (hypocitraturia) is one of the most common, treatable causes of kidney stones. This was first reported by Boothby and Adams in 1934 and later confirmed by Kissin and Locks in 1941. This information was largely ignored or attributed to bacterial consumption of citrate until 1962 when Hodgkinson first suggested hypocitraturia as a unique urinary chemical disorder present in nephrolithiasis patients.Hypocitraturia is officially defined as less than 320 mg of urinary citrate excretion a day, but this definition has been questioned by many experts as it is based on statistical analyses of large numbers of 24-hour urine tests from the general population and not on saturation ratios, supersaturation, pH, crystallization points, stone chemical composition or the minimal concentrations necessary to prevent urinary stones. Currently, optimal levels of urinary chemistries like citrate are not even reported in standard laboratory reports. It is estimated that hypocitraturia is found in about 30% (10% to 60%) of all stone formers, but this will vary according to the particular definition of hypocitraturia used and the stone type. It is the sole, identifiable stone promoting chemical abnormality in about 10% of all calcium stone-forming patients and is a contributing factor associated with other metabolic problems in about half.

Background Hypokalemic periodic paralysis is a rare neuromuscular disorder characterized by transient episodes of flaccid paralysis due to a defect in muscle ion channels. Most cases are hereditary, but it can be acquired. We present a case of acquired hypokalemic periodic paralysis associated with hyperthyroidism and renal tubular acidosis. Clinical Case. A 38-year-old female with a history of Graves' disease presented to the emergency department with generalized weakness and associated nausea, vomiting, and weight loss. Examination was significant for diffuse weakness in all extremities. Labs showed hypokalemia, hyperthyroidism, and nonanion gap metabolic acidosis with a positive urine anion gap. She was treated for hypokalemic periodic paralysis and renal tubular acidosis. Potassium replacement, propranolol, methimazole, and sodium bicarbonate were initiated. Her potassium gradually corrected with resolution of her symptoms. Further investigation revealed a history of dry eyes, dry mouth, and recurrent dental carries. She had positive ANA, SS-A, and SS-B antibodies. She was diagnosed with Sjögren's syndrome, which may have been associated with her Graves' disease and thus contributed to both her RTA and hyperthyroidism. Conclusion Early recognition and treatment of thyrotoxic periodic paralysis are important to prevent cardiac complications. Management includes potassium replacement with careful monitoring to prevent rebound hyperkalemia. The definitive treatment is to achieve euthyroid status.

Ahmed, Moeed; Ramadan, Bashar; Magliulo, Eric; Salas, Dongpo M.; Taylor, Jocelyn A.; Bashir, Khalid Author Information

ESRD patients receiving hemodialysis (HD) were excluded from landmark trials evaluating direct-acting oral anticoagulants (DOACs) in atrial fibrillation (AF). The objective was to evaluate prescribing and bleeding with DOACs compared to warfarin in AF patients with chronic HD. A retrospective, observational study of patients receiving warfarin or DOAC from April 2010-April 2016 from area health system hospitals and Dialysis Clinics, Inc. records. Data was analyzed using descriptive statistics, ANOVA, and chi-square. Ninety-one patients were included with warfarin as the initial OAC in most patients (n = 76) at average dose of 29 mg/week. Fifteen patients were initially prescribed apixaban (n = 12) or dabigatran (n = 3). Most switches in OAC therapy were to apixaban. When the initial OAC was a DOAC, it was not dosed appropriately in five with one bleed, two dosed appropriately had bleeds. When initial warfarin was switched to a DOAC, it was not dosed appropriately in seven with five bleeds. More bleeds occurred with warfarin alone (n = 18) vs. those on warfarin switched to DOAC (n = 5) vs. DOAC alone (n = 3), p = 0.022. All but four patients that bled had HAS-BLED scores three or higher. Warfarin was most often prescribed and associated with a higher incidence of bleeding compared to DOACs in this population of patients at high risk for bleeding. Larger studies should be conducted to analyze the impact of DOAC dose appropriateness on safety and clinical outcomes.

Tumor lysis syndrome is a clinical condition that can occur spontaneously or after initiation of chemotherapy associated with the following metabolic disorders: hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia leading to end-organ damage. It is most common in patients with solid tumors.Tumor lysis syndrome is a metabolic and oncologic emergency frequently encountered in clinical practice. This condition is prevalent in both adult and pediatric oncology patients undergoing chemotherapy. Most of the symptoms seen in patients with tumor lysis syndrome are related to the release of intracellular chemical substances that cause impairment in the functions of target organs. This can lead to acute kidney injury (AKI), fatal arrhythmias, and even death.Cancer is a leading cause of morbidity and mortality in the United States and the second leading cause of death. Cancer, as a disease entity, has a wide range of pathologies. Moreover, the primary origin of cancerous cells is different. This, coupled with the variability in the life cycle of cancerous cells, creates a profound derangement of the host's metabolic response.Tumor lysis syndrome usually develops after the initiation of chemotherapy treatment. However, there are more cases of spontaneous development of tumor lysis syndrome with high-grade hematology-oncology malignancies. Because this condition is very lethal, it is imperative to identify patients at high risk for developing tumor lysis syndrome and start early preventative therapy. Quick and early recognition of the renal and metabolic derangement associated with tumor lysis syndrome and initiation of treatment can save a patient's life.

ACE inhibitors are medications used in the treatment and management of hypertension, which is a significant risk factor for coronary disease, heart failure, stroke, and a host of other cardiovascular conditions. Most cases are primary and not attributable to any specific etiology. This activity reviews the indications, contraindications, activity, adverse events, and other key elements of ACE inhibitor therapy in the clinical setting related to the essential points needed by members of an interprofessional team managing the care of patients with hypertension and its related conditions and sequelae.

Roughly half of all symptomatic renal calculi are potentially preventable if patients were properly diagnosed and treated for their underlying chemical stone promoting risk factors. There is little question that our current level of medical evaluation and prophylactic therapy of recurrent nephrolithiasis is badly underutilized and generally inadequate. In 2012, the yearly direct and indirect costs were estimated at over $10 billion. This figure is predicted to exceed $15 billion by the year 2030 due not only to general population growth, but also to the increasing prevalence of diabetes, metabolic syndrome and obesity, all risk factors for kidney stone disease, in our society. Additionally, quality of life scores are dramatically lowered in nephrolithiasis patients, even in those with asymptomatic stones. There may be no other body of chemistry tests in any branch of medical practice that is potentially as useful and so often indicated, yet so infrequently utilized, as the 24-hour urine test for nephrolithiasis prophylaxis. In a large series of almost 29,000 high-risk stone formers, only 7.4% of patients underwent 24-hour urine testing within six months of their kidney stone. Nephrolithiasis patients were three times more likely to do 24-hour urine testing if they were treated by a nephrologist or urologist compared to a primary care physician. Repeat testing within six months of the initial 24-hour urine test, which is highly recommended to verify treatment efficacy and compliance, was only 16%.There are multiple reasons for this. Like all 24-hour urine collection tests, doing the collection itself is often considered tedious by patients as it drastically limits their activities the day of the specimen collection. Portions of the urinary chemistry are sometimes sent to different reference laboratories which often leads to unacceptable delays and incomplete results that cannot be easily interpreted. The most critical results are often buried amid paragraphs of obligatory boilerplate, again making it almost impossible to identify the most critical results. Even worse, results are often presented as 24-hour totals that are either high or low or normal or abnormal without regard for concentration, pH or what optimal levels of these chemistries would be because providing such information is not readily available or legally required.Once the critical data is available, analysis and treatment selection still needs to be done. Evaluation and interpretation of the laboratory results is often erroneously perceived as overly complex and complicated. There are many different ways the various chemistry reference laboratories hide the data or otherwise make it confusing. Even for experienced experts, finding and clarifying the critical data can be challenging.The purpose of this review is to simplify the analysis and evaluation of 24-hour urine collections as well as treatment selection, so local practitioners will be more comfortable using and interpreting this important test for their nephrolithiasis patients.

Renal collecting ducts are microscopic passages that connect to multiple nephrons. Tubular fluid passes through the collecting ducts to reach the calyces and renal pelvis. While traveling through the collecting ducts, the composition of tubular fluid undergoes alterations. These alterations pertain primarily to reabsorption and secretion of electrolytes, acid, and water. Different cell types line the collecting duct lumen to mediate the alterations. These cell types are under the regulation of chemical messengers originating from both different organ systems and the kidneys themselves.

Acute decompensated heart failure (ADHF) is one of the leading causes of hospital admissions and a significant burden on the healthcare system. It can be attributed to medication noncompliance, comorbidities, diet, modifiable risk factors, disease progression, and/or treatment failure. The standard treatment is usually pharmacologic involving intravenous (IV) diuresis, mainly with loop diuretics. However, chronic diuretic therapy use is associated with negative neuro-hormonal effects which may lead to diuretic resistance and worsening renal function which in turn can lead to increased morbidity and mortality. There has been a growing interest in alternative strategies to manage volume overload in ADHF patients. The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) guidelines recommend pharmacological and non-pharmacological interventions to treat volume overload. Extracorporeal ultrafiltration (UF) is, therefore, an emerging alternative therapy of interest for treating volume overload in ADHF patients.