The kidney protects against sepsis by producing systemic uromodulin.

Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. Although electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We have previously demonstrated that systemic Tamm-Horsfall protein (THP; uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we showed that the kidney increases circulating THP by enhancing the basolateral release of THP from medullary thick ascending limb cells. In patients with sepsis, changes in circulating THP were positively associated with a critical illness. THP was also found de novo in injured lungs. Genetic ablation of THP in mice led to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo led macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis, and chemotaxis, and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/- mice with exogenous systemic THP improved survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function, and systemic THP has therapeutic potential in sepsis.NEW & NOTEWORTHY Specific therapies to improve outcomes in sepsis with kidney injury have been limited by an unclear understanding of how kidney injury increases sepsis mortality. Here, we identified Tamm-Horsfall protein, known to protect in ischemic acute kidney injury, as protective in preclinical sepsis models. Tamm-Horsfall protein also increased in clinical sepsis without severe kidney injury and concentrated in injured organs. Further study could lead to novel sepsis therapeutics.

Past, Present, and Future of Phosphate Management.

Cardiovascular (CV) disease (CVD) accounts for >50% of deaths with known causes in patients on dialysis. Elevated serum phosphorus levels are an important nontraditional risk factor for bone mineral disease and CVD in patients with chronic kidney disease (CKD). Given that phosphorus concentrations drive other disorders associated with increased CV risk (e.g., endothelial dysfunction, vascular calcification, fibroblast growth factor-23, parathyroid hormone), phosphate is a logical target to improve CV health. Phosphate binders are the only pharmacologic treatment approved for hyperphosphatemia. Although their safety has improved since inception, the mechanism of action leads to characteristics that make ingestion difficult and unpleasant; large pill size, objectionable taste, and multiple pills required for each meal and snack make phosphate binders a burden. Side effects, especially those affecting the gastrointestinal (GI) system, are common with binders, often leading to treatment discontinuation. The presence of "hidden" phosphates in processed foods and certain medications makes phosphate management even more challenging. Owing to these significant issues, most patients on dialysis are not consistently achieving and maintaining target phosphorus concentrations of <5.5 mg/dl, let alone more normal levels of <4.5 mg/dl, indicating novel approaches to improve phosphate management and CV health are needed. Several new nonbinder therapies that target intestinal phosphate absorption pathways have been developed. These include EOS789, which acts on the transcellular pathway, and tenapanor, which targets the dominant paracellular pathway. As observational evidence has established a strong association between phosphorus concentration and clinical outcomes, such as mortality, phosphate is an important target for improving the health of patients with CKD and end-stage kidney disease (ESKD).

Postdialysis serum phosphate equilibrium in hemodialysis patients on a controlled diet and no binders.

BACKGROUND: Studies evaluating the change in serum phosphate post hemodialysis (HD) demonstrate an initial decline during dialysis but a rebound post dialysis. However, previous studies were done on usual diet and phosphate binders, with limited number of blood draws, confounding conclusions. We determined serum phosphate reduction, rebound, and equilibrium over 48 h in HD patients consuming a controlled, low phosphorus diet without binders. METHODS: Serum phosphate (mg/dL) was analyzed before and after a HD treatment and frequently during the ensuing 48 h intradialytic period in the clinical research unit. Thirteen subjects were enrolled and had been off phosphate binders for 10 days and consumed a standardized low phosphate (900 mg/day) diet for 3 weeks prior to the assessments. Linear regression was used to determine relationships between the pre-HD serum phosphate, decline post-HD (post-HD drop); and a 48 h area under curve (AUC) using the trapezoidal method as a measure of overall phosphate levels from the end of dialysis to 48 h post dialysis. Repeated Measures ANOVA with Dunnett's posthoc test was used to determine rebound. RESULTS: Five of 13 subjects returned to >90% of their pre-HD serum phosphate within the first 24 h post-HD, and serum phosphate was 94 ± 0.11% (range 63%-113%) by 48 h after the completion of HD. The 48 h AUC of serum phosphate during the interdialytic period was correlated with both pre dialysis phosphorus (r = 0.85; p = 0.0002) and the pre-post drop in serum phosphate during dialysis (r = 0.69; p = 0.0085). In contrast, the net ultrafiltration was not related to the 48 h AUC of serum phosphorus (r = 0.20; p = 0.51). CONCLUSIONS: In hemodialysis patients on standard low phosphorus diet and no phosphate binders, the interdialytic serum phosphorus level, assessed as AUC, is determined by the pre dialysis phosphorus and net-change in serum phosphorus during the dialysis treatment, but not the ultrafiltration volume [Correction added on 25 January, after first online publication: In the last sentence of the Abstract, the word "potassium" has been replaced with "phosphorus" to improve accuracy.].

Living Donor Gifted Lithiasis: Long-Term Outcomes in Recipients.

OBJECTIVES: Presence of nephrolithiasis in a living donor has been at least a relative contraindication to living donor nephrectomy. The concern for stone recurrence and outcomes has been one of the reasons for reluctance to consider these medically complex donors. We evaluate long-term outcomes in recipients of kidney grafts from donors with nephrolithiasis, or history of nephrolithiasis, and provide results from our experience at Indiana University. MATERIALS AND METHODS: We retrospectively reviewed 57 donor-recipient pairs, where the allograft was received from a living donor with symptomatic calculi, or with imaging evidence of kidney stones, between 2003 and 2018. This research study was done in compliance with the ethical standards set forth in the Helsinki Congress. RESULTS: The mean age of recipients was 46±19 years and 58% were male. Kidney recipients were followed for a median of 3.5 years and 59.6% of patients had follow-up imaging studies. None of the recipients had obstructing renal calculi or related infections. None of the recipients required any interventions for recurrent calculi and no stone episode lead to adverse event to the graft. Hyperoxaluria and hypercalciuria were the most common risk factors in 24-hour urine collections obtained from donors. CONCLUSIONS: Our findings from a single large center looking at kidney recipient outcomes over a long follow-up period found that gifted lithiasis is a safe procedure. Careful selection of "medically complex donors" with kidney stones based on appropriate guidelines is a key step. Further studies are needed to help develop consensus guidelines.

EOS789, a broad-spectrum inhibitor of phosphate transport, is safe with an indication of efficacy in a phase 1b randomized crossover trial in hemodialysis patients.

The treatment of hyperphosphatemia remains challenging in patients receiving hemodialysis. This phase 1b study assessed safety and efficacy of EOS789, a novel pan-inhibitor of phosphate transport (NaPi-2b, PiT-1, PiT-2) on intestinal phosphate absorption in patients receiving intermittent hemodialysis therapy. Two cross-over, randomized order studies of identical design (ten patients each) compared daily EOS789 50 mg to placebo with meals and daily EOS789 100 mg vs EOS789 100 mg plus 1600 mg sevelamer with meals. Patients ate a controlled diet of 900 mg phosphate daily for two weeks and began EOS789 on day four. On day ten, a phosphate absorption testing protocol was performed during the intradialytic period. Intestinal fractional phosphate absorption was determined by kinetic modeling of serum data following oral and intravenous doses of 33Phosphate (33P). The results demonstrated no study drug related serious adverse events. Fractional phosphate absorption was 0.53 (95% confidence interval: 0.39,0.67) for placebo vs. 0.49 (0.35,0.63) for 50 mg EOS789; and 0.40 (0.29,0.50) for 100 mg EOS789 vs. 0.36 (0.26,0.47) for 100 mg EOS789 plus 1600 mg sevelamer (all not significantly different). The fractional phosphate absorption trended lower in six patients who completed both studies with EOS789 100 mg compared with placebo. Thus, in this phase 1b study, EOS789 was safe and well tolerated. Importantly, the use of 33P as a sensitive and direct measure of intestinal phosphate absorption allows specific testing of drug efficacy. The effectiveness of EOS789 needs to be evaluated in future phase 2 and phase 3 studies.

Strategies to Reduce Rehospitalization in Patients with CKD and Kidney Failure.

Readmissions in patients with nondialysis-dependent CKD and kidney failure are common and are associated with significant morbidity, mortality, and economic consequences. In 2013, the Centers for Medicare and Medicaid Services implemented the Hospital Readmissions Reduction Program in an attempt to reduce high hospitalization-associated costs. Up to 50% of all readmissions are deemed avoidable and present an opportunity for intervention. We describe factors that are specific to the patient, the index hospitalization, and underlying conditions that help identify the "high-risk" patient. Early follow-up care, developing volume management strategies, optimizing nutrition, obtaining palliative care consultations for seriously ill patients during hospitalization and conducting goals-of-care discussions with them, instituting systematic advance care planning during outpatient visits to avoid unwanted hospitalizations and intensive treatment at the end of life, and developing protocols for patients with incident or prevalent cardiovascular conditions may help prevent avoidable readmissions in patients with kidney disease.

Chronic kidney disease as a risk factor for peripheral nerve impairment in older adults: A longitudinal analysis of Health, Aging and Body Composition (Health ABC) study.

INTRODUCTION: Sensory and motor nerve deficits are prevalent in older adults and are associated with loss of functional independence. We hypothesize that chronic kidney disease predisposes to worsening sensorimotor nerve function over time. MATERIALS AND METHODS: Participants were from the Health, Aging and Body Composition Study (N = 1121) with longitudinal data between 2000-01 (initial visit) and 2007-08 (follow-up visit). Only participants with non-impaired nerve function at the initial visit were included. The predictor was presence of CKD (estimated GFR ≤ 60 ml/min/1.73m2) from the 1999-2000 visit. Peripheral nerve function outcomes at 7-year follow-up were 1) Motor: "new" impairments in motor parameters (nerve conduction velocity NCV < 40 m/s or peroneal compound motor action potential < 1 mv) at follow-up, and 2) Sensory: "new" impairment defined as insensitivity to standard 10-g monofilament or light 1.4-g monofilament at the great toe and "worsening" as a change from light to standard touch insensitivity over time. The association between CKD and "new" or "worsening" peripheral nerve impairment was studied using logistic regression. RESULTS: The study population was 45.9% male, 34.3% Black and median age 75 y. CKD participants (15.6%) were older, more hypertensive, higher in BMI and had 2.37 (95% CI 1.30-4.34) fold higher adjusted odds of developing new motor nerve impairments in NCV. CKD was associated with a 2.02 (95% CI 1.01-4.03) fold higher odds of worsening monofilament insensitivity. CKD was not associated with development of new monofilament insensitivity. CONCLUSIONS: Pre-existing CKD leads to new and worsening sensorimotor nerve impairments over a 7-year time period in community-dwelling older adults.

Chronic kidney disease and peripheral nerve function in the Health, Aging and Body Composition Study.

BACKGROUND: Chronic kidney disease (CKD) is associated with poor mobility. Peripheral nerve function alterations play a significant role in low mobility. We tested the hypothesis that early CKD is associated with altered sensory, motor and autonomic nerve function. METHODS: Participants in the Health, Aging and Body Composition cohort who had kidney function measures in Year 3 (1999-2000) and nerve function measurements at Year 4 (2000-01) were analyzed (n = 2290). Sensory (vibration threshold, monofilament insensitivity to light and standard touch), motor [compound motor action potentials (CMAPs), nerve conduction velocities (NCVs)] and autonomic (heart rate response and recovery after a 400-m walk test) nerve function as well as participant characteristics were compared across cystatin C- and creatinine-based estimated glomerular filtration rate categorized as ≤60 (CKD) or >60 mL/min/1.73 m2 (non-CKD). The association between CKD and nerve function was examined with logistic regression adjusted for covariates. RESULTS: Participants with CKD (n = 476) were older (77 ± 3 versus 75 ± 3 years; P < 0.05) and had a higher prevalence of diabetes (20.6% versus 13.1%; P < 0.001). CKD was associated with higher odds for vibration detection threshold {odds ratio [OR] 1.7 [95% confidence interval (CI) 1.1-2.7]} and light touch insensitivity [OR 1.4 (95% CI 1.1-1.7)]. CMAPs and NCVs were not significantly different between CKD and non-CKD patients. In adjusted analyses, participants with CKD had higher odds of an abnormal heart rate response [OR 1.6 (95% CI 1.1-2.2)] and poor heart rate recovery [OR 1.5 (95% CI 1.1-2.0)]. CONCLUSIONS: CKD is associated with changes in sensory and autonomic nerve function, even after adjustment for demographics and comorbidities, including diabetes. Longitudinal studies in CKD are needed to determine the contribution of nerve impairments to clinically important outcomes.

Diagnosis and Management of Type 2 Diabetic Kidney Disease.

Type 2 diabetic kidney disease (DKD) is the most common cause of CKD and ESRD worldwide, and carries with it enormous human and societal costs. The goal of this review is to provide an update on the diagnosis and management of DKD based on a comprehensive review of the medical literature. Topics addressed include the evolving presentation of DKD, clinical differentiation of DKD from non-DKD, a state-of-the-art evaluation of current treatment strategies, and promising emerging treatments. It is expected that the review will help clinicians to diagnose and manage patients with DKD.

The frequency, cost, and clinical outcomes of hypernatremia in patients hospitalized to a comprehensive cancer center.

PURPOSE: To study the frequency of hypernatremia in hospitalized cancer patients and its impact on clinical outcomes and healthcare cost. METHODS: Cross-sectional analysis of data obtained from patients admitted to the University of Texas M. D. Anderson Cancer Center over a 3-month period in 2006. The clinical outcomes and hospital costs were compared among hypernatremics, eunatremics, and hyponatremics (serum sodium values include >147, 135-147, and <135 mEq/L, respectively). RESULTS: Of 3,446 patients with at least one serum sodium value, 51.4 % were eunatremic, 46.0 % hyponatremic, and 2.6 % hypernatremic with most of the hypernatremia (90 %) acquired during hospital stay. The multivariate hazard ratio (HR) for mortality in hypernatremic was 5-fold higher than eunatremic (HR for 90 days-5.09 (95 % CI, 3.32-7.81); p < 0·01) and over 2-fold higher than hyponatremic (HR for 90 days-2.79 (95 % CI, 1.91-4.11), p < 0.01). The length of hospital stay in hypernatremic was 2-fold higher than in hyponatremic and 4-fold higher than in eunatremic (e.g., 27 ± 22 days in hypernatremic vs. 6 ± 5 days in eunatremic; mean ± SD, p < 0.01). The hospital bill was higher for hypernatremic compared with the rest of the groups (46 % over eunatremic and 37 % over hyponatremic, p < 0.01 for both). CONCLUSIONS: Although hypernatremia was far less frequent than hyponatremia in the hospitalized cancer patients, most hypernatremia were acquired in the hospital and had substantially higher mortality, hospital stay, and hospital bills than eunatremic or even hyponatremic patients. Studies are warranted to determine whether avoidance of hypernatremia or its prompt and sustained correction improves clinical outcomes.

The impact of statin and macrolide use on early survival in patients with pneumococcal pneumonia.

BACKGROUND: Mortality in pneumococcal pneumonia remains high despite early antibiotic eradication of bacteria. Most deaths occur within the first week, the time of peak inflammatory responses. Statins and macrolides have broad immunosuppressive activity; their impact, separately and together, on survival in patients with pneumococcal pneumonia was evaluated. METHODS: All patients with pneumococcal pneumonia seen at a single medical center from 2000 through 2010 were included in this retrospective cohort study. A multivariate-adjusted Cox proportional hazard model was used to evaluate survival. RESULTS: Of 347 patients with pneumococcal pneumonia, 90 (26%) were taking a statin at presentation and 126 (36%) were started on treatment with a macrolide. Thirty-two (9%) statin users were treated with a macrolide. Statin users were older than non-statin users, with a higher prevalence of diabetes, coronary artery disease and chronic kidney disease and a lower prevalence of alcohol consumption and liver disease. Statin users had higher mean Pneumonia Patient Outcomes Research Team scores. Patients treated with a macrolide were not different from those who received other antibiotics. The risk of mortality among statin users was reduced at 7, 14, 20 and 30 days after admission. Mortality was not reduced in patients treated with a macrolide or with a macrolide plus a statin compared with those who did not receive a macrolide. CONCLUSIONS: Patients who are receiving statins at the time of admission for pneumococcal pneumonia have better clinical outcomes than those who are not. Treatment with a macrolide does not appear to confer a survival benefit.

Incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a comprehensive cancer center.

BACKGROUND AND OBJECTIVES: Incidence of AKI in hospitalized patients with cancer is increasing, but reports are scant. The objective of this study was to determine incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a cancer center. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Cross-sectional analysis of prospectively collected data on 3558 patients admitted to the University of Texas M.D. Anderson Cancer Center over 3 months in 2006. RESULTS: Using modified RIFLE (Risk, Injury, Failure, Loss, ESRD) criteria, 12% of patients admitted to the hospital had AKI, with severity in the Risk, Injury, and Failure categories of 68%, 21%, and 11%, respectively. AKI occurred in 45% of patients during the first 2 days and in 55% thereafter. Dialysis was required in 4% of patients and nephrology consultation in 10%. In the multivariate model, the odds ratio (OR) for developing AKI was significantly higher for diabetes (OR, 1.89; 95% confidence interval [CI], 1.51-2.36), chemotherapy (OR, 1.61; 95% CI, 1.26-2.05), intravenous contrast (OR, 4.55; 95% CI, 3.51-5.89), hyponatremia (OR, 1.97; 95% CI, 1.57-2.47), and antibiotics (OR, 1.52; 95% CI, 1.15-2.02). In patients with AKI, length of stay (100%), cost (106%), and odds for mortality (4.7-fold) were significantly greater. CONCLUSION: The rate of AKI in patients admitted to a comprehensive cancer center was higher than the rate in most noncancer settings; was correlated significantly with diabetes, hyponatremia, intravenous contrast, chemotherapy, and antibiotics; and was associated with poorer clinical outcomes. AKI developed in many patients after admission. Studies are warranted to determine whether proactive measures may limit AKI and improve outcomes.

The incidence of necrotizing changes in adults with pneumococcal pneumonia.

BACKGROUND: Necrotizing pneumonia is generally considered a rare complication of pneumococcal infection in adults. We systematically studied the incidence of necrotizing changes in adult patients with pneumococcal pneumonia and examined the severity of infection, role of causative serotypes, and association with bacteremia. METHODS: We used a database of all pneumococcal infections identified at our medical center between 2000 and 2010. Original readings of chest X-rays (CXR) and computerized tomography (CT) were noted. Images were then independently reevaluated by 2 radiologists. The severity of disease at admission was assessed using SMART-COP and Pneumonia Outcomes Research Team (PORT) scoring systems. RESULTS: In 351 cases of pneumococcal pneumonia, necrosis was reported in no (0%) original CXR readings and in 6 of 136 (4.4%) CTs. With rereading, 8 of 351 (2.3%) CXR and 15 of 136 (11.0%) CT had necrotizing changes. Overall, these changes were identified in 23 of 351 (6.6%) patients. The incidence of bacteremia and the admitting SMART-COP and PORT scores were similar in patients with and without necrosis (P = 1.00, P = .32, and P = .54, respectively). Type 3 pneumococcus was more commonly isolated from patients with necrosis than from patients without necrosis (P = .05), but 10 other serotypes were also implicated in 16 cases for which the organism was available for typing. CONCLUSIONS: Necrotizing changes in the lungs were seen in 6.6% of a large series of adults with pneumococcal pneumonia but were often overlooked on initial readings. Patients with necrosis were not more likely to have bacteremia or more severe disease. Type 3 pneumococcus was the most commonly identified serotype.

Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes.

BACKGROUND: Hyponatremia is the most common electrolyte abnormality in clinical practice, yet little is known about its frequency in patients with cancer or its impact on their clinical outcomes. STUDY DESIGN: Retrospective analysis of prospectively collected data. SETTING & PARTICIPANTS: Patients with cancer admitted to the University of Texas M.D. Anderson Cancer Center in 2006 for 3 months. PREDICTOR: Serum sodium levels categorized as eunatremia (serum sodium, 135-147 mEq/L) and mild (134-130 mEq/L), moderate (129-120 mEq/L), and severe (<120 mEq/L) hyponatremia. OUTCOMES: (1) Length of hospital stay and (2) 90-day mortality. RESULTS: In 4,702 admissions in 3,357 patients with cancer, hyponatremia (serum sodium <135 mEq/L) was noted in 47% of admissions. It was mild in 36%, moderate in 10%, and severe in 1%. Hyponatremia was acquired during the hospital stay in 24%. Using the first admission data, mean length of stay was 5.6 ± 5.0 days for patients with eunatremia and 9.9 ± 9.2, 13.0 ± 14.1, and 11.5 ± 12.6 days for those with mild, moderate, and severe hyponatremia, respectively. The respective HRs in the multivariate Cox model for longer hospital stay, using patients with eunatremia as reference, were 1.92 (95% CI, 1.75-2.13; P < 0.01), 2.94 (95% CI, 2.56-3.45; P < 0.01), and 2.32 (95% CI, 1.32-4.00; P = 0.01). 283 (8.4%) deaths occurred during 90 days, and in the multivariate model, the respective HRs for 90-day mortality for mild, moderate, and severe hyponatremia were 2.04 (95% CI, 1.42-2.91; P < 0.01); 4.74 (95% CI, 3.21-7.01; P < 0.01), and 3.46 (95% CI, 1.05-11.44; P = 0.04). These findings were consistent when analyses were repeated with sodium levels in tertiles. LIMITATIONS: Observational study, retrospective, inability to adjust for all comorbid conditions. CONCLUSION: Hyponatremia in patients with cancer is associated with longer hospital stay and higher mortality. Whether long-term correction of hyponatremia would improve these outcomes remains to be determined.

Bacteraemia from an unrecognized source (occult bacteraemia) occurring during Clostridium difficile infection.

BACKGROUND: The purpose of this investigation was to determine if disruption of the colonic epithelium during Clostridium difficile infection (CDI) is associated with bacteraemia due to secondary bacterial invasion by enteric organisms. METHODS: We reviewed the medical records of 505 randomly selected individuals from a database of patients who tested positive for C. difficile toxin and identified bacteraemias that occurred in 2 periods-the pre-CDI and post-CDI periods. Medical records were reviewed to determine a source for each case of bacteraemia. Staphylococcal bacteraemias were excluded from the analysis. RESULTS: In the pre-CDI period, 28 of 505 (5.5%) patients had non-staphylococcal bacteraemia. A focus of infection was found in 24 of 28 (85.7%) cases. During CDI, 30 of 505 (5.9%) patients had non-staphylococcal bacteraemia; in the majority (19 cases, 63.3%) a focus of infection was not identified (p < 0.001). In the pre-CDI period, 16 of 28 (57.1%) blood cultures yielded Gram-negative pathogens compared to 9 of 30 (30%) in the CDI period (p = 0.04). Seven of 28 (25%) blood cultures in the pre-CDI period yielded enterococci compared to 15 of 30 (50%) in the CDI period (p = 0.05). CONCLUSIONS: The incidence of non-staphylococcal bacteraemias in the pre- and post-CDI periods was nearly the same. Cases of bacteraemias in the CDI period more frequently involved organisms of unknown source and uncertain pathogenicity, and were usually not found to require antimicrobial therapy. The data favour the assumption that CDI-associated bacteraemia may be associated with bacterial invasion of the damaged colonic epithelium.