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Background: Understanding factors which predict progression of renal failure is of great interest to clinicians. Objectives: We examined machine learning methods to predict the composite outcome of death, dialysis or doubling of serum creatinine using the modification of diet in renal disease (MDRD) data set. Methods: We specifically evaluated a generalized linear model, a support vector machine, a decision tree, a feed-forward neural network and a random forest evaluated within the context of 10 fold validation using the CARET package available within the open source architecture R program. Results: We found that using clinical parameters available at entry into the study, these computer learning methods trained on 70% of the MDRD population had prediction accuracies ranging from 66-77% on the remaining 30%. Although the support vector machine methodology appeared to have the highest accuracy, all models studied worked relatively well. Conclusions: These results illustrate the utility of employing machine learning methods within R to address the prediction of long term clinical outcomes using initial clinical measurements.

A cute agitation in the pregnant patient should be treated as an obstetric emergency, as it jeopardizes the safety of the patient and fetus, as well as others in the emergency room. Uncontrolled agitation is associated with obstetric complications such as preterm delivery, placental abnormalities

Objectives To analyze correlations between major determinants of blood pressure (BP), in efforts to generate and compare predictive models that explain for variance in systolic, diastolic, and mean BP amongst participants of the Intersalt study. Methods Data from the Intersalt study, consisting of nearly 10,000 subjects from 32 different countries, were reviewed and analyzed. Published mean values of 24 hour urinary electrolyte excretion (Na+, K+), 24 hour urine creatinine excretion, body mass index (BMI, kg/m^2), and blood pressure data were extracted and imported into Matlab™ for stepwise linear regression analysis. Results As shown earlier, strong correlations between urinary sodium excretion (UNaV) and systolic, diastolic and mean blood pressure were noted as well as between UNaV and the age dependent increase in systolic blood pressure. Of interest, BMI and urinary creatinine excretion rate (UCrV) also both correlated with systolic blood pressure, but the ratio of BMI/UCrV, constructed to be a measure of obesity, correlated negatively with systolic blood pressure. Conclusions Our results offer population-based evidence suggesting that increased size due to muscle mass rather than adiposity may correspond more to blood pressure. Additional data bases will need to be sampled and analyzed to further validate these observations.

Background The United States is faced with an unprecedented epidemic of drug abuse. Every year thousands of Americans visit the emergency departments all over the country with illicit drug related complaints. These drugs have been known to be associated with a range of renal pathologies, from reversible acute kidney injuries to debilitating irreversible conditions like renal infarction. So far, no comprehensive study or systematic review has been published that includes the commonly used street drugs and designer drugs with potential nephrotoxic outcomes. Methods We conducted a systematic review of published case reports, case series, and cross sectional studies of nephrotoxicities related to drugs of abuse. Literature review was conducted using PubMed/Medline from January 1, 2005 -December 31, 2016 to search for publications related to drug abuse with a defined renal outcome. Publications which reported renal injury in relation to the use of illicit drugs were selected, specifically those cases with raised creatinine levels, clinically symptomatic patients, for instance those with oliguria and proven renal biopsies. Results A total of 4798 publications were reviewed during the search process and PRISMA flow chart and Moose protocol regarding systematic reviews were followed. 110 articles were shortlisted for the review. A total of 169 cases from case reports and case series, and 14 case studies were analyzed. Renal manifestations of specific illicit drug abuse were included in this review. Conclusion Based on the evidence presented, a wide range of renal manifestations were found to be associated with drug abuse. If the trend of increasing use of illicit drug use continues, it will put a significant percentage of the population at an elevated risk for poor renal outcomes. This study is limited by the nature of the literature reviewed being primarily case reports and case series.

Cardiotonic steroids (such as ouabain) signaling through Na/K-ATPase regulate sodium reabsorption in the renal proximal tubule. We report here that reactive oxygen species are required to initiate ouabain-stimulated Na/K-ATPase·c-Src signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine prevented ouabain-stimulated Na/K-ATPase·c-Src signaling, protein carbonylation, redistribution of Na/K-ATPase and sodium/proton exchanger isoform 3, and inhibition of active transepithelial (22)Na(+) transport. Disruption of the Na/K-ATPase·c-Src signaling complex attenuated ouabain-stimulated protein carbonylation. Ouabain-stimulated protein carbonylation is reversed after removal of ouabain, and this reversibility is largely independent of de novo protein synthesis and degradation by either the lysosome or the proteasome pathways. Furthermore, ouabain stimulated direct carbonylation of two amino acid residues in the actuator domain of the Na/K-ATPase α1 subunit. Taken together, the data indicate that carbonylation modification of the Na/K-ATPase α1 subunit is involved in a feed-forward mechanism of regulation of ouabain-mediated renal proximal tubule Na/K-ATPase signal transduction and subsequent sodium transport.

Background We have demonstrated that cardiotonic steroids, such as ouabain, signaling through the Na/K‐ ATP ase, regulate sodium reabsorption in the renal proximal tubule. By direct carbonylation modification of the Pro222 residue in the actuator (A) domain of pig Na/K‐ ATP ase α1 subunit, reactive oxygen species are required for ouabain‐stimulated Na/K‐ ATP ase/c‐Src signaling and subsequent regulation of active transepithelial 22 Na + transport. In the present study we sought to determine the functional role of Pro222 carbonylation in Na/K‐ ATP ase signaling and sodium handling. Methods and Results Stable pig α1 knockdown LLC ‐ PK 1‐originated PY ‐17 cells were rescued by expressing wild‐type rat α1 and rat α1 with a single mutation of Pro224 (corresponding to pig Pro222) to Ala. This mutation does not affect ouabain‐induced inhibition of Na/K‐ ATP ase activity, but abolishes the effects of ouabain on Na/K‐ ATP ase/c‐Src signaling, protein carbonylation, Na/K‐ ATP ase endocytosis, and active transepithelial 22 Na + transport. Conclusions Direct carbonylation modification of Pro224 in the rat α1 subunit determines ouabain‐mediated Na/K‐ ATP ase signal transduction and subsequent regulation of renal proximal tubule sodium transport.

We previously reported that cardiotonic steroids stimulate collagen synthesis by cardiac fibroblasts in a process that involves signaling through the Na-K-ATPase pathway (Elkareh et al. Hypertension 49: 215–224, 2007). In this study, we examined the effect of cardiotonic steroids on dermal fibroblasts collagen synthesis and on wound healing. Increased collagen expression by human dermal fibroblasts was noted in response to the cardiotonic steroid marinobufagenin in a dose- and time-dependent fashion. An eightfold increase in collagen synthesis was noted when cells were exposed to 10 nM marinobufagenin for 24 h ( P < 0.01). Similar increases in proline incorporation were seen following treatment with digoxin, ouabain, and marinobufagenin (10 nM × 24 h, all results P < 0.01 vs. control). The coadministration of the Src inhibitor PP2 or N-acetylcysteine completely prevented collagen stimulation by marinobufagenin. Next, we examined the effect of digoxin, ouabain, and marinobufagenin on the rate of wound closure in an in vitro model where human dermal fibroblasts cultures were wounded with a pipette tip and monitored by digital microscopy. Finally, we administered digoxin in an in vivo wound healing model. Olive oil was chosen as the digoxin carrier because of a favorable partition coefficient observed for labeled digoxin with saline. This application significantly accelerated in vivo wound healing in rats wounded with an 8-mm biopsy cut. Increased collagen accumulation was noted 9 days after wounding (both P < 0.01). The data suggest that cardiotonic steroids induce increases in collagen synthesis by dermal fibroblasts, as could potentially be exploited to accelerate wound healing.

It has been postulated for some time that endogenous digitalis-like substances, also called cardiotonic steroids (CTS), exist, and that these substances are involved in sodium handling. Within the past 20 years, these substances have been unequivocally identified and measurements of circulating and tissue concentrations have been made. More recently, it has been identified that CTS also mediate signal transduction through the Na/K-ATPase, and consequently been implicated in profibrotic pathways. This review will discuss the mechanism of CTS in renal sodium handling and a potential "trade-off" effect from their role in inducing tissue fibrosis.

We have demonstrated that ouabain regulates protein trafficking of the Na/K-ATPase a1 subunit and NHE3 (Na/H exchanger, isoform 3) via ouabain-activated Na/K-ATPase signaling in porcine LLC-PK1 cells. To investigate whether this mechanism is species-specific, ouabain-induced regulation of the a1 subunit and NHE3 as well as transcellular 22 Na ? transport were compared in three renal proximal tubular cell lines (human HK-2, por- cine LLC-PK1, and AAC-19 originated from LLC-PK1 in which the pig a1 was replaced by ouabain-resistant rat a1). Ouabain-induced inhibition of transcellular 22 Na ? transport is due to an ouabain-induced redistribution of the a1 sub- unit and NHE3. In LLC-PK1 cells, ouabain also inhibited the endocytic recycling of internalized NHE3, but has no significant effect on recycling of endocytosed a1 subunit. These data indicated that the ouabain-induced redistribu- tion of the a1 subunit and NHE3 is not a species-specific phenomenon, and ouabain-activated Na/K-ATPase signal- ing influences NHE3 regulation.

Because of the plethora of genetic manipulations available in the mouse, we performed a partial nephrectomy in the mouse and examined whether the phenotypical features of uremic cardiomyopathy described in humans and rats were also present in the murine model. A nephrectomy was performed using a combination of electrocautory to decrease renal mass on the left kidney and right surgical nephrectomy. This procedure produced substantial and persistent hypertension as well as increases in circulating concentrations of marinobufagenin. Invasive physiological measurements of cardiac function demonstrated that the nephrectomy resulted in impairment of both active and passive left ventricular relaxation at 4 wk whereas tissue Doppler imaging detected changes in diastolic function after 6 wk. Morphologically, hearts demonstrated enlargement and progressive fibrosis, and biochemical measurements demonstrated downregulation of the sarcoplasmic reticulum calcium ATPase as well as increases in collagen-1, fibronectin, and vimentin expression. Our results suggest that partial nephrectomy in the mouse establishes a model of uremic cardiomyopathy which shares phenotypical features with the rat model as well as patients with chronic renal failure.