Subodh J. Saggi

Diagnostic and Prognostic Stratification in the Emergency Department Using Urinary Biomarkers of Nephron Damage: A Multicenter Prospective Cohort Study

OBJECTIVES This study aimed to determine the diagnostic and prognostic value of urinary biomarkers of intrinsic acute kidney injury (AKI) when patients were triaged in the emergency department. BACKGROUND Intrinsic AKI is associated with nephron injury and results in poor clinical outcomes. Several urinary biomarkers have been proposed to detect and measure intrinsic AKI. METHODS In a multicenter prospective cohort study, 5 urinary biomarkers (urinary neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid binding protein, urinary interleukin-18, and cystatin C) were measured in 1,635 unselected emergency department patients at the time of hospital admission. We determined whether the biomarkers diagnosed intrinsic AKI and predicted adverse outcomes during hospitalization. RESULTS All biomarkers were elevated in intrinsic AKI, but urinary neutrophil gelatinase-associated lipocalin was most useful (81% specificity, 68% sensitivity at a 104-ng/ml cutoff) and predictive of the severity and duration of AKI. Intrinsic AKI was strongly associated with adverse in-hospital outcomes. Urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule 1 predicted a composite outcome of dialysis initiation or death during hospitalization, and both improved the net risk classification compared with conventional assessments. These biomarkers also identified a substantial subpopulation with low serum creatinine at hospital admission, but who were at risk of adverse events. CONCLUSIONS Urinary biomarkers of nephron damage enable prospective diagnostic and prognostic stratification in the emergency department.

Reimbursement of Dialysis: A Comparison of Seven Countries

Reimbursement for chronic dialysis consumes a substantial portion of healthcare costs for a relatively small proportion of the total population. Each country has a unique reimbursement system that attempts to control rising costs. Thus, comparing the reimbursement systems between countries might be helpful to find solutions to minimize costs to society without jeopardizing quality of treatment and outcomes. We conducted a survey of seven countries to compare crude reimbursement for various dialysis modalities and evaluated additional factors, such as inclusion of drugs or physician payments in the reimbursement package, adjustment in rates for specific patient subgroups, and pay for performance therapeutic thresholds. The comparison examines the United States, the province of Ontario in Canada, and five European countries (Belgium, France, Germany, The Netherlands, and the United Kingdom). Important differences between countries exist, resulting in as much as a 3.3-fold difference between highest and lowest reimbursement rates for chronic hemodialysis. Differences persist even when our data were adjusted for per capita gross domestic product. Reimbursement for peritoneal dialysis is lower in most countries except Germany and the United States. The United Kingdom is the only country that has implemented an incentive if patients use an arteriovenous fistula. Although home hemodialysis (prolonged or daily dialysis) allows greater flexibility and better patient outcomes, reimbursement is only incentivized in The Netherlands. Unfortunately, it is not yet clear that such differences save money or improve quality of care. Future research should focus on directly testing both outcomes.

Psychosocial Intervention Improves Depression, Quality of Life, and Fluid Adherence in Hemodialysis

Patients with ESRD have high rates of depression, which is associated with diminished quality of life and survival. We determined whether individual cognitive behavioral therapy (CBT) reduces depression in hemodialysis patients with elevated depressive affect in a randomized crossover trial. Of 65 participants enrolled from two dialysis centers in New York, 59 completed the study and were assigned to the treatment-first group (n=33) or the wait-list control group (n=26). In the intervention phase, CBT was administered chairside during dialysis treatments for 3 months; participants were assessed 3 and 6 months after randomization. Compared with the wait-list group, the treatment-first group achieved significantly larger reductions in Beck Depression Inventory II (self-reported, P=0.03) and Hamilton Depression Rating Scale (clinician-reported, P<0.001) scores after intervention. Mean scores for the treatment-first group did not change significantly at the 3-month follow-up. Among participants with depression diagnosed at baseline, 89% in the treatment-first group were not depressed at the end of treatment compared with 38% in the wait-list group (Fishers exact test, P=0.01). Furthermore, the treatment-first group experienced greater improvements in quality of life, assessed with the Kidney Disease Quality of Life Short Form (P=0.04), and interdialytic weight gain (P=0.002) than the wait-list group, although no effect on compliance was evident at follow-up. In summary, CBT led to significant improvements in depression, quality of life, and prescription compliance in this trial, and studies should be undertaken to assess the long-term effects of CBT on morbidity and mortality in patients with ESRD.

Evidence for pH sensitivity of tumor necrosis factor-alpha release by alveolar macrophages.

Abstract. Alveolar macrophages (mφ) participate in inflammatory and immune responses in acidic microenvironments such as the interstitial fluids of tumors and abscesses. Two plasmalemmal H+ extruders interact to control the acid-base status of alveolar mφ, namely a V-type H+ pump (V-ATPase) and a Na+/H+ exchanger. The present study examined the effects of extracellular pH (pHo) and H+ transport inhibitors on tumor necrosis factor-α (TNF-α) release induced by endotoxin (lipopolysaccharide) in rabbit alveolar mφ. The amount and activity of TNF-α in mφ-conditioned media were determined by enzyme-linked immunosorbent assay and L929 fibroblast bioassay, respectively. TNF-α release was suppressed progressively at lower pHo values (≤7.0). Also, bafilomycin A1 (a specific inhibitor of V-ATPases) significantly reduced the amount and activity of TNF-α in mφ-conditioned media (pHo 7.4). However, bafilomycin caused a significant increase in the nonspecific cytotoxicity (i.e. bioactivity insensitive to TNF-α antibody) of mφ-conditioned media. The effects of bafilomycin specifically on TNF-α release followed a time course similar to that of acidic pHo, suggesting that both treatments acted on similar events in the lipopolysaccharide signal transduction pathway. Amiloride (an inhibitor of Na+ transporters including the Na+/H+ exchanger) also suppressed TNF-α release but displayed a time course of action different from the acidic pHo or bafilomycin.

Considerations in the optimal preparation of patients for dialysis

Every year, more than 110,000 Americans are newly diagnosed with end-stage renal disease and in the overwhelming majority, maintenance dialysis therapy is initiated. However, most patients, having received no predialysis nephrology care or dietary counseling, are inadequately prepared for starting treatment; furthermore, the majority of patients do not have a functioning permanent dialysis access. Annualized mortality in the USA in the first 3 months after starting dialysis treatment is approximately 45%; this high rate is possibly in part due to inadequate preparation for renal replacement therapy. Data from the Dialysis Outcomes and Practice Patterns study suggest that similar challenges exist in many parts of the world. Implementation of strategies that mitigate the risk of adverse consequences when starting dialysis are urgently needed. In this Review we present a step-by-step approach to tackling inadequate patient preparation, which includes identifying individuals with chronic kidney disease (CKD) who are most likely to need dialysis in the future, referring patients for education, timely placement of dialysis access and timely initiation of dialysis therapy. Treatment with dialysis might not be appropriate for some patients with progressive CKD; these individuals can be optimally managed with nondialytic, maximum conservative management.

Randomized Controlled Trial of Strain-Specific Probiotic Formulation (Renadyl) in Dialysis Patients

Background. Primary goal of this randomized, double-blind, placebo-controlled crossover study of Renadyl in end-stage renal disease patients was to assess the safety and efficacy of Renadyl measured through improvement in quality of life or reduction in levels of known uremic toxins. Secondary goal was to investigate the effects on several biomarkers of inflammation and oxidative stress. Methods. Two 2-month treatment periods separated by 2-month washout and crossover, with physical examinations, venous blood testing, and quality of life questionnaires completed at each visit. Data were analyzed with SAS V9.2. Results. 22 subjects (79%) completed the study. Observed trends were as follows (none reaching statistical significance): decline in WBC count (−0.51 × 109/L, P = 0.057) and reductions in levels of C-reactive protein (−8.61 mg/L, P = 0.071) and total indoxyl glucuronide (−0.11 mg%, P = 0.058). No statistically significant changes were observed in other uremic toxin levels or measures of QOL. Conclusions. Renadyl appeared to be safe to administer to ESRD patients on hemodialysis. Stability in QOL assessment is an encouraging result for a patient cohort in such advanced stage of kidney disease. Efficacy could not be confirmed definitively, primarily due to small sample size and low statistical power—further studies are warranted.

Unique Transcriptional Programs Identify Subtypes of AKI.

Two metrics, a rise in serum creatinine concentration and a decrease in urine output, are considered tantamount to the injury of the kidney tubule and the epithelial cells thereof (AKI). Yet neither criterion emphasizes the etiology or the pathogenetic heterogeneity of acute decreases in kidney excretory function. In fact, whether decreased excretory function due to contraction of the extracellular fluid volume (vAKI) or due to intrinsic kidney injury (iAKI) actually share pathogenesis and should be aggregated in the same diagnostic group remains an open question. To examine this possibility, we created mouse models of iAKI and vAKI that induced a similar increase in serum creatinine concentration. Using laser microdissection to isolate specific domains of the kidney, followed by RNA sequencing, we found that thousands of genes responded specifically to iAKI or to vAKI, but very few responded to both stimuli. In fact, the activated gene sets comprised different, functionally unrelated signal transduction pathways and were expressed in different regions of the kidney. Moreover, we identified distinctive gene expression patterns in human urine as potential biomarkers of either iAKI or vAKI, but not both. Hence, iAKI and vAKI are biologically unrelated, suggesting that molecular analysis should clarify our current definitions of acute changes in kidney excretory function.

A Preliminary Investigation of Depression and Kidney Functioning in Patients with Chronic Kidney Disease

Background: The incidence and prevalence of Chronic Kidney Disease (CKD) is growing rapidly. Understanding the factors associated with declining renal function is of clinical significance. The current studys main goal was to identify variables that could predict decline in glomerular filtration rate (GFR) over time in outpatients with varying stages of CKD. Methods: Seventy CKD patients completed psychological questionnaires and medical variables were extracted from the medical charts. Follow-up GFR was collected 6 months later. CKD patients with elevated depression scores were compared to patients with subclinical depression on medical and psychological variables. Results: Average Beck Depression Inventory (BDI) score was 10.0 ± 7.8, placing the mean below the cut-off for clinical elevation. GFR was significantly different for the two groups (nondepressed, 40.0 ± 11.3 vs. depressed 29.6 ± 8.9; p < 0.05). Similarly, patients with elevated depression scores reported lower quality of life (Short Form 36 Health Survey; p < 0.05) inferior social support (Interpersonal Support Evaluation List; p < 0.05), and worse community integration (Community Integration Questionnaire; p < 0.05). Utilizing a regression, with a model correcting for baseline GFR, the BDI explained 19% of the variance in GFR score (t = -2.0, p < 0.05) for subjects with decreased GFR. Conclusions: Increased levels of preexisting depression were associated with inferior quality of life, social support and kidney functioning. Depression scores explained a significant amount of variance in GFR scores at 6 months even when corrected for baseline variability. Elevated depression scores are prevalent in CKD populations and further research on the impact of depression interventions is warranted.

Cyclosporin induces renal proto-oncogene RNA message and increased transforming growth factor-beta prior to renal fibrosis: Modification by calcium channel blockade in the salt replete rat.

Background:  Chronic cyclosporin (CsA) administration has been shown to result in the replacement of epithelial cells in the kidney with fibrous tissue. These changes are kidney‐specific, as they do not occur in any other organ.

Dose Escalation, Safety and Impact of a Strain-Specific Probiotic (Renadyl™) on Stages III and IV Chronic Kidney Disease Patients

The primary goal of the open label study of Renadyl™ in stage 3 and 4 chronic kidney disease patients was to confirm the safety and tolerability of several doses of Renadyl™ (90, 180, 270 billion colony forming units). Secondary goals were to quantify quality of life improvement, to confirm efficacy in reducing commonly known uremic toxins, and to investigate the effects on several biomarkers of inflammation and oxidative stress. Participants underwent physical examinations and venous blood testing, and completed quality of life questionnaires. Data were analyzed with SAS V9.2. Of 31 subjects, 28 (90%) completed the study (2 lost to follow-up). The primary goal was met, as no significant adverse events were noted during the dose escalation phase. All patients tolerated the maximum dose (note: 1 subject reported nausea upon initial use). The escalation efficacy was shown in statistically significant changes of serum creatinine (months 2 to 6: -0.23 mg/dL, p<0.05), C-reactive protein (months 2 to 6: -0.28 mg/L, p<0.05), and hemoglobin (base to month 6: 0.35 mg/dL, p<0.01, months 1 to 6: 0.46 mg/dL, p<0.001, months 2 to 6: 0.58 mg/dL, p<0.0001). Trends, but not statistical significance, were noted in blood urea nitrogen (base to month 4: -3.56 mg/dL, p<0.09; months 1 to 4: -3.81 mg/dL, p<0.07). The secondary goal was also met, as QOL measure of physical functioning improved (base to month 6, p<0.05) and a strong trend in reduction of pain was observed (base to month 6, p<0.08).