Blockade of sodium-glucose co-transporters improves peritoneal ultrafiltration in uraemic rodent models.

BACKGROUND: The most used PD fluids contain glucose as a primary osmotic agent. Glucose peritoneal absorption during dwell decreases the osmotic gradient of peritoneal fluids and causes undesirable metabolic consequences. Inhibitors of sodium-glucose co-transporter (SGLT) type 2 are wildly used for the treatment of diabetes, heart and kidney failure. Previous attempts to use SGLT2 blockers in experimental peritoneal dialysis yielded contrasting results. We studied whether peritoneal SGLTs blockade may improve ultrafiltration (UF) via partial inhibition of glucose uptake from dialysis fluids. METHODS: Kidney failure was induced in mice and rats by bilateral ureteral ligation, and dwell was performed by injection of glucose-containing dialysis fluids. The effect of SGLT inhibitors on glucose absorption during fluid dwell and UF was measured in vivo. RESULTS: Diffusion of glucose from dialysis fluid into the blood appeared to be sodium-dependent, and blockade of SGLTs by phlorizin and sotagliflozin attenuated blood glucose increment thereby decreasing fluid absorption. Specific SGLT2 inhibitors failed to reduce glucose and fluid absorption from the peritoneal cavity in a rodent kidney failure model. CONCLUSIONS: Our study suggests that peritoneal non-type 2 SGLTs facilitate glucose diffusion from dialysis solutions, and we propose that limiting glucose reabsorption by specific SGLT inhibitors may emerge as a novel strategy in PD treatment to enhance UF and mitigate the deleterious effects of hyperglycaemia.

Can Dialysis Patients Identify and Diagnose Pulmonary Congestion Using Self-Lung Ultrasound?

BACKGROUND: With the recent developments in automated tools, smaller and cheaper machines for lung ultrasound (LUS) are leading us toward the potential to conduct POCUS tele-guidance for the early detection of pulmonary congestion. This study aims to evaluate the feasibility and accuracy of a self-lung ultrasound study conducted by hemodialysis (HD) patients to detect pulmonary congestion, with and without artificial intelligence (AI)-based automatic tools. METHODS: This prospective pilot study was conducted between November 2020 and September 2021. Nineteen chronic HD patients were enrolled in the Soroka University Medical Center (SUMC) Dialysis Clinic. First, we examined the patient's ability to obtain a self-lung US. Then, we used interrater reliability (IRR) to compare the self-detection results reported by the patients to the observation of POCUS experts and an ultrasound (US) machine with an AI-based automatic B-line counting tool. All the videos were reviewed by a specialist blinded to the performer. We examined their agreement degree using the weighted Cohen's kappa (Kw) index. RESULTS: A total of 19 patients were included in our analysis. We found moderate to substantial agreement between the POCUS expert review and the automatic counting both when the patient performed the LUS (Kw = 0.49 [95% CI: 0.05-0.93]) and when the researcher performed it (Kw = 0.67 [95% CI: 0.67-0.67]). Patients were able to place the probe in the correct position and present a lung image well even weeks from the teaching session, but did not show good abilities in correctly saving or counting B-lines compared to an expert or an automatic counting tool. CONCLUSIONS: Our results suggest that LUS self-monitoring for pulmonary congestion can be a reliable option if the patient's count is combined with an AI application for the B-line count. This study provides insight into the possibility of utilizing home US devices to detect pulmonary congestion, enabling patients to have a more active role in their health care.

Safety and Efficacy of Combined Low-Dose Lithium and Low-Dose Aspirin: A Pharmacological and Behavioral Proof-of-Concept Study in Rats.

Despite established efficacy in bipolar disorder patients, lithium (Li) therapy has serious side effects, particularly chronic kidney disease. We examined the safety and behavioral effects of combined chronic low-dose aspirin plus low-dose Li in rats to explore the toxicity and therapeutic potential of this treatment. Rats were fed regular or Li-containing food (0.1% [low-dose, LLD-Li] or 0.2% [standard-dose, STD-Li]) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. Renal function and gastric mucosal integrity were assessed. The effects of the combination treatment were evaluated in depression-like and anxiety-like behavioral models. Co-treatment with aspirin did not alter plasma Li levels. Chronic STD-Li treatment resulted in significant polyuria and polydipsia, elevated blood levels of creatinine and cystatin C, and increased levels of kidney nephrin and podocin-all suggestive of impaired renal function. Aspirin co-treatment significantly damped STD-Li-induced impairments in kidney parameters. There were no gastric ulcers or blood loss in any treatment group. Combined aspirin and LLD-Li resulted in a significant increase in sucrose consumption, and in the time spent in the open arms of an elevated plus-maze compared with the LLD-Li only group, suggestive of antidepressant-like and anxiolytic-like effects, respectively. Thus, we demonstrate that low-dose aspirin mitigated the typical renal side effects of STD-Li dose and enhanced the beneficial behavioral effects of LLD-Li therapy without aggravating its toxicity.

Elevated Circulating Cell-Free DNA in Hemodialysis-Treated Patients Is Associated with Increased Mortality.

BACKGROUND: Predicting the mortality risk of patients un-dergoing hemodialysis (HD) is challenging. Cell-free DNA (cfDNA) is released into circulation from dying cells, and its elevation is predictive of unfavorable outcome. In a pilot study, we found post-HD cfDNA level to be a predictor of all-cause mortality. Thus, the aim of this study was to confirm the prognostic power of cfDNA in a larger prospective cohort study conducted at 2 medical centers. METHODS: CfDNA levels were measured by a rapid fluorometric assay on sera obtained before and after 1 HD session. One hundred fifty-three patients were followed up to 46 months for mortality during which time 47 patients died. We compared the predictive value of cfDNA to age, comorbidities, and standard blood tests. RESULTS: Examining standard blood tests, only post-HD cfDNA levels were elevated in the non-survivor group compared to survivors (959 vs. 803 ng/mL, p = 0.04). Pre- and post-HD cfDNA levels correlated with age and diabetes. Patients with elevated cfDNA (>850 ng/mL) showed lower survival than those with normal levels. A Cox proportional hazard regression model demonstrated a significant hazard ratio of 1.92 for post-HD cfDNA levels. Logistic regression models showed that post-HD cfDNA was a significant predictor of mortality at 1-3 years with odd ratios of 4.61, 4.36, and 6.22, respectively. CONCLUSIONS: Post-HD cfDNA level was superior to standard blood tests and could serve as a biomarker to assist in decision-making for HD-treated patients.

Atrial Fibrillation Characteristics in Patients on Haemodialysis vs. Peritoneal Dialysis.

Atrial fibrillation (AF) is highly prevalent in dialysis patients, however whether its impact differs between patients on haemodialysis (HD) vs. peritoneal dialysis (PD) is unknown. We aimed to compare the association of AF and clinical outcomes in different dialysis modalities. We performed a population based retrospective cohort study, including adult patients who initiated dialysis between the years 2002 and 2015. Clinical, echocardiographic and laboratory data were reviewed and correlated with outcomes in HD vs. PD. During the study period, 1,130 patients began dialysis. Of the 997 patients without AF before dialysis initiation, 17% developed new-onset AF after the initiation of dialysis (17.3% of HD vs. 13.7% of PD patients, p = 0.27). Using multivariate analysis, only enlarged left atrium at dialysis initiation (hazard ratio (HR) 2.82, CI95% 2.00-3.99) and age (HR 1.04, CI95% 1.03-1.06) were significantly associated with AF. Dialysis modality was not a significant predictor of AF in either univariate or multivariate analysis. In conclusion, our study demonstrated that AF is common in dialysis patients irrespective of modality. In our cohort, the risk factors associated with AF were older age and enlarged left atrium. AF was associated with increased rates of heart failure and mortality, but not stroke.

Lithium nephrotoxicity.

Reports of toxic effects on the kidney of lithium treatment emerged very soon after lithium therapy was introduced. Lithium-induced nephrogenic diabetes insipidus is usually self-limiting or not clinically dangerous. Some reports of irreversible chronic kidney disease and renal failure were difficult to attribute to lithium treatment since chronic kidney disease and renal failure exist in the population at large. In recent years, large-scale epidemiological studies have convincingly shown that lithium treatment elevates the risk of chronic kidney disease and renal failure. Most patients do not experience renal side effects. The most common side effect of polyuria only weakly predicts increasing creatinine or reduced kidney function. Among those patients who do experience decrease in creatinine clearance, some may require continuation of lithium treatment even as their creatinine increases. Other patients may be able to switch to a different mood stabilizer medication, but kidney function may continue to deteriorate even after lithium cessation. Most, but not all, evidence today recommends using a lower lithium plasma level target for long-term maintenance and thereby reducing risks of severe nephrotoxicity.

The effects of hemodialysis on blood glutamate levels in chronic renal failure: implementation for neuroprotection.

PURPOSE: The purpose of the present study is to investigate whether hemodialysis (HD) is effective in lowering blood glutamate levels. In addition, we examined the effect of HD on glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) levels in the blood and described the rate and pattern of blood glutamate clearance during HD. MATERIALS AND METHODS: Blood samples were taken from 45 patients with stage V chronic kidney disease immediately after initiation of HD and hourly, for a total of 5 blood samples. Samples were sent for determination of glutamate, glucose, GOT, GPT, hemoglobin, hematocrit, urea, and creatinine levels. A blood sample from 25 healthy volunteers without chronic renal failure was used as a control for the determination of baseline blood levels of glutamate, GOT, and GPT. RESULTS: Glutamate and GPT levels in patients on HD were higher at baseline compared with healthy controls (P < .001). In the first 3 hours after HD, there was a decrease in blood glutamate levels compared with baseline levels (P < .00001). At the fourth hour, there was an increase in blood glutamate levels compared with the third hour (P < .05). CONCLUSIONS: Hemodialysis may be a promising method of reducing blood glutamate levels.

Successful treatment of mediastinal seminoma in a hemodialysis patient.

BACKGROUND: Extragonadal germ cell tumors (GCTs) are relatively uncommon neoplasms, affecting primarily men during the third and fourth decades of life. CASE REPORT: We describe an unusual case of mediastinal seminoma in a 21-year-old male on chronic peritoneal dialysis for renal failure of uncertain etiology. The patient was treated with chemotherapy consisting of etoposide and cisplatin (EP) combined with hemodialysis. Cisplatin (20 mg/m(2)), and etoposide (50 mg/m(2)) were given on days 1, 3, and 5 for induction. Hemodialysis was started 1 h after completion of etoposide infusion. Following this course of treatment, another 4 cycles of cisplatin (20 mg/m(2)), and etoposide (50 mg/m(2)) were given on successive days from day 1 to 5. Hemodialysis was carried out daily, prior to the start of chemotherapy. Subcutaneous PEG-filgrastim was given on day 6 in all cycles. The patient's status after the first post-induction treatment was complicated by a pseudomonas infection. Tumor response to chemotherapy was prompt with remission lasting to date, 17 months after diagnosis. CONCLUSION: This case report is the second description of chemotherapy given to a hemodialysis patient with extragonadal GCT. We suggest that treatment with EP combined with hemodialysis according to the presented protocol is feasible, and may result in a favorable outcome.

Prolonged fever following kidney biopsy: a case report.

This case report describes a patient with prolonged fever following a kidney biopsy. Workup disclosed a large perirenal and retroperitoneal hematoma. Neither imaging nor blood cultures supported an infective cause of his fever. Although the patient was initially treated with antibiotics, fever eventually resolved spontaneously. A review of the literature is provided addressing the association of fever with resorption of hematoma. Fever should be added to the list of potential complications of kidney biopsy. A conservative management is advocated.

Erythropoietin prevents dialysis fluid-induced apoptosis of mesothelial cells.

BACKGROUND: In peritoneal dialysis (PD)-treated patients, denudation of the mesothelium correlates with peritoneal fibrosis and vascular changes. Since recombinant human erythropoietin (rHuEPO) induces a range of cytoprotective cellular responses, rHuEPO treatment may reduce PD fluid (PDF)-induced damage. METHODS: To investigate the antiapoptotic effect and mechanism of rHuEPO in peritoneal mesothelial cells (PMCs), isolated mice PMCs were used for in vitro characterization of rHuEPO effects. To confirm the in vitro effects, active caspase-3 was analyzed in imprints of liver visceral peritoneum of mice pretreated overnight with rHuEPO (5000 U/kg intraperitoneally) and exposed to PDF (Dianeal 4.25%; Baxter Healthcare, Deerfield, Illinois, USA) for 4 hours. RESULTS: Mouse PMCs expressed EPO-receptor mRNA and protein. Short exposure to rHuEPO (5 U/mL) induced phosphorylation of JAK2, STAT5, and ERK1/2. PMCs pretreated for 1 hour with rHuEPO showed reduced PDF-induced caspase-3 activation (49.6%) and DNA fragmentation (38.4%) in comparison to cells treated by PDF alone (p < 0.05). rHuEPO treatment induced an increase in ERK1/2 phosphorylation and reduced levels of PDF-induced phospho-P38. PD98059, a specific inhibitor of ERK activation, fully blocked the protective effect of rHuEPO. In mice, rHuEPO reduced the apoptotic effect of PDF, as assessed by the level of active caspase-3. CONCLUSIONS: Our study presents new insights into clinical use of rHuEPO in the setting of PD. We found that rHuEPO provides ERK1/2-dependent protection to PMCs from PDF-induced apoptosis. The use of rHuEPO, or any of its new derivatives that do not stimulate erythropoiesis, should be considered for peritoneal preservation.

Spectrum of mycobacterial infections: tuberculosis and Mycobacterium other than tuberculosis in dialysis patients.

BACKGROUND: Patients with end-stage renal disease are at high risk of mycobacterial infection. OBJECTIVES: To analyze the difficulties in reaching an accurate diagnosis of tuberculosis in dialysis patients. METHODS: We conducted a retrospective follow-up of patients who attended our peritoneal and hemodialysis units during the 10 year period 1995-2005. RESULTS: Our dialysis unit diagnosed 10 cases of tuberculosis caused by Mycobacterium tuberculosis and 9 cases of Mycobacterium other than tuberculosis. In the former group, five patients had Mycobacterium in the sputum, which was diagnosed by intraabdominal mass biopsy in one, culture of the gastric juices in one, and pleural fluid culture or pleural biopsy in three. One of these patients was suffering from pleural TB as well as Potts disease. Of the patients with Mycobacterium other than tuberculosis, five were diagnosed by sputum cultures, three by urine cultures and one in peritoneal fluid. Differences in treatment and outcome were also reviewed. CONCLUSIONS: The diagnosis of TB in dialysis patients should be approached with a high index of suspicion. It is clear that extensive diagnostic procedures are required to ensure an accurate diagnosis of the disease. Tuberculosis incurs a significant added burden due to the need for isolation of infected patients within the dialysis unit. Treatment of patients with Mycobacterium other than tuberculosis should be addressed individually.

Post-reperfusion rapidly progressive glomerulonephritis in post-transplant IgA nephropathy.

Rapidly progressive glomerulonephritis (RPGN) is a rare occurrence in IgA nephropathy (IgAN) in renal transplant patients on immunosuppressive therapy. RPGN post ischemia-reperfusion has not been previously reported. We report a 62 year old male patient on azathioprine therapy, 9 years after left cadaveric renal transplantation due to end stage renal disease of unknown etiology, who presented with progressive deterioration in renal function and hematuria. Renal biopsy was consistent with IgAN. Duplex and CT scan demonstrated a decreased renal graft perfusion, due to severe atherosclerosis and stenosis of iliac arteries. The patient underwent left axilo-femoral bypass graft surgery with improvement in kidney graft perfusion and function. However, few weeks later, patient presented with pulmonary edema and advanced renal failure and he was initiated on hemodialysis. Repeated renal biopsy demonstrated crescentic GN. To the best of our knowledge, this is the first report of RPGN following reversal of ischemia and reperfusion. There was no evidence for atherembolic disease which is not uncommon after vascular surgery and it has been reported to be rarely associated to crescentic GN. Theoretical explanations for exacerbation of IgAN to crescentic GN, following successful reperfusion, could be enhancement of capillary damage, inflammation and oxidative stress. Putative mechanisms for these phenomena may be interaction of reperfusion-induced hyperfiltration, high intraglomerular capillary pressure, oxidative stress, increased polymorphonucler cells infiltration and inflammation; the presence of IgA immune deposits and azathioprine metabolites, both can also be associated to enhancement of oxidative stress.

Iron-mobilizing properties of the gadolinium-DTPA complex: clinical and experimental observations.

BACKGROUND: Gadolinium (Gd) magnetic resonance imaging (MRI) contrast agents are considered to be safe in patients with impaired renal function. Our study investigates a mechanism of severe iron intoxication with life-threatening serum iron levels in a haemodialysis patient following MRI with Gd-diethylenetriaminepentaacetic acid (Gd-DTPA) administration. His previous history was remarkable for multiple blood transfusions and biochemical evidence of iron overload. We hypothesized that Gd-DTPA may have an iron-mobilizing effect in specific conditions of iron overload combined with prolonged exposure to the agent. METHODS: For the in vitro study, Gd-DTPA was added to mice liver homogenate and iron metabolism parameters were measured after incubation in comparison with the same samples incubated with saline only. For the in vivo study, an experimental model of acute renal failure in iron-overloaded rats was designed. Previously iron-overloaded and normally fed rats underwent bilateral nephrectomy by renal pedicle ligation, followed by Gd-DTPA or saline injection. Iron and iron saturation levels were checked before and 24 h after Gd-DTPA or vehicle administration. RESULTS: Significant mobilization of iron from mice liver tissue homogenate in mixtures with Gd in vitro was seen in the control (saline) and in the experimental (Gd) groups (513+/-99.1 vs 1117.8+/-360.8 microg/dl, respectively; P<0.05). Administration of Gd-DTPA to iron-overloaded rats after renal pedicle ligation caused marked elevation of serum iron from baseline 143+/-3.4 to 570+/-8 microg/dl (P<0.0001). There were no changes of the named parameter, either in iron-overloaded anuric rats after saline injection or in normal diet uraemic animals, following Gd-DTPA administration. CONCLUSIONS: The combination of iron overload and lack of adequate clearance of Gd chelates may cause massive liberation of iron with dangerous elevation of free serum iron. It is highly recommended that after Gd contrast study, end-stage renal disease patients with probable iron overload should undergo prompt and intensive haemodialysis for prevention of this serious complication.

CD40 is expressed on human peritoneal mesothelial cells and upregulates the production of interleukin-15 and RANTES.

Limited data are available concerning the interaction between lymphocytes and human peritoneal mesothelial cells (HPMC) during peritonitis. CD40 is a member of the tumor necrosis factor (TNF) family of receptors whose ligand (CD154) is mainly expressed on the membrane of activated CD4-positive lymphocytes. CD154-CD40 cross-linking is a central event in antigen presentation, B-cell activation by T cells, and regulation of cytokine secretion from various types of cells. The goal of this study was to demonstrate in vitro the presence of CD40 on HPMC and to test its functionality in inducing interleukin-15 (IL-15) and RANTES. We assayed the levels of CD40 by reverse transcription-PCR and flow cytometry and IL-15 and RANTES by enzyme-linked immunosorbent assay. Genetically modified L cells that express elevated levels of CD154 (CD40L cells) were used to stimulate CD40. HPMC express CD40 mRNA and protein. After stimulation with interferon-gamma (IFNgamma, 5U/ml) or TNFalpha (1 ng/ml), there was a small increase in CD40 mRNA and protein levels; when both cytokines were applied, the increase in CD40 levels was more than threefold. CD40 ligation induced IL-15 production by HPMC and was additive to IFNgamma stimulation. CD40 ligation was strongly synergistic with IFNgamma in induction of RANTES (20-fold as compared with unstimulated HPMC), whereas neither ligation nor IFNgamma alone could induce RANTES. Pretreatment of HPMC with TNFalpha and IFNgamma increased the response to CD40 ligation in magnitudes that correlated with the elevation of CD40 levels induced by the pretreatment. To conclude, the presence of a functional CD40 on HPMC whose ligation induced IL-15 and RANTES production was detected. It is possible that this receptor acts as a major mediator of T-cell-regulated immune and inflammatory response during peritonitis.