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.

Admission of kidney patients to a closed staff nephrology department results in a better short-term survival.

BACKGROUND: The outcome of patients with chronic kidney disease (CKD) and acute kidney injury (AKI) is often dismal and measures to ameliorate their course are scarce. When admitted to the hospital, kidney patients are often hospitalized in general Medicine wards rather than in a specialized Nephrology department. In the current study, we compared the outcome of two cohorts of kidney patients (CKD and AKI) admitted either to general open-staff (with rotating physicians) Medicine wards or to a closed-staff (non-rotating Nephrologists) Nephrology ward. METHODS: In this population-based retrospective cohort study, we enrolled 352 CKD patients and 382 AKI patients admitted to either Nephrology or General Medicine wards. Short-term (< = 90 days) and long-term (>90 days) outcomes were recorded for survival, renal outcomes, cardiovascular outcomes, and dialysis complications. Multivariate analysis was performed using logistic regression and negative binomial regression adjusting to potential sociodemographic confounders as well as to a propensity score based on the association of all medical background variables to the admitted ward, to mitigate the potential admittance bias to each ward. RESULTS: One hundred and seventy-one CKD patients (48.6%) were admitted to the Nephrology ward and 181 (51.4%) were admitted to general Medicine wards. For AKI, 180 (47.1%) and 202 (52.9%) were admitted to Nephrology and general Medicine wards, respectively. Baseline age, comorbidities and the degree of renal dysfunction differed between the groups. Using propensity score analysis, a significantly reduced mortality rate was observed for kidney patients admitted to the Nephrology ward vs. general Medicine in short term mortality (but not long-term mortality) among both CKD patients admitted (OR = 0.28, CI = 0.14-0.58, p = 0.001), and AKI patients (or = 0.25, CI = 0.12-0.48, p< 0.001). Nephrology ward admission resulted in higher rates of renal replacement therapy (RRT), both during the first hospitalization and thereafter. CONCLUSIONS: Thus, a simple measure of admission to a specialized Nephrology department may improve kidney patient outcome, thereby potentially affecting future health care planning.

The accuracy of 8-hour ambulatory blood pressure monitoring, adjusted to seasons.

Ambulatory blood pressure monitoring (ABPM) is considered the most reliable and accurate measurement of blood pressure (BP). However, the use of ABPM has some limitations, which make it difficult to complete for the entire 24 h. We aimed to establish in which part of the day BP measurements are in highest correlation with full ABPM (over 24 h) results. We performed a retrospective cross-sectional study which included 3113 full ABPM. Each ABPM was divided into 6- and 8-hour segments, and mean BP in each time segment was calculated. Linear mix models for describing BP by BP in each time segment were performed. A total of 3113 ABPM measurements carried out on 2676 patients (mean age 57.78 ± 14.74) were included in the study. Linear mix models demonstrated significant association between mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) in full ABPM, and SBP and DBP between 2-10 PM, respectively (SBP: ß = 0.902, p < 0.001; DBP: ß = 0.839, p < 0.001), adjusted for gender, age, season, and relevant interactions. This section had higher coefficient correlations than other sections which were examined. The study findings indicate high correlation between BP between 2-10 PM, and BP in full-ABPM, by each season. This time segment may be ideal for short-term BP monitoring as an initial screening test and for patients who are unable to complete full ABPM. However, since this time segment does not include nighttime hours, there is a risk of underdiagnosis of non-dipper.

Renal Tubular Acidosis Type I with Prominent Hypokalemia and Nephrolithiasis as a Presentation of Sjögren's/Systemic Lupus Erythematosus Disease.

Female patient, suffering from nephrolithiasis, at the age of 32 was admitted for renal colic caused by a stone obstructing UP junction with left hydronephrosis. Nephrostomy was placed, resulting in brisk diuresis. Severe metabolic acidosis with normal anion gap and urine pH of 6.5 was noted. Potassium level dropped to extremely low level (1.6 mEq/L), causing muscle paralysis and respiratory failure, necessitating mechanical ventilation. The patient was treated by potassium chloride infusion, followed by correction of severe metabolic acidosis by sodium bicarbonate. Diagnosis of distal type renal tubular acidosis type I (dRTA) was made based on normal anion gap metabolic acidosis, alkaline urine, hypokalemia, and nephrolithiasis. Five years later, the patient presented with severe hypoxia, lung opacities, and bronchiolitis obliterans organizing pneumonia which was confirmed by bronchoscopy with lung tissue biopsy. Concurrently, the patient presented with dry mouth, pruritus, skin rash with hypocomplementemia, elevated anti-DNA, anti-Ro, and anti-SmAb. Diagnosis of overlap Sjögren's/systemic lupus erythematosus disease was done and treatment by hydroxychloroquine, prednisone, and azathioprine was started. Possible presence of Sjögren's syndrome should be considered in adult patients with unexplained dRTA.

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.

Treatment of extreme hypercalcaemia: the role of haemodialysis.

A patient with extremely high calcium level of 23.9 mg/dL (5.97 mmol/L) was admitted to our department unconscious with pathological ECG recording, demonstrating shortening of QT interval. The patient was treated by fluid resuscitation, bisphosphonates, salmon calcitonin and steroids. Haemodialysis with low calcium bath had been promptly provided with improvement of consciousness and calcium level. ECG changes disappeared. Subsequent investigations revealed hyperparathyroidism and a large parathyroid adenoma was then surgically removed. Extreme and rapid calcium elevation (parathyroid crisis) is rarely seen in primary hyperparathyroidism and usually is distinctive for malignancy. In the context of acute kidney injury and refractory hypercalcaemia with life-threatening complications (coma, ECG changes with impending danger of arrhythmia), haemodialysis may effectively decrease calcium levels. It should be pointed out that dialysis is an efficient method of treatment of refractory hypercalcaemia, parathyroid crisis, but it is rarely used due to its invasive nature.

Clinical manifestations of adult tubulointerstitial nephritis and uveitis (TINU) syndrome.

To describe the clinical manifestations and response to therapy of adult patients with tubulointerstitial nephritis and uveitis (TINU) syndrome and to provide suggested work-up and treatment. We retrospectively examined medical records of all adult patients suffering from TINU at Soroka University Medical Center (SUMC) over the past 15 years. Characteristics of ocular and nephrologic manifestations were investigated with particular attention given to age, presenting signs and symptoms, treatment and course of disease. Five adult patients (median age 44 years) were diagnosed with TINU syndrome and followed from 1991-2006 at SUMC. As renal involvement was present at initial evaluation in all patients, they were all treated with steroids. They all suffered from moderate to severe ocular inflammation and most of them relapsed; they also suffered from TINU-related non-specific symptoms. The uveitis in our adult patients was more severe than previously reported. Renal failure and TINU-related non-specific symptoms were observed in all patients and led to the diagnosis of TINU and to systemic therapy which is more aggressive than the usual therapy for uvetis. Thus, early suspicion and diagnosis of TINU may help to direct the appropriate therapy for the degree of uveitis observed in these patients.

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.

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.

Minor impairment of oral iron absorption in non-diabetic new dialysis patients.

BACKGROUND: Iron absorption is impaired in end-stage renal disease (ESRD). ESRD duration and diabetes mellitus (DM) are prominent risk factors in ESRD patients, associated with multi-system complications involving the gastrointestinal tract. Therefore, we suggest that DM and ESRD duration contribute to iron absorption impairment in ESRD. Since we administer oral iron during hemodialysis (HD) sessions, we assessed the relationship of DM and ESRD duration to intradialytic iron absorption. METHODS: A 4-hr intradialytic oral iron absorption test was performed in 22 non-diabetic patients and 21 diabetic chronic HD patients. Elemental iron, 100 mg (iron(III)-hydroxide-polymaltose) was administered at dialysis start. Serum iron levels were measured hourly since iron ingestion, and standardized according to transferrin levels to correct for intradialytic blood volume changes. The primary end point was peak increase in standardized serum iron level (DeltaI). ESRD duration and DM were defined as months on dialysis and the presence of DM before dialysis initiation, respectively. Evaluated confounding factors included age, gender, dry weight (DW), ultrafiltration volume (UF), UF/DW, eKt/V, transferrin saturation (%SAT), ferritin, parathyroid hormone (PTH), C-reactive protein (CRP) and erythropoietin (EPO) dosage. RESULTS: DeltaI was significantly inversely correlated with ESRD duration. DM was significantly associated with lower DeltaI after statistically controlling for ESRD duration. These relationships remained significant after statistically controlling for %SAT, UF and UF/DW. %SAT was significantly inversely correlated with DeltaI, but contributed to lower variability of DeltaI (11%) than DM (15.2%) and ESRD duration (16.5%). CONCLUSIONS: Intradialytic iron absorption was less impaired in non-diabteic patients with shorter ESRD duration. Therefore, intradialytic oral iron therapy could be successful in these patients.

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.