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.

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.

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.

Blocking adenosine A2A receptor reduces peritoneal fibrosis in two independent experimental models.

BACKGROUND: Long-term peritoneal dialysis (PD) is associated with peritoneal fibrosis and loss of function. It has been shown that activation of the adenosine A(2A) receptor (A(2A)R) promotes tissue repair, wound healing and extracellular matrix (ECM) production. We have previously shown that adenosine is a potent regulator of inflammation in the peritoneum. In the current study, we explored the role of adenosine and the A(2A)R in two experimental models. METHODS: Collagen deposition was evaluated in primary peritoneal fibroblasts following treatment with an A(2A)R agonist and antagonist. In addition, peritoneal fibrosis was induced by i.p. injection of either chlorhexidine gluconate for 2 weeks or 4.25% glucose peritoneal dialysis fluid (PDF) for 1 month. The development of fibrosis was compared between wild-type (WT) and WT mice treated with caffeine (an A(2A)R antagonist) in drinking water or between (A(2A)R(+/+)) mice and A(2A)R-deficient mice (A(2A)R(-/-)). RESULTS: Adenosine or the A(2A)R agonist CGS21680 stimulated collagen production by peritoneal fibroblasts in vitro and A(2A)R antagonists (ZM241385 and caffeine) blocked this effect. Consistent with these results, caffeine-treated WT or A(2A)R(-/-) mice had reduced submesothelial thickness, collagen deposition and mRNA levels of fibroblast-specific protein (FSP-1) and connective tissue growth factor (CTGF). In addition, treatment with caffeine in vitro and in vivo diminished A(2A)R and A(2B)R mRNA levels induced by CG or PDF while it upregulated A(1)R levels. CONCLUSION: Our data suggest that adenosine through its A(2A)R promotes peritoneal fibrosis and therefore should be considered as a target for pharmacological intervention.

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.

Dynamic component chemiluminescent sensor for assessing circulating polymorphonuclear leukocyte activity of peritoneal dialysis patients.

Recurrent bacterial peritonitis is a major complication in peritoneal dialysis (PD) patients, which is associated with polymorphonuclear leukocyte (PMN) functional changes and can be assessed by a chemiluminescent (CL) reaction. We applied a new approach of a dynamic component chemiluminescence sensor for the assessment of functional states of PMNs in a luminol-amplified whole-blood system. This method is based on the evaluation of CL kinetic patterns of stimulated PMNs, while the parallel measurements of intracellular and extracellular production of reactive oxygen species (ROS) from the same sample can be conducted. Blood was drawn from diabetic and nondiabetic patients during follow-up, and during peritonitis. Healthy medical personnel served as the control group. Chemiluminescence curves were recorded and presented as a sum of three biological components. CL kinetic parameters were calculated, and functional states of PMNs were assessed. Data mining algorithms were used to build decision tree models that can distinguish between different clinical groups. The induced classification models were used afterward for differentiating and classifying new blind cases and demonstrated good correlation with medical diagnosis (84.6% predictive accuracy). In conclusion, this novel method shows a high predictive diagnostic value and may assist in detection of PD-associated clinical states.

Sporadic culture-negative peritonitis in peritoneal dialysis patients--absence of endotoxin in dialysate.

BACKGROUND: Indiscriminate use of broad-spectrum antibiotics in peritonitis may have either unwanted side effects or contribute to the development of antibiotic resistance. It is tempting to use broad-spectrum antibiotics in cases of culture-negative peritonitis. This study examines whether Gram-negative agents have to be considered in the management of culture-negative peritonitis. Gram-negative agents are manifested by endotoxin easily detected by the Limulus amebocyte lysate (LAL) test. METHODS: 138 episodes of Gram-negative and culture-negative peritonitis have been retrospectively analyzed; episodes of Gram-negative peritonitis were controls. Correlation between LAL and culture results was compared between the two groups. The LAL test was performed using a commercial kit by incubating a mixture of dialysate effluent and LAL reagent at 37 degrees C. Development of a stable solid clot was considered positive. RESULTS: In controls, 80 out of 117 Gram-negative peritonitis were LAL positive (68%). None of the 21 culture-negative episodes was LAL positive. In 7 recurrences of Gram-negative peritonitis, the LAL test turned from negative to positive but in none of the recurrences of culture-negative peritonitis. The difference in correlation was highly significant. CONCLUSIONS: Gram-negative organisms do not seem to be involved in sporadic culture-negative peritonitis. In episodes of peritonitis in which bacteriologic cultures stay negative for 48 h, initial coverage of Gram-negative organisms may be dropped.

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.

Induction of protein oxidation by intravenous iron in hemodialysis patients: role of inflammation.

BACKGROUND: Oxidative stress and inflammation contribute to the high prevalence and severity of atherosclerosis, infections, and beta2-microglobulin amyloidosis; and thus, to reduced survival rate and quality of life in hemodialysis (HD) patients. Inflammation induces oxidative stress by production of the oxidants: superoxide anion, hydrogen peroxide, and hypochlorite. Intravenous iron (IVIR), administered in HD patients to correct anemia, can release free iron, that may react with hydrogen peroxide to produce the strong oxidant hydroxyl radical. Inflammation-induced lipid and protein oxidation and IVIR-induced lipid oxidation were shown in HD patients. However, IVIR-induced protein oxidation and a relationship between inflammation and IVIR-induced oxidative stress have not been reported to date. METHODS: We examined the effect of IVIR administration on markers of protein oxidation in HD patients (advanced oxidation protein products [AOPPs], thiol, and dityrosine) in relation to such inflammatory markers as C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-alpha). Iron saccharate, 100 mg, was administered to 19 HD patients for 1 hour after 3.5 hours of high-flux dialysis. Blood samples were drawn pre-HD, pre-IVIR, and post-IVIR for iron, transferrin, TNF-alpha, AOPP, thiol, total antioxidant capacity (TEAC), and dityrosine levels and pre-HD for ferritin and CRP levels. RESULTS: IVIR administration induced a 37% increase in AOPP level (P < 0.001), which correlated positively with pre-HD CRP level (r = 0.72; P < 0.05) and was greater in patients with a greater pre-HD TNF-alpha level (P < 0.05). IVIR administration did not affect TEAC, thiol, dityrosine, or TNF-alpha levels. CONCLUSION: IVIR administration induced an increase in protein oxidation (AOPP levels) that was related to the degree of inflammation.