losartan-potassium and Nephritis--Interstitial

Topics: Adult; Anemia; Anti-Bacterial Agents; Appendicitis; Erythropoietin; Female; Humans; Infant, Newborn; Iron; Kidney Failure, Chronic; Meningomyelocele; Nephritis, Interstitial; Polyradiculopathy; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic; Pregnancy Outcome; Renal Dialysis; Urinary Bladder, Neurogenic; Urinary Tract Infections

The renal interstitial compartment, situated between basement membranes of epithelia and vessels, contains two contiguous cellular networks. One network is formed by interstitial fibroblasts, the second one by dendritic cells. Both are in intimate contact with each other. Fibroblasts are interconnected by junctions and connected to basement membranes of vessels and tubules by focal adhesions. Fibroblasts constitute the "skeleton" of the kidney. In the renal cortex, fibroblasts produce erythropoietin and are distinguished from other interstitial cells by their prominent F-actin cytoskeleton, abundance of rough endoplasmic reticulum, and by ecto-5'-nucleotidase expression in their plasma membrane. The resident dendritic cells belong to the mononuclear phagocyte system and fulfil a sentinel function. They are characterized by their expression of MHC class II and CD11c. The central situation of fibroblasts suggests that signals from tubules, vessels, and inflammatory cells converge in fibroblasts and elicit an integrated response. Following tubular damage and inflammatory signals fibroblasts proliferate, change to the myofibroblast phenotype and increase their collagen production, potentially resulting in renal fibrosis. The acquisition of a profibrotic phenotype by fibroblasts in renal diseases is generally considered a main causal event in the progression of chronic renal failure. However, it might also be seen as a repair process.

Topics: 5'-Nucleotidase; Actins; Animals; Dendritic Cells; Erythropoietin; Fibroblasts; Fibrosis; Humans; Kidney Cortex; Kidney Failure, Chronic; Mice; Nephritis, Interstitial

The present work reviews the mechanisms and close association between glomerular and tubular damage and its relationship to renal functional impairment. In addition, we present an overview of the pathways involved in the progression of tubulointerstitial fibrosis and a brief summary of the treatments used to retard the progression to end-stage renal failure.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Progression; Erythropoietin; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Neovascularization, Physiologic; Nephritis, Interstitial; Renal Insufficiency

IL-17-producing CD4+ cells (TH17) are pathogenically linked to autoimmunity including to autoimmune kidney disease. Erythropoietin's (EPO) newly recognized immunoregulatory functions and its predominant intra-renal source suggested that EPO physiologically regulates TH17 differentiation, thereby serving as a barrier to the development of autoimmune kidney disease. Using in vitro studies of human and murine cells and in vivo models, we show that EPO ligation of its receptor (EPO-R) on CD4+ T cells directly inhibits TH17 generation and promotes trans-differentiation of TH17 into IL-17-FOXP3+CD4+ T cells. Mechanistically, EPO/EPO-R ligation abrogates upregulation of SGK1 gene expression and blocks p38 activity to prevent SGK1 phosphorylation, thereby inhibiting RORC-mediated transcription of IL-17 and IL-23 receptor genes. In a murine model of TH17-dependent aristolochic acid (ArA)-induced, interstitial kidney disease associated with reduced renal EPO production, we demonstrate that transgenic EPO overexpression or recombinant EPO (rEPO) administration limits TH17 formation and clinical/histological disease expression. EPO/EPO-R ligations on CD4+ T cells abrogate, while absence of T cell-expressed EPO-R augments, TH17 induction and clinical/histological expression of pristane-induced glomerulonephritis (associated with decreased intrarenal EPO). rEPO prevents spontaneous glomerulonephritis and TH17 generation in MRL-lpr mice. Together, our findings indicate that EPO physiologically and therapeutically modulate TH17 cells to limit expression of TH17-associated autoimmune kidney disease.

Topics: Animals; Aristolochic Acids; Cells, Cultured; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Humans; Immediate-Early Proteins; Interleukin-17; Lupus Nephritis; Male; Mice; Mice, Inbred MRL lpr; Mice, Transgenic; Nephritis, Interstitial; Phosphorylation; Primary Cell Culture; Protein Serine-Threonine Kinases; Receptors, Erythropoietin; Receptors, Interleukin; Severity of Illness Index; T-Lymphocytes, Regulatory; Th17 Cells

Tubulointerstitial inflammation is the characteristics of renal ischemia reperfusion injury (IRI) that is inevitable in kidney transplantation. Erythropoietin (EPO) has recently been shown to have protective effects on renal IRI by anti-apoptosis and anti-oxidation. Here, the effect and mechanism of EPO on renal IRI were further investigated, with a focus on tubulointerstitial inflammation.. Male Sprague-Dawley rats were administrated with saline or EPO prior to IRI induced by bilateral renal pedicle clamping. Twenty-four hours following reperfusion, the effects of EPO on renal IRI were assessed by renal function and structure, tubulointerstitial myeloperoxidase (MPO) positive neutrophils, and proinflammatory mediator gene expression. The translocation and activity of NF-κB in renal tissues were also evaluated.. Compared with control groups, the EPO treated group exhibited lower serum urea and creatinine levels, limited tubular necrosis with a lower score of renal histological lesion. MPO positive cells in the tubulointerstitial area were greatly increased by IRI, but significantly reduced by the treatment of EPO. The gene expression of proinflammatory cytokines (IL-1β, IL-6, IL-10, and TNF-α) and chemokine (MCP-1) was also significantly decreased by EPO. In addition, less activation and nuclear-translocation of NF-κB was observed in the kidney treated by EPO as well.. EPO improved renal function and structure in IRI rats via reducing neutrophils in the tubulointerstitium, the production of proinflammatory cytokines and chemokine, as well as the activation and nuclear-translocation of NF-κB. EPO may have potential clinical applications as an anti-inflammation agent clinically for a wide range of injury.

Topics: Animals; Apoptosis; Creatinine; Cytokines; Erythropoietin; Kidney; Male; Models, Animal; Necrosis; Nephritis, Interstitial; NF-kappa B; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Topics: Animals; Erythropoietin; Kidney; Male; Nephritis, Interstitial; Reperfusion Injury

Topics: Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nephritis, Interstitial; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Pleiotropic effects of recombinant human erythropoietin (EPO) have recently been discovered in many non-renal animal models. The renoprotective effects of EPO and carbamylated-erythropoietin (CEPO), a novel EPO which has a small stimulatory effect on hemoglobin, have never been explored in unilateral ureteral obstruction (UUO), a chronic tubulointerstitial (TI) disease model which is independent of systemic factors.. In order to examine the effects of EPO and CEPO treatments on renal TI injury, 36 male Sprague-Dawley rats, weighing 250-320 g, underwent: UUO without treatment (group 1, n = 12), UUO with EPO (groups 2, n = 12), and UUO with CEPO (group 3, n = 12). EPO and CEPO were injected subcutaneously at a dose of 5000 u/kg to each respective rat at 1 day pre-UUO and at day 3, 7 and 10 post-UUO. After days 3, 7, and 14 of UUO, TI injury, collagen, alpha-smooth muscle actin (alpha-SMA) positive cell, ED1-positive cell, terminal deoxynucleotidyl transferase (TdT) mediated nick-end labeling (TUNEL)-positive cell, and transforming growth factor-beta1 (TGF-beta1) messenger ribonucleic acid (mRNA) were determined. Bcl-2 expression was also assessed to verify the mechanism of apoptosis.. At day 14 UUO caused severe TI injury with a significant increase in collagen, alpha-SMA, ED1-positive cell, TUNEL-positive cell, and TGF-beta1 mRNA expression. Administration of EPO and CEPO significantly attenuated TI injury, collagen, ED1-positive cells, and TUNEL-positive cells. Only CEPO-treated rats had decreased alpha-SMA positive cells and TGF-beta1 mRNA. The expression of Bcl-2 was demonstrated only in EPO-treated rats. The hematocrit levels in EPO-treated rats were higher than the control and CEPO-treated rats.. EPO and CEPO can limit 14-day UUO-induced TI injury by reducing inflammation, interstitial fibrosis, and tubular apoptosis.

Topics: Animals; Erythropoietin; Kidney Tubules; Male; Nephritis, Interstitial; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Ureteral Obstruction

Several studies have shown that erythropoietin (EPO) can protect the kidneys from ischemia-reperfusion injury and can raise the hemoglobin (Hb) concentration. Recently, the EPO molecule modified by carbamylation (CEPO) has been identified and was demonstrated to be able to protect several organs without increasing the Hb concentration. We hypothesized that treatment with CEPO would protect the kidneys from tubular apoptosis and inhibit subsequent tubulointerstitial injury without erythropoiesis. The therapeutic effect of CEPO was evaluated using a rat ischemia-reperfusion injury model. Saline-treated kidneys exhibited increased tubular apoptosis with interstitial expression of alpha-smooth muscle actin (alpha-SMA), while EPO treatment inhibited tubular apoptosis and alpha-SMA expression to some extent. On the other hand, CEPO-treated kidneys showed minimal tubular apoptosis with limited expression of alpha-SMA. Moreover, CEPO significantly promoted tubular epithelial cell proliferation without erythropoiesis. In conclusion, we identified a new therapeutic approach using CEPO to protect kidneys from ischemia-reperfusion injury.

Topics: Animals; Apoptosis; Cell Proliferation; Erythropoiesis; Erythropoietin; Kidney; Kidney Diseases; Male; Nephritis, Interstitial; Phosphatidylinositol 3-Kinases; Proto-Oncogene Protein c-ets-1; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction

To recognize the characteristics of anemia in patients with drug-associated renal parenchymal ARF and to investigate the possible relations among Hb, serum level of EPO and the renal tubulointerstitial injury.. Sixteen in-patients with drug-associated renal parenchymal ARF (including ATN and ATIN groups) for the last five years and 8 healthy volunteers (control group) were assessed in this study. The general information of these patients was analyzed retrospectively. Anemia related laboratory parameters, serum EPO, serum creatinine (Scr) and the renal tubular function from the samples on the time of renal biopsy in each group were compared. For pathological comparison of renal tubulointerstitial pathological changes, renal biopsy specimens from 5 patients with mild non-IgA mesangial proliferative glomerulonephritis were used as negative controls. The pathological changes in renal tubules and interstitial area were semi-quantitive scored by a computer imaging system. The correlations between Hb and EPO levels, as well as EPO level and renal function or pathological injury index were analyzed, respectively.. There was no significant difference among the ages, genders and the time intervals both from the administration to the onset of the disease and from the onset to the kidney biopsy among ATN and ATIN groups. Scr level was all higher than that in the control group (P<0.05). The renal tubular function injury index and the tubular interstitial pathologic injury index in the two groups were relatively elevated, in which the ATIN group had the highest indexes compared to the others (P<0.01). There were more anemia patients in ATIN group. It showed much lower levels of Hb, Hct and RBC than those in the control group (P<0.01). ATN group possessed fewer anemia patients and the levels of Hb, Hct and RBC remained in the normal range. The remarkable decline of EPO levels was found as 84.8% and 70.7% in the ATN and ATIN groups, respectively (P<0.01). In all patients with renal parenchyma ARF, the levels of Hb and EPO showed an obvious positive correlation (r=0.589, P<0.01), but the negative correlations existed between EPO and Scr, the renal tubular function injury index and renal tubular interstitial pathological injury index, respectively (P<0.05).. The mechanism of the anemia in the drug-associated parenchymal ARF patients may be due to the lack of intrinsic EPO secretion, mainly induced by acute renal tubular interstitial injury, which contributes to the decreased genesis of red blood cells.

Topics: Acute Kidney Injury; Adult; Anemia; Creatinine; Erythropoietin; Female; Humans; Male; Nephritis, Interstitial; Retrospective Studies

The hematopoietic cytokine erythropoietin has cytoprotective effects in endothelial cells in vitro that are mediated through direct activation of the pro-survival Akt tyrosine kinase signaling pathway. We tested the hypothesis that low-dose therapy with the long-acting recombinant human erythropoietin analogue darbepoetin alpha protects vascular endothelium in vivo in a classic remnant kidney rat model characterized by severe endothelial damage, progressive vascular sclerosis, and ischemia-induced tissue fibrosis.. Using a parallel group study design, we randomly assigned animals after 5/6 nephrectomy to treatment with either saline (n=36) or 0.1 microg/kg body wt darbepoetin (n=24) subcutaneously once weekly. We monitored hematocrit, blood pressure, and serum creatinine regularly and obtained renal tissue 6 weeks after nephrectomy for morphological and immunohistochemical analysis. Darbepoetin-treated animals had significantly improved survival compared with saline-treated controls (63% versus 33%; P<0.05), although hematocrit levels were similar in both groups. Darbepoetin treatment ameliorated endothelial damage; attenuated the composite tissue injury score (saline 1.9+/-0.4; darbepoetin 0.4+/-0.2; P<0.001), which included vascular sclerosis, glomerulosclerosis, and tubulointerstitial damage; and preserved renal function. We found persistent activation of the pro-survival Akt signaling pathway in endothelial and epithelial glomerular cells in darbepoetin-treated animals, accompanied by a significant reduction of apoptotic cell death in renal tissue.. Low-dose darbepoetin treatment confers vascular and tissue protection that is associated with persistent stimulation of the pro-survival Akt signaling pathway. The use of recombinant human erythropoietin or analogues may have utility in preventing ischemia-related progressive vascular injury and organ failure.

Topics: Animals; Apoptosis; Darbepoetin alfa; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Endothelium, Vascular; Erythropoietin; Glomerulosclerosis, Focal Segmental; Hematocrit; Hematopoietic Stem Cell Mobilization; Hypertension, Renal; Ischemia; Kidney; Life Tables; Male; Multiple Organ Failure; Nephrectomy; Nephritis, Interstitial; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Random Allocation; Rats; Rats, Sprague-Dawley; Signal Transduction

In 1980, the first Moroccan hemodialysis center was founded in Casablanca. The number of centers has been increasing since then, to reach 61 centers to wards the of 1996. There are 1800 hemodialysed (males 59%, females 41%) with and average age of 51 +/- 4 years. In about one third of the cases, the cause of the end stage renal failure remains unknown. However, chronic glomerulonephritis comes at the head of known causes (25%), followed by interstitial nephritis (19%). A temporary vascular access (catheter) was necessary in 81% of cases when dialysis has started in emergency in 61% of patients. Infections were the most frequent complications (21%) namely septicaemia (8%) and tuberculosis (7%). The vaccination against hepatitis B virus is done systematically in all the centers, and the number of chronic carriers of HBS Ag is about 7%. Further more, serological C virus is positive in 40% of the hemodialysed patients. Cardio-vascular complications were dominated by percarditis (13%) especially at the beginning of the dialysis. Anaemia remains very frequent and often very important requiring multiple blood transfusions (35%) in the absence of erythropoietin treatment. The death rate, which is very difficult to estimate, is of about 18%. Peritoneal dialysis was used in 50 patients but only four patient continued on peritoneal dialysis therapy. 108 patients were transplanted (23 cases in Morocco, 85 in other countries) with a waiting list of 0 to 12 years. Hemodialysed Moroccan's population is characterised by the high number of unknown causes and the gravity of the admission stage. A renal effort in prophylactic should be performed to avoid certain causes of renal failure.

Topics: Adolescent; Adult; Aged; Ambulatory Care Facilities; Anemia; Cardiovascular Diseases; Carrier State; Catheters, Indwelling; Child; Child, Preschool; Comorbidity; Erythropoietin; Female; Glomerulonephritis; Hepatitis, Viral, Human; Humans; Infant; Infections; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Morocco; Nephritis, Interstitial; Peritoneal Dialysis; Renal Dialysis; Transfusion Reaction; Vaccination

Familial juvenile nephronophthisis (NPH) is a hereditary form of chronic tubulointerstitial nephritis with onset in childhood. About one-third of patients develop anaemia before renal insufficiency. We investigated the pathogenetic mechanisms leading to anaemia by comparing 6 patients with NPH and 12 reference patients with other renal diseases. We studied their iron metabolism and measured transferrin receptor-ferritin ratios. There was no evidence for iron deficiency or haemolysis. The serum erythropoietin concentrations of the patients with NPH (12 +/- 2.3 U/I) were low compared with the 12 reference patients (25 +/- 18.9 U/I). In the 2 patients with NPH who were fully investigated, the pharmacokinetics of recombinant human erythropoietin appeared normal. Thus, anaemia in patients with NPH does not result from iron deficiency or correlate with impaired iron status. The mechanism underlying the anaemia of NPH appears to affect the function or regulation of the cells producing erythropoietin.

Topics: Adolescent; Anemia; Child; Erythropoietin; Female; Humans; Iron; Male; Nephritis, Interstitial

Thyroid function has been assessed in 36 clinically euthyroid patients undergoing regular haemodialysis. The influence of erythropoietin administration on the thyroid function tests has been determined. Thyroid-stimulating hormone (TSH) has been found to be elevated in 8% of the patients. Free tri-iodothyronine was below the normal range in 67% of the population. Free thyroxine (FT4) was low in 67% of the patients when tested by an analogue method. FT4 tested by a 2-stage method in a subgroup of 22 patients was abnormally low in only 23% of the patients. Erythropoietin did not seem to improve these thyroid abnormalities despite a partial correction of the anaemia. A rise in FT4 was also observed after haemodialysis without a concomitant change in TSH concentration. This FT4 elevation was attributed to the effect of heparin.

Topics: Adult; Aged; Erythropoietin; Female; Glomerulonephritis; Humans; Injections, Subcutaneous; Male; Middle Aged; Nephritis, Interstitial; Radioimmunoassay; Renal Dialysis; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Adult; Aged; Erythropoiesis; Erythropoietin; Female; Glomerular Filtration Rate; Glomerulonephritis; Hemoglobinometry; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Nephritis, Interstitial; Polycystic Kidney Diseases

We have investigated anemia in patients at different stages of the evolution of three chronic renal diseases: Balkan endemic nephropathy (BEN), chronic pyelonephritis (PN) and chronic glomerulonephritis (GN). A total of 88 patients with creatinine clearances from 9 to 118 ml/min and hemoglobin concentrations from 70 to 160 g/l were studied with regard to the relationship, if any, between erythropoietin production and the type and stage of nephropathy. Anemia in BEN was a particular focus of interest since it had been stated that in BEN, anemia precedes renal failure. Our data neither prove nor disprove this statement. A significant positive correlation between creatinine clearance and hemoglobin concentration was found in all three nephropathies, indicating that in the patients studied the severity of anemia increased with the impairment of renal function regardless of the underlying disease. Serum levels of immunoreactive erythropoietin were in the normal range in 54 patients, moderately increased in 20 and slightly decreased in 14. The erythropoietin level appears to be unrelated to the stage of renal failure or the type of nephropathy. The only exception was the subgroup where the patients with glomerulonephritis and normal renal function had increased serum erythropoietin levels and significantly higher parameters of red blood cell concentration than the patients from the same subgroup with tubulointerstitial nephropathies. In patients with severe renal failure and anemia, serum erythropoietin levels were inappropriately low for the degree of anemia, indicating that erythropoietin plays a role in the pathogenesis of the anemia.

Topics: Adult; Aged; Anemia; Balkan Nephropathy; Creatinine; Erythropoietin; Female; Glomerulonephritis; Humans; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Nephritis, Interstitial; Pyelonephritis

Five women aged 50-64 years with chronic renal failure, due to interstitial nephritis, enlisted in a regular dialyzation programme were treated for three months with human recombinant erythropoietin. The blood haemoglobin level rose from 78.0 +/- 6.9 g/l to 108.4 +/- 15.5 g/l, the haematocrit from 21.8 +/- 1.8% to 33.6 +/- 4.9%. The serum ferritin concentration declined from 2213 +/- 1892 micrograms/l to 850 +/- 953 micrograms/l. Contrary to the period before treatment, during erythropoietin administration no blood transfusion had to be administered. The general condition of the patients improved. There were no serious complications. The action of erythropoietin persisted for two months. Human recombinant erythropoietin is significant help in the treatment of patients with chronic renal failure.

Topics: Anemia; Blood Cell Count; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Middle Aged; Nephritis, Interstitial; Recombinant Proteins; Renal Dialysis

The authors investigated the influence exerted on some lymphocyte and granulocyte functions during treatment with human recombinant erythropoietin in five female patients with renal failure due to chronic interstitial nephritis, who were included in a regular dialyzation programme. The authors revealed a significant increase of the candidacidal capacity of phagocytizing cells of the peripheral blood stream and an increased capacity of blastic transformation of lymphocytes after stimulation with the mitogen phytohaemagglutinin. In these changes the improved oxygen metabolism may participate by a correction of anaemia, when this preparation is administered, but it cannot be ruled out that erythropoietin interferes by some hitherto unknown mechanism with immune processes.

Topics: Anemia; Erythropoietin; Female; Granulocytes; Humans; Lymphocyte Activation; Middle Aged; Nephritis, Interstitial; Phagocytosis; Recombinant Proteins; Renal Dialysis

Topics: Adult; Blood Pressure; Creatinine; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Glomerulonephritis; Hematocrit; Hemoglobinometry; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Nephritis, Interstitial; Phenolphthaleins; Urea