7 men and 3 women (mean age 62 +/- 11 years) with end-stage renal disease, who were on continuous ambulatory peritoneal dialysis, underwent a peritoneal equilibration test to determine the rate of peritoneal ultrafiltration and creatinine transfer. The test is based on glucose absorption into the plasma from the peritoneal solution and the diffusion of creatinine into the peritoneal fluid after 2-4 hours. Patients with rapid absorption of glucose have low drain water ultrafiltration volumes but higher creatinine clearances, and therefore need adjustment of the therapy plan or else should be on hemodialysis. No correlation was found between the time the patients were on treatment and glucose absorption or creatinine diffusion.

Peritoneal equilibration test

In the light of the enthusiasm regarding the use of recombinant human erythropoietin (Epo) and its analogues for treatment of the anaemias of chronic renal failure and malignancies it is worth remembering that today's success has been based on a century of laborious research. The concept of the humoral regulation of haematopoiesis was first formulated in 1906. The term ‘erythropoietin’ for the erythropoiesis-stimulating hormone was introduced in 1948. Native human Epo was isolated in 1977 and its gene cloned in 1985. During the last 15 yr, major progress has been made in identifying the molecules controlling Epo gene expression, primarily the hypoxia-inducible transcription factors (HIF) that are regulated by specific O2 and oxoglutarate requiring Fe2+-containing dioxygenases. With respect to the action of Epo, its dimeric receptor (Epo-R) has been characterised and shown to signal through protein kinases, anti-apoptotic proteins and transcription factors. The demonstration of Epo-R in non-haematopoietic tissues indicates that Epo is a pleiotropic viability and growth factor. The neuroprotective and cardioprotective potentials of Epo are reviewed with a focus on clinical research. In addition, studies utilising the Epo derivatives with prolonged half-life, peptidic and non-peptidic Epo mimetics, orally active drugs stimulating endogenous Epo production and Epo gene transfer are reviewed.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1600-0609.2007.00818.x

Erythropoietin after a century of research: younger than ever.

Erythropoietin (EPO) has recently been shown to exert important cytoprotective and anti-apoptotic effects in experimental brain injury and cisplatin-induced nephrotoxicity. The aim of the present study was to determine whether EPO administration is also renoprotectivein both in vitro and in vivo models ofischaemic acute renal failure Methods. Primary cultures of human proximal tubule cells (PTCs) were exposed to either vehicle or EPO (6.25–400 IU/ml) in the presence of hypoxia (1% O2), normoxia (21% O2) or hypoxia followed by normoxia for up to 24 h. The end-points evaluated included cell apoptosis (morphology and in situ end labelling [ISEL], viability [lactate dehydrogenase (LDH release)], cell proliferation [proliferating cell nuclear antigen (PCNA)] and DNA synthesis (thymidine incorporation). The effects of EPO pre-treatment (5000 U/kg) on renal morphology and function were also studied in rat models of unilateral and bilateral ischaemia–reperfusion (IR) injury. Results. In the in vitro model, hypoxia (1% O2) induced a significant degree of PTC apoptosis, which was substantially reduced by co-incubation with EPO at 24 h (vehicle 2.5±0.5% vs 25 IU/ml EPO 1.8±0.4% vs 200 IU/ml EPO 0.9±0.2%, n = 9, P<0.05). At high concentrations (400 IU/ml), EPO also stimulated thymidine incorporation in cells exposed to hypoxia with or without subsequent normoxia. LDH release was not significantly affected. In the unilateral IR model, EPO pre-treatment significantly attenuated outer medullary thick ascending limb (TAL) apoptosis (EPO 2.2±1.0% of cells vs vehicle 6.5±2.2%, P<0.05, n = 5) and potentiated mitosis (EPO 1.1±0.3% vs vehicle 0.5±0.3%, respectively, P<0.05) within 24 h. EPO-treated rats exhibited enhanced PCNA staining within the proximal straight tubule (6.9±0.7% vs vehicle 2.4±0.5% vs sham 0.3±0.2%, P<0.05), proximal convoluted tubule (2.3±0.6% vs vehicle 1.1±0.3% vs sham 1.2±0.3%, P<0.05) and TAL (4.7±0.9% vs vehicle 0.6±0.3% vs sham 0.3±0.2%, P<0.05). The frequency of tubular profiles with luminal cast material was also reduced (32.0±1.6 vs vehicle 37.0±1.3%, P = 0.05). EPO-treated rats subjected to bilateral IR injury exhibited similar histological improvements to the unilateral IR injury model, as well as significantly lower peak plasma creatinine concentrations than their vehicle-treated controls (0.04±0.01 vs 0.21±0.08 mmol/l, respectively, P<0.05). EPO had no effect on renal function in sham-operated controls. Conclusions. The results suggest that, in addition to its well-known erythropoietic effects, EPO inhibits apoptotic cell death, enhances tubular epithelial regeneration and promotes renal functional recovery in hypoxic or ischaemic acute renal injury.

/pdf/erythropoietin-protects-against-ischaemic-acute-renal-injury-1edwiec6uk.pdf

Erythropoietin protects against ischaemic acute renal injury

Erythropoietin is a hypoxia-induced hormone that is essential for normal erythropoiesis. The production of recombinant human erythropoietin (rHuEpo) has revolutionized the treatment of anemia associated with chronic renal failure and chemotherapy, and has been used as prophylaxis to prevent anemia after surgery. The erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes. Epo has potentially beneficial effects on the endothelium including anti-apoptotic, mitogenic and angiogenic activities. On the other hand, some reports suggest that rHuEpo may have pro-thrombotic or platelet-activating effects. Hypertension develops in 20-30% of renal patients treated with rHuEpo. Many patients with heart failure have anemia. Despite some potential adverse effects, early studies in heart failure patients with anemia suggest that rHuEpo therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Further studies are warranted to define the role of rHuEpo in chronic heart failure and other cardiovascular settings.

The cardiovascular effects of erythropoietin

http://if-pan.krakow.pl/pjp/pdf/2012/1_31.pdf

Animal models of acute renal failure

Background Recently rat vascular smooth-muscle cells (VSMC) have been shown to possess Epo receptor, and respond to various cytokines for producing nitric oxide (NO). In the present study we examined the effect of pharmacological dose of human recombinant erythropoietin (rHuEpo) on the IL-1beta-induced NO and cGMP production as well as inducible nitric oxide synthase (iNOS) in cultured rat VSMC. Methods Nitrite, a stable metabolite of NO, and intracellular cGMP contents were assayed by Griess method and enzyme immunoassay. iNOS mRNA expression was analysed by Northern blotting. Results RHuEpo inhibited IL-1beta-induced nitrite production in a dose- and time-dependent manner with concomitant changes of intracellular cGMP contents. On the other hand, rHuEpo did not inhibit atrial natriuretic peptide- (ANP) or sodium nitroprusside (SNP)-induced nitrite and cGMP production at all. While rHuEpo inhibited IL-1beta-induced iNOS mRNA expression, rHuEpo vehicle did not affect IL-1beta-induced iNOS mRNA expression. Conclusions It is suggested that a pharmacological dose of rHuEpo inhibits IL-1beta-induced NO and cGMP production as well as iNOS mRNA expression, presumably via the Epo receptor.

Human recombinant erythropoietin inhibits interleukin-1beta-stimulated nitric oxide and cyclic guanosine monophosphate production in cultured rat vascular smooth-muscle cells.

Background
Osteoporosis and chronic kidney disease are common conditions in older adults, and often occur concurrently. Bone disease is caused by increased bone turnover accompanying secondary hyperparathyroidism, and by factors such as bone metabolic disorder accompanying kidney disease and postmenopausal or age-related osteoporosis, even in hemodialysis patients. Raloxifene is commonly used for the treatment of postmenopausal osteoporosis in the general population, and may be a treatment option for osteoporosis in hemodialysis patients. However, the effects of raloxifene in hemodialysis patients with type 2 diabetes have not been examined in detail.

/pdf/effects-of-raloxifene-on-bone-metabolism-in-hemodialysis-48rcn1odbo.pdf

Effects of raloxifene on bone metabolism in hemodialysis patients with type 2 diabetes.

Background/objectiveHuman recombinant erythropoietin (rHuEPO) induces cytosolic free calcium ([Ca2+]i) mobilization, an activation of mitogen-activated protein (MAP) kinase and DNA synthesis in several tissues. We explored the mechanism of rHuEPO-induced [Ca2+]i mobilization and its role in the acti

Involvement of erythropoietin-induced cytosolic free calcium mobilization in activation of mitogen-activated protein kinase and DNA synthesis in vascular smooth muscle cells.

Background Long-term peritoneal dialysis (PD) leads to peritoneal injury with high solute transport of the peritoneal membrane. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis with an extremely high mortality rate. To perform PD safely and adequately, it is necessary to monitor peritoneal injury. The aim of this study was to investigate the potential of matrix metalloproteinases (MMPs) as new indicators of peritoneal injury. Methods The subjects included 215 PD patients with end-stage renal disease at 20 centres in Japan. MMPs or tissue inhibitors of MMP (TIMPs) in the drained dialysate were quantified with enzyme-linked immunosorbent assay. The peritoneal solute transport rate was assessed to estimate peritoneal injury and PD efficiency by the peritoneal equilibration test (PET). Results MMP-2, MMP-3 and TIMP-1 levels in the drained dialysate obtained by the PET were correlated with the D/P Cr ratios (ρ = 0.69, ρ = 0.52, ρ = 0.55, respectively) and the D/D0 glucose ratios (ρ = -0.60, ρ = -0.47, ρ = -0.48, respectively). The measured D/S ratios of MMP-2 and TIMP-1 were significantly higher than the expected D/S ratios when MMP-2 and TIMP-1 would have been transported from only the circulation. The measured D/S ratios of MMP-3 nearly corresponded to the expected ratios. MMP-1 and TIMP-2 in the drainage were undetected in most patients. Conclusions From these results, most MMP-2 in the drained dialysate may be produced from the peritoneum, and MMP-2 is expected to be a useful marker of peritoneal injury or change in peritoneal solute transport.

/pdf/matrix-metalloproteinase-levels-in-the-drained-dialysate-1ftpo2d81m.pdf

Matrix metalloproteinase levels in the drained dialysate reflect the peritoneal solute transport rate: a multicentre study in Japan

IgG4-related systemic disease encompasses multi-organ disorders, including tubulointerstitial nephritis. This disease is accompanied by a high serum IgG4 concentration and IgG4-positive plasma cell infiltration. We herein describe a 63-year-old woman with renal failure and dryness of the eyes and mouth, who had been treated with antituberculosis agents for urinary tract tuberculosis. She had a negative finding for a PCR analysis for Mycobacterium tuberculosis, a positive QuantiFERON-TB test, high serum IgG4 concentrations (2,660 mg/dl), and low serum IgM and IgA concentrations (34 and 82 mg/dl, respectively). Imaging tests revealed swelling in the submandibular glands, pancreas, and right kidney. A renal biopsy showed IgG4-positive plasma cell infiltration in the interstitium and tubular atrophy. This case was diagnosed as IgG4-related systemic disease. Corticosteroid therapy improved renal failure and swelling in the submandibular glands, pancreas, and right kidney. The case suggests that an abnormal reaction to tuberculosis may be associated with a predominance of type-2 helper T-cell immunity, thus resulting in IgG4-related systemic disease.

Makoto Inoue

Papers

Human recombinant erythropoietin inhibits interleukin-1beta-stimulated nitric oxide and cyclic guanosine monophosphate production in cultured rat vascular smooth-muscle cells.

Effects of raloxifene on bone metabolism in hemodialysis patients with type 2 diabetes.

Involvement of erythropoietin-induced cytosolic free calcium mobilization in activation of mitogen-activated protein kinase and DNA synthesis in vascular smooth muscle cells.

Matrix metalloproteinase levels in the drained dialysate reflect the peritoneal solute transport rate: a multicentre study in Japan

A case of IgG4-related tubulointerstitial nephritis with left hydronephrosis after a remission of urinary tract tuberculosis.