Association between Increases in Normalized Protein Catabolic Rate and Increases in Creatinine Generation Rate in Dialysis Patients.

The older dialysis population is growing, and malnutrition and wasting syndrome are great concerns in this population. The management of these syndromes includes appropriate nutritional intake and physical activity. However, whether management in the form of an increase in protein intake has a beneficial effect on muscle mass has not been demonstrated. In this study, we investigated an association between changes of normalized protein catabolic rate (nPCR), as a proxy for protein intake and percent creatinine generation rate (%CGR), as a proxy for muscle mass in patients receiving hemodialysis. Multiple linear regression models were employed, and we included several sensitivity analyses. The results showed that increases in nPCR were associated with increases in %CGR. The association was stronger in patients with baseline %CGR levels below 100%. This was the first study to demonstrate that an increase in dietary protein intake might increase the muscle mass, but this study had certain limitations. Future interventional studies will be needed to investigate whether increases in protein intake have a beneficial effect on sarcopenia, protein-energy wasting, and frailty.

Effect of Taurine on Hemodiafiltration in Patients With Chronic Heart Failure.

Taurine, an important factor in the living body, is essential for cardiovascular function and development and function of skeletal muscle, retina and central nervous system. In the present study, its effect on cardiovascular function was specifically taken into consideration. In hemodiafiltration (HDF) patients, the effect of taurine on patients with chronic heart failure (CHF), in whom dry weight was difficult to control, was evaluated. All patients who were subjected to regular HDF for 4 h three times per week at Joban hospital were included in this study. Patients with chronic heart failure, in whom dry weight was difficult to control (N = 4), were included in the evaluation of clinical status. X-ray and echocardiography were determined before and after taurine treatment. Almost all patients were taking nitric acid, warfarin, anti-platelet agents and vasopressors. Because vital signs were unstable in chronic heart failure, all cases withheld antihypertensive drugs during HDF. For unstable vital signs during HDF, pulmonary congestion was chronically recognized. After taurine was started, vital signs stabilized and lowering of dry weight was possible. In addition, X-ray and cardiac diastolic failure on echocardiography improved. Taurine was effective for CHF patients on HDF in whom dry weight was difficult to control in spite of various medications.

Relationship between anaemia management at haemodialysis initiation and patient prognosis.

AIM: It has been suggested that anaemia management during a transition period to haemodialysis could influence prognosis. In this paper, we have conducted a retrospective investigation on how Hb levels at haemodialysis initiation in patients with chronic kidney disease (CKD) influence the risk of cerebral infarction and cardiovascular events. METHODS: Seventy-two patients who underwent initial haemodialysis between May 2012 and April 2014 were designated as subjects of the study and the patients were divided into a cohort with Hb levels ≥8 g/dL and a cohort with <8 g/dL at haemodialysis initiation. The occurrence of cardiovascular events was analyzed using the Kaplan-Meier method and Cox proportional hazards model. RESULTS: The cohort with <8 g/dL Hb levels at haemodialysis initiation demonstrated a tendency toward low dosage of ESA or iron preparation in the pre-haemodialysis (maintenance) phase. Significant incidence of cardiovascular (log rank, P = 0.002) and cerebrovascular (log rank, P = 0.02) events was observed. The results of multivariate analysis of the Cox proportional hazards model indicated that anaemia with <8 g/dL Hb levels at haemodialysis initiation was a significant risk factor for coronary artery (hazard ratio = 12.85, P = 0.003) and cerebrovascular (hazard ratio = 5.11, P = 0.04) diseases post-haemodialysis. CONCLUSION: The results of this investigation indicate the possible involvement of low Hb levels at haemodialysis initiation as a factor in cardio- and cerebrovascular events. There, our results suggested that the administration of adequate dosage of iron preparations and ESA in the pre-haemodialysis period could help prevent cardio- and cerebrovascular events.

Sphingosine-1-phosphate acts as a key molecule in the direct mediation of renal fibrosis.

The major sphingolipid metabolite, sphingosine-1-phosphate (S1P), has important biological functions. S1P serves as a ligand for a family of five G-protein-coupled receptors with distinct signaling pathways regulating important biological pathways. S1P induces renal fibrosis through an inflammatory pathway. However, its direct fibrosis-inducing effect on the kidney has not been shown. The role of S1P as a direct mediator of renal fibrosis was investigated in normal rat kidney interstitial fibroblast (NRK-49F) cells (in vitro) and kidneys of a unilateral ureteral obstruction (UUO) mouse model (in vivo). To clarify the role of S1P in renal fibrosis, we adopted nude UUO mice with immune response deficits. NRK-49F cells were stimulated with various concentrations of exogenous S1P and FTY720 (a S1P receptor agonist) or N,N-dimethylsphingosine (DMS; a sphingosine kinase inhibitor). C57BL6 and nude UUO mice were pretreated with FTY720, DMS, or saline. Expression levels of alpha-smooth muscle actin (a-SMA), E-cadherin, collagen type 1 (COL1), collagen type 4 (COL4), tissue inhibitor of matrix metalloproteinase-1 (TIMP1), and plasminogen activator inhibitor-1 (PAI1) were examined. S1P stimulated fibrosis in NRK-49F cells and UUO mice. Increased a-SMA, COL1, COL4, TIMP1, and PAI1 and decreased E-cadherin expression levels were observed in both the S1P-stimulated cells and UUO mice. Nude UUO mouse kidneys expressed fibrotic markers. Fibrotic changes were successfully induced in both UUO and nude UUO mice, evident through prominent fibronectin and COL1 staining. These S1P-induced fibrotic changes were suppressed by FTY720 and DMS both in vitro and in vivo. Thus, S1P essentially and directly mediates renal fibrosis.

Rituximab treatment for adult patients with focal segmental glomerulosclerosis.

We present two cases with steroid-resistant nephrotic syndrome (SRNS) and two cases with steroid-dependent nephrotic syndrome (SDNS) due to focal segmental glomerulonephritis (FSGS) who were treated with a single dose of rituximab (375 mg/m(2)). Although the two cases with SRNS showed no response, the two cases with SDNS achieved complete remission. The patients in whom the peripheral B-cell counts subsequently increased after the administration of rituximab demonstrated a relapse. Rituximab may be an effective treatment agent for SDNS with FSGS and the peripheral B-cell count may be a useful marker in such patients for preventing disease relapse.

Reduced Klotho expression level in kidney aggravates renal interstitial fibrosis.

Renal expression of the klotho gene is markedly suppressed in chronic kidney disease (CKD). Since renal fibrosis is the final common pathology of CKD, we tested whether decreased Klotho expression is a cause and/or a result of renal fibrosis in mice and cultured renal cell lines. We induced renal fibrosis by unilateral ureteral obstruction (UUO) in mice with reduced Klotho expression (kl/+ mice) and compared them with wild-type mice. The UUO kidneys from kl/+ mice expressed significantly higher levels of fibrosis markers such as α-smooth muscle actin (α-SMA), fibronectin, and transforming growth factor-ß(1) (TGF-ß(1)) than those from wild-type mice. In addition, in cultured renal fibroblast cells (NRK49F), the levels of α-SMA and PAI1 expression were significantly suppressed by addition of recombinant Klotho protein to the medium. The similar effects were observed by a TGF-ß(1) receptor inhibitor (ALK5 inhibitor). These observations suggest that low renal Klotho expression enhances TGF-ß(1) activity and is a cause of renal fibrosis. On the other hand, TGF-ß(1) reduced Klotho expression in renal cultured epithelial cells (inner medullary collecting duct and human renal proximal tubular epithelium), suggesting that low renal Klotho expression is a result of renal fibrosis. Taken together, renal fibrosis can trigger a deterioration spiral of Klotho expression, which may be involved in the pathophysiology of CKD progression.

[Successful rituximab therapy for MALT lymphoma complicating cryoglobulinemic glomerulonephritis].

We report a case of nephrotic syndrome associated with MALT lymphoma. The patient was a 66-year-old woman who had a 21-year history of MALT lymphoma. She was admitted to our hospital for the evaluation of systemic edema and purpura during two months. Urinary protein excretion was quantified at 3.3 g/24h. Serum creatinine was elevated to 1.63 mg/dL. An immunoserological investigation showed the presence of IgM-kappa type monoclonal cryoglobulin accompanied by a decreased serum complement level. HCV infection was negative. A renal biopsy specimen revealed membranoproliferative glomerulonephritis (MPGN) with cryoglobulin deposition and focal atypical lymphoid cells infiltration in the renal interstitium. Immunoperoxidase staining of the atypical lymphoid cell population was positive for CD20 and CD79. Combined therapy with prednisolone, plasma exchange and rituximab was commenced. Her proteinuria disappeared and renal function improved after rituximab therapy. In our case, nephrotic syndrome due to cryoglobulinemic glomerulonephritis was successfully treated mainly by rituximab.

Effect of the antiplatelet agent cilostazol on endovascular inflammatory biochemical parameters and the clinical symptoms of peripheral artery disease and restless legs syndrome in hemodialysis patients.

BACKGROUND: Peripheral artery disease (PAD) is a common complication in patients receiving hemodialysis (HD). Cilostazol is used for the treatment of ischemic symptoms in patients with PAD, based on its antiplatelet and vasodilating effects. In addition to these beneficial effects on clinical symptoms in PAD patients, cilostazol has been proposed to have additional effects on clinical symptoms in patients with restless legs syndrome (RLS) via the upregulation of dopamine. We performed an observational, prospective study to evaluate the effect of cilostazol on several clinical and biochemical parameters in HD patients with PAD and RLS. METHODS: All the study patients received cilostazol treatment for 12 months. During the study period, several biochemical parameters, such as high-sensitivity CRP, von Willebrand antigen (VW-Ag), triglyceride (TG), high-density lipoprotein (HDL) and malondialdehyde-modified low-density lipoprotein, were monitored. A questionnaire on the physical status of PAD and RLS was also completed. 45 HD patients who received cilostazol were compared with a control group of 22 patients. RESULTS: The patients who continued cilostazol treatment exhibited a improvement in their serum inflammatory and biochemical parameters (VW-Ag, TG, HDL). Although PAD and RLS scores were not improved by multivariate analysis, several patients showed improvement of signs and symptoms which were included in the PAD or RLS scores. CONCLUSION: The treatment of HD patients with cilostazol improved some of the lipid-related and endovascular inflammatory biochemical parameters associated with PAD, and relieved the clinical symptoms and physical status of PAD in some cases.

Risedronate therapy for the prevention of steroid-induced osteoporosis in patients with minimal-change nephrotic syndrome.

BACKGROUND: Minimal-change nephrotic syndrome (MCNS) is treated by the administration of prednisolone (PSL) at high doses. Steroid-induced osteoporosis is a serious adverse effect of this drug. METHODS: Patients with MCNS were randomly assigned to two groups, the risedronate (2.5 mg/day) + alfacalcidol (0.25 µg/day) group (n=20) and the alfacalcidol (0.25 µg/day)-alone group (n=20). All the patients had received PSL and the clinical characteristics were compared between the two groups at baseline and at 12 months. RESULTS: A significant decrease of the mean bone mineral density (BMD) of the lumbar spine from 0.710±0.162 (g/cm(2)) to 0.588±0.125 was observed in the alfacalcidol-alone group (p=0.02), while no such decrease of the bone mineral density was found in the risedronate + alfacalcidol group (0.663±0.169 at baseline and 0.626±0.129 at 12 months). No significant differences in the results of other biochemical tests performed at the baseline and at 12 months were observed between the two groups. The likelihood of development of steroid-induced osteoporosis was influenced by the cumulative dose of PSL, the mean BMD at the baseline, occurrence of disease relapse, and risedronate therapy. CONCLUSION: Risedronate appears to be effective in preventing steroid-induced osteoporosis. It is necessary to use bisphosphonates to maintain the BMD in patients with MCNS receiving prolonged steroid therapy.

Clinical effects of calcium channel blockers and renin-angiotensin-aldosterone system inhibitors on changes in the estimated glomerular filtration rate in patients with polycystic kidney disease.

BACKGROUND: In the tubular cells of patients with polycystic kidney disease (PKD), a reduced intracellular Ca(2+) level accelerates cell proliferation, resulting in cyst formation. Thus, whether calcium channel blockers (CCB) are useful for the treatment of hypertension in patients with PKD is questionable. METHODS: Thirty-two outpatients with autosomal dominant PKD (ADPKD) were treated at Tokyo Women's Medical University between 2003 and 2008; these patients were studied retrospectively. Periods during which the antihypertensive drug prescriptions for CCB and/or renin-angiotensin-aldosterone system inhibitors (RAAS-I; including angiotensin converting enzyme inhibitor and angiotensin II receptor blocker) had not been changed for at least 1 year and during which time a diuretic agent had not been prescribed were selected from among the clinical histories of the 32 outpatients. Consequently, 31 periods of 31 patients were analyzed, and mean treatment duration was 2.4 years in this study. The estimated glomerular filtration rate (eGFR) was used to evaluate renal function. To evaluate the influence of CCB and RAAS-I with respect to the decrease of the eGFR, analysis of covariance (ANCOVA), including confounding factors [baseline eGFR, mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP)], was used. Only CCB significantly contributed to a reduction in ∆eGFR in both a univariable ANCOVA and a multivariable ANCOVA. None of the confounding factors, RAAS-I, the baseline eGFR, or blood pressure, contributed to reductions in ∆eGFR. CONCLUSION: These results suggest that from a renoprotective perspective, CCB should possibly be avoided in patients with PKD unless treatment for resistant hypertension is necessary.

Recombinant human erythropoietin mitigates reductions in renal klotho expression.

BACKGROUND: Erythropoietin (EPO) and Klotho expression have both been detected in the kidney. Since a recent study suggested that both EPO and Klotho mitigate kidney damage, we explored the relation between EPO and Klotho in a doxorubicin hydrochloride (DXR)-induced rat nephropathy model treated with recombinant human erythropoietin (rhEPO). METHODS: Male Sprague-Dawley rats were subjected to DXR-induced nephropathy. The rhEPO group was intracutaneously injected with rhEPO twice weekly at 4-16 weeks after the DXR injection. The rats were sacrificed at 16 weeks after the DXR administration. Expression of renal Klotho, HSP70, alpha-smooth-muscle actin and E-cadherin were assessed using real-time PCR or western blotting. The hematocrit, plasma creatinine and phosphate levels were also determined. Immunohistochemical studies and Masson-trichrome staining were performed. RESULTS: The renal Klotho mRNA and Klotho protein expressions were significantly reduced in the DXR nephropathy group. Treatment with rhEPO improved the serum creatinine, phosphate level and histological changes observed in the DXR nephropathy group. The reduction in Klotho expression induced by DXR nephropathy was mitigated by rhEPO administration. CONCLUSION: rhEPO is involved in the pathophysiology of DXR nephropathy. rhEPO mitigated elevated plasma phosphate concentrations in an experimental model of chronic kidney disease via the expression of Klotho.

Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70.

BACKGROUND: High Klotho expression has been detected in the kidney, and since the results of a recent study suggested that Klotho induction mitigates ischaemic damage in the kidney, in the present study we explored the mechanism by which Klotho expression reduces renal ischaemia-reperfusion injury (IRI). METHODS: Male mice were subjected to bilateral renal ischaemia for 30 min and reperfusion for 24 h, or to a sham operation. Both the IRI group and the sham group were intravenously injected with an adenovirus harbouring the mouse Klotho gene (ad-kl) before renal IRI. In addition, mIMCD3 cells induced to overexpress Klotho by transferring the Klotho gene with ad-kl were analysed by DNA microarray and real-time PCR. Renal expression of Klotho and several genes selected by DNA microarray were assessed by real-time PCR or Western blotting, and TUNEL staining was performed to assess apoptosis. RESULTS: Prior administration of ad-kl to the mice resulted in robust induction of Klotho mRNA in the kidney and liver. Ad-kl transfer improved the plasma creatinine values and mitigated the histological damage and apoptosis induced by IRI. Expression of several genes was altered in mIMCD3 cells as a result of the change in Klotho expression, and expression of heat shock protein 70 (HSP70), in particular, was up-regulated in ad-kl mouse kidneys and HK2 cells. CONCLUSION: The results suggest that Klotho is involved in the pathophysiology of IRI. Klotho mitigates apoptosis in experimental ischaemic acute kidney injury via expression of HSP70.

ATF3 protects against renal ischemia-reperfusion injury.

Oxidative stress-induced cell death plays a major role in the progression of ischemic acute renal failure. Using microarrays, we sought to identify a stress-induced gene that may be a therapeutic candidate. Human proximal tubule (HK2) cells were treated with hydrogen peroxide (H2O2) and RNA was applied to an Affymetrix gene chip. Five genes were markedly induced in a parallel time-dependent manner by cluster analysis, including activating transcription factor 3 (ATF3), p21(WAF1/CiP1) (p21), CHOP/GADD153, dual-specificity protein phosphatase, and heme oxygenase-1. H2O2 rapidly induced ATF3 approximately 12-fold in HK2 cells and approximately 6.5-fold in a mouse model of renal ischemia-reperfusion injury. Adenovirus-mediated expression of ATF3 protected HK2 cells against H2O2-induced cell death, and this was associated with a decrease of p53 mRNA and an increase of p21 mRNA. Moreover, when ATF3 was overexpressed in mice via adenovirus-mediated gene transfer, ischemia-reperfusion injury was reduced. In conclusion, ATF3 plays a protective role in renal ischemia-reperfusion injury and the mechanism of the protection may involve suppression of p53 and induction of p21.

Protective effect of carbon monoxide donor compounds in endotoxin-induced acute renal failure.

BACKGROUND: Sepsis is a common cause of acute renal failure (ARF) in clinical practice. However, the precise mechanism of endotoxin-induced ARF is not fully understood. There have been several reports that inhalation of carbon monoxide (CO) gas could be protective against acute rejection in intestine, lung, and kidney transplantation. Thus, we investigated the direct effect of CO in an experimental ARF model of septic shock induced by lipopolysaccharide (LPS). METHOD: Mice were pretreated with [Ru(CO)3Cl2]2 (CO donor compounds) at various concentrations (0.5, 1.0 and 2.0 microg) which were intravenously injected 24 h before intraperitoneal LPS injection. Biomarkers including myeloperoxidase activity and histochemical staining were evaluated. RESULTS: The elevation of plasma creatinine was suppressed in CO donor-pretreated mice compared with vehicle-treated mice (creatinine 0.35 vs. 0.25; p < 0.05) 24 h after LPS injection. Renal myeloperoxidase activity slightly decreased in CO donor-pretreated mice. In the histological examination, neutrophil infiltration was significantly diminished in CO donor-treated mice. Real-time polymerase chain reaction revealed significant improvements in inflammatory related genes, such as TNFalpha, MCP-1, RANTES and IL4. CONCLUSION: Our results suggest the protective effect of the CO donor against endotoxin-induced renal injury; however, further study is needed to elucidate the mechanism.

A case report of the effect of acetate-free biofiltration on arrhythmia in a hemodialysis patient.

This case report concerns a hemodialysis patient with arrhythmia. A 71-year-old man had undergone hemodiafiltration (HDF) for 17 years for the treatment of chronic glomerulonephritis. Because of repeated heart failure and chronic atrial fibrillation, he could not continue receiving standard hemodialysis, which is hemodialysis using bicarbonate dialysate including a small amount of acetate. Neither elevating the sodium concentration of the dialysate nor changing the HDF modality was effective. Acetate-free biofiltration (AFB) was initiated and this treatment dramatically ameliorated the patient's intradialytic acute hypotension and arrhythmia. The patient's quality of life subsequently improved and his scores on the Short-form 36 questionnaire (a measure of quality of life) increased. AFB is an HDF technique based on the continuous postdilution infusion of a sterile isotonic bicarbonate solution. Previous studies have reported that acetate induces chemical cytokines and vasodilator substances. AFB may be effective for preventing acute hypotension and arrhythmia during dialysis and may improve quality of life, including mental status.

[A case of microscopic polyangitis with sepsis due to pyelonephritis].

A 69-year-old woman, who had been diagnosed with interstitial pneumonia at 66 years of age, was admitted to our hospital because of high fever, purpura occurring on her arms and legs, and renal dysfunction. At the time of admission, her renal function had severely deteriorated (sCr 8.2 mg/dl, 24 h Ccr 6 ml/min), she had a severe high fever (BT 39.5 degrees C), back pain, a white blood cell count of 19,540/,microl, and a CRP level of 26.7 mg/dl. Blood and urine cultures yielded identical strains of E. coli. We diagnosed sepsis caused by pyelonephritis, and started intravenous meropenem trihydrate(MEPM) at 0.5 g/day. Her renal dysfunction was severe, so we started hemodialysis therapy. Immunological examination revealed the presence of ANCA-associated glomerulonephritis. Renal biopsy before steroid therapy confirmed the diagnosis of pauci-immune-type crescentic glomerulonephritis. Based on purpura and interstitial pneumonia, along with rapidly MPO-ANCA-positive progressive glomerulonephritis (RPGN) with acute renal failure, we diagnosed microscopic polyangitis (MPA). To treat sepsis and severe pyelonephritis, we started intravenous immunoglobulin 5 g (100 mg/kg)/day for 5 days before starting immunosuppressive steroid therapy (m-PSL 1 g/day, PSL 20 mg/day) for 3 days. These treatments improved her general condition and immediately improved her renal function. It is important to prevent infection during treatment using conventional immunosuppressive therapy. These findings suggest immunoglobulin therapy to be a safe immuno-suppressive treatment that is efficacious against ANCA-associated glomerulonephritis.