[Clinical investigation of extracorporeal endotoxin adsorption therapy in septic urinary tract infections].

OBJECTIVE: Severe urinary tract infection may lead to sepsis in some cases. In these cases, treatment must not only include drainage of the source of infection, but also management of systemic inflammatory response syndrome (SIRS). Blood purification therapy focused on endotoxin adsorption is thought to be a useful treatment method for this purpose. Herein, we clinically investigated the cases in which this treatment method was applied. SUBJECTS AND METHODS: A total of 22 patients underwent endotoxin adsorption therapy following diagnosis of sepsis at the department of urology, Hokkaido Social Welfare Association Furano Hospital during the last six years. Of these patients, six patients whose primary disease was urinary tract infection were included in the study. RESULTS: Patients comprised four men and two women with either pyelonephritis (n = 5; complicated by prostatitis in one patient) or pyonephrosis (n = 1). Primary diseases included urolithiasis (n = 4), vesicoureteral reflux (n = 1), and ureteric stenosis (n = 1). Urinary tract drainage included ureteral stent (n = 4), nephrostomy (n = 1), and cystostomy (n = 1), with concomitant use of continuous hemodiafiltration in one patient. Serum endotoxin levels were 3.2 pg/ml on average, and returned to normal following endotoxin adsorption therapy in all patients. A total of four strains of Escherichia coli and one strain of Klebsiella pneumoniae were identified as pathogenic bacteria. CONCLUSION: Hemodynamics was markedly stabilized following endotoxin adsorption therapy, and all patients survived. These findings indicate that endotoxin adsorption therapy should be actively considered as a treatment method for patients with sepsis secondary to urinary tract infection.

Chronic pyelonephritis presenting as multiple tumor-like renal lesions.

We encountered a 49-year-old Japanese man in whom tumor-like renal lesions developed as a result of chronic Staphylococcus aureus pyelonephritis. The patient complained of general fatigue, weight loss, and anorexia for 6 months. Contrast-enhanced computed tomography (CT) of the abdomen revealed multiple low-density lesions in both kidneys and paraaortic lymphadenopathy. A strong uptake of Ga67 citrate in the lesions and elevation of serum soluble interleukin-2 receptor and thymidine kinase activity were strongly suggestive of primary renal lymphoma; however, histologic examination of renal biopsy specimens revealed severe tubulointerstitial change, consistent with chronic pyelonephritis. Following systemic antibiotic treatment, multiple tumor-like lesions regressed 4 months later. This case suggested that chronic pyelonephritis could present as bilateral renal tumors.

Inhibition of p21 modifies the response of cortical proximal tubules to cisplatin in rats.

The purpose of this study was to evaluate whether upregulated p21, a cell cycle-inhibitory protein, contributes to cisplatin (CDDP)-induced acute renal failure (ARF) and to acquired resistance to rechallenge injury with CDDP in rats. ARF was induced in rats by injection of CDDP (5 mg/kg) and rechallenge injury to CDDP by the same dose of CDDP 14 days after the first CDDP injection. Rats were treated with p21 antisense oligodeoxynucleotide (ODN) or its vehicle, p21 sense ODN, every 36 h from days 0 to 5 for single CDDP and from days 13 to 19 for rechallenge injury and killed at day 3, 5, 16, or 19. The uptake of FITC-labeled p21 antisense ODNs by cortical proximal tubule (PT) cells was much greater than by PT cells in the outer stripe of outer medulla (OSOM). Administration of antisense induced partial downregulation of p21 mRNA and protein levels in whole kidneys with single CDDP treatment and its rechallenge injury. Antisense significantly aggravated PT necrosis and decreased the number of p21-positive PT cells in the cortex but not in the OSOM in both CDDP-induced ARF and its rechallenge injury. However, antisense did not alter serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Our findings suggested that p21 plays, at least in part, a cytoprotective role in cortical PTs exposed to CDDP, although this does not contribute to renal dysfunction when judged by Scr and BUN levels. Because antisense may not adequately be taken up and/or function in PTs in the OSOM, the role of p21 in PTs in the OSOM in CDDP-induced ARF remains to be clarified.

Urinary marker for oxidative stress in kidneys in cisplatin-induced acute renal failure in rats.

BACKGROUND: Establishment of non-invasive urinary biomarkers for the prediction of acute renal failure (ARF) is important. We evaluated whether urinary oxidative stress markers reflect intrarenal oxidative stress in cisplatin (CDDP)-induced ARF, and whether these markers can be used for the prediction of future ARF. METHODS: Urinary malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured up to day 14 post-CDDP (6 mg/kg) injection in rats. MDA and 8-OHdG expressions were examined in kidneys. RESULTS: CDDP induced an increase in serum creatinine (Scr), blood urea nitrogen (BUN), and tubular damage at day 5, increased urinary MDA excretion and MDA expression in kidneys at day 1 (but returned to basal values by day 3), increased urinary excretion of 8-OHdG at day 5 till day 14 (though the number of 8-OHdG-positive tubular cells increased at day 5 and then gradually decreased). Urinary MDA levels at day 1 correlated significantly with Scr (rho = 0.721, P < 0.01) and tubular damage score (rho = 0.840, P < 0.01) at day 5. CONCLUSION: Our findings demonstrated divergent changes of urinary oxidative stress markers in CDDP-induced ARF, and suggested that urinary MDA may be a useful marker for the prediction of the development of CDDP-induced ARF.

High dose chemotherapy and stem cell support in a patient of light- and heavy-chain deposition disease with abnormal marrow cell surface antigens and no monoclonal protein.

A 53-year-old man with nephrotic syndrome and severe renal failure was diagnosed with light- and heavy-chain deposition disease (LHCDD) by renal biopsy. The patient had no monoclonal protein and mild marrow plasmacytosis (6%), but marrow plasma cells expressed CD19(-)CD56+ and predominant monoclonal kappa-chain, indicating plasma cell dyscrasia. Conventional chemotherapy was ineffective and did not improve renal failure. High dose chemotherapy/peripheral blood stem cell transplantation (HDC/PBSCT) was introduced even after hemodialysis to eliminate aberrant clone and normalization of bone marrow cell surface markers. Immunophenotypic analysis of marrow cells facilitates clinical decision making regarding the use of HDC/PBSCT for LHCDD patients without monoclonal protein.

Transient myofibroblast differentiation of interstitial fibroblastic cells relevant to tubular dilatation in uranyl acetate-induced acute renal failure in rats.

To investigate the mechanisms of myofibroblast differentiation of interstitial fibroblastic cells (FCs) in rats with uranyl acetate-induced acute renal failure (ARF), we examined the relationship between the expression of alpha-smooth muscle actin (alpha-SMA), myofibroblast phenotype and tubular dilatation as well as cell shape and adhesion of FCs. Peritubular alpha-SMA-positive myofibroblasts appeared after induction of ARF and extended along the damaged, dilated proximal tubules and then almost disappeared after proximal tubular recovery. The perimeter of proximal tubules correlated with fractional areas stained for alpha-SMA (P<0.001). Most alpha-SMA-positive cells did not incorporate [3H]-thymidine, indicating a low proliferative activity. Transmission electron microscopy showed that FCs increasingly attached to the tubular basement membrane by elongated cytoplasm-containing microfilament bundles, which formed abundant adherens and gap junctions from day 4 to day 7. Scanning electron microscopy showed hypertrophic FCs covering large areas of tubules after induction of ARF. Administration of chlorpromazine, which can inhibit cytoskeletal movement, after induction of ARF partially inhibited myofibroblast differentiation of FCs immunohistochemically and morphologically and resulted in more dilated proximal tubules in concert with aggravation of renal dysfunction and inhibition of regenerative repair at day 4 than vehicle-administered rats. Our results indicate that mechanical tension, judged by tubular dilatation, may contribute to the induction of alpha-SMA phenotype with increased stress fiber formation and intercellular junctions in FCs to support damaged nephron structures by adjusting tensional homeostasis in rats with uranyl acetate-induced ARF.

The induction of cell cycle regulatory and DNA repair proteins in cisplatin-induced acute renal failure.

The purpose of this study was to evaluate the expressions and the roles of proteins involved in cell cycle regulation and DNA repair in cis-diamminedichloroplatinum (II) (cisplatin or CDDP)-induced acute renal failure (ARF). Treatment with CDDP (6 mg/kg, iv) induced tubular damage and increased serum creatinine (Scr) and the number of TUNEL-positive cells in the outer stripe of the outer medulla in rats, which reached peak levels at 5 days after CDDP. The expressions of cyclin-dependent kinase inhibitors (p21 and p27), cyclin B1, cyclin D1, PCNA, GADD 45, and GADD 153 were significantly increased in the outer medulla, reaching peak levels at 3 days after CDDP. Increments of p27 and PCNA were observed in the same nuclei. Sodium arsenite (SA), a heavy metal, attenuated tubular damage and increased Scr- and TUNEL-positive cells at 5 days after CDDP. SA augmented CDDP-induced increment of p27 but suppressed the increased expression of cyclin B1 and cyclin D1 at 3 days after CDDP. SA-induced attenuation of nephrotoxicity was associated with enhanced expression of proliferating cell nuclear antigen (PCNA) and growth-arrest and DNA damage (GADD) 153 in damaged tubular cells. Our findings indicated that (1) proteins related to cell cycle regulation and DNA repair are induced in CDDP nephrotoxicity, (2) the SA-induced attenuation of CDDP nephrotoxicity is associated with increased expression of p27 and decreased expression of cyclin B1 and cyclin D1, they all induce cell cycle arrest at G1/S and G2/M, and (3) enhanced expression of DNA repair-related proteins is also associated with attenuation of CDDP-nephrotoxicity.

Clinicopathologic findings relevant to disappearance or relapse of proteinuria following corticosteroid treatment in IgA nephropathy patients with proteinuria of 0.5 to 2.0 g/day.

BACKGROUND: We investigated the clinical and pathological findings relevant to the efficacy of corticosteroid treatment in IgA nephropathy patients with 0.5 to 2.0 g/day of proteinuria at the initiation of corticosteroid treatment. METHODS: In 27 IgA nephropathy patients who received 2-year prednisolone treatment, we analyzed the differences in clinical and pathological parameters (1) between patients with and without disappearance of proteinuria (less than 0.15 g/day), and (2) between patients with and without relapse of proteinuria (more than 0.5 g/day) at the end of follow-up. RESULTS: The levels of proteinuria and mesangial proliferation at the initiation of prednisolone treatment were significantly lower in patients with disappearance of proteinuria at the end of follow-up than in those without. The levels of active extraglomerular lesions and tubulointerstitial mononuclear cell infiltration and/or fibrosis, and the activity index, were significantly higher in patients with relapse of proteinuria than in those without. CONCLUSIONS: In IgA nephropathy patients with 0.5 to 2.0 g/day of proteinuria, disappearance of proteinuria following 2-year prednisolone treatment can be expected in patients with less proteinuria and less mesangial proliferation at the initiation of the prednisolone treatment. Furthermore, active extraglomerular lesions, the activity index, and tubulointerstitial cell infiltration and/or fibrosis appear to be more suitable risk markers for relapse of proteinuria than the initial levels of proteinuria.

Rapid improvement of acute pulmonary edema with angiotensin converting enzyme inhibitor under hemodialysis in a patient with renovascular disease.

A 71-year-old man with bilateral renovascular disease was admitted to Hamamatsu University hospital because of appetite loss and acute shortness of breath due to acute pulmonary edema (APE) with accelerated hypertension and renal failure. Hypertension and APE were controlled by an angiotensin converting enzyme inhibitor (ACEI) and four sessions of hemodialysis with reduction of 1.8 kg bodyweight. Renal function was later stabilized and the patient required no ACEI or hemodialysis. A trial of right renal angioplasty 1 month after admission failed and renal function deteriorated (serum creatinine 7.1 mg/dL) with accelerated hypertension, gain of bodyweight and APE. Even after four sessions of hemodialysis with adequate reduction of bodyweight, APE was not controlled, but it rapidly improved after administration of an ACEI, without major bodyweight change. As no apparent cardiac dysfunction was evident, APE might have been caused by a direct action of angiotensin II on hyperpermeability in pulmonary capillaries. Blocking of angiotensin II should be considered in such patients even after introduction of hemodialysis.

Impact of serum parathyroid hormone concentration and its regulatory factors on arterial stiffness in patients undergoing maintenance hemodialysis.

BACKGROUND: Cardiovascular mortality is extremely high in patients on hemodialysis. Among a variety of pathophysiological conditions, deranged calcium homeostasis including secondary hyperparathyroidism may be one of the factors contributing to cardiovascular disease in patients on hemodialysis. This study was designed to evaluate the role of the serum parathyroid hormone (PTH) concentration and its regulatory factors in serum on arterial stiffness in patients on maintenance hemodialysis. METHODS: Arterial stiffness was assessed by pulse wave velocity (PWV) in 73 non-diabetic patients undergoing maintenance hemodialysis. At the same time, serum concentrations of calcium, phosphate, and intact PTH were measured. RESULTS: Single regression analyses revealed that arterial PWV was positively correlated with age (r = 0.505, p < 0.0001), systolic blood pressure (r = 0.250, p = 0.043), and pulse pressure (r = 0.306, p = 0.012). It was inversely correlated with the serum phosphate concentration (r = -0.240, p = 0.041) and the duration of hemodialysis treatment (r = -0.343, p = 0.003), but not with serum concentrations of calcium and intact PTH or the calcium x phosphate product in serum. By multiple regression analysis age was found to be the most significant variable affecting arterial PWV, and the duration of hemodialysis treatment negatively influenced arterial PWV. CONCLUSION: Age is an independent risk factor for arterial stiffness in patients on maintenance hemodialysis, and the serum PTH concentration and its regulatory factors in the serum are not.

The diagnostic value of serum concentrations of 2-(alpha-mannopyranosyl)-L-tryptophan for normal renal function.

BACKGROUND: We have previously reported that the serum concentration of 2-(alpha-mannopyranosyl)-L-tryptophan (MPT), tryptophan glycoconjugate, is a more accurate measure of renal function than that of serum creatinine concentration. The aim of the present study was to compare the diagnostic value of serum concentrations of MPT and creatinine as a measure of normal renal function. METHODS: A total of 156 subjects with serum creatinine concentration < or =1.60 mg/dL aged 0 to 88 years were recruited. Serum concentrations of MPT and creatinine, and creatinine clearance calculated by Cockcroft-Galt formula were determined. A diagnostic accuracy of serum concentrations of MPT and creatinine for normal renal function was analyzed by using receiver-operating characteristics (ROC) curves. In 82 subjects with normal renal function defined as calculated creatinine clearance > or =80 mL/min (aged 6 to 68 years), the correlations between age and/or urinary creatinine excretion, which is related to muscle mass, and serum concentrations of MPT or creatinine, were determined. RESULTS: In the ROC curve, the area under the curve (AUC) in serum MPT concentration was significantly greater than that of creatinine (0.855 versus 0.800, respectively, P < 0.001) and the cut-off levels associated with the greatest diagnostic accuracy were 90 ng/mL for serum MPT concentration and 0.70 mg/dL for serum creatinine concentration. The sensitivity, specificity, and positive and negative predictive values were 69.5%, 85.1%, 83.8%, and 71.6% for serum MPT concentration, and 53.7%, 81.1%, 75.9%, and 61.2% for serum creatinine concentration. A close correlation existed between serum creatinine concentration and age (r= 0.798, P < 0.0001) in 23 subjects aged 20 years or younger. Conversely, serum MPT concentration remained unchanged regardless of age (r=-0.135, P= 0.228). Furthermore, a close correlation existed between serum creatinine concentration and urinary creatinine excretion (r= 0.817, P < 0.0001), but not between serum MPT concentration and urinary creatinine excretion (r= 0.082, P= 0.461). CONCLUSION: The concentration of serum MPT is a more reliable diagnostic parameter than that of serum creatinine as a measure of normal renal function, and renal function can be compared in subjects independently of age and muscle mass when serum MPT concentration is measured.

Supplementation with Alfacalcidol increases protein intake and serum albumin concentration in patients undergoing hemodialysis with hpoalbumineamia.

BACKGROUND: We have reported that vitamin D deficiency may be implicated in the pathogenesis of hypoalbuminemia observed in patients with end-stage renal disease, but the mechanism remains to be clarified. The aim of the present study was to determine whether supplementation with alfacalcidol might increase protein intake in hemodialyzed patients with hypoalbuminemia. METHODS: Twelve patients with hypoalbuminemia under 3.5 g/dl undergoing maintenance hemodialysis and not taking active forms of vitamin D were orally supplemented with 0.5 microg of alfacalcidol daily for 8 weeks. Normalized protein catabolic rate (nPCR), an index of protein intake, and serum concentrations of albumin, interleukin-6 (IL-6), IL-1beta, and soluble tumor necrosis factor-alpha receptor-II (sTNFR-II), an index of tumor necrosis factor-alpha activity, were determined before and after supplementation with alfacalcidol. RESULTS: Supplementation with alfacalcidol increased nPCR from 0.96 +/- 0.20 to 1.16 +/- 0.15 g/kg/day (p < 0.005), thereby increasing serum albumin concentration from a baseline of 3.13 +/- 0.35 to 3.32 +/- 0.29 g/dl (p < 0.05). The baseline serum concentrations of sTNFR-II and IL-6 were markedly elevated, whereas those of IL-1beta were under the detection limit. Supplementation with alfacalcidol significantly decreased serum concentration of sTNFR-II from 23.8 +/- 4.38 to 19.7 +/- 3.93 ng/ml (p < 0.001) but did not alter serum IL-6 concentration. CONCLUSION: Supplementation with alfacalcidol can increase protein intake and serum albumin concentration in hemodialyzed patients with hypoalbuminemia, probably through the suppressed tumor necrosis factor activity.

Protective effect of vitamins K2 and D3 on prednisolone-induced loss of bone mineral density in the lumbar spine.

BACKGROUND: Although vitamin K2 has been shown to prevent prednisolone-induced loss of bone mineral density of the lumbar spine in patients with chronic glomerulonephritis, the magnitude of this effect remains to be clarified. The aim of this prospective study is to compare the protective effect of vitamin K2 with that of vitamin D3 on prednisolone-induced loss of bone mineral density in patients with chronic glomerulonephritis. METHODS: Sixty patients (28 men, 32 women) were randomly divided into 4 groups (n = 15 each group): control (group C), vitamin D3 alone (alfacalcidol, 0.5 microg/d; group D), vitamin K2 alone (menatetrenone, 45 mg/d; group K), and vitamins D3 plus K2 (group D + K). Alfacalcidol and menatetrenone therapy were started at the same time as prednisolone. Bone mineral density of the lumbar spine (L2 to L4) was determined by means of dual-energy X-ray absorptiometry, and various biochemical parameters of calcium and bone homeostasis were assessed before and at the end of week 8 of treatment. RESULTS: Treatment with prednisolone alone caused loss of bone mineral density, which could be fully prevented in groups D, K, and D + K. However, marked reductions in levels of several biochemical markers of both bone formation and resorption also were observed in all groups. The preventive effect in groups K and D + K on loss of bone mineral density induced by prednisolone was similar to that in group D. The elevation in serum calcium levels observed in group D was attenuated in group D + K. CONCLUSION: Protective effects of vitamin K2 or vitamins D3 and K2 on prednisolone-induced loss of bone mineral density are similar to that of vitamin D3.

Longterm complete remission of AL-amyloid-related nephrotic syndrome.

We describe a 59-year-old man with nephrotic syndrome that was diagnosed as suspected minimal change nephrotic syndrome by the routine examination of renal tissues at first biopsy, because renal histology showed segmental mild mesangial expansion with argyrophilic staining and partial foot process fusion without any deposition. Prednisolone therapy induced complete remission of nephrotic syndrome. Relapse occurred after 4 years of complete remission, and the second renal biopsy revealed amyloid light-chain (AL)-amyloidosis. Re-examination of the first biopsy tissues by Congo red staining confirmed a small amount of amyloid deposition in the mesangial areas although the mesangial areas showed argyrophilic staining, which is atypical for amyloid deposition. This case raises a caution that even when renal histology is not suggestive of amyloidosis and prednisolone therapy is very effective, when a renal histology diagnosis is not confirmed, the clinician should suspect amyloidosis and should, at least, undertake Congo red staining to definitively rule out amyloidosis.