[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.

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.

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.

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.

Withdrawal of interferon-alpha results in prompt resolution of thrombocytopenia and hemolysis but not renal failure in hemolytic uremic syndrome caused by interferon-alpha.

This case report describes 2 patients with chronic myeloid leukemia in whom hemolytic uremic syndrome developed while being treated with interferon-alpha and hydroxycarbamide. Hemolytic uremic syndrome was recognized by progressive renal dysfunction, thrombocytopenia, microangiopathic hemolytic anemia, and histologic features of thrombotic microangiopathy in the kidney. Although renal dysfunction progressed to dialysis-dependent renal failure in one patient despite treatment with prednisolone and plasmapheresis but not in other, withdrawal of the treatment resulted in a prompt resolution of thrombocytopenia and microangiopathic hemolytic anemia in both patients.

Important role for fibronectin-EIIIA during renal tubular repair and cellular recovery in uranyl acetate-induced acute renal failure of rats.

The present study was designed to identify the source and kinetics of an alternatively spliced "embryonic" cellular fibronectin EIIIA (cFn-EIIIA) in relation to regenerating renal tubules in uranyl acetate (UA)-induced acute renal failure (ARF) in rats. Damage of the proximal tubules was found as early as day 2 after induction of ARF, peaked at day 5, and was almost substituted by epithelial relining by day 7. Immunohistochemistry showed de novo deposition of cFn-EIIIA in peritubular regions as early as day 2, then on the tubular basement membrane (TBM) after day 4. beta1 Integrin, the receptor for Fn, was mainly found at the basal side of tubules in the normal control and increased in the interstitium after induction of ARF, but the staining pattern gradually returned to the control after day 7. Immunoelectron microscopy revealed that cFn-EIIIA was produced initially by the peritubular endothelium and later by fibroblastic cells and was deposited to the TBM, on which regenerating tubules proliferated, probably with cFn-EIIIA production. beta1 Integrin was expressed in cFn-EIIIA-producing cells, especially in regenerating tubular cells, suggesting that cFn-EIIIA signal transduction affects regenerating tubules. Transforming growth factor (TGF)-beta1 was found in some damaged proximal tubules and interstitial cells after induction of ARF and later in the regenerating tubules. CFn-EIIIA and beta1 integrin mRNA levels were upregulated as early as day 2. TGF-beta1 mRNA level significantly increased after day 3, suggesting a modulatory role for TGF-beta1 on cFn-EIIIA production, but not by day 2. Our data suggest that cFn-EIIIA production by the endothelium during the very early response to tubular injury and by fibroblastic cells and regenerating tubules may play an important role in the cellular recovery of UA-induced ARF in rats.

A case of thrombotic microangiopathy complicated with systemic lupus erythematosus.

A woman was admitted to the hospital with joint pain. She was also found to have pericardial effusion, renal dysfunction, pancytopenia, and positive antinuclear antibody; a diagnosis of systemic lupus erythematosus (SLE) was made. Although she had neither neurological symptoms nor fever, laboratory tests showed microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. Therefore, we diagnosed her illness as SLE complicated by thrombotic microangiopathy (TMA). Plasmapheresis was performed in addition to immunosuppressive therapy. TMA improved rapidly and renal function improved gradually. The number of patients with SLE complicated by TMA is relatively small and the mortality rate is extremely high. A diagnosis of TMA is difficult to determine in patients with SLE because of the overlapping clinical symptoms. The data suggest that prompt induction of plasmapheresis in addition to immunosuppressive therapy is necessary in SLE patients having symptoms suspicious of TMA even before they fulfill the 5 symptoms typical of TMA.

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.

A patient with sarcoidosis presenting with acute renal failure: implication for granulomatous interstitial nephritis and hypercalcemia.

A woman was admitted for acute renal failure and erythematous lesions. She was diagnosed with sarcoidosis after analysis of biopsy specimens revealed noncaseating epithelioid granulomas, elevated serum angiotensin-converting enzyme levels, and bilateral hilar lymphadenopathy. Serum concentrations of ionized calcium and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] were extremely high. Serum intact osteocalcin concentration and urinary deoxypyridinoline excretion were within reference ranges. Treatment with prednisolone induced a prompt improvement with normalization of serum concentrations of ionized calcium and 1,25-(OH)2D3. Serum intact osteocalcin concentration was markedly suppressed and urinary deoxypyridinoline excretion increased. It is possible suppressed bone resorption may be associated with overproduction of 1,25-(OH)2D3.

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.

Transient leukopenia and anaphylatoxin production during granulocyte apheresis as treatment for ulcerative colitis.

It is well known that transient leukopenia due to activation of the alternative pathway of the complement system accompanies hemodialysis when cellulose acetate dialyzers are used. However, it has not been evaluated whether leukopenia also occurs during granulocyte apheresis (GCAP) as treatment for ulcerative colitis, in which an extracorporeal column is filled with cellulose acetate beads in order to remove circulating leukocytes. The aim of the present study was to evaluate whether transient leukopenia and activation of the alternative pathway of the complement system were observed during GCAP. In 8 patients undergoing GCAP weekly for 10 weeks, circulating leukocyte counts and plasma concentrations of C3a, a product of the activated alternative pathway of the complement system, were determined. GCAP elicited a rapid decline in the number of circulating leukocytes to 61.8 +/- 13.8% of the baseline value after 15 minutes of GCAP (P < 0.02). Thereafter, the number of circulating leukocytes returned to approximately baseline after 60 minutes. The baseline plasma C3a concentration was 123 +/- 61 ng/mL, and a significant increase to 425 +/- 123 ng/mL was observed after 15 minutes of GCAP (P < 0.02). The plasma C3a concentration reached 417 +/- 96 ng/mL after 60 minutes (P < 0.02). It thus follows that GCAP activates the alternative pathway of the complement system, resulting in anaphylatoxin production.