Granulomatous interstitial nephritis in a renal allograft.

We describe a middle-aged woman in whom granulomatous interstitial nephritis (GIN) developed in a renal allograft. She had undergone bowel resection due to an uncertain diagnosis of active granulomatous bowel disease 30 years earlier. Thereafter, frequent hyperoxaluria as well as calcium oxalate stone and recurrent urinary tract infections had resulted in a progressive deterioration in kidney function over a period of 20 years. She underwent living donor kidney transplantation; however, her kidney function progressively deteriorated, despite transplantation. A biopsy of the renal allograft revealed GIN with granulomatous vasculitis accompanied by calcium oxalate crystals. These as well as the laboratory findings indicated a diagnosis of sarcoidosis. We considered that the aggravated granulomatous inflammation on the allograft was caused by recurrent sarcoidosis accompanied by hyperoxaluria.

Localization of nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis.

The nephritis-associated plasmin receptor is a recently identified nephritogenic antigen associated with acute poststreptococcal glomerulonephritis and proposed to play a pathogenic role, but its precise glomerular localization in acute poststreptococcal glomerulonephritis has not been elucidated. We therefore analyzed renal biopsy sections from 10 acute poststreptococcal glomerulonephritis patients by using immunofluorescence staining with anti-nephritis-associated plasmin receptor antibody and various markers of glomerular components. Nephritis-associated plasmin receptor was detected in the glomeruli of all patients, and double staining for nephritis-associated plasmin receptor and collagen IV showed nephritis-associated plasmin receptor to be predominantly on the inner side of the glomerular tufts. Nephritis-associated plasmin receptor-positive areas within glomerular tufts were further characterized with markers for neutrophils, mesangial cells, endothelial cells, and macrophages. In 6 of the patients, nephritis-associated plasmin receptor staining was seen mainly in neutrophils and to a lesser degree in mesangial and endothelial cells. In the other 4 patients, nephritis-associated plasmin receptor staining was seen mainly in mesangial cells and to a lesser degree in neutrophils and endothelial cells. In all patients, macrophages showed little staining. Elevated plasmin activity in glomerular neutrophils was identified by combining in situ zymography staining for plasmin activity and immunofluorescence staining for neutrophils. The glomerular localizations of nephritis-associated plasmin receptor and another nephritogenic antigen, streptococcal pyrogenic exotoxin B, were compared by double immunofluorescence staining and found to be similar. These findings indicate the nephritogenic potential of nephritis-associated plasmin receptor and offer valuable information with respect to the pathogenic mechanism of acute poststreptococcal glomerulonephritis.

Elevated urinary plasmin activity resistant to alpha2-antiplasmin in acute poststreptococcal glomerulonephritis.

BACKGROUND: A pathogenic role of intraglomerular plasmin bound to nephritogenic antigen (nephritis-associated plasmin receptor, NAPlr) and resistant to physiologic inhibitors such as alpha(2)-antiplasmin (alpha(2)-AP) has recently been proposed in acute poststreptococcal glomerulonephritis (APSGN). To confirm this concept, we analysed the urinary profile of plasmin cascade in APSGN patients. METHODS: Urine samples from 10 patients with APSGN, 12 patients with IgA nephropathy (IgAN), 10 patients with streptococcal infection without nephritis (SI) and 10 healthy control subjects were analysed. The alpha(2)-AP-resistant plasmin activity was assessed by a chromogenic assay after alpha(2)-AP was added to each urine sample. Urinary plasminogen activator (PA) and plasmin were further analysed by polyacrylamide gel zymography. Urinary NAPlr was assessed by western blot analysis in selected samples. RESULTS: Urinary alpha(2)-AP-resistant plasmin activity corrected for creatinine concentration (units/g x creatinine) was significantly higher in patients with APSGN (2.99 +/- 0.63) than in patients with IgAN (1.02 +/- 0.20, P < 0.01), SI (0.79 +/- 0.17, P < 0.01), or in healthy control subjects (0.73 +/- 0.18, P < 0.01). This tendency was confirmed by casein gel zymography. However urinary PA activity assessed by plasminogen-casein gel zymography did not differ between groups. NAPlr was detected in the urine of APSGN patients. CONCLUSIONS: We found elevated urinary plasmin activity resistant to alpha(2)-AP, which may be due to urinary excretion of NAPlr in patients with APSGN. This result supports the pathogenic role of the NAPlr-plasmin complex in the development of APSGN. Furthermore, alpha(2)-AP-resistant urinary plasmin activity may be useful as a diagnostic marker for APSGN.

Osteopontin expression in vascular smooth muscle cells in patients with end-stage renal disease.

beta-glycerophosphate, a phosphate donor, and uremic sera induce osteopontin (OPN) expression in bovine vascular smooth muscle cells (VSMCs). However, the correlations of serum phosphorus level with OPN expression, and blood urea nitrogen (BUN) level with OPN expression in humans have not previously been reported. The purpose of the current study is to compare the expression of OPN in VSMCs with clinical data in patients with end-stage renal disease (ESRD). The radial arteries of 33 patients (21 male and 12 female patients) were examined to determine the expression of OPN and collagen type I (Col I) by immunohistochemistry. The correlation of the expression of bone matrix proteins with clinical data was analyzed. Between the low-serum phosphorus (<6 mg/dL) group and high-serum phosphorus (> or =6 mg/dL) group, significant differences were detected in the expression of OPN (P = 0.0049) and the levels of BUN (P = 0.0005), serum phosphorus (P < 0.0001) and calcium x phosphorus products (P < 0.0001). Moreover, between the low-BUN (<70 mg/dL, N = 19) group and high-BUN (> or =70 mg/dL) group, significant differences were detected in the expression of OPN (P = 0.0039) and the levels of BUN (P = 0.0002), serum phosphorus (P = 0.0002) and calcium x phosphorus products (P = 0.0003). We have shown that hyperphosphatemia or azotemia is associated with the expression of OPN in VSMCs in patients with ESRD.

[Focal segmental glomerulosclerosis in a patient with polycythemia vera].

Herein we describe the case of a patient with focal segmental glomerulosclerosis (FSGS) following polycythemia vera (PV) on whom hemodialysis was started 7 years later. A 66-year-old woman who had been treated for PV with hydroxyurea and phlebotomy for three years was referred to our hospital because of nephrotic syndrome. Renal biopsy performed at her local hospital revealed FSGS. Although she had received prednisolone at an initial dose of 45 mg/day, no significant improvement of proteinuria was achieved. The dose of prednisolone was tapered because the second renal biopsy revealed sclerosing glomerulopathy. We considered that FSGS was associated with PV because renal hemodynamic alterations in PV could result in FSGS as in any other secondary FSGS and there was no proteinuria at the initial detection of PV. On January 29, 1999, she developed massive proteinuria (9.6 g/day) and the findings of the third renal biopsy worsened in comparison with that of the first renal biopsy. Thereafter, hydroxyurea or ranimustine was used in treating PV at an outpatient clinic. However severe thrombocytosis was difficult to control, and progressive renal dysfunction finally necessitated hemodialysis on January 18, 2005. In conclusion, physicians should be aware of the risk of progressive renal failure in patients with FSGS following PV, particularly in patients with persistent thrombocytosis.

Microscopic polyangiitis after silicone breast implantation.

We describe the case of a patient who developed microscopic polyangiitis (MPA) after silicone breast implantation. A 60-year-old woman who had undergone silicone breast implantation was admitted to our hospital with complaints of general malaise and hematoproteinuria. She was diagnosed as having MPA with evidence of acute progressive renal failure, pulmonary hemorrhage, and positivity for myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA). A renal biopsy showed severe necrotizing and crescentic glomerulonephritis with arteriolitis. The patient received high-dose steroids and plasma exchange treatment, but died of progressive pulmonary hemorrhage and multiple cerebral hemorrhage. Silicone implantation is associated with scleroderma, systemic lupus erythematosus, and rheumatoid arthritis. This case report indicates the possibility of the development of MPA after silicone breast implantation.

[Case of paroxysmal nocturnal hemoglobinuria complicated with IgA nephropathy who developed acute renal failure induced by hemolytic crisis].

A 60-year-old man, who had been diagnosed as having paroxysmal nocturnal hemoglobinuria(PNH) in 1994, was admitted to our hospital with general fatigue, and dark urine after a common-cold in January 2001. In the peripheral blood, the red blood cell count was 136 x 10(4)/microl, hemoglobin 4.0 g/dl and hematocrit 12.4%. The serum creatinine level was 9.9 mg/dl. Kidney biopsy revealed focal and segmental proliferation of mesangial cells, mesangial matrix expansion, acute tubular necrosis, interstitial fibrosis and hemosiderine deposits in the tubular epithelial cells confirmed by Berlin-blue staining. Immunofluorescence microscopy showed IgA and C3 deposition in the mesangium. Electron microscopy revealed electron dense deposits in the mesangial area and heavy electron-dense hemosiderin pigments in proximal tubular epithelial cells. After the transfusion of six units of washed red blood cells and two sessions of hemodialysis, the renal function returned to the levels before admission.

Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy.

BACKGROUND: The predominant deposition of IgG4 in idiopathic membranous nephropathy indicates that its presence characterizes the systemic immune response of the disease. METHODS: We analyzed the expressions of CD3, CD19, CD4, and CD8 on peripheral blood mononuclear cells (PBMCs) by flow cytometry, and the levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), interferon (IFN)-gamma, interleukin (IL)-4, IL-10, and IL-13 mRNAs in PBMCs using real-time reverse transcription-polymerase chain reaction (RT-PCR) in 14 patients with idiopathic membranous nephropathy and 14 normal control donors. The levels of IgG subclasses in the B-cell culture supernatant in the presence or absence of cytokines were quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: Idiopathic membranous nephropathy patients showed an increased CD4(+)/CD8(+) ratio, although the numbers of peripheral T and B cells were comparable to those of the normal control group. IL-10 and IL-13 mRNA expression levels increased in the idiopathic membranous nephropathy group. The levels of spontaneous production of each IgG subclass by B cells were identical in the two groups. In the presence of Th2 cytokines, B cells from several individuals of the idiopathic membranous nephropathy group augmented the production of IgG4. When the individual levels of each IgG subclass in the presence of cytokines were compared with those in the absence of cytokines in each sample, a significant increase in the production of IgG4 in the presence of IL-4 was observed in the idiopathic membranous nephropathy group. CONCLUSION: These results indicate that the altered functions of T cells to produce Th2 cytokines and the increased production of IgG4 by B cells in response to these cytokines characterize the immune response in idiopathic membranous nephropathy.

Adjuvant-induced macrophage-dominant nephrotoxic serum nephritis in rats.

BACKGROUND: To investigate cellular mechanisms responsible for the development of crescentic glomerular lesions, we have studied the effects of complete adjuvant (CA) on subnephritogenic nephrotoxic serum (NTS) nephritis (NTS-N) in Brown Norway rats. METHODS: A subnephritogenic dose of NTS, 0.02 ml per rat, was intravenously injected into rats that were previously (14 days earlier) treated intradermally with CA, incomplete adjuvant, or PBS. RESULTS: Proteinuria developed by day 2 only in CA-treated rats. Also, severe glomerular lesions associated with cellular crescent formation developed by day 2 only in the CA-treated rats. The glomerular extent of infiltration of IL-1beta-positive cells, MCP-1 expression level, and the number of ED1 and PCNA double-positive activated macrophages peaked on day 4 and decreased thereafter. The numbers of T lymphocytes and polymorphonuclear neutrophils did not significantly increase throughout the experiments. CONCLUSIONS: These results indicate that CA can potently induce crescentic NTS-N characterized by the infiltration of activated macrophages, which presumably bind to rabbit IgG on the glomerular basement membrane and may play a critical role in the development of severe NTS-N associated with crescent formation.

Glomerular plasmin-like activity in relation to nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis.

A nephritogenic antigen for acute poststreptococcal glomerulonephritis (APSGN) was isolated recently from group A streptococcus and termed nephritis-associated plasmin receptor (NAPlr). In vitro experimental data indicate that the pathogenic role of NAPlr occurs through its ability to bind to plasmin and maintain its proteolytic activity. However, the mechanism whereby this antigen induces glomerular damage in vivo has not been fully elucidated. Renal biopsy tissues from 17 patients with APSGN, 8 patients with rapidly progressive glomerulonephritis, and 10 normal kidneys were analyzed in this study. Plasmin-like activity was assessed on cryostat sections by in situ zymography with a plasmin-sensitive synthetic substrate. Serial sections were simultaneously assessed for NAPlr deposition by immunofluorescence staining. Glomerular plasmin-like activity was absent or weak in normal controls and in patients with rapidly progressive glomerulonephritis, although tubulointerstitial activity was occasionally detected. Prominent glomerular plasmin-like activity was found in patients who had APSGN and in whom glomerular NAPlr was positive, whereas it was absent or weak in patients who had APSGN and in whom glomerular NAPlr was negative. The distribution of glomerular plasmin-like activity was identical to that of NAPlr deposition but was generally different from that of fibrin(ogen) deposition as assessed by double staining. The activity was abolished by the addition of aprotinin to the reaction mixture but was not altered by the addition of a matrix metalloprotease inhibitor, a cysteine protease inhibitor, or inhibitors of plasminogen activators. Thus, upregulated glomerular plasmin-like activity in relation to NAPlr deposition in APSGN was identified. This result supports the nephritogenic character of NAPlr and offers insight into the mechanism whereby this antigen induces nephritis.

A randomized open-label comparative study of conventional therapy versus mizoribine onlay therapy in patients with steroid-resistant nephrotic syndrome (postmarketing survey).

BACKGROUND: A previous double-blind 24-week clinical trial of mizoribine (MZ) vs placebo in steroid-resistant primary nephrotic syndrome (SRPNS) showed that MZ was more effective than placebo in reducing the rate of deterioration of renal function. The present study was conducted to evaluate the efficacy and safety of MZ in patients with SRPNS after 2 years' treatment. METHODS: A multicenter randomized open-label controlled trial in patients with SRPNS was conducted as a 2-year prospective postmarketing study. RESULTS: There was a significant imbalance in the baseline serum albumin level (s-Alb) between the conventional therapy (CT) and MZ onlay therapy groups. Early dropouts were more frequent in the subset of patients in the CT group having a baseline s-Alb < or =3 g/dl. Therefore, the primary analysis (urinary protein level (UP)-improving effect) was performed using a mixed-effects model, with stratification according to the baseline s-Alb value. The analysis revealed that, in the subset of 34 patients with membranous nephropathy (MN) within the stratum of patients with baseline s-Alb < or =3 g/dl (n = 52), the rate of change (slope of change in the UP level/month), in terms of the log (UP+0.2), was -0.0577 in those allocated to the MZ group and -0.0227 in those allocated to the CT group (P = 0.058). In the stratum of patients with a baseline s-Alb >3 g/dl (n = 97), there were no significant differences in the UP between the two treatment groups. Hence, MZ onlay therapy was not considered to be efficacious in this group of patients. No serious adverse reactions to the drug were observed. CONCLUSIONS: The present study yielded significant results, in that it suggested the possibility that long-term MZ therapy may afford further reduction of the UP, in addition to that obtained following CT, in particular, in MN patients in a severe nephrotic state.

Nephritis-associated plasmin receptor and acute poststreptococcal glomerulonephritis: characterization of the antigen and associated immune response.

The role of nephritis-associated antigen as a virulence factor for acute poststreptococcal glomerulonephritis (APSGN) remains to be fully clarified. Nephritis-associated plasmin receptor (NAPlr) was previously isolated from group A streptococcus (GAS) and shown to bind plasmin(ogen). The nucleotide sequence of the naplr gene from GAS isolates obtained from patients with APSGN was determined. The sequence of the putative open reading frame (1011 bp) showed 99.8% identity among isolated strains. Homology screen revealed an exact match with streptococcal glyceraldehyde-3-phosphate dehydrogenase (GAPDH). NAPlr exhibited GAPDH activity in zymography, and it activated the complement pathway in vitro. In APSGN kidney biopsy specimens, NAPlr was observed mainly in the early stage of the disease (1 to 14 d after onset) but was not colocalized with either C3 or IgG as assessed by double immunofluorescence staining. Sera of patients with APSGN, patients with GAS infection without renal involvement, nonrenal pediatric patients, and healthy adults as controls were assayed for anti-NAPlr antibody titers. Anti-NAPlr antibodies were present most frequently in APSGN sera, and antibody titers were also significantly higher than in patients with GAS infection alone or in other control patients. Moreover, antibody titers remained elevated during the entire 10-yr follow-up period.

Renoprotective effect of losartan in comparison to amlodipine in patients with chronic kidney disease and hypertension--a report of the Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients (JLIGHT) study.

A 12-month, multicenter (57 clinical institutions), randomized, open-labeled trial was undertaken to compare the efficacy of the angiotensin II receptor antagonist losartan and the calcium channel blocker amlodipine in patients with proteinuric chronic kidney disease (CKD) and hypertension. A total of 117 patients (79, chronic glomerulonephritis; 14, diabetic nephropathy; 24, other CKD) were randomly allocated into two treatment groups. Losartan and amlodipine exerted the same efficacy for blood pressure (BP) control; however, losartan significantly reduced the 24-h urinary protein excretion at months 3, 6, and 12, with the reduction of 20.7%, 35.2%, 35.8%, whereas amlodipine did not change the amount of proteinuria over the 12-month study period. When patients were stratified into groups according to the level of BP control at 3 months, the reduction in urinary protein excretion by losartan was evident in the group for which a BP of <140/90 mmHg was achieved, as well as in the group for which the goal BP (<130/85 mmHg) for treatment of CKD was not achieved. When patients were stratified according to baseline urinary protein excretion, those with > or = 2 g/day showed a reduction in proteinuria by losartan of 23.3%, 39.4%, and 47.9% at months 3, 6, and 12, and those with <2 g/day showed a reduction of 18.5% and 31.2% at months 3 and 6, respectively. No fatal adverse events were experienced in either drug group. We conclude that losartan reduced proteinuria in patients with CKD and hypertension. This positive effect may contribute to the renal protective benefit of losartan, and is beyond the magnitude of BP control.

Interim evidence of the renoprotective effect of the angiotensin II receptor antagonist losartan versus the calcium channel blocker amlodipine in patients with chronic kidney disease and hypertension: a report of the Japanese Losartan Therapy Intended for Global Renal Protection in Hypertensive Patients (JLIGHT) Study.

BACKGROUND: Insufficiency of renal function and high blood pressure influence each other and eventually result in life-threatening endstage renal disease. It has been proposed that proteinuria per se is a determinant of the progression of chronic kidney disease (CKD). The therapeutic strategy for patients with proteinuric CKD and hypertension should therefore be targeted with a view not merely toward blood pressure reduction but also toward renoprotection. METHODS: We examined the effect of the angiotensin (AT)1 receptor antagonist losartan and the calcium channel blocker amlodipine, throughout a period of 12 months, on reduction of blood pressure and renoprotection. This was done by assessing amounts of urinary protein excretion, serum creatinine (SCr), and creatinine clearance (CCr) in patients with hypertension (systolic blood pressure [SBP] > or = 140 mmHg or diastolic blood pressure [DBP] > or = 90 mmHg) and CKD (male, body weight [BW] > or = 60 kg: 1.5 < or = SCr < 3.0 mg/dl; female or male BW < 60 kg: 1.3 < or = SCr < 3.0 mg/dl), manifesting proteinuria of 0.5 g or more/day. Losartan was administered once daily at doses of 25 to 100 mg/day, and amlodipine was given once daily at 2.5 to 5 mg/day. No antihypertensive combination therapy was allowed during the first 3-month period. RESULTS: A 3-month interim analysis revealed that, despite there being no difference in blood pressure between the two groups, there was a significant reduction in 24-h urinary protein excretion in the losartan group ( n = 43), but there was no change in the amlodipine group ( n = 43). Analysis of stratified subgroups with proteinuria of 2 g or more/day and less than 2 g/day showed that losartan lowered proteinuria by approximately 24% in both subgroups, while amlodipine lowered proteinuria by 10%, but only in the subgroup of less than 2 g/day (NS). SCr and CCr did not change throughout the period of 3 months in either group. No severe or fatal adverse event was experienced in either group during the study period. CONCLUSIONS: Losartan appeared to be efficacious for renoprotection in patients with proteinuric CKD and hypertension, with the mechanism being independent of its antihypertensive action.

Acquired reactive perforating collagenosis in a nondiabetic hemodialysis patient: successful treatment with allopurinol.

The authors present a case of acquired reactive perforating collagenosis developed in a nondiabetic hemodialysis patient, who was treated successfully with allopurinol. Treatment of acquired reactive perforating collagenosis is difficult and often ineffective. The patient had been unresponsive to conventional treatments, but the pruritus was controlled, and skin lesions subsequently resolved after the treatment with allopurinol. Possible mechanisms of allopurinol treatment for acquired reactive perforating collagenosis are discussed.

Propylthiouracil-induced antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis in a patient with a predisposition to autoimmune abnormalities.

Abstract A 65-year-old woman with a history of primary biliary cirrhosis was diagnosed as having myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated crescentic glomerulonephritis (GN) during propylthiouracil (PTU) therapy for Graves' disease. Antinuclear antibodies, as well as various thyroid-associated autoantibodies, had been detected since the diagnosis of Graves' disease was made. The patient carried human leukocyte antigens (HLAs) DR4 and DR9, the two HLA haplotypes that have been reported to be related to ANCA-associated vasculitis. Withdrawal of PTU and the administration of prednisolone resulted in a decrease in the titer of MPO-ANCA, together with an improvement in renal function. It is suggested that in addition to the PTU therapy, her genetic predisposition to autoimmunity had played a role in the production of MPO-ANCA and the development of crescentic GN.