BACKGROUND/AIMS: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. METHODS: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. RESULTS: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor beta (TGF-beta) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-beta in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. CONCLUSIONS: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.
Amides/*pharmacology ; Angiotensin II/pharmacology ; Animals ; Disease Models, Animal ; Fibrosis ; Fumarates/*pharmacology ; Kidney/*drug effects/metabolism/pathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Nephritis, Interstitial/genetics/metabolism/pathology/*prevention & control ; RNA, Messenger/genetics/metabolism ; Renin/*antagonists & inhibitors/metabolism ; Renin-Angiotensin System/*drug effects ; Toll-Like Receptor 2/deficiency/drug effects/genetics/*metabolism ; Ureteral Obstruction/*drug therapy/genetics/metabolism/pathology

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and severe drug-induced hypersensitivity syndrome characterized by hematological abnormalities and multiorgan involvement. Liver involvement is the most common visceral manifestation. However, renal failure has been rarely described. The common culprit drugs are anticonvulsants and allopurinol. We experienced a patient with DRESS syndrome with acute interstitial nephritis caused by concomitant administration of quinolone and non-steroidal anti-inflammatory drugs (NSAIDs). A 41-year-old man presented with a diffuse erythematous rash and fever which developed after administration of quinolone and NSAIDs for a month due to prostatitis. He was diagnosed with DRESS syndrome. Skin rash, fever, eosinophilia, and elevations of liver enzymes improved with conservative treatment and discontinuation of the causative drugs. However, deterioration of his renal function occurred on day 8 of admission. The levels of blood urea nitrogen and serum creatinine increased and oliguria, proteinuria and urinary eosinophils were observed. Ultrasonography showed diffuse renal enlargement. The clinical features were compatible with acute interstitial nephritis. Despite intravenous rehydration and diuretics, renal function did not improve. After hemodialysis, his renal function recovered completely within 2 weeks without administration of systemic corticosteroid.
Adult ; Allopurinol ; Anti-Inflammatory Agents, Non-Steroidal ; Anticonvulsants ; Blood Urea Nitrogen ; Creatinine ; Diuretics ; Drug Hypersensitivity ; Drug Hypersensitivity Syndrome* ; Eosinophilia ; Eosinophils ; Exanthema ; Fever ; Fluid Therapy ; Humans ; Hypersensitivity ; Liver ; Nephritis, Interstitial* ; Oliguria ; Prostatitis ; Proteinuria ; Renal Dialysis ; Renal Insufficiency ; Ultrasonography

Megalocytic interstitial nephritis is a rare form of kidney disease caused by chronic inflammation. We report a case of megalocytic interstitial nephritis occurring in a 45-yrold woman who presented with oliguric acute kidney injury and acute pyelonephritis accompanied by Escherichia coli bacteremia. Her renal function was not recovered despite adequate duration of susceptible antibiotic treatment, accompanied by negative conversion of bacteremia and bacteriuria. Kidney biopsy revealed an infiltration of numerous histiocytes without Michaelis-Gutmann bodies. The patient's renal function was markedly improved after short-term treatment with high-dose steroid.
Acute Disease ; Acute Kidney Injury/complications/*drug therapy/pathology ; Anti-Bacterial Agents/therapeutic use ; Azithromycin/therapeutic use ; Bacteremia/*drug therapy/microbiology/pathology ; Cefotaxime/therapeutic use ; Creatinine/blood ; Escherichia coli ; Escherichia coli Infections/*drug therapy/microbiology/pathology ; Female ; Humans ; Kidney/pathology ; Methylprednisolone/therapeutic use ; Middle Aged ; Nephritis, Interstitial/*drug therapy/immunology/pathology ; Pyelonephritis/complications/*drug therapy/pathology ; Renal Dialysis ; Shock, Septic/drug therapy/microbiology

Infliximab is a chimeric anti-tumor necrosis factor-alpha monoclonal antibody. Infusion related reactions and infection are well known side effects of infliximab; however, renal complications have not been well recognized. We report on a patient with late onset-acute tubulointerstitial nephritis (ATIN) after treatment with infliximab and mesalazine for Crohn's disease. A 25-year-old woman was admitted with a purpuric rash on both lower extremities and arthralgia. She had been diagnosed with Crohn's disease 5.6 years previously and had been treated with mesalazine and infliximab. Serum creatinine level, last measured one year ago, was elevated from 0.6 mg/dL to 1.9 mg/dL. Results of urinalysis, ultrasound, and serologic examinations were normal. With a tentative diagnosis of Henoch-Schonlein purpura, oral prednisolone was given, and serum creatinine decreased to 1.46 mg/dL, but was elevated to 2.6 mg/dL again at two months after discontinuation of prednisolone. Renal biopsy indicated that ATIN was probably induced by drug, considering significant infiltration of eosinophils. Concomitant use of infliximab with mesalazine was supposed to trigger ATIN. Oral prednisolone was administered, and serum creatinine level showed partial recovery. Thus, ATIN should be suspected as a cause of renal impairment in Crohn's disease even after a long period of maintenance treatment with infliximab and mesalazine.
Adalimumab/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Creatine/blood ; Crohn Disease/*drug therapy ; Drug Therapy, Combination ; Eosinophils/immunology ; Female ; Humans ; Infliximab/*adverse effects/*therapeutic use ; Kidney/pathology ; Mesalamine/*adverse effects/*therapeutic use ; Nephritis, Interstitial/*diagnosis/drug therapy/*etiology ; Prednisolone/therapeutic use

Metabolic acidosis is a cause of renal disease progression, and alkali therapy ameliorates its progression. However, there are few reports on the role of renal acid-base transporters during alkali therapy. We evaluated the effect of sodium bicarbonate therapy and the role of acid-base transporters on renal disease progression in rats with a remnant kidney. Sprague-Dawley rats consumed dietary sodium bicarbonate (NaHCO3) or sodium chloride (NaCl) with 20% casein after a 5/6 nephrectomy. After being provided with a casein diet, the NaHCO3-treated group had higher levels of serum bicarbonate than the control group. At week 4, the glomerular filtration rate in the NaHCO3 group was higher than that in the NaCl group, and the difference became prominent at week 10. The glomerulosclerosis and tubulointerstitial damage indices in the NaHCO3 group were less severe compared with controls at week 4 and 10. The expression of the Na/H exchanger (NHE) was decreased, and apical reactivity was decreased in the NaHCO3 group, compared with the NaCl group. Endothelin-1 levels in the kidney were also decreased in the NaHCO3 group. Dietary sodium bicarbonate has the effects of ameliorating renal disease progression, which may be related to the altered expression of NHE in the remaining kidney.
Acidosis/*drug therapy ; Alkalies/*therapeutic use ; Animals ; Caseins/administration & dosage ; Disease Progression ; Glomerular Filtration Rate/drug effects ; Glomerulosclerosis, Focal Segmental/drug therapy ; Kidney/injuries ; Male ; Nephrectomy ; Nephritis, Interstitial/drug therapy ; Rats ; Rats, Sprague-Dawley ; Renal Insufficiency/*drug therapy ; Sodium Bicarbonate/*therapeutic use ; Sodium Chloride/administration & dosage ; Sodium-Hydrogen Antiporter/*antagonists & inhibitors

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease entity usually occurring in children. In the present study a case of TINU syndrome in an elderly patient is described and relevant literature is reviewed. A 61-year-old man presented with bilateral flank pain, urinary frequency, and foamy urine. A kidney ultrasonography revealed an increase in kidney parenchyma echogenicity. Following a kidney biopsy, the patient was diagnosed with acute tubulointerstitial nephritis. An ophthalmology examination initially performed for floater symptoms, revealed anterior uveitis in both eyes. Acute tubulointerstitial nephritis and anterior uveitis in both eyes responded to treatment with oral prednisolone, furosemide, carvedilol, and a topical steroid. TINU syndrome can occur in the elderly and should be part of the differential diagnosis when seeing a patient who has uveitis in association with renal disease; any therapy should be managed by both an internist and an ophthalmologist.
Biopsy ; Diagnosis, Differential ; Glucocorticoids/therapeutic use ; Humans ; Male ; Middle Aged ; Nephritis, Interstitial/*diagnosis/drug therapy ; Uveitis/*diagnosis/drug therapy

BACKGROUNDIt was reported that combination of mycophenolate mofetil (MMF) and enalapril could reduce proteinuria, improve renal function, and down-regulate diabetes-induced macrophage recruitment and expression of monocyte chemotactic protein 1 (MCP-1) and transforming growth factor beta (TGF-beta) in diabetic renal tissue. But there are no compelling data available for the combination of MMF and angiotensin converting enzyme inhibitor (ACEI) for suppressing tubulointerstitial fibrosis in chronic kidney diseases. The present study was to disclose the effect of MMF combined with benazapril on delaying tubulointerstitial fibrosis and its possible mechanisms in 5/6 nephrectomized rats.

METHODSFifty male SD rats underwent 5/6 nephrectomy (5/6 NX) were randomized into the following groups: NX (5/6 nephrectomized rats, distilled water, n = 10), MMF (MMF 20 mg x kg(-1) x d(-1), p.o., n = 10), Ben (benazepril 10 mg x kg(-1) x d(-1), p.o., n = 10), MMF/Ben (MMF 20 mg x kg(-1) x d(-1), p.o., and benazapril 10 mg x kg(-1) x d(-1), p.o., n = 10). They were monitored for proteinuria and systolic blood pressure every two weeks. After 8 weeks of treatment, serum creatinine and blood urea nitrogen were assayed and pathological damage to the kidney were evaluated. Renal expression and serum levels of platelet-derived growth factor-BB (PDGF-BB), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metaloproteinase-1 (TIMP-1) were detected by immunohistochemistry and ELISA methods.

RESULTSAfter 8 weeks of treatment, 24-hour proteinuria, serum creatinine and blood urea nitrogen were significantly lower in treated groups compared with the untreated rats. MMF and benazepril combination therapy had a greater effect than either drug alone. MMF alone had no effect on systolic blood pressure, but benazapril and MMF/benazapril could significantly reduce blood pressure. Rats that underwent 5/6 nephrectomy had greater tubulointerstitial inflammatory cell infiltration and collagen accumulation than sham-operated rats; all treatments, especially MMF/benazepril, ameliorated these effects. Tubules in 5/6 nephrectomized rats expressed higher levels of PDGF-BB and TIMP-1 and lower MMP-9 compared with sham-operated rats. MMF and benazepril similarly reversed these phenomenons and combination therapy almost completely restored the expression of these cytokines in renal tissue and their plasma concentration.

CONCLUSIONSMMF, especially combined with benazepril, can reduce proteinuria, improve renal function, ameliorate tubulointerstitial fibrosis in 5/6 nephrectomized rats. These effects might be, in part, associated with down-regulation of PDGF-BB and TIMP-1, and MMP-9 up-regulation in renal tissues.

Animals ; Benzazepines ; therapeutic use ; Enzyme-Linked Immunosorbent Assay ; Immunohistochemistry ; Immunosuppressive Agents ; therapeutic use ; Male ; Matrix Metalloproteinase 9 ; metabolism ; Mycophenolic Acid ; analogs & derivatives ; therapeutic use ; Nephrectomy ; Nephritis, Interstitial ; drug therapy ; metabolism ; pathology ; Platelet-Derived Growth Factor ; metabolism ; Proto-Oncogene Proteins c-sis ; Rats ; Rats, Sprague-Dawley ; Tissue Inhibitor of Metalloproteinase-1 ; metabolism

Total saponins of Panax notoginseng (PNS) have been shown to ameliorate renal interstitial fibrosis. Ginsenoside Rg1, a panaxatriol saponin, is one of the major active molecules from PNS. The present study was undertaken to investigate the effect of ginsenoside Rg1 on renal fibrosis in rats with unilateral ureteral obstruction (UUO). The rats were randomly divided into 3 groups: sham-operation (n=15), UUO (n=15) and UUO with ginsenoside Rg1 treatment (n=15, 50 mg per kg body weight, intraperitoneally (i.p.) injected). The rats were sacrificed on Days 7 and 14 after the surgery. Histological examination demonstrated that ginsenoside Rg1 significantly inhibited interstitial fibrosis including tubular injury as well as collagen deposition. alpha-smooth muscle actin (alpha-SMA) and E-cadherin are two markers of tubular epithelial-myofibroblast transition (TEMT). Interestingly, ginsenoside Rg1 notably decreased alpha-SMA expression and simultaneously enhanced E-cadherin expression. The messenger RNA (mRNA) of transforming growth factor-beta1 (TGF-beta1), a key mediator to regulate TEMT, in the obstructed kidney increased dramatically, but was found to decrease significantly after administration of ginsenoside Rg1. Further study showed that ginsenoside Rg1 considerably decreased the levels of both active TGF-beta1 and phosphorylated Smad2 (pSmad2). Moreover, ginsenoside Rg1 substantially suppressed the expression of thrombospondin-1 (TSP-1), a cytokine which can promote the transcription of TGF-beta1 mRNA and the activation of latent TGF-beta1. These results suggest that ginsenoside Rg1 inhibits renal interstitial fibrosis in rats with UUO. The mechanism might be partly related to the blocking of TEMT via suppressing the expression of TSP-1.
Actins ; biosynthesis ; Animals ; Cadherins ; biosynthesis ; Collagen Type I ; genetics ; metabolism ; Fibronectins ; genetics ; metabolism ; Ginsenosides ; pharmacology ; Immunohistochemistry ; Male ; Nephritis, Interstitial ; drug therapy ; genetics ; metabolism ; pathology ; Panax notoginseng ; chemistry ; RNA, Messenger ; biosynthesis ; genetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Smad2 Protein ; biosynthesis ; Thrombospondin 1 ; biosynthesis ; genetics ; Transforming Growth Factor beta1 ; biosynthesis ; genetics ; Ureteral Obstruction ; metabolism ; pathology

A 60 year-old woman was admitted with generalized edema. The patient had bronchogenic adenocarcinoma which was diagnosed 8 months ago, and treated with 3 cycles of etoposide and cisplatin and 6 cycles of paclitaxel and carboplatin. After completion of chemotherapeutic cycles, massive proteinuria (18, 018 mg/day) developed. Renal biopsy revealed minimal change disease, acute tubular necrosis and chronic interstitial nephritis. In spite of continuous chemotherapy, there was no evidence of remission of cancer lesion on a serial consecutive radiographic study. She quitted continuing chemotherapy, and alternative day high dose of prednisolone was initiated for minimal change disease. Proteinuria was decreased dramatically (180 mg/day) after 2 months, and did not recur during tapering of prednisolone. Although bone metastasis on the right femur was newly detected after 2 months, proteinuria did not develop. We experienced minimal change disease during chemotheraphy of bronchogenic adenocarcinoma, thus we report it with article review.
Adenocarcinoma* ; Biopsy ; Carboplatin ; Cisplatin ; Drug Therapy* ; Edema ; Etoposide ; Female ; Femur ; Humans ; Middle Aged ; Necrosis ; Neoplasm Metastasis ; Nephritis, Interstitial ; Nephrosis, Lipoid* ; Paclitaxel ; Prednisolone ; Proteinuria

Behcet's Disease (BD) is a chronic inflammatory disorder characterized by vasculitis of unknown cause, involving multiple organs. In the past years, renal involvement has not been regarded as a feature of BD. However, renal lesions in BD, although uncommon, have increasingly been recognized in recent years. Five categories of renal lesions associated with BD have been identified, including glomerulonephritis, amyloidosis, renal vascular involvement, interstitial nephritis, and other problems, such as complications of drug therapy or abnormalities of the genitourinary tract. On the other hand, regional differences in the disease expression of BD are well appreciated. Renal lesions accompanied by BD have rarely been reported in Korea, although it have been described occasionally in the Middle Eastern countries. Hereby, we described a 46-year-old female patient who had BD with persistent hematuria and proteinuria, whose renal biopsy specimens were consistent with thin glomerular basement membrane disease. Interestingly, some portions of her glomerular capillary walls were filled with fuchsinophilic fibrin-like materials.
Amyloidosis ; Basement Membrane ; Biopsy ; Capillaries ; Drug Therapy ; Female ; Glomerular Basement Membrane* ; Glomerulonephritis ; Hand ; Hematuria ; Humans ; Korea ; Middle Aged ; Nephritis, Interstitial ; Proteinuria ; Vasculitis