Inhibition of lysyl oxidase­like 2 ameliorates folic acid­induced renal tubulointerstitial fibrosis.

Tubulointerstitial fibrosis is characterized by accumulation of the extracellular matrix in the interstitium. Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family, is known for promoting cancer metastasis, invasion and stromal fibrosis in various organs. Our previous study demonstrated expression of LOXL2 in kidney podocytes and tubular epithelial cells, and the association between elevated LOXL2 and tubulointerstitial fibrosis. The present study evaluated the effect of LOXL2 inhibition using an inhibitory monoclonal antibody (AB0023) on tubulointerstitial fibrosis in a folic acid-induced tubulointerstitial fibrosis mouse model. The association of LOXL2 with epithelial-mesenchymal transformation-related molecules was also evaluated in vitro using HK-2 cells. The present data demonstrated that AB0023 prevented the progression of tubulointerstitial fibrosis significantly, as determined by trichrome and picro-sirius red staining, as well as the total collagen assay. The mean expression of phosphorylated Smad2 and Smad4 was lower in the AB0023-treated group although it was not statistically significant. Following transforming growth factor-ß (TGF-ß) challenge, LOXL2-deficient HK-2 cells exhibited significantly lower expression of the mesenchymal markers vimentin and fibronectin than control HK-2 cells. In conclusion, LOXL2 inhibition ameliorates renal fibrosis through the TGF-ß/Smad signalling pathway.

Glomerular subepithelial microparticles - a footprint for podocyte injury.

The aim of this study was to clarify the nature and clinical significance of glomerular subepithelial microparticles (SMPs), located between the basal surface of the podocytes and the glomerular basement membrane. Ultrastructural morphology of 79 renal biopsy samples (obtained from 25 native and 54 transplanted kidneys), showing SMPs in the last 3 years, was reevaluated with regard to the podocyte changes and clinical condition of the patients. One hundred and nine SMPs were identified, with 32.9% of the samples having two or more per glomerulus. Overall, they were most frequently located in the open capillary loops (55%). However, in the native kidney samples with mesangial deposits, 64.3% of SMPs were present in the mesangium-bound areas. Each vesicle ranged from 46.9 to 87.1 nm, and vesicles were admixed with curved strands in larger SMPs. Diffuse effacement of the foot processes and condensation of the actin filaments were present in 56.0% and 62.4% of the samples, respectively. SMPs were associated with hematuria, proteinuria of ≥ 1 gm, and immune complex deposition in the patients with native kidneys, whereas they were related to hyperglycemia and elevated serum creatinine levels in the patients with renal allografts. Patients with native and transplanted kidneys most commonly presented with IgA nephropathy and allograft rejection, respectively. Finding SMPs in the renal biopsy samples is not rare and they may act as a footprint of podocyte injury caused by diverse etiologies. Considering their size, podocyte exosomes could be a possible source of SMPs.

Renal tissue elasticity by acoustic radiation force impulse: A prospective study of healthy kidney donors.

BACKGROUND: Some studies reported the correlations between renal parenchymal stiffness measured by transient elastography or acoustic radiation force impulse (ARFI) and the extent of interstitial fibrosis. This study was prospectively designed to evaluate the correlation between clinical, histological findings and the kidney shear wave velocity (SWV, m/s) assessed by ARFI elastography to identify factors affecting the kidney SWV in normal patients. METHODS: Seventy-three adult living kidney transplantation donors were enrolled in our center between September 2010 and January 2013. Before transplantation, all donors were evaluated by ARFI elastography to identify the range of SWV in kidneys. Time-zero biopsies were performed on all graft kidneys before implantation. RESULTS: Mean age of donors was 42.0 ±â€Š11.3 years. The mean SWV and depth were 2.21 ±â€Š0.58 m/s and 5.37 ±â€Š1.06 cm. All histological findings showed mild degree of the Banff score, only grade I. In univariate analyses, the SWV was not associated with all histological parameters. Age (r = -0.274, P = .019) diastolic blood pressure (DBP, r = -0.255, P = .030) and depth for SWV measurement (r = -0.345, P = .003) were significantly correlated with the SWV. In multivariate linear regression analysis, age, gender, body mass index (BMI), and depth for SWV measurement were significantly correlated with the SWV (P = .003, .005, .002, and .004, respectively). CONCLUSIONS: We demonstrated that all histological findings are not correlated with the SWV of donor kidney. Otherwise, factors influencing the kidney SWV assessed by ARFI elastography are age, gender, BMI, and depth for the SWV measurement in donors for kidney transplantation.

Reduction in proteinuria after immunosuppressive therapy and long-term kidney outcomes in patients with immunoglobulin A nephropathy.

BACKGROUND/AIMS: Despite controversy regarding the benefits of immunosuppressive therapy in immunoglobulin A nephropathy (IgAN), clinical outcomes may vary depending on the patient's responsiveness to this therapy. This study evaluated long-term kidney outcomes according to the extent of proteinuria reduction after immunosuppression in IgAN patients. METHODS: Among 927 patients with biopsy-proven IgAN, 127 patients underwent immunosuppression. Time-averaged urine protein-creatinine ratio before and within 1 year after start of immunosuppression were calculated, and responsiveness to immunosuppression was assessed as the reduction of proteinuria between the two periods. Patients were classified into tertiles according to the extent of proteinuria reduction. We compared the slopes of estimated glomerular filtration rate (eGFR) decline using a linear mixed model, and estimated hazard ratios (HRs) for disease progression (defined as development of a ≥ 30% decline in eGFR or end-stage renal disease) using a Cox proportional hazard model. RESULTS: Median extent of proteinuria reduction was -2.1, -0.9, and -0.2 g/gCr in the first, second, and third tertiles, respectively. There were concomitant changes in the slopes of annual eGFR decline: -2.03, -2.44, and -4.62 mL/min/1.73 m2 among the first, second, and third tertiles, respectively. In multivariable Cox analysis, the HRs (95% confidence intervals) for disease progression were 0.30 (0.12 to 0.74) in the first tertile and 0.70 (0.34 to 1.45) in the second tertile compared with the thirdtertile. CONCLUSION: This study showed that greater proteinuria reduction after immunosuppression was associated with a lower risk of disease progression in patients with IgAN, suggesting that responsiveness to immunosuppression may be an important determinant of kidney outcomes.

CD71 mesangial IgA1 receptor and the progression of IgA nephropathy.

The transferrin receptor (CD71) is known as a receptor for IgA1 on mesangial cells, but the role of CD71 in IgA nephropathy (IgAN) is unknown. We studied clinical implication of mesangial CD71 in 282 patients with biopsy-proven IgAN (2005-2018). The transcript and protein expression of glomerular CD71 was determined by real-time polymerase chain reaction and immunohistochemistry. Ten subjects with microscopic hematuria only and no evidence of histologic abnormalities on kidney biopsy were considered as controls. Human mesangial cells (HMCs) were treated with sera from IgAN patients and expression levels of CD71 and inflammatory cytokine markers were compared according to disease status. Disease progression was defined as a ≥30% decline in estimated glomerular filtration rate from the baseline value. During a mean follow up of 53.5 (18.3-75.9) months, 80 (28.4%) patients developed disease progression. The mRNA expression of CD71 was significantly higher in progressors than in nonprogressors (P = 0.001). Among the Oxford classification scores, patients with M1 had significantly higher CD71 expression levels than those with M0. In a multivariable Cox model, elevated transcript levels of CD71 were significantly associated with 4.32-fold higher risk of disease progression (P = 0.009). Furthermore, CD71 expression levels independently predicted the increase in proteinuria of ≥50% from the baseline (P = 0.03). Finally, HMCs treated with sera from IgAN patients with the higher Oxford score (M1E1S1T0) more increased the mRNA expression of CD71 and inflammatory markers than those with sera from negative score (M0E0S0T0). However, silencing CD71 significantly reduced expression levels of the inflammatory cytokine genes. Our results show that mesangial CD71 is significantly associated with disease progression and may play a biologic role in IgAN.

Renal intravascular large B cell lymphoma: the first case report in Korea and a review of the literature.

Herein, we describe the first case of renal intravascular large B cell lymphoma in Korea occurring in a 66-year-old female. She presented with mild fever and dyspnea. On physical and laboratory evaluations, hemophagocytic lymphohistiocytosis was suspected, but the bone marrow biopsy results were unremarkable. During the work-up, massive proteinuria developed, which led to a renal biopsy. The renal architecture was relatively well-preserved, but the glomeruli were hypercellular with the infiltration of atypical, large lymphoid cells with increased nucleus-cytoplasm ratio and clumped chromatin. Similar cells were also present in the peritubular capillaries. The tumor cells exhibited membranous staining for CD20 and CD79a. After the diagnosis of intravascular large B cell lymphoma, the patient received rituximab-based chemotherapy under close follow-up.

Predictive value of mesangial C3 and C4d deposition in IgA nephropathy.

We aimed to determine the relative contribution of each complement (C3 and C4d) deposition to the progression of IgA nephropathy (IgAN). We enrolled a total of 380 patients with biopsy-confirmed IgAN. Mesangial deposition of C3(<2+ vs. ≥2+) and C4d(positive vs. negative) was evaluated by immunofluorescence staining and immunohistochemistry, respectively. Study endpoint was the composite of a 30% decline in eGFR or ESRD. The risk of reaching the primary outcome was significantly higher in patients having C3 ≥ 2+ and C4d(+) than in corresponding counterparts. Adding C3 deposition to clinical data acquired at kidney biopsy modestly increased the area under the receiver-operating characteristic curve, net reclassification improvement, and integrated discrimination improvement (IDI); adding C4d increased IDI only. In conclusion, mesangial C3 and C4d deposition was an independent risk factor for progression of IgAN. C3 showed better predictability than C4d, suggesting that lectin pathway alone has limited clinical prognostic value.

Relationship between complement deposition and the Oxford classification score and their combined effects on renal outcome in immunoglobulin A nephropathy.

BACKGROUND: Complement activation has been highlighted in immunoglobulin (Ig) A nephropathy pathogenesis. However, whether the complement system can affect the downstream phenotype of IgA nephropathy remains unknown. Herein, we investigated the association of mesangial C3 deposition with the Oxford classification and their joint effects on worsening kidney function. METHODS: We investigated 453 patients with biopsy-proven IgA nephropathy. C3 deposition was defined as an immunofluorescence intensity of C3 ≥2+ within the mesangium. The subjects were classified according to the combination of C3 deposition and Oxford classification lesions. The primary endpoint was a composite of ≥30% decline in the estimated glomerular filtration rate or an increase in proteinuria ≥3.5 g/g during follow-up. RESULTS: Among the Oxford classification lesions, mesangial hypercellularity (M1), segmental glomerulosclerosis (S1) and tubulointerstitial fibrosis (T1-2) and crescentic lesion significantly correlated with C3 deposition. During a median follow-up of 33.0 months, the primary endpoint occurred more in patients with M1, S1, T1-2 and mesangial C3 deposition than in those without. In individual multivariable-adjusted Cox analyses, the presence of M1, S1, T1-2 and C3 deposition was significantly associated with higher risk of reaching primary endpoint. In the combined analyses of C3 deposition and the Oxford classification lesions, the hazard ratios for the composite outcome were significantly higher in the presence of C3/M1, C3/S1 and C3/crescent than in the presence of each lesion alone. CONCLUSIONS: Complement deposition can strengthen the significance of the Oxford classification, and the presence of both components portends a poorer prognosis in IgA nephropathy.

Transplant outcomes in positive complement-dependent cytotoxicity- versus flow cytometry-crossmatch kidney transplant recipients after successful desensitization: a retrospective study.

BACKGROUND: Despite the obvious survival benefit compared to that among waitlist patients, outcomes of positive crossmatch kidney transplantation (KT) are generally inferior to those of human leukocyte antigen (HLA)-compatible KT. This study aimed to compare the outcomes of positive complement-dependent cytotoxicity (CDC) crossmatch (CDC + FC+) and positive flow cytometric crossmatch (CDC-FC+) with those of HLA-compatible KT (CDC-FC-) after successful desensitization. METHODS: We retrospectively analyzed 330 eligible patients who underwent KTs between June 2011 and August 2017: CDC-FC- (n = 274), CDC-FC+ (n = 39), and CDC + FC+ (n = 17). Desensitization protocol targeting donor-specific antibody (DSA) involved plasmapheresis, intravenous immunoglobulin (IVIG), and rituximab with/without bortezomib for positive-crossmatch KT. RESULTS: Death-censored graft survival and patient survival were not different among the three groups. The median estimated glomerular filtration rate was significantly lower in the CDC + FC+ group than in the compatible group at 6 months (P < 0.001) and 2 years (P = 0.020). Biopsy-proven rejection within 1 year of CDC-FC-, CDC-FC+, and CDC + FC+ were 15.3, 28.2, and 47.0%, respectively. Urinary tract infections (P < 0.001), Pneumocystis jirovecii pneumonia (P < 0.001), and cytomegalovirus viremia (P < 0.001) were more frequent in CDC-FC+ and CDC + FC+ than in CDC-FC-. CONCLUSIONS: This study showed that similar graft and patient survival was achieved in CDC-FC+ and CDC + FC+ KT compared with CDC-FC- through DSA-targeted desensitization despite the higher incidence of rejection and infection than that in compatible KT.

Clinical Significance of Revised Banff Criteria in the Diagnosis of Antibody-Mediated Rejection.

BACKGROUND: The diagnostic criteria of antibody-mediated rejection (ABMR) has been significantly changed since Banff 2013. The most important revision was adopting microvascular inflammation (MVI) as immunopathologic evidence for ABMR even in C4d-negative cases. In this study, we retrospectively reviewed previous allograft biopsy results and evaluated the impact of this change. METHODS: We reviewed results of 536 renal allograft biopsies at Severance Hospital during 2011 to 2013, which were diagnosed according to the Banff 2009 criteria. All biopsy results were reassessed according to the Banff 2017 criteria. RESULTS: According to the Banff 2009 criteria, antibody-mediated changes were observed in 48 cases out of the 536 allograft biopsies (9.0%). According to the Banff 2017 criteria, 28 additional cases (5.2%) were reclassified as antibody-mediated changes. Twenty-six of these cases were C4d-negative ABMR. The most frequent diagnostic finding in these cases was MVI comprising glomerulitis and peritubular capillaritis. Donor-specific antibodies were investigated in 14 of these cases, which revealed positive results in 12 cases. CONCLUSION: The incidence rate of ABMR has increased after the recent revision of the Banff criteria. The MVI in C4d-negative ABMR cases is the major cause for this increase.

Tubulointerstitial Infiltration of M2 Macrophages in Henoch-Schönlein Purpura Nephritis Indicates the Presence of Glomerular Crescents and Bad Clinical Parameters.

Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children, and renal involvement (HSP nephritis, HSPN) is a severe manifestation. HSPN is histologically classified by the International Study of Kidney Disease in Children (ISKDC) based on mesangial hypercellularity and the extent of glomerular crescents. Macrophages, categorized as M1 or M2, frequently infiltrate in various glomerular and tubulointerstitial diseases and infiltration of specific subtypes is associated with disease progression. Therefore, to identify whether infiltration of M1 or M2 macrophages has clinical significance, we quantified the subtypes of macrophages in 49 HSPN specimens and correlated the counts with histologic features and clinical parameters. Higher tubulointerstitial M2 counts were associated with chronic renal failure (CRF), ISKDC classes III-IV, and crescents (P<0.001, 0.002, 0.001). Glomerular M2 counts were significantly related to ISKDC classes III-IV and crescents (area under curve, AUC 0.804, 0.833). Tubulointerstitial M2 counts were associated with CRF, ISKDC classes III-IV, and crescents (AUC 0.872, 0.778, 0.830). Tubulointerstitial M2 counts also revealed higher AUC than tubulointerstitial M1 counts for CRF (P=0.036) and ISKDC classes III-IV (P=0.047). Glomerular M2 counts revealed higher AUC than glomerular M1 counts for ISKDC classes III-IV (P=0.024). Tubulointerstitial M2 counts were the most powerful parameter for CRF (AUC 0.872) and revealed even higher AUC than ISKDC classification (AUC 0.716) with borderline significance (P=0.086) for CRF. In summary, tubulointerstitial M2 counts were a superior parameter to tubulointerstitial M1 counts and even to ISKDC classification indicating the presence of CRF.

Association between post-transplant uric acid level and renal allograft fibrosis: Analysis using Banff pathologic scores from renal biopsies.

Several experimental studies implicate uric acid in renal injury and fibrosis. The objective of this study was to examine the association between uric acid level and allograft fibrosis after kidney transplantation. 241 adult patients who underwent kidney transplantation between 2003 and 2014 were divided into three groups according to the sex specific tertiles of mean uric acid level within the first post-transplant year. The renal biopsies performed during 1 to 5 post-transplant year were analyzed to compare the degree of interstitial fibrosis and tubular atrophy (IF/TA). Mean interval between kidney transplantation and biopsy was similar between groups (23.7 ± 15.3 vs. 30.0 ± 18.6 vs. 27.5 ± 18.5 months, P = 0.072). The higher tertile uric acid level was, the more advanced grade of IF/TA was shown (P = 0.001). Multivariate analysis identified uric acid tertile was independent risk factor for severe IF/TA (odds ratio [95% confidence interval] was 3.16 [1.13-8.82] for tertile 2 and 3.70 [1.25-10.93] for tertile 3, versus tertile 1, respectively). Other independent factors were estimated glomerular filtration rate at 1year post-transplant (0.80 [CI 0.65-0.98]) and biopsy-proven rejection (2.34 [1.05-5.21]). Graft survival over 10 years was significantly lower in tertile 3 (P = 0.041). The results showed that higher uric acid level after kidney transplantation was associated with more severe IF/TA.

Successful kidney transplantation across a positive complement-dependent cytotoxicity crossmatch by using C1q assay-directed, bortezomib-assisted desensitization: A case report.

RATIONALE: Human leukocyte antigen (HLA) is the major immunologic barrier in kidney transplantation (KT). Various desensitization protocols to overcome the HLA barrier have increased the opportunity for transplantation in sensitized patients. In addition, technological advances in solid-phase assays have permitted more comprehensive assessment of donor-specific antibodies. Although various desensitization therapies and immunologic techniques have been developed, the final transplantation decision is still based on the classic complement-dependent cytotoxicity (CDC) crossmatch (XM) technique. Some patients who fail to achieve negative XM have lost their transplant opportunities, even after receiving sufficient desensitization therapies. PATIENT CONCERNS: A 57-year-old male with end-stage renal disease secondary to chronic glomerulonephritis was scheduled to have a second transplant from his son, but CDC XM was positive. DIAGNOSES: Initial CDC XM (Initial T-AHG 1:32) and flow-cytometry XM were positive. Anti-HLA-B59 donor specific antibody was detected by Luminex single antigen assay. INTERVENTIONS: Herein, we report a successful case of KT across a positive CDC XM (T-AHG 1:8 at the time of transplantation) by using C1q assay-directed, bortezomib-assisted desensitization. After confirming a negative conversion in the C1q donor-specific antibody, we decided to perform KT accepting a positive AHG-CDC XM of 1:8 at the time of transplantation. OUTCOMES: The posttransplant course was uneventful and a protocol biopsy at 3 months showed no evidence of rejection. The patient had excellent graft function at 12 months posttransplant. LESSONS: The results of XM test and solid-phase assay should be interpreted in the context of the individual patient.

Lysyl oxidase­like 2 is expressed in kidney tissue and is associated with the progression of tubulointerstitial fibrosis.

Tubulointerstitial fibrosis is a common end point of chronic kidney diseases, and preventing its progression is key to avoiding renal failure. Transforming growth factor­ß (TGF­ß) and associated molecules promote tubulointerstitial fibrosis; however, effective therapies targeting these molecules have yet to be developed. Lysyl oxidase­like 2 (LOXL2), which is involved in invasive growth and metastasis of malignant neoplasms, has recently been reported to serve a key role in hepatic and pulmonary fibrosis. However, little is currently known regarding LOXL2 expression in the kidney and its involvement in tubulointerstitial fibrosis. The present study evaluated LOXL2 expression in human and mouse kidney tissues, as well as in cultured renal cells. LOXL2 protein expression was detected in glomerular capillary loops and tubular epithelial cells in human and mouse kidneys. Glomerular LOXL2 was localized to the cytoplasm of podocytes, as determined by double immunofluorescence microscopy using a podocyte marker (synaptopodin). This result was supported by western blot analysis, which demonstrated that LOXL2 protein expression is present in cultured human podocytes and HK­2 human proximal tubular cells. In addition, the mRNA and protein expression levels of LOXL2 were higher in a mouse model of tubulointerstitial fibrosis compared with in control mice. In addition, immunohistochemistry results demonstrated that LOXL2 is present in the fibrous interstitium and infiltrating mononuclear cells in a mouse model of tubulointerstitial fibrosis. The present study demonstrated that LOXL2 is expressed in compartments of renal tissue, where it appears to contribute to the progression of tubulointerstitial fibrosis.

Successful launch of an ABO-incompatible kidney transplantation program to overcome the shortage of compatible living donors: experience at a single center
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AIMS: ABO-incompatible (ABOi) kidney transplantation (KT) is being increasingly performed to overcome donor shortages. However, debate persists regarding the post-transplant outcomes of ABOi KT vs. that of ABO-compatible (ABOc) KT. METHODS: A total 454 recipients who underwent living-donor KT (LDKT) between June 2010 and July 2014 at Severance Hospital (Seoul) were retrospectively reviewed. 100 ABOi and 354 ABOc KTs were compared. Recipients with a pretransplant positive crossmatch to their donors, pretransplant donor-specific anti-HLA antibody (DSA), or high panel reactive antibody (PRA ≥ 50%) were excluded from both the ABOi and ABOc KT groups. Finally, the authors compared the transplant outcomes of 95 of these ABOi KTs and 121 ABOc KTs performed over the same period. RESULTS: No significant difference in incidence of biopsy-proven acute rejection was observed between the ABOi and ABOc KT groups (p = 0.230), and group glomerular filtration rate of ABOi KT was comparable to that of ABOc KT (p > 0.05 at all time points). 3-year death-censored graft survival rates were similar (96.8 vs. 96.6%, respectively; p = 0.801). However, the incidences of postoperative bleeding, cytomegalovirus infection, fungal infection, and serious infection rates were significantly higher after ABOi KT. CONCLUSIONS: In this study, graft renal function and survival after ABOi KT were excellent, and the incidence of acute rejection was similar to that of ABOc KT. However, efforts are needed to reduce hemorrhagic and infectious complications after ABOi KT. ABOi KT can be a good strategy to overcome ABO antibody barriers and relieve donor shortage.
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Tubuloreticular inclusions in peritubular capillaries of renal allografts.

BACKGROUND: Tubuloreticular inclusions (TRIs) are anastomosing networks of microtubules that are frequently found in autoimmune diseases and viral infections. In renal allografts, TRIs have been reported in glomerular endothelial cells in association with viral infections and donor specific antibodies (DSAs), but their presence in peritubular capillaries has not been explored. METHODS: We collected seven cases with TRIs out of 148 consecutive renal allograft biopsies taken from Dec. 2015 to Dec. 2016. RESULTS: TRIs were present in peritubular capillaries in seven cases and were concomitantly present in glomerular endothelial cells in two cases. The diagnoses included polyomavirus nephropathy (n=2), acute T cell-mediated rejection (ACR) (n=1), combined ACR and antibody-mediated rejection (AMR) (n=1), suspicious for ACR (n=1), chronic active AMR (n=1), and moderate tubular atrophy and interstitial fibrosis (n=1). Six patients had recent or current viral infections (BK polyomavirus, hepatitis B virus, herpes simplex virus, and cytomegalovirus in two, two, one, and one case, respectively). DSA was positive in one case. Five cases had moderate to severe interstitial inflammation and four cases had peritubular capillaritis. CONCLUSION: TRIs are not rare in peritubular capillaries. They are associated with various viral infections and their appearance seems to be related to peritubular capillary injury.

Successful treatment of tubulointerstitial nephritis and uveitis with steroid and azathioprine in a 12-year-old boy.

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease, often underdiagnosed or misdiagnosed in children. We describe the case of a 12-year-old boy who presented to Severance Hospital with a 1-month history of bilateral conjunctival injection. He was first evaluated by an Ophthalmologist in another hospital and diagnosed with panuveitis. Laboratory tests indicated renal failure, and a renal biopsy confirmed the diagnosis of acute tubulointerstitial nephritis. An extensive exclusion of all possible causes allowed a diagnosis of TINU syndrome. The patient was treated with a systemic corticosteroid (initially prednisolone, 2 mg/kg and later deflazacort 1 mg/kg) and topical steroid drops for 1 month. Azathioprine was later added to the treatment regimen and the systemic steroid was slowly tapered. The final outcome of renal-ocular disease was favorable in the patient. However, long-term follow-up is necessary to properly manage frequent relapses and incomplete renal recovery. TINU should be considered as a differential diagnosis in children with uveitis or acute renal failure.

Fibroblast Growth Factor Receptor 1 Overexpression Is Associated with Poor Survival in Patients with Resected Muscle Invasive Urothelial Carcinoma.

PURPOSE: To examine the usefulness of various receptor tyrosine kinase expressions as prognostic markers and therapeutic targets in muscle invasive urothelial cancer (UC) patients. MATERIALS AND METHODS: We retrospectively analyzed the data of 98 patients with muscle invasive UC who underwent radical cystectomy between 2005 and 2010 in Yonsei Cancer Center. Using formalin fixed paraffin embedded tissues of primary tumors, immunohistochemical staining was done for human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 3 (FGFR3). RESULTS: There were 41 (41.8%), 44 (44.9%), and 14 (14.2%) patients who have over-expressed HER2, FGFR1, and FGFR3, respectively. In univariate analysis, significantly shorter median time to recurrence (TTR) (12.9 months vs. 49.0 months; p=0.008) and overall survival (OS) (22.3 months vs. 52.7 months; p=0.006) was found in patients with FGFR1 overexpression. By contrast, there was no difference in TTR or OS according to the HER2 and FGFR3 expression status. FGFR1 remained as a significant prognostic factor for OS with hazard ratio of 2.23 (95% confidence interval: 1.27-3.90, p=0.006) in multivariate analysis. CONCLUSION: Our result showed that FGFR1 expression, but not FGFR3, is an adverse prognostic factor in muscle invasive UC patients after radical cystectomy. FGFR1 might be feasible for prognosis prediction and a potential therapeutic target after thorough validation in muscle invasive UC.

The significance of tubulointerstitial lesions in childhood Henoch-Schönlein nephritis.

BACKGROUND: Little information is currently available on the development of tubulointerstitial lesions in children with Henoch-Schönlein nephritis (HSN). To identify the impact of the development of tubulointerstitial changes in HSN, we retrospectively analyzed renal biopsies obtained from children with HSN. METHODS: Twenty-eight children with HSN from whom serial renal biopsies had been obtained before and after immunosuppressive therapy were enrolled in the study. The patients were divided into two groups according to the observed change in tubulointerstitial lesion development: group I (n = 15), with stable or improved tubulointerstitial lesions, and group II (n = 13), with worsened tubulointerstitial lesions. Group II patients had longer duration of proteinuria than group I patients (3.7 ± 3.7 years vs. 1.7 ± 1.7 years, p = 0.052). RESULTS: The change in serum albumin level was negatively correlated with the change in tubulointerstitial scores before and after treatment (γ = -0.444, p = 0.018). Group II patients showed a significant decrease in immunoglobulin G (IgG) and IgA deposits after treatment (p = 0.039 and 0.003, respectively), while group II patients did not (p = 0.458 and 0.506, respectively). CONCLUSIONS: Although the International Study of Kidney Disease in Children classification of HSN does not include tubulointerstitial lesions, they can progress during treatment and could have significant clinical implications in association with the duration of proteinuria.

De novo C3 glomerulonephritis in a renal allograft.

C3 glomerulonephritis (C3GN) is a recently described, rare glomerular disease characterized by predominant or sole glomerular C3 deposits. Morphologic features of C3GN are similar to those of dense deposit disease (DDD); however, ribbon-like intramembranous electron-dense deposits are absent in the former. We report a case of de novo C3GN in a renal allograft with morphologic transformation to DDD. A 6-year-old boy presented with congenital left renal agenesis and right ureteropelvic junction obstruction. The patient underwent pyeloplasty but experienced recurrent urinary tract infections. At the age of 22 years, he received a renal allograft from a living related donor. C3GN was diagnosed after 1 year of transplantation; initial histology showed minimal mesangiopathy and this progressed to mesangial proliferation and membranoproliferative features over the next 7 years. Serum creatinine levels were stabilized with anti-rejection treatments for combating repeated episodes of acute rejection; however, glomerular and tubular band-like electron-dense deposits became evident.