Kidney lesions and risk of cardiovascular events in biopsy-proven diabetic kidney disease with type 2 diabetes.

BACKGROUND: This study assessed the association of pathological kidney lesions with cardiovascular events in biopsy-proven diabetic kidney disease (DKD) with type 2 diabetes. METHODS: This multicenter, retrospective study involved 244 patients with no previous cardiovascular events before biopsy, estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 at biopsy (baseline), and ≥ 1 year of observation after biopsy. The outcomes were the first occurrence of cardiovascular events (cardiovascular death, non-fatal myocardial infarction, coronary intervention, or non-fatal stroke), and non-cardiovascular deaths before cardiovascular events were considered competing events. The association between the severity of each pathological lesion and cardiovascular events was investigated. RESULTS: During follow-up (median: 6.4 years), 43 patients experienced cardiovascular events. The baseline clinical characteristics did not differ according to cardiovascular events. The cumulative incidence of cardiovascular events was higher in patients with mesangiolysis, global glomerulosclerosis ≥ 50%, moderate/severe interstitial inflammation, and moderate/severe arteriolar hyalinosis than in those having less advanced each lesion. Fine-Gray regression models revealed that global glomerulosclerosis ≥ 50% (subdistribution hazard ratio [SHR]: 3.85; 95% confidence interval [95% CI] 1.28-11.52), moderate/severe interstitial inflammation (SHR: 2.49; 95% CI 1.18-5.29), and moderate/severe arteriolar hyalinosis (SHR: 3.51; 95% CI 1.15-10.69) were linked to increased risk of cardiovascular events, after adjusting for clinical variables including RAAS inhibitors use at baseline. Adding the severity of these lesions to clinical variables improved the predictive value for cardiovascular events. CONCLUSIONS: In DKD with type 2 diabetes, advanced glomerulosclerosis, interstitial inflammation, and arteriolar hyalinosis were associated with cardiovascular events, adding predictive value to clinical features.

Deep learning analysis of clinical course of primary nephrotic syndrome: Japan Nephrotic Syndrome Cohort Study (JNSCS).

BACKGROUND: Prognosis of nephrotic syndrome has been evaluated based on pathological diagnosis, whereas its clinical course is monitored using objective items and the treatment strategy is largely the same. We examined whether the entire natural history of nephrotic syndrome could be evaluated using objective common clinical items. METHODS: Machine learning clustering was performed on 205 cases from the Japan Nephrotic Syndrome Cohort Study, whose clinical parameters, serum creatinine, serum albumin, dipstick hematuria, and proteinuria were traceable after kidney biopsy at 5 measured points up to 2 years. The clinical patterns of time-series data were learned using long short-term memory (LSTM)-encoder-decoder architecture, an unsupervised machine learning classifier. Clinical clusters were defined as Gaussian mixture distributions in a two-dimensional scatter plot based on the highest log-likelihood. RESULTS: Time-series data of nephrotic syndrome were classified into four clusters. Patients in the fourth cluster showed the increase in serum creatinine in the later part of the follow-up period. Patients in both the third and fourth clusters were initially high in both hematuria and proteinuria, whereas a lack of decline in the urinary protein level preceded the worsening of kidney function in fourth cluster. The original diseases of fourth cluster included all the disease studied in this cohort. CONCLUSIONS: Four kinds of clinical courses were identified in nephrotic syndrome. This classified clinical course may help objectively grasp the actual condition or treatment resistance of individual patients with nephrotic syndrome.

Impact of the relationship between hemoglobin levels and renal interstitial fibrosis on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy.

BACKGROUND: Progression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy. METHODS: A total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality. RESULTS: At baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality. CONCLUSIONS: Impacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

Relationship between autoantibodies to erythropoietin receptor and renal outcome in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis.

Purpose: We examined the relationship between autoantibodies to erythropoietin receptor (EPOR) and renal outcome in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).Materials and methods: Sixty-three Japanese patients with AAV were enrolled and followed for a median of 31.4 months. Patients were screened for serum anti-EPOR antibodies using an enzyme-linked immunosorbent assay. Associations of anti-EPOR antibodies with clinical parameters were analyzed using logistic-regression models.Results: Anti-EPOR antibodies were detected in 7 (11%) of the 63 patients, and levels of the antibodies decreased with immunosuppressive therapy. The presence of anti-EPOR antibodies was associated with a higher Birmingham vasculitis activity score. In addition, anti-EPOR antibodies were more frequently observed in patients with renal outcomes, which was defined as a sustained 50% reduction in the estimated glomerular filtration rate from baseline, than in those without. Multiple logistic regression analysis revealed that presence of anti-EPOR antibodies, as well as age at disease onset, were as risk factors for the renal outcome.Conclusion: Anti-EPOR antibodies were associated with the progression of renal dysfunction in patients with AAV.

Better remission rates in elderly Japanese patients with primary membranous nephropathy in nationwide real-world practice: The Japan Nephrotic Syndrome Cohort Study (JNSCS).

BACKGROUND: The aim of the present study was to clarify the prevalence of immunosuppressive drug use and outcomes in elderly and non-elderly patients with primary membranous nephropathy (MN) in nationwide real-world practice in Japan. PATIENTS AND METHODS: Between 2009 and 2010, 374 patients with primary nephrotic syndrome were enrolled in the cohort study (The Japan Nephrotic Syndrome Cohort Study, JNSCS), including 126 adult patients with MN. Their clinical characteristics were compared with those of nephrotic patients with primary MN registered in a large nationwide registry (The Japan Renal Biopsy Registry, J-RBR). Outcomes and predictors in the elderly (≥ 65 years) and non-elderly groups were identified. RESULTS: Similar clinical characteristics were observed in JNSCS patients and J-RBR patients (n = 1808). At the early stage of 1 month, 84.1% of patients were treated with immunosuppressive therapies. No significant differences were observed in therapies between age groups. However, elderly patients achieved complete remission (CR) more frequently than non-elderly patients, particularly those treated with therapies that included corticosteroids. No significant differences were noted in serum creatinine (sCr) elevations at 50 or 100%, end-stage kidney disease, or all-cause mortality between age groups. Corticosteroids were identified as an independent predictor of CR (HR 2.749, 95%CI 1.593-4.745, p = 0.000) in the multivariate Cox's model. sCr levels, hemoglobin levels, immunosuppressants, clinical remission, and relapse after CR were independent predictors of sCr × 1.5 or × 2.0. CONCLUSION: Early immunosuppressive therapy including corticosteroids for primary MN showed better remission rates in elderly patients in a nationwide cohort study.

Incidence of remission and relapse of proteinuria, end-stage kidney disease, mortality, and major outcomes in primary nephrotic syndrome: the Japan Nephrotic Syndrome Cohort Study (JNSCS).

BACKGROUND: Despite recent advances in immunosuppressive therapy for patients with primary nephrotic syndrome, its effectiveness and safety have not been fully studied in recent nationwide real-world clinical data in Japan. METHODS: A 5-year cohort study, the Japan Nephrotic Syndrome Cohort Study, enrolled 374 patients with primary nephrotic syndrome in 55 hospitals in Japan, including 155, 148, 38, and 33 patients with minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other glomerulonephritides, respectively. The incidence rates of remission and relapse of proteinuria, 50% and 100% increases in serum creatinine, end-stage kidney disease (ESKD), all-cause mortality, and other major adverse outcomes were compared among glomerulonephritides using the Log-rank test. Incidence of hospitalization for infection, the most common cause of mortality, was compared using a multivariable-adjusted Cox proportional hazard model. RESULTS: Immunosuppressive therapy was administered in 339 (90.6%) patients. The cumulative probabilities of complete remission within 3 years of the baseline visit was ≥ 0.75 in patients with MCD, MN, and FSGS (0.95, 0.77, and 0.79, respectively). Diabetes was the most common adverse events associated with immunosuppressive therapy (incidence rate, 71.0 per 1000 person-years). All-cause mortality (15.6 per 1000 person-years), mainly infection-related mortality (47.8%), was more common than ESKD (8.9 per 1000 person-years), especially in patients with MCD and MN. MCD was significantly associated with hospitalization for infection than MN. CONCLUSIONS: Patients with MCD and MN had a higher mortality, especially infection-related mortality, than ESKD. Nephrologists should pay more attention to infections in patients with primary nephrotic syndrome.

Age differences in the relationships between risk factors and loss of kidney function: a general population cohort study.

BACKGROUND: Annual decline in kidney function is a widely applied surrogate outcome of renal failure. It is important to understand the relationships between known risk factors and the annual decline in estimated glomerular filtration rate (eGFR) according to baseline age; however, these remain unclear. METHODS: A community-based retrospective cohort study of adults who underwent annual medical examinations between 1999 and 2013 was conducted. The participants were stratified into different age groups (40-49, 50-59, 60-69, 70-79, and ≥ 80 years) to assess the risk for loss of kidney function. A mixed-effects model was used to estimate the association between risk factors and annual changes in eGFR. RESULTS: In total, 51,938 participants were included in the analysis. The age group of ≥80 years included 8127 individuals. The mean annual change in eGFR was - 0.39 (95% confidence interval: - 0.41 to - 0.37) mL/min/1.73 m2 per year. Older age was related to faster loss of kidney function. In the older age group, higher systolic blood pressure, proteinuria, and current smoking were related to faster loss of kidney function (p trend < 0.01, 0.03, and < 0.01, respectively). Conversely, each age group showed similar annual loss of kidney function related to lower hemoglobin levels and diabetes mellitus (p trend 0.47 and 0.17, respectively). CONCLUSIONS: Higher systolic blood pressure, proteinuria, and smoking were related to faster loss of kidney function, and a greater effect size was observed in the older participants. More risk assessments for older people are required for personalized care.

Regional variations in immunosuppressive therapy in patients with primary nephrotic syndrome: the Japan nephrotic syndrome cohort study.

BACKGROUND: The lack of high-quality clinical evidences hindered broad consensus on optimal therapies for primary nephrotic syndromes. The aim of the present study was to compare prevalence of immunosuppressive drug use in patients with primary nephrotic syndrome across 6 regions in Japan. METHODS: Between 2009 and 2010, 380 patients with primary nephrotic syndrome in 56 hospitals were enrolled in a prospective cohort study [Japan Nephrotic Syndrome Cohort Study (JNSCS)], including 141, 151, and 38 adult patients with minimal change disease (MCD), membranous nephropathy (MN), and focal segmental glomerulosclerosis (FSGS), respectively. Their clinical characteristics were compared with those of patients registered in a large nationwide registry of kidney biopsies [Japan Renal Biopsy Registry (J-RBR)]. The regional prevalence of use of each immunosuppressive drug was assessed among adult MCD, MN, and FSGS patients who underwent immunosuppressive therapy in the JNSCS (n = 139, 127, and 34, respectively). Predictors of its use were identified using multivariable-adjusted logistic regression models. RESULTS: The clinical characteristics of JNSCS patients were comparable to those of J-RBR patients, suggesting that the JNSCS included the representatives in the J-RBR. The secondary major immunosuppressive drugs were intravenous methylprednisolone [n = 33 (24.6%), 24 (19.7%), and 9 (28.1%) in MCD, MN, and FSGS, respectively] and cyclosporine [n = 25 (18.7%), 62 (50.8%), and 16 (50.0%), respectively]. The region was identified as a significant predictor of use of intravenous methylprednisolone in MCD and MN patients. CONCLUSION: Use of intravenous methylprednisolone for MCD and MN differed geographically in Japan. Its efficacy should be further evaluated in a well-designed trial.

Risk factors associated with relapse or infectious complications in Japanese patients with microscopic polyangiitis.

BACKGROUND: The prevention of relapse and infection complications during remission maintenance therapy is required to improve the prognosis of patients with microscopic polyangiitis (MPA) showing rapidly progressive glomerulonephritis (RPGN). The clinicopathological characteristics of patients with ANCA-positive MPA were examined to determine the risk factors for relapse or infectious complications after remission induction therapy. PATIENTS AND METHODS: The study population consisted of 52 patients diagnosed as ANCA-positive MPA showing RPGN from 2002 to 2012, after publication of the Japanese guideline for RPGN. The clinicopathological findings were examined between the presence and absence of relapse or infectious complications. RESULTS: The value of vasculitis damage index (VDI) was high for the relapse group and VDI value was identified as the leading factor associated with relapse [hazard ratio (HR) 3.36, 95 % confidence interval (CI) 1.58-7.12, P < 0.01]. On the other hand, the values of Birmingham Vasculitis Activity Score, clinical grade category of RPGN at diagnosis, and VDI at remission were high in the infectious group. Furthermore, clinical grade category of RPGN was the leading factor associated with infectious complications (HR 5.30, 95 % CI 1.41-19.9, P = 0.01). CONCLUSION: The disease activity at diagnosis and severity of organ damage at remission were associated with relapse and infectious complications during remission maintenance therapy and infectious complication affected kidney survival and all-cause mortality in patients with ANCA-positive MPA exhibiting RPGN.

Impact of kidney function and urinary protein excretion on pulmonary function in Japanese patients with chronic kidney disease.

BACKGROUND: Although the cardiorenal relationship in chronic kidney disease has been investigated, information about the lung-kidney relationship is limited. Here, we investigated the impact of kidney function and urinary protein excretion on pulmonary dysfunction. METHODS: The data from pulmonary function tests and kidney function (estimated glomerular filtration rate [eGFR] and urinary protein) between 1 April 2005 and 30 June 2010 were selected from our laboratory database. Data were classified into 4 categories according to eGFR and proteinuria. Category 1, eGFR ≥60 ml/min/1.73 m(2) and urinary protein <0.3 g/gCr; category 2, eGFR <60 ml/min/1.73 m(2) and urinary protein <0.3 g/gCr; category 3, eGFR ≥60 ml/min/1.73 m(2) and urinary protein ≥0.3 g/gCr; and category 4, eGFR <60 ml/min/1.73 m(2) and urinary protein ≥0.3 g/gCr. Pulmonary function data were evaluated according to these 4 categories. RESULTS: A total of 133 participants without major respiratory disease, abnormal computed tomography and smoking history were enrolled. Hemoglobin (Hb)-adjusted percentage carbon monoxide diffusing capacity (%DLCO) in category 4 (46.2 ± 7.5) and category 2 (63.6 ± 17.8) were significantly lower than in category 1 (75.8 ± 18.9) (P < 0.05). In addition, Hb-adjusted %DLCO was weakly correlated with eGFR in participants with urinary protein <0.3 g/gCr (R = 0.30, P = 0.001). Hb-adjusted %DLCO was strongly correlated with eGFR in participants with urinary protein ≥0.3 g/gCr (R = 0.81, P < 0.001). Other pulmonary function test markers (percentage (%) vital capacity, % forced expiratory volume in one second (FEV1), FEV1/forced vital capacity, % total lung capacity, and % residual volume) were not significantly different between categories. CONCLUSION: This study suggests that decreased eGFR is associated with decreased %DLCO in proteinuric patients.

A case of acute lithium poisoning and hypermagnesemia involving advanced colon cancer-induced colonic obstruction.

An 83-year-old woman presented with disturbance of consciousness and hand tremor. She had taken lithium carbonate 300 mg/day for bipolar disorder and magnesium oxide 660 mg/day for constipation. Blood tests revealed lithium poisoning, hypermagnesemia and acute kidney injury. Computed tomography showed colonic obstruction caused by cancer of the descending colon. In the outpatient section, her blood pressure decreased to 89/54 mmHg, and her heart rate dropped to 40 bpm. We considered that the obstructive ileus induced intravascular dehydration, which led to toxic serum concentrations of lithium and magnesium, triggering the emergence of severe arrythmia induced by sinus dysfunction. The patient was treated with fluid resuscitation and hemodialysis, followed by endoscopic stent replacement for the descending colon cancer obstruction. These treatments improved her general condition and alleviated the lithium poisoning, hypermagnesemia and colonic obstruction. Such a case is considered extremely rare.

Long-term observations of clinicopathological characteristics and outcome of Japanese patients with pauci-immune crescentic glomerulonephritis.

BACKGROUND: The clinicopathological characteristics and outcome with pauci-immune crescentic glomerulonephritis (CreGN) are presumed to vary over time. We examined the characteristics and outcome of Japanese patients with CreGN according to the treatment periods. PATIENTS AND METHODS: From 1968 to 2011, we examined a total of 102 patients diagnosed with pauci-immune CreGN by renal biopsy. The patients were divided into three groups according to the treatment periods-Group I (1968-1988, n = 18), Group II (1989-2001, n = 37; when the nationwide survey of rapidly progressive glomerulonephritis [RPGN] was performed in Japan), and Group III (2002-2011, n = 47; after publication of the Japanese guideline for RPGN). RESULTS: There were no significant differences in blood pressure, renal function or anti-neutrophil cytoplasmic antibody titer between groups. On the other hand, the rate of crescent formation and degree of interstitial inflammatory cell infiltration were decreased in Group III. Serum creatinine (<3.0, 3.0-6.0, ≥6.0 mg/dL) and crescent formation (<30, 30-50, 50-80, ≥80 %) were significant renal prognostic factors in Group III [serum creatinine: hazard ratio (HR) 4.79, 95 % confidence interval (CI) 1.43-16.1, P = 0.011; crescent formation: HR 2.86, 95 % CI 1.06-7.73, P = 0.039]. Furthermore, renal survival rate of patients with crescent formation <50 % and patient survival rate of patients with serum creatinine <3 mg/dL were improved in Group III. CONCLUSION: Patients with CreGN were diagnosed in the early phase of crescent formation and outcome has improved in recent years.

Japan Diabetic Nephropathy Cohort Study: study design, methods, and implementation.

BACKGROUND: Diabetic nephropathy, leading to end-stage renal disease, has a considerable impact on public health and the social economy. However, there are few national registries of diabetic nephropathy in Japan. The aims of this prospective cohort study are to obtain clinical data and urine samples for revising the clinical staging of diabetic nephropathy, and developing new diagnostic markers for early diabetic nephropathy. METHODS: The Japanese Society of Nephrology established a nationwide, web-based, and prospective registry system. On the system, there are two basic registries; the Japan Renal Biopsy Registry (JRBR), and the Japan Kidney Disease Registry (JKDR). In addition to the two basic registries, we established a new prospective registry to the system; the Japan Diabetic Nephropathy Cohort Study (JDNCS), which collected physical and laboratory data. RESULTS: We analyzed the data of 321 participants (106 female, 215 male; average age 65 years) in the JDNCS. Systolic and diastolic blood pressure was 130.1 and 72.3 mmHg, respectively. Median estimated glomerular filtration rate (eGFR) was 33.3 ml/min/1.73 m(2). Proteinuria was 1.8 g/gCr, and serum levels of albumin were 3.6 g/dl. The majority of the JDNCS patients presented with preserved eGFR and low albuminuria or low eGFR and advanced proteinuria. In the JRBR and JKDR registries, 484 and 125 participants, respectively, were enrolled as having diabetes mellitus. In comparison with the JRBR and JKDR registries, the JDNCS was characterized by diabetic patients presenting with low proteinuria with moderately preserved eGFR. CONCLUSIONS: There are few national registries of diabetic nephropathy to evaluate prognosis in Japan. Future analysis of the JDNCS will provide clinical insights into the epidemiology and renal and cardiovascular outcomes of type 2 diabetic patients in Japan.

Validation of a newly proposed histopathological classification in Japanese patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: A new histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis was recently proposed. We evaluated the predictive value of this classification for renal outcome in Japanese patients. METHODS: We enrolled 122 patients with ANCA-associated glomerulonephritis diagnosed at several institutions in Japan between January 2000 and March 2010. Twenty patients were excluded because of observation durations of <1 year, and/or because their biopsy specimens contained <10 glomeruli. Renal biopsy specimens were categorized into four classes according to the proposed classification. We evaluated the predictive value of immunohistochemical staining for α-smooth muscle actin (SMA), Wilm's tumor 1 (WT1), CD68, and cytokeratin for end-stage renal disease (ESRD). RESULTS: The study population included 54 men and 48 women. Age, estimated glomerular filtration rate (eGFR), and proteinuria were 66.3 ± 11.3 years, 21.6 ml/min. and 1.10 g/24 h, respectively. Eighty-six patients were positive for myeloperoxidase-ANCA, five were positive for proteinase 3-ANCA, and 11 were negative for both antibodies. Median follow-up time was 41.0 months. Twenty-three patients (22.5%) developed ESRD during the follow-up period. Twelve patients died during follow up; 7/12 patients developed ESRD before death, and 5/12 patients died without ESRD. The incidence of ESRD increased with sequential categories: focal, 2/46 (4.3%); crescentic, 9/32 (28%); mixed, 8/18 (44%); and sclerotic, 4/6 (67%). The focal class had the best renal survival and the sclerotic class had the worst renal survival (p < 0.001). Kaplan-Meier renal survival analysis was similar to that of the new classification system proposal. In the multivariate analysis, the classification system tended to be a prognostic factor for ESRD (p = 0.0686, crescentic, mixed and sclerotic vs. focal, hazard ratio (HR) [95% confidence interval, CI]; 2.99 [0.61-22.7], 5.04 [1.11-36.4] and 9.93 [1.53-85.7], respectively). α-SMA-positivity also tended to be associated with ESRD (p = 0.1074). CONCLUSION: The new histopathological classification was associated with eGFR at 1 year and tended to be associated with ESRD in our Japanese cohort with ANCA-associated glomerulonephritis. α-SMA positivity might be an additional prognostic factor for ESRD.

Three cases of pneumatosis intestinalis presenting in autoimmune diseases.

Pneumatosis intestinalis (PI) is a comparatively rare disease characterized by the presence of intramural gas in the gastrointestinal tract. PI is known to be associated with several clinical conditions, such as pulmonary diseases, gastrointestinal diseases, and traumatic injury, as well as autoimmune disorders. In particular, PI is commonly seen in systemic sclerosis (SSc) but rarely in systemic lupus erythematosus and dermatomyositis (DM). In this report, we present three cases of PI presenting in autoimmune diseases, including DM, Sjögren's syndrome, and limited SSc, and further discuss its background characteristics.

[Reversed clinicopathological conference (R-CPC)--interpreting laboratory data in the same way as physical findings].

Routine laboratory data are discussed by time series analysis in reversed clinicopathological conferences (R-CPC) at Shinshu University School of Medicine. We can identify fine changes in the laboratory data and the importance of negative data (without any changes) using time series analysis. Routine laboratory tests can be performed repeatedly and relatively cheaply, and time series analysis can be performed. The examination process of routine laboratory data in the R-CPC is almost the same as the process of taking physical findings. Firstly, general findings are checked and then the state of each organ is examined. Although routine laboratory data are cheap, we can obtain much more information about a patient's state than from physical examinations. In this R-CPC, several specialists in the various fields of laboratory medicine discussed the routine laboratory data of a patient, and we tried to understand the detailed state of the patient. R-CPC is an educational method to examine laboratory data and we, reconfirmed the usefulness of R-CPC to elucidate the clinical state of the patient.

[Recognition of the importance of reversed CPC in CPC].

Clinicopathological conferences (CPC) are one of the most important clinical conferences, and processes of both diagnosis and treatment performed in an autopsy case are retrospectively and finely checked to offer better medical treatment in the future. In CPC, the medical history, physical findings, laboratory data, image findings, diagnosis and treatment are discussed in the order that a physician examines a patient. Differential diagnoses usually decrease and several important diagnoses remain as the CPC discussion progresses. Medical treatment is also reexamined to identify a better approach. In this CPC, several medical doctors in various special fields try to understand the detailed state of the patient from each standpoint, and such a CPC is called an Expert CPC at Shinshu University School of Medicine. This CPC is carried out followed by reversed-CPC (R-CPC) of the same case. The purpose of this CPC is to understand the importance of R-CPC and to understand the correct interpretation of routine laboratory data.

Matrix metalloproteinase-2 (MMP-2) and membrane-type 1 MMP (MT1-MMP) affect the remodeling of glomerulosclerosis in diabetic OLETF rats.

BACKGROUND: We reported previously that diabetic glomerular nodular-like lesions were formed during the reconstruction process of mesangiolysis. However, the precise mechanism has yet to be elucidated. Here, we investigated the roles of matrix metalloproteinase (MMP)-2, which is activated from proMMP-2 by membrane-type (MT)-MMP in the sclerotic and endothelial cell injury process of a type II diabetic model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. METHODS: Monocrotaline (MCT) or saline only was injected three times every 4 weeks in 36-week-old OLETF rats and control Long-Evans Tokushima Otsuka rats. Glomerular expression and enzymatic activity of MMP-2 and MT1-MMP were assessed by immunohistochemistry, gelatin zymography of cultured glomerular supernatants, in situ enzymatic detection and reverse transcription-polymerase chain reaction. RESULTS: Mesangial matrix increased in OLETF rats. In addition, mesangiolysis and nodular-like mesangial expansion were observed only in MCT-injected endothelial injured OLETF rats. MMP-2 and MT1-MMP proteins increased in the expanded mesangial lesions in OLETF rats. Gelatin zymography revealed an increase in 62-kDa activated MMP-2 in the culture supernatants of isolated glomeruli from OLETF rats. In situ enzymatic activity of MMP in the mesangial areas was also detected in 50-week-old MCT-injected OLETF rats. CONCLUSION: These results suggest that MMP-2 and MT1-MMP are produced and activated in glomeruli through the progression of diabetic nephropathy and may have some effect on the remodeling of the glomerular matrix in diabetic nephropathy.