OBJECTIVEClinicopathological characteristics, renal prognosis, and mortality in patients with type 2 diabetes and reduced renal function without overt proteinuria are scarce. RESEARCH DESIGN AND METHODSWe retrospectively assessed 526 patients with type 2 diabetes and reduced renal function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m 2 ), who underwent clinical renal biopsy and had follow-up data, from Japan's nationwide multicenter renal biopsy registry. For comparative analyses, we derived oneto-two cohorts of those without proteinuria versus those with proteinuria using propensity score-matching methods addressing the imbalances of age, sex, diabetes duration, and baseline eGFR. The primary end point was progression of chronic kidney disease (CKD) defined as new-onset end-stage renal disease, decrease of eGFR by ‡50%, or doubling of serum creatinine. The secondary end point was all-cause mortality. RESULTS Eighty-two patients with nonproteinuria (urine albumin-to-creatinine ratio [UACR]<300 mg/g) had lower systolic blood pressure and less severe pathological lesions compared with 164 propensity score-matched patients with proteinuria (UACR ‡300 mg/g). After a median follow-up of 1.9 years (interquartile range 0.9-5.0 years) from the date of renal biopsy, the 5-year CKD progression-free survival was 86.6% (95% CI 72.5-93.8) for the nonproteinuric group and 30.3% (95% CI 22.4-38.6) for the proteinuric group (log-rank test P < 0.001). The lower renal risk was consistent across all subgroup analyses. The all-cause mortality was also lower in the nonproteinuric group (log-rank test P 5 0.005). CONCLUSIONSPatients with nonproteinuric diabetic kidney disease had better-controlled blood pressure and fewer typical morphological changes and were at lower risk of CKD progression and all-cause mortality.
Many of the tripartite motif (TRIM) proteins function as E3 ubiquitin ligases and are assumed to be involved in various events, including oncogenesis. In regard to tripartite motif-containing 44 (TRIM44), which is an atypical TRIM family protein lacking the RING finger domain, its pathophysiological significance in breast cancer remains unknown. We performed an immunohistochemical study of TRIM44 protein in clinical breast cancer tissues from 129 patients. The pathophysiological role of TRIM44 in breast cancer was assessed by modulating TRIM44 expression in MCF-7 and MDA-MB-231 breast cancer cells. TRIM44 strong immunoreactivity was significantly associated with nuclear grade (p = 0.033), distant disease-free survival (p = 0.031) and overall survival (p = 0.027). Multivariate analysis revealed that the TRIM44 status was an independent prognostic factor for distant disease-free survival (p = 0.005) and overall survival (p = 0.002) of patients. siRNA-mediated TRIM44 knockdown significantly decreased the proliferation of MCF-7 and MDA-MB-231 cells and inhibited the migration of MDA-MB-231 cells. Microarray analysis and qRT–PCR showed that TRIM44 knockdown upregulated CDK19 and downregulated MMP1 in MDA-MB-231 cells. Notably, TRIM44 knockdown impaired nuclear factor-kappa B (NF-κB)-mediated transcriptional activity stimulated by tumor necrosis factor α (TNFα). Moreover, TRIM44 knockdown substantially attenuated the TNFα-dependent phosphorylation of the p65 subunit of NF-κB and IκBα in both MCF-7 and MDA-MB-231 cells. TRIM44 would play a role in the progression of breast cancer by promoting cell proliferation and migration, as well as by enhancing NF-κB signaling.
BackgroundWhile denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy.MethodsTo analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions.ResultsThe study population consisted of 277 patients who had received a median of 10 doses (range, 1–79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77–4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF.ConclusionsWe found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.
ObjectiveThe predictive value of diabetic retinopathy on end-stage kidney disease (ESKD) has not been fully addressed in patients with type 2 diabetes and diabetic kidney disease.Research design and methodsWe studied 232 patients with type 2 diabetes and biopsy-proven diabetic kidney disease who were screened for diabetic retinopathy during the 1 month of kidney biopsy. We examined the association between retinopathy progression and renal lesions. We used Cox regression analyses to explore the risk of ESKD adjusting for known risk demographic and clinical variables. We assessed the incremental prognostic value of ESKD by adding diabetic retinopathy to the clinical variables.ResultsThe diabetic retinopathy progression positively correlated with all scores of renal lesions, especially with the glomerular-based classification (r=0.41), scores of interstitial fibrosis (r=0.41) and diffuse lesion (r=0.48). During a median follow-up of 5.7 years, 114 patients developed ESKD. Adjusting for known risk factors of ESKD, the HR for ESKD (patients with no apparent retinopathy as a reference) were 1.96 (95% CI 0.62 to 6.17) for patients with mild non-proliferative diabetic retinopathy (NPDR), 3.10 (95% CI 1.45 to 6.65) for patients with moderate NPDR, 3.03 (95% CI 1.44 to 6.37) for patients with severe NPDR, and 3.43 (95% CI 1.68 to 7.03) for patients with proliferative diabetic retinopathy, respectively. Addition of the retinopathy grading to the clinical model alone improved the prognostic value (the global χ2 statistic increased from 155.2 to 164.5; p<0.001), which is an improvement equivalent to the addition of the renal lesion grading to the clinical model.ConclusionsRetinopathy progression appeared to be associated with renal lesions and the development of ESKD. Our findings suggest that diabetic retinopathy and kidney disease share the same magnitude of disease progression, and therefore diabetic retinopathy may be useful for prognosticating the clinical course for diabetic kidney disease.
The study implies that in addition to the traditional markers of eGFR and UACR, we may explore the markers of serum albumin and hemoglobin A1c, which are widely available but not routinely measured in patients with nephrosclerosis, and the biopsy data, especially the data on the severity of interstitial damage, for the better prediction of CKD progression in patients with nephrosclerosis.
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