Synthesis of Polysubstituted Enamides by Hydrogen Atom Transfer Alkene Isomerization Using Dual Cobalt/Photoredox Catalysis.

M-HAT isomerization is a highly reliable method to access thermodynamically stable alkenes with high functional group tolerance. However, synthesis of heteroatom-substituted alkenes by M-HAT isomerization reaction is still underdeveloped. Herein, we report an enamide synthesis using M-HAT via a combination of cobalt and photoredox catalysis. This method tolerates a variety of functional groups including haloarenes, heteroarenes, free hydroxy groups, non-protected indoles, and drug derivatives. Furthermore, this method can isomerize styrene derivatives in good yield and E/Z selectivity.

Photocatalytic Deuterium Atom Transfer Deuteration of Electron-Deficient Alkenes with High Functional Group Tolerance.

Due to its mild reaction conditions and unique chemoselectivity, hydrogen atom transfer (HAT) hydrogenation represents an indispensable method for the synthesis of complex molecules. Its analog using deuterium, deuterium atom transfer (DAT) deuteration, is expected to enable access to complex deuterium-labeled compounds. However, DAT deuteration has been scarcely studied for synthetic purposes, and a method that possesses the favorable characteristics of HAT hydrogenations has remained elusive. Herein, we report a protocol for the photocatalytic DAT deuteration of electron-deficient alkenes. In contrast to the previous DAT deuteration, this method tolerates a variety of synthetically useful functional groups including haloarenes. The late-stage deuteration also allows access to deuterated amino acids as well as donepezil-d2 . Thus, this work demonstrates the potential of DAT chemistry to become the alternative method of choice for preparing deuterium-containing molecules.

Vitamin B12 biosynthesis of Cetobacterium ceti isolated from the intestinal content of captive common bottlenose dolphins (Tursiops truncatus).

In comparison with terrestrial mammals, dolphins require a large amount of haemoglobin in blood and myoglobin in muscle to prolong their diving time underwater and increase the depth they can dive. The genus Cetobacterium is a common gastrointestinal bacterium in dolphins and includes two species: C. somerae and C. ceti. Whilst the former produces vitamin B12, which is essential for the biosynthesis of haem, a component of haemoglobin and myoglobin, but not produced by mammals, the production ability of the latter remains unknown. The present study aimed to isolate C. ceti from dolphins and reveal its ability to biosynthesize vitamin B12. Three strains of C. ceti, identified by phylogenetic analyses with 16S rRNA gene and genome-based taxonomy assignment and biochemical features, were isolated from faecal samples collected from two captive common bottlenose dolphins (Tursiops truncatus). A microbioassay using Lactobacillus leichmannii ATCC 7830 showed that the average concentration of vitamin B12 produced by the three strains was 11 (standard deviation: 2) pg ml-1. The biosynthesis pathway of vitamin B12, in particular, adenosylcobalamin, was detected in the draft genome of the three strains using blastKOALA. This is the first study to isolate C. ceti from common bottlenose dolphins and reveal its ability of vitamin B12 biosynthesis, and our findings emphasize the importance of C. ceti in supplying haemoglobin and myoglobin to dolphins.

A metabolic profile of routine needle biopsies identified tumor type specific metabolic signatures for breast cancer stratification: a pilot study.

INTRODUCTION: Metabolomics has recently emerged as a tool for understanding comprehensive tumor-associated metabolic dysregulation. However, only limited application of this technology has been introduced into the clinical setting of breast cancer. OBJECTIVES: The aim of this study was to determine the feasibility of metabolome analysis using routine CNB/VAB samples from breast cancer patients and to elucidate metabolic signatures using metabolic profiling. METHODS: After breast cancer screenings, 20 consecutive patients underwent CNB/VAB, and diagnosed with benign, DCIS and IDC by histology. Metabolome analysis was performed using CE-MS. Differential metabolites were then analyzed and evaluated with MetaboAnalyst 4.0. RESULTS: We measured 116-targeted metabolites involved in energy metabolism. Principal component analysis and unsupervised hierarchical analysis revealed a distinct metabolic signature unique to namely "pure" IDC samples, whereas that of DCIS was similar to benign samples. Pathway analysis unveiled the most affected pathways of the "pure" IDC metabotype, including "pyrimidine," "alanine, aspartate, and glutamate" and "arginine and proline" pathways. CONCLUSIONS: Our proof-of-concept study demonstrated that CE-MS-based CNB/VAB metabolome analysis is feasible for implementation in routine clinical settings. The most affected pathways in this study may contribute to improved breast cancer stratification and precision medicine.

Increased centrosome number in BRCA-related breast cancer specimens determined by immunofluorescence analysis.

BRCA-related breast carcinoma can be prevented through prophylactic surgery and an intensive follow-up regimen. However, BRCA genetic tests cannot be routinely performed, and some BRCA mutations could not be defined as deleterious mutations or normal variants. Therefore, an easy functional assay of BRCA will be useful to evaluate BRCA status. As it has been reported that BRCA functions in the regulation of centrosome number, we focused on centrosome number in cancer tissues. Here, 70 breast cancer specimens with known BRCA status were analyzed using immunofluorescence of γ-tubulin (a marker of centrosome) foci. The number of foci per cell was higher in cases with BRCA mutation compared to wild-type cases, that is, 1.9 (95% confidence interval [CI], 1.5-2.3) vs 0.5 (95% CI, 0.2-0.8) (P < .001). Specifically, foci numbers per cell in BRCA1 and BRCA2 mutation cases were 1.2 (95% CI, 0.6-1.8) and 2.2 (95% CI, 1.7-2.6), respectively, both higher than those in wild-type cases (P = .042 and P < .0001, respectively). The predictive value of γ-tubulin foci as determined by area under the curve (AUC = 0.86) for BRCA status was superior to BRCAPRO (AUC = 0.69), Myriad Table (AUC = 0.61), and KOHBRA BRCA risk calculator (AUC = 0.65) pretest values. The use of γ-tubulin foci to predict BRCA status had sensitivity = 83% (19/23), specificity = 89% (42/47), and positive predictive value = 77% (20/26). Thus, γ-tubulin immunofluorescence, a functional assessment of BRCA, can be used as a new prospective test of BRCA status.

Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial.

BACKGROUND: Mammography is the only proven method for breast cancer screening that reduces mortality, although it is inaccurate in young women or women with dense breasts. We investigated the efficacy of adjunctive ultrasonography. METHODS: Between July, 2007, and March, 2011, we enrolled asymptomatic women aged 40-49 years at 42 study sites in 23 prefectures into the Japan Strategic Anti-cancer Randomized Trial (J-START). Eligible women had no history of any cancer in the previous 5 years and were expected to live for more than 5 years. Randomisation was done centrally by the Japan Clinical Research Support Unit. Participants were randomly assigned in 1:1 ratio to undergo mammography and ultrasonography (intervention group) or mammography alone (control group) twice in 2 years. The primary outcome was sensitivity, specificity, cancer detection rate, and stage distribution at the first round of screening. Analysis was by intention to treat. This study is registered, number UMIN000000757. FINDINGS: Of 72,998 women enrolled, 36,859 were assigned to the intervention group and 36,139 to the control group. Sensitivity was significantly higher in the intervention group than in the control group (91·1%, 95% CI 87·2-95·0 vs 77·0%, 70·3-83·7; p=0·0004), whereas specificity was significantly lower (87·7%, 87·3-88·0 vs 91·4%, 91·1-91·7; p<0·0001). More cancers were detected in the intervention group than in the control group (184 [0·50%] vs 117 [0·32%], p=0·0003) and were more frequently stage 0 and I (144 [71·3%] vs 79 [52·0%], p=0·0194). 18 (0·05%) interval cancers were detected in the intervention group compared with 35 (0·10%) in the control group (p=0·034). INTERPRETATION: Adjunctive ultrasonography increases sensitivity and detection rate of early cancers. FUNDING: Ministry of Health, Labour and Welfare of Japan.

Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study.

INTRODUCTION: The status of tumor-infiltrating lymphocytes (TILs) has been recently proposed to predict clinical outcome of patients with breast cancer. We therefore studied the prognostic significance of CD8(+) TILs and FOXP3(+) TILs in residual tumors after neoadjuvant chemotherapy (NAC) and the alterations in these parameters before and after NAC in patients with triple-negative breast cancer (TNBC). METHODS: One hundred thirty-one TNBC patients who received NAC at three institutions were examined. CD8(+) TIL and FOXP3(+) TIL in residual tumors and biopsy specimens were evaluated by double-staining immunohistochemistry. The CD8(+) TIL and FOXP3(+) TIL status of the residual tumors was assessed, and the rates of their changes before and after NAC were calculated. RESULTS: TNBC patients with high CD8(+) TIL levels or a high CD8/FOXP3 ratio in residual tumors had significantly better recurrence-free survival (RFS) and breast cancer-specific survival (BCSS) than patients with low values of these parameters. In multivariate analyses, CD8(+) TIL exhibited strong prognostic significance for RFS, with a hazard ratio (HR) of 3.09 (95 % confidence interval (CI) 1.537-6.614, P=0.0013). The CD8/FOXP3 ratio was also significantly correlated with RFS (HR=2.07, 95 % CI 1.029-4.436, P=0.0412). TNBC with larger residual tumor size and positive lymph node status, which are known prognostic factors, was independently associated with worse RFS (P=0.0064 and P=0.0015, respectively). High CD8(+) TIL levels were a markedly powerful indicator of improved BCSS, with an HR of 3.59 (95 % CI 1.499-9.581, P=0.0036). Nodal status was also associated with BCSS (P=0.0024). TNBC with a high rate of CD8(+) TIL changes was associated with significantly better RFS compared with the low group (P=0.011). Higher rates of changes in the CD8/FOXP3 ratio were significantly correlated with both better RFS and BCSS compared with lower rates (P=0.011 and P=0.023, respectively). CONCLUSIONS: This is the first study to demonstrate that high CD8(+) TIL and a high CD8/FOXP3 ratio in residual tumors and increment of these parameters following NAC and accurately predict improved prognosis in TNBC patients with non-pathological complete response following NAC. These parameters could serve as a surrogate one for adjuvant treatment in patients with residual disease in the neoadjuvant setting.

Tumor-infiltrating CD8+ and FOXP3+ lymphocytes in triple-negative breast cancer: its correlation with pathological complete response to neoadjuvant chemotherapy.

The anti-tumor immune response was recently reported to play a critical role in the chemotherapeutic sensitivity of breast cancer. Therefore, we investigated the correlation between CD8+ and FOXP3+ tumor-infiltrating lymphocytes and the pathological complete response (pCR) following neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC), in conjunction with neoangiogenesis, basal and proliferation markers. CD8+ and FOXP3+ lymphocytes were assessed in biopsy specimens by double-staining immunohistochemistry, in combination with immunostaining of vasohibin-1, CD31, EGFR, CK5/6, and Ki-67. Earlier age, pre-menopausal status, smaller tumor size, and high Ki-67 were significantly associated with pCR, as in high CD8+, high CD8+/FOXP3+ ratio, and low vasohibin-1 positive ratio. Multivariate analysis did reveal that a high CD8+/FOXP3+ ratio was a strong predictor of pCR with an odds ratio of 5.32 (P = 0.005). High Ki-67 was also significantly associated with pCR (P = 0.002). TNBCs with a high CD8+/FOXP3+ ratio and high Ki-67 had the highest pCR rate (70%) following NAC. However, the pCR rate of the patients with low CD8+/FOXP3+ ratio and low Ki-67 was only 5%. The pCR rates of a high CD8+/FOXP3+ ratio and low Ki-67 patients and those with a low CD8+/FOXP3+ ratio and high Ki-67 were 24 and 21%, respectively. TNBCs with a high CD8+/FOXP3+ ratio were more sensitive to anthracycline and taxane-based chemotherapeutic regimens, and the CD8+/FOXP3+ ratio in conjunction with Ki-67 could predict pCR following NAC in TNBC. This predictor may represent a new surrogate for testing the efficacy of investigational agents in the neoadjuvant setting.

Controversies in breast cancer screening for women aged 40-49 years.

Mammography is the only method of breast cancer screening that has established evidence of a mortality reduction. However, mammography does not achieve sufficient accuracy in the high-density breasts of patients<50 years of age. In 2009, the US Preventive Services Task Force revised its recommendation for breast cancer screening in women aged 40-49 years from Grade B to C because the net benefit was relatively small for this age bracket. The net benefit of screening is the sum of benefits and harm and should always be monitored especially in population screening. A high recall rate, an inefficient number needed to invite for screening to prevent one breast cancer death, a high false-positive rate and unnecessary additional imaging for women aged 40-49 years are great concerns of mammography screening. Overdiagnosis is also a detriment of mammography screening; however, it may have a limited effect on women aged 40-49 years. Establishment of new evidence for breast cancer screening, such as ultrasonography screening, is needed in order to create a more effective screening system.

A randomized controlled trial to verify the efficacy of the use of ultrasonography in breast cancer screening aged 40-49 (J-START): 76 196 women registered.

OBJECTIVE: The objective of the Japan Strategic Anti-cancer Randomized Trial was to verify the efficacy of the use of ultrasonography in breast cancer screening among women aged 40-49 years. The purpose of this paper was to report the design and recruitment result of this study. METHODS: In this study of women in their 40s, the participants were divided into two groups, one of which (the intervention group) was subjected to mammography and ultrasonography (using a standardized ultrasonography examination), while the other (the control group) was examined with mammography, in a randomized controlled trial, with the objective of verifying the accuracy and efficacy of examinations by comparing the two groups. RESULTS: The cumulative total number of participants registered in the study was 76 196 (38 313 in the intervention group and 37 883 in the control group). 71.0% of participants registered to the study were under individual randomized controlled trial, 25.0% were under cluster randomized controlled trial and 3.9% were under non-randomized controlled group. The study was designed so that participants registered at their first examination underwent examinations by the same method for the subsequent two years. 74.1% of participants scheduled for a second examination had undertaken it, while information regarding the presence of interval cancer had been obtained from a further 20.6% using a questionnaire. At July 2013, the status of 5.3% of all participants was unclear. CONCLUSIONS: It was the first large-scale randomized controlled trial carried out in Japan. The scheduled second examinations were completed at the end of fiscal 2012. Once the proportion of participants whose status is unclear has fallen to ≤5%, the authors plan to collate the data relating to the primary end points, and publish the results.

[A patient with advanced breast cancer who developed bacterial meningitis after chemotherapy].

A 76-year-old woman was admitted to our hospital because of a right breast tumor and a skin ulcer. The patient was diagnosed as having advanced breast cancer T4bN2M1(lung), Stage IV. A regimen of 5-fluorouracil(500mg/m2)with epirubicin(100mg/m / 2)and cyclophosphamide(500mg/m2)(FEC100)was administered. However, the patient was hospitalized 12 days later because of febrile neutropenia. The patient experienced a stiff neck the next day, and bacterial meningitis was diagnosed on the basis of cerebrospinal fluid examination. Antibacterial agents were administered according to the clinical practice guidelines of bacterial meningitis. The patient recovered and was discharged from our hospital 24 days after admission. Bacterial meningitis after chemotherapy is rare, but this could be progress to a serious condition. Early diagnosis and treatment are paramount in such cases.

Arteriolar Hyalinosis Predicts the Onset of Both Macroalbuminuria and Impaired Renal Function in Patients with Type 2 Diabetes.

INTRODUCTION: Arteriolar hyalinosis (AH) has been shown to be associated with albuminuria and GFR. In this study, we investigated whether or not index of AH (IAH) is a predictor of the onset of macroalbuminuria and impaired renal function (eGFR <60 mL/min/1.73 m2 [eGFR <60]) in type 2 diabetic patients with early diabetic nephropathy. METHODS: The study population consisted of 35 patients with type 2 diabetes (25 men; age: 47 ± 9 years; eGFR: 92.7 ± 18.0 mL/min/1.73 m2) with normo- or microalbuminuria who underwent percutaneous renal biopsy. These patients were followed for at least 5 (18 ± 6, range: 6-28) years. The study endpoint was the onset of macroalbuminuria or eGFR <60. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate glomerular and interstitial structural changes. RESULTS: During the observation period, 9 out of the 35 patients progressed to macroalbuminuria, and 15 out of the 35 patients developed eGFR <60. The annual rate of eGFR decline was significantly correlated with IAH (r = -0.40, p = 0.016). Kaplan-Meier analysis demonstrated that AH was associated with a significantly higher risk of onset of macroalbuminuria and eGFR <60, and microalbuminuria is associated with the onset of macroalbuminuria but not the onset of eGFR <60. CONCLUSIONS: Aggravated AH is a histological risk factor which predicts the onset of macroalbuminuria and eGFR <60 in patients with type 2 diabetes. These findings provide novel insights into the mechanism of progression of diabetic nephropathy.

The Japanese breast cancer society clinical practice guidelines for breast cancer screening and diagnosis, 2022 edition.

This article provides updates to readers based on the newly published Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer Screening and Diagnosis, 2022 Edition. These guidelines incorporate the latest evaluation of evidence from studies of diagnostic accuracy. For each clinical question, outcomes for benefits and harms were established, and qualitative or quantitative systematic reviews were conducted. Recommendations were determined through voting by a multidisciplinary group, and guidelines were documented to facilitate shared decision-making among patients and medical professionals. The guidelines address screening, surveillance, and pre- and postoperative diagnosis of breast cancer. In an environment that demands an integrated approach, decisions are needed on how to utilize modalities, such as mammography, ultrasound, MRI, and PET/CT. Additionally, it is vital to understand the appropriate use of new technologies, such as tomosynthesis, elastography, and contrast-enhanced ultrasound, and to consider how best to adapt these methods for individual patients.

Familial Intraductal Papillary Mucinous Neoplasm Associated With the Germline MSH6 Missense Variant and Progression of Pancreatic cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasm (IPMN) in individuals with at least one first-degree relative with IPMN is defined as familial IPMN. However, few studies have reported on familial IPMN, its clinical characteristics, or the associated genetic factors. MATERIALS AND METHODS: We report the case of a 58-year-old woman with multifocal IPMN and a mural nodule in the pancreatic body. The patient underwent a distal pancreatectomy and developed pancreatic head cancer 1 year and 6 months postoperatively. The patient had a family history of multifocal IPMN in her father. Therefore, a genetic predisposition to IPMN and pancreatic cancer was suspected. The patient was analyzed for germline variants, and the resected IPMN was subjected to immunohistochemical and somatic variant analyses. RESULTS: Next-generation sequencing revealed a heterozygous germline missense variant in exon 5 of MSH6 (c.3197A>G; Tyr1066Cys). The pathogenicity of this variant of uncertain significance was suspected based on multiple in silico analyses, and the same MSH6 variant was identified in the patient's father's colonic adenoma. The mural nodule in the pancreatic body was pathologically diagnosed as a high-grade IPMN with ossification and somatic KRAS and PIK3CA variants. CONCLUSIONS: This case revealed a possible genetic factor for familial IPMN development and presented interesting clinicopathological findings.

Management of thyroid carcinoma showing thymus-like differentiation (CASTLE) invading the trachea.

PURPOSE: To define the clinicopathological features and discuss the optimal management of carcinoma showing thymus-like differentiation (CASTLE). METHODS: We retrospectively analyzed six patients with CASTLE. RESULTS: The subjects comprised two men and four women (average age at initial diagnosis, 61 years, range 47-75 years). Preoperative biopsy yielded a correct diagnosis in two patients. Five patients underwent surgery and one was treated with radiation therapy alone. Four had extrathyroidal invasion and three had lymph node metastasis. During the clinical course, tracheal invasion was detected in five patients, the upper extent of the tumor being the lower half of the first tracheal ring. Two of these patients underwent tracheal sleeve resection. Two patients received postoperative radiotherapy for nodal metastasis, and one, after palliative surgery. The median follow-up period was 67 months (range 38-129). Recurrence was found 10 years post-therapy in the patient treated with radiation therapy only, resulting in death soon after. Although local recurrence was not found in the remaining five patients, new pulmonary metastases were diagnosed in the patient who underwent non-curative surgery. CONCLUSIONS: CASTLE can be diagnosed preoperatively by core needle biopsy and CD5 staining. Curative resection with neck dissection followed by radiotherapy can yield a good outcome. Larynx-sparing complete resection may be more feasible for CASTLE, even though it has a higher incidence of tracheal invasion than differentiated thyroid carcinoma.

Draft genome sequences of Pantoea sp. strains QMID1-QMID4 isolated from the midgut of Japanese honey bee (Apis cerana japonica).

We report the draft genome sequences of Pantoea sp. strains QMID1-QMID4 that were recovered from the midgut of Japanese honey bee (Apis cerana japonica). The strains possess the carotenoid biosynthetic gene cluster. The genome information expands our knowledge of their potential use as probiotics and/or prebiotics in honey bees.

Comparison of RNA-Seq analysis data between tracheal mite-infested and uninfested Japanese honey bees (Apis cerana japonica).

OBJECTIVE: The purpose of this data set is to investigate differences in RNA-Seq transcriptome profiles between Acarapis woodi-infested and uninfested Japanese honey bees (Apis cerana japonica). The data set is strengthened by data collected from different body parts (head, thorax, and abdomen). The data set will support future studies of molecular biological changes in mite-infested honey bees. DATA DESCRIPTION: We collected 5 mite-infested and 5 uninfested A. cerana japonica workers from each of 3 different colonies (designated as A, B, and C). Workers were dissected into 3 body sites (i.e., heads, thoraces, and abdomen), and 5 of each body site were pooled together for RNA extraction, generating a total of 18 RNA-Seq samples (2 infection status × 3 colonies × 3 body sites). FASTQ data files of each sample that were generated by a DNBSEQ-G400 sequencer with the 2 × 100 bp paired-end sequencing protocol are available in the DDBJ Sequence Read Archive under accession number DRA015087 (RUN: DRR415616-DRR415633, BioProject: PRJDB14726, BioSample: SAMD00554139-SAMD00554156, Experiment: DRX401183-DRX401200). The data set is a fine-scale analysis of gene expression in the mite-infested A. cerana japonica workers because 18 RNA-Seq samples are separated by 3 body sites.

Difference in sulfur regulation mechanism between tube-dwelling and free-moving polychaetes sympatrically inhabiting deep-sea hydrothermal chimneys.

The environment around deep sea hydrothermal vents is characterized by an abundance of sulfur compounds, including toxic hydrogen sulfide. However, numerous communities of various invertebrates are found in it. It is suggested that invertebrates in the vicinity of hydrothermal vents detoxify sulfur compounds by biosynthesis of taurine-related compounds in the body. On the other hand, the vent endemic polychaete Alvinella pompejana has spherocrystals composed of sulfur and other metals in its digestive tract. It was considered that the spherocrystals contribute to the regulation of sulfur in body fluids. Paralvinella spp. and Polynoidae. gen. sp. live sympatrically and in areas most affected by vent fluid. In this study, we focused on the digestive tract of Paralvinella spp. and Polynoidae. gen. sp. to examine whether they have spherocrystals. We also investigated the possible involvement of bacteria in the digestive tract in spherulization. Examination with a scanning electron microscope (SEM) equipped with Energy Disperse X-ray Spectroscopy (EDS) detected spherocrystals containing sulfur and iron in the digestive tract of Paralvinella spp. In contrast, such spherocrystals were not observed in that of Polynoidae. gen. sp. although sulfur is detected there by inductively coupled plasma-optical emission spectrometry (ICP-OES). Meta-16S rRNA analysis indicated that the floras of the digestive tracts of the two species were very similar, suggesting that enteric bacteria are not responsible for spherocrystal formation. Analysis of taurine-related compounds indicated that the digestive tissues of Polynoidae. gen. sp. contain a higher amount of hypotaurine and thiotaurine than those of Paralvinella spp. Therefore, the two sympatric polychaetes use different strategies for controlling sulfur, i.e., Paralvinella spp. forms spherocrystals containing elemental sulfur and iron in the digestive tract, but Polynoidae. gen. sp. accumulates taurine-related compounds instead of spherocrystals. Such differences may be related to differences in their lifestyles, i.e., burrow-dweller or free-moving, or may have been acquired phylogenetically in the evolutionary process.

Glucose control, diabetic retinopathy, and hemodialysis induction in subjects with normo-microalbuminuric type 2 diabetic patients with normal renal function followed for 15 years.

AIMS: A high urinary albumin excretion (UAE) and low glomerular filtration rate (GFR) are risk factors for progressive renal function loss in type 2 diabetic patients. In addition, diabetic retinopathy (DR) is also a risk factor for progressive renal function decline in microalbuminuric type 2 diabetic patients. We aimed to elucidate the factors, including DR, associated with a more severe situation of diabetic nephropathy, i.e., hemodialysis (HD) induction in normo- and microalbuminuric type 2 diabetic patients without renal dysfunction. METHODS: Normo- and microalbuminuric type 2 diabetic patients with normal renal function whose GFRs had been measured by iohexol injection in 1995-1997 and had been followed for over 5 years were analyzed (n = 199). HbA1c levels was divided into HbA1c ≥ 7.0 (n = 146) and <7.0 (n = 53) groups. The UAE levels were classified as normoalbuminuria (NA, n = 114) and microalbuminuria (MA, n = 85). Seventy-two patients had DR, and 96 had hypertension. Patients were followed up for 15.7 ± 6.0 years and frequency of and duration to the HD induction were evaluated. RESULTS: During the study period, 8 patients received HD induction. There were no remarkable differences in the rates of HD induction between patients with and without HbA1c ≥7.0, microalbuminuria, DR or hypertension. A Kaplan-Meier analysis revealed that HbA1c ≥7.0 (p = 0.037) and DR (p = 0.037) were associated with a significantly higher risk of HD induction than HbA1c <7.0 and no DR, respectively while albuminuria grade and hypertension were not associated with the risk of HD induction. There was significant negative correlation between HbA1c and annual decline rate of eGFR and annual decline rate of eGFR in the patients with prepro-proliferative DR (PDR) was significantly higher than that in the patients without DR. In the multivariate analysis, HbA1c and PDR showed significant relationships with the annual decline rate of eGFR. CONCLUSIONS: It was reasonable that poorer glycemic control affected HD induction for 16 years follow-up. However, DR, especially PDR, should also be considered a substantial risk factor for HD induction although microalbuminuria and hypertension did not predict it at the early stage of diabetic nephropathy in type 2 diabetic patients with normal renal function.