Three-dimensional visualization and quantitative analysis of embryonic and fetal thigh muscles using magnetic resonance and phase-contrast X-ray imaging.

The musculoskeletal system around the human hip joint has acquired a suitable structure for erect bipedal walking. However, little is known about the process of separation and maturation of individual muscles during the prenatal period, when muscle composition is acquired. Understanding the maturation process of the normal musculoskeletal system contributes to elucidating the acquisition of bipedal walking in humans and to predicting normal growth and detecting congenital muscle disorders and anomalies. In this study, we clarify the process of thigh muscle maturation from the embryonic stage to the mid-fetal stage using serial sections, phase-contrast X-ray computed tomography, and magnetic resonance imaging. We also provide a 4D atlas of human thigh muscles between 8 and 23 weeks of gestation. As a result, we first show that muscle separation in the lower thigh tends to progress from the superficial to the deep layers and that all musculoskeletal components are formed by Carnegie Stage 22. Next, we show that femur and muscle volume grow in correlation with crown-rump length. Finally, we show that the anterior, abductor, and posterior muscle groups in the thigh contain a high percentage of monoarticular muscle volume by the end of the embryonic period. This ratio approaches that of adult muscle composition during normal early fetal development and is typical of bipedal walking. This study of fetal muscle composition suggests that preparation for postnatal walking may begin in early fetal period.

Use of biologic agents and methotrexate improves renal manifestation and outcome in patients with rheumatoid arthritis: a retrospective analysis.

BACKGROUND AND PURPOSE: We examined whether advances in treatment strategies from older disease-modifying antirheumatic drugs (DMARDs) to new biologic agents and methotrexate improved renal complications and outcome in patients with rheumatoid arthritis (RA). METHODS: We reviewed records of 156 patients with RA who underwent kidney biopsy at our institute between January 1990 and December 2019. All patients were assigned to one of three periods: period 1, 1990-1999 (n = 48); period 2, 2000-2009(n = 57); period 3, 2010-2019 (n = 51). RESULTS: Membranous nephropathy, nephrosclerosis, AA-amyloidosis, and IgA nephropathy were the four major renal manifestations of RA. AA-amyloidosis was diagnosed by kidney biopsy in 21 patients: period 1, 7 patients (15%); period 2, 10 patients (18%); and period 3, 4 patients (8%). The 4 patients in period 3 were in the years 2010-2014, and no new case of AA-amyloidosis was recorded from 2015 to 2019. In all 21 of the patients with AA-amyloidosis, neither a biologic agent nor methotrexate was administered. Fifteen of the 21 patients required dialysis, and 13 died in periods 1-3 because of amyloid-related cardiac dysfunction less than 2 years after the initiation of dialysis. Two of them are doing well using biologic agent despite dialysis. The remaining three patients who received a biologic agent or methotrexate does not progress to end-stage renal failure. In addition, the other renal complications showing progression to dialysis also decreased over time. CONCLUSION: Advances in treatment strategies have improved renal outcome and reduced mortality in patients with RA.

Central fibrous area in the glomerular vascular pole consists of fibrous collagens and is associated with advanced age: a cross-sectional study.

BACKGROUND: For the optimal management of patients with both allograft kidneys and native kidney diseases, the recognition of the histological features associated with older age is important. This is because most pathological findings are non-specific. Central fibrous areas (CFAs) have recently been proposed to be age-related. However, the components of CFAs and whether CFAs are observed in various kidney diseases remain undetermined. This cross-sectional study was undertaken to clarify the histological features, epidemiology, and clinicopathological features of CFAs. METHODS: One hundred and one consecutive kidney needle biopsy specimens were retrospectively collected from seven facilities in the Hokuriku region and diagnosed at the Kanazawa University Hospital in 2015. First, the components of CFAs were analyzed using normal histostaining, immunostaining, and electron microscopy. Second, the patients were divided into two groups (CFA [+] or CFA [-]) according to the presence of CFA in the obtained samples. Clinical and histological features were compared between the two groups, and factors associated with CFA formation were determined using univariate and multivariate analyses. The number of CFAs per specimen was counted in the CFA (+) group. Third, the presence of myofibroblasts in CFA was examined by immunostaining. RESULTS: CFAs were observed in 56 of 101 patients (55.4%) with various kidney diseases. CFAs consist of fibrillar collagens (collagen I and III) in addition to non-fibrillar collagens (collagen IV and VI), as confirmed by electron microscopy. Clinically, the CFA (+) group was older and had a significantly higher prevalence of hypertension and hyperlipidemia than the CFA (-) group. Histologically, elastofibrosis of the interlobular artery, arteriolar hyalinosis, and membranous nephropathy were significantly more evident in the CFA (+) group than in the CFA (-) group. Multivariate analysis revealed that older age was the sole factor associated with CFA formation. Finally, 27 of 58 (46.6%) CFA-containing glomeruli in 26 cases included alpha-smooth muscle actin-positive cells in or adjacent to the CFA. CONCLUSIONS: CFAs consist of fibrous collagens in addition to matrix collagens. CFA formation is associated with older age and was observed in various kidney diseases.

The development of the tensor vastus intermedius during the human embryonic period and its clinical implications.

The tensor vastus intermedius (TVI) is a newly discovered muscle located in the anterolateral thigh area and is considered the fifth component of the quadriceps femoris muscle. There have been several papers describing its anatomical and morphological features in detail; however, many features of this muscle, such as its ontology or kinetic functions, remain unknown. The purpose of this study was to determine the initial appearance of the TVI muscle in human embryonic development and to investigate its growth and development. Histological observations were performed on 30 lower limbs of 15 human embryos from Carnegie stage (CS) 21, 22, and 23 (with crown-rump length ranging from 18.7 to 28.7 mm). Myocyte clusters of the TVI were observed between the vastus lateralis and intermedius muscles in 7 out of 10 limbs in CS 22, indicating that the TVI arises during this stage. In CS 23, the TVI was clearly present in all specimens except one. However, neither the aponeurosis nor the tendonous structure of the TVI were observed in these embryonic stages. Formation of the conventional four components of the quadriceps muscle is completed within CS 21; therefore, our results suggest that the TVI is the last element to develop in the quadriceps femoris complex. It is posited that after the embryonic period, the TVI continues to grow, while forming the tendinous structure toward the patella and receiving vascular supply from certain vascular branches. The clinical significance of these findings is that orthopedists and plastic surgeons who perform surgical procedures within the anterolateral thigh (ALT) area should be aware of the anatomy and development of the TVI in order to reduce surgical complications. Our present research aims to contribute to a deeper understanding of the morphogenesis of the TVI and the other femoral extensor muscles.

Validation of the diagnostic criteria for IgG4-related kidney disease (IgG4-RKD) 2011, and proposal of a new 2020 version.

BACKGROUND: In 2011, the IgG4-related kidney disease (IgG4-RKD) working group of the Japanese Society of Nephrology proposed diagnostic criteria for IgG4-RKD. The aim of the present study was to validate those criteria and develop a revised version. METHODS: Between April 2012 and May 2019, we retrospectively collected Japanese patients with kidney disease, for whom data on serum IgG4 values and/or immunohistological staining for IgG4 in renal biopsy samples were available. These patients were classified as IgG4-RKD or non-IgG4-RKD based on the diagnostic criteria for IgG4-RKD 2011, and the results were evaluated by expert opinion. Accordingly, we developed some revised versions of the criteria, and the version showing the best performance in the present cohort was proposed as the IgG4-RKD criteria for 2020. RESULTS: Of 105 included patients, the expert panel diagnosed 55 as having true IgG4-RKD and 50 as mimickers. The diagnostic criteria for IgG4-RKD 2011 had a sensitivity of 72.7% and a specificity of 90.0% in this cohort. Of the 15 patients with true IgG4-RKD who were classified as non-IgG4-RKD, all lacked biopsy-proven extra-renal lesions, although many had clinical findings highly suggestive of IgG4-RD. The revised version to which "bilateral lacrimal, submandibular or parotid swelling, imaging findings compatible with type 1 autoimmune pancreatitis or retroperitoneal fibrosis" was added as an item pertaining to extra-renal organ(s) improved the sensitivity to 90.9% while the specificity remained at 90.0%. CONCLUSION: The revised version has considerably improved test performance after addition of the new extra-renal organ item (imaging and clinical findings).

Medullary thick ascending limb impairment in the GlatmTg(CAG-A4GALT) Fabry model mice.

A main feature of Fabry disease is nephropathy, with polyuria an early manifestation; however, the mechanism that underlies polyuria and affected tubules is unknown. To increase globotriaosylceramide (Gb3) levels, we previously crossbred asymptomatic Glatm mice with transgenic mice that expressed human Gb3 synthase (A4GALT) and generated the GlatmTg(CAG-A4GALT) symptomatic Fabry model mice. Additional analyses revealed that these mice exhibit polyuria and renal dysfunction without remarkable glomerular damage. In the present study, we investigated the mechanism of polyuria and renal dysfunction in these mice. Gb3 accumulation was mostly detected in the medulla; medullary thick ascending limbs (mTALs) were the most vacuolated tubules. mTAL cells contained lamellar bodies and had lost their characteristic structure ( i.e., extensive infolding and numerous elongated mitochondria). Decreased expression of the major molecules-Na+-K+-ATPase, uromodulin, and Na+-K+-2Cl- cotransporter-that are involved in Na+ reabsorption in mTALs and the associated loss of urine-concentrating ability resulted in progressive water- and salt-loss phenotypes. GlatmTg(CAG-A4GALT) mice exhibited fibrosis around mTALs and renal dysfunction. These and other features were consistent with pathologic findings in patients with Fabry disease. Results demonstrate that mTAL dysfunction causes polyuria and renal impairment and contributes to the pathophysiology of Fabry nephropathy.-Maruyama, H., Taguchi, A., Nishikawa, Y., Guili, C., Mikame, M., Nameta, M., Yamaguchi, Y., Ueno, M., Imai, N., Ito, Y., Nakagawa, T., Narita, I., Ishii, S. Medullary thick ascending limb impairment in the GlatmTg(CAG-A4GALT) Fabry model mice.

Vasa recta hyalinosis reflects severe arteriolopathy in renal allografts.

AIM: We examined the clinicopathologic significance of hyalinosis in the vasa recta in the medulla of allograft kidney biopsies. METHOD: We analyzed biopsy specimens from January 2010 to December 2015, obtained from both the cortex and medulla (including the vasa recta) ≥ 1 year after living-donor kidney transplantation. We excluded biopsy specimens from recipients who had undergone transplantation due to diabetic nephropathy or who had diabetes mellitus after transplantation. We evaluated hyaline arteriolopathy in the cortex using the aah score determined by the Banff 2007 classification. RESULT: Among 381 biopsy specimens obtained from 248 transplant recipients ≥ 1 year after transplantation, 36 specimens obtained from 34 recipients showed vasa recta hyalinosis (VRH) in the medulla. Among these 36 specimens, 17 had a score of aah3, 16 had a score of aah2, and 3 had a score of aah1. The incidence of VRH was 1.9% at ≥ 1 to < 4 years, 7.1% at ≥ 4 to < 8 years, and 50.0% at ≥ 8 years. The aah scores and the proportion of hyalinosis in the arteriolar media among all muscular arterioles in the cortex were significantly higher in the VRH group at ≥ 8 years in the late-phase biopsy (P < 0.01). The graft survival was worse in the VRH group (P = 0.024), although there was no significant difference in the graft survival between the ≥ aah2 and < aah2 groups at ≥ 8 years in the late-phase biopsy (P = 0.159). CONCLUSION: VRH in renal allografts reflects severe arteriolopathy of the cortex. VRH in the late-phase biopsy may be a prognostic factor for graft survival.

Analysis of facial skeletal asymmetry during foetal development using µCT imaging.

OBJECTIVES: Asymmetry has been noted in the human craniofacial region in several pathological conditional and growth abnormalities, often with a directional predilection. Physiological asymmetry has also been reported in normal adults and adolescents, with certain regions of the cranioskeleton, such as the mandible, displaying prevalent asymmetry. However, the timing at which such asymmetries arise has not been evaluated. The objectives of this study were to assess the degree of asymmetry in facial bones during the foetal stages of human development. MATERIAL AND METHODS: Twenty-one preserved conceptuses from the Congenital Anomaly Research Center at Kyoto University, between ages 15 and 20 weeks of gestation, were studied using high-resolution µCT imaging. Asymmetry analysis was performed on digitally segmented facial bone pairs, using geometric morphometric (GM) approaches as well as adapted deformation-based asymmetry (DBA) methods. RESULTS: GM analysis revealed that the developing facial bones display statistically significant fluctuating and directional asymmetry. DBA methods suggest that the magnitude of asymmetry in facial bones is low and does not appear to be correlated to the estimate of overall size of conceptus. Additionally, the patterns of asymmetry are highly variable between individual specimens. CONCLUSIONS: The developing foetal facial skeleton displays variable patterns of low magnitude asymmetry. GM and DBA methods offer unique advantages to assess facial asymmetry quantitatively and qualitatively.

Critical Growth Processes for the Midfacial Morphogenesis in the Early Prenatal Period.

BACKGROUND: Congenital midfacial hypoplasia often requires intensive treatments and is a typical condition for the Binder phenotype and syndromic craniosynostosis. The growth trait of the midfacial skeleton during the early fetal period has been assumed to be critical for such an anomaly. However, previous embryological studies using 2-dimensional analyses and specimens during the late fetal period have not been sufficient to reveal it. OBJECTIVE: To understand the morphogenesis of the midfacial skeleton in the early fetal period via 3-dimensional quantification of the growth trait and investigation of the developmental association between the growth centers and midface. METHODS: Magnetic resonance images were obtained from 60 human fetuses during the early fetal period. Three-dimensional shape changes in the craniofacial skeleton along growth were quantified and visualized using geometric morphometrics. Subsequently, the degree of development was computed. Furthermore, the developmental association between the growth centers and the midfacial skeleton was statistically investigated and visualized. RESULTS: The zygoma expanded drastically in the anterolateral dimension, and the lateral part of the maxilla developed forward until approximately 13 weeks of gestation. The growth centers such as the nasal septum and anterior portion of the sphenoid were highly associated with the forward growth of the midfacial skeleton (RV = 0.589; P < .001). CONCLUSIONS: The development of the midface, especially of the zygoma, before 13 weeks of gestation played an essential role in the midfacial development. Moreover, the growth centers had a strong association with midfacial forward growth before birth.

The Kyoto Collection of Human Embryos and Fetuses: History and Recent Advancements in Modern Methods.

The Kyoto Collection of Human Embryos and Fetuses, the largest collection of human embryos worldwide, was initiated in the 1960s, and the Congenital Anomaly Research Center of Kyoto University was established in 1975 for long-term storage of the collection and for the promotion of research into human embryonic and fetal development. Currently, the Kyoto Collection comprises approximately 45,000 specimens of human embryonic or fetal development and is renowned for the following unique characteristics: (1) the collection is considered to represent the total population of fetal specimens nationwide in Japan, (2) it comprises a large number of specimens with a variety of external malformations, and (3) for most specimens there are clinical and epidemiological data from the mothers and the pregnancies concerned. Therefore, the specimens have been used extensively for morphological studies and could potentially be used for epidemiological analysis. Recently, several new approaches such as DNA extraction from formalin-fixed specimens or geometric morphometrics have been adopted and it is to be expected that further technological advances will facilitate new studies on the specimens of the Kyoto Collection as well as of other human embryo collections worldwide. Permanent preservation of the Kyoto Collection is, therefore, of paramount importance so that it will continue to contribute to human embryological studies in the future.

Clinicopathological study of de novo membranous nephropathy of 'stage 0' after kidney transplantation.

AIM: De novo membranous nephropathy (dnMN) contributes to graft failure, but the pathophysiology of the disease remains poorly understood. We defined cases exhibiting granular Immunoglobulin G (IgG) immunofluorescence staining but lacking dense deposits on electron microscopy as being of 'dnMN stage 0'; we studied the associated clinicopathological features. METHODS: We studied 4653 allograft biopsy specimens (from 1747 cases treated in the Department of Urology, Tokyo Women's Medical University) and found 42 cases of allograft membranous nephropathy, of which 28 (1.6%) were diagnosed as dnMN. Of these, five cases (0.06%) fulfilled the criteria for dnMN stage 0. RESULTS: All five cases were diagnosed based on biopsies indicating increased serum levels of creatinine. Proteinuria status varied from negative to 2+. The median period from transplantation to allograft biopsy was 4068 days. Four of the five cases exhibited suspicious antibody-mediated rejection together with dnMN. The glomerular capillaries of all cases were C4d-positive, as were the peritubular capillaries of three of the four ABO-compatible transplants. In terms of IgG subclass, IgG1 and IgG3 predominated in all cases, and phospholipase A2 receptor status (evaluated via immunoreactivity) was negative in all cases. We examined two cases by immunoelectron microscopy using anti-IgG and anti-C4d antibodies. We found subendothelial and intramembranous deposits expressing both IgG and C4d, corresponding to positivity in immunofluorescence analysis. CONCLUSION: We confirmed the existence of dnMN stage 0 by focusing on granular IgG immunofluorescence positivity.

Interlobular hyaline arteriopathy reflects severe arteriolopathy in renal allografts.

AIM: The present study was performed to examine the clinicopathological significance of hyaline deposits in the smooth muscle of the interlobular artery (interlobular hyaline arteriopathy [IHA]) in renal allografts. METHODS: Tissue specimens that included the interlobular artery from biopsies performed from January 2012 to December 2015, as well as specimens from biopsies performed ≥1 year after living kidney transplantation were analyzed. Biopsies of recipients with new-onset diabetes mellitus after transplantation were excluded, as well as those of recipients who had undergone transplantation because of diabetic nephropathy. Arteriolopathy was evaluated using the aah score determined by the Banff 2007 classification. RESULTS: In total, 51 specimens with IHA lesions were identified among 381 biopsies obtained from 243 recipients performed ≥1 year after kidney transplantation. Among these 51 biopsies, 18 specimens had a score of aah3, 29 had a score of aah2, and four had a score of aah1. The incidence of IHA lesions was 3.6% at ≥1 to <4 years, 18.5% at ≥4 to <8 years, and 54.1% at ≥8 years. Older kidney grafts exhibited more IHA lesions. Among the biopsy specimens obtained ≥8 years after transplantation, no significant differences in the recipient or donor age, duration after transplantation, or prevalence of hypertension were observed between the IHA and non-IHA groups. The aah scores were significantly higher in the IHA group ≥8 years after transplantation as determined by the mean score test (P < 0.01). CONCLUSION: IHA in renal allografts is associated with severe arteriolopathy.

Predominant but silent C1q deposits in mesangium on transplanted kidneys - long-term observational study.

BACKGROUND: C1q nephropathy (C1qN) was first described as glomerular disease characterized by predominant meangial C1q deposits in patients with proteinuria and no evidence of systemic lupus erythematosus. Several studies, however, revealed the clinical heterogeneity of C1qN, showing some cases with normal urinalysis. To confirm the existence of cases with predominant mesangial C1q deposits and negative or mild proteinuria and/or hematuria, we investigated renal graft biopsy specimens showing negative to mild proteinuria (less than or equal to 1+ by dip stick test) and/or hematuria. METHODS: Eligible participants were kidney transplant cases who corresponded to the criteria for C1qN and were followed more than 10 years. Their medical records were reviewed to determine the age at detection of predominant mesangial C1q deposits, gender, original renal disease and reason for renal graft biopsy, blood pressure, degree of proteinuria and hematuria, and serum creatinine levels. RESULTS: From 414 cases in adults and children, five pediatric patients (the male to female ratio, 1:1.5) were eligible. At the time when predominant mesangial C1q deposits were detected, 2 cases presented with mild proteinuria without hematuria, but the other 3 cases showed normal urinalysis. Light microscopy revealed minor glomerular abnormality in all the cases. Immunofluorescent study showed predominant mesangial C1q deposits with IgG, IgM and C3 in all cases. All selected specimens presented electron dense-depos in the mesangium. Ten years later from the detection, 2 cases continued to be normal urinalysis and 3 cases had mild proteinuria without hematuria. During this follow-up period, no cases presented with persistent proteinuria and/or hematuria greater than or equal to 2+ by dip stick test. And no cases developed systemic lupus erythematosus. Follow-up renal graft biopsies were performed once in 2 cases 8 years later from the detection. They showed minor glomerular abnormalities. C1q deposit disappeared in one case. In another case, immunofluorescent study was not examined. CONCLUSIONS: This long-term observational study on transplanted kidneys confirms the existence of cases with predominant but silent C1q deposits in the mesangium who have negative or mild proteinuria.

Maternally inherited diabetes and deafness complicated by mesangial galactose-deficient IgA1 deposits: a case report.

BACKGROUND: Maternally inherited diabetes and deafness (MIDD), a mitochondrial genetic disorder, typically affects the kidneys and results in end-stage renal disease. Early diagnosis of MIDD is challenging when renal manifestations precede other key clinical features such as diabetes and deafness and/or when the disease is complicated by other renal pathologies. CASE PRESENTATION: Here, we present the case of a 33-year-old Japanese woman who had initially been diagnosed with IgA nephropathy but was found to have MIDD 6 years later. Two renal biopsies were conducted six years apart. While assessment of the first biopsy specimen with the monoclonal antibody (KM55) revealed mesangial IgA deposits (containing the galactose-deficient IgA1 variant [Gd-IgA1]), examination of the second specimen showed no mesangial IgA deposits and newly-developed glomerular global scleroses and tubular damage. Granular swollen epithelial cells (GSECs), characterised by abnormal mitochondria, were observed among the tubules and collecting ducts in both biopsy specimens. Mitochondrial DNA analysis revealed an m.3243A > G mutation. CONCLUSIONS: We rediscovered the usefulness of GSECs as a pathologically distinctive feature of mitochondrial nephropathy and reviewed the literature regarding MIDD complicated by mesangial IgA deposition. Furthermore, we demonstrate that the mesangial IgA deposits in this patient consisted of the galactose-deficient IgA1 variant. The monoclonal antibody (KM55) might be a useful tool to distinguish IgAN from latent IgA deposits.

Quantitation of nasal development in the early prenatal period using geometric morphometrics and MRI: a new insight into the critical period of Binder phenotype.

OBJECTIVES: Disturbance of the development of the nasal septum in the early prenatal period causes congenital facial anomalies characterized by a flat nose and defects of the anterior nasal spine (ANS), such as Binder phenotype. The present research aimed to assess the development of the nasal septum and the ANS with growth in the early prenatal period. METHODS: Magnetic resonance images were obtained from 56 specimens. Mid-sagittal images were analyzed by using geometric morphometrics for the development of the nasal septum, and angle analysis was performed for the development of the ANS. Additionally, we calculated and visualized the ontogenetic allometry of the nasal septum. RESULTS: Our results showed that the nasal septum changed shape in the anteroposterior direction in smaller specimens, while it maintained an almost isometric shape in larger specimens. Furthermore, mathematical evidence revealed that the maturation periods of the shapes of the ANS and the nasal septum were around 12 and 14 weeks of gestation, respectively. CONCLUSION: The anteroposterior development of the nasal septum is specific until 14 weeks of gestation, and it is important for nasal protrusion and the development of the ANS. Therefore, the disturbance of such development could induce low nasal deformity, including Binder phenotype. © 2017 John Wiley & Sons, Ltd.

Estimation of the number of histological diagnosis for IgG4-related kidney disease referred to the data obtained from the Japan Renal Biopsy Registry (J-RBR) questionnaire and cases reported in the Japanese Society of Nephrology Meetings.

BACKGROUND: More than 2 years have passed since the proposal of the diagnostic criteria for IgG4-related kidney disease (IgG4-RKD). The aim of this study was to estimate the number of histological diagnosis for IgG4-RKD throughout Japan and to clarify the regional distribution of the development of this disease. METHODS: A questionnaire was supplied to 140 research facilities registered in the Japan Renal Biopsy Registry (J-RBR). The items of the questionnaire were the total number of renal biopsies performed and the number of cases diagnosed as IgG4-RKD in 2012 and 2013 at each facility. Age, sex, and diagnosis category were also included for the IgG4-RKD cases. The geographic distribution of the disease development was evaluated using clinical case reports presented at the Eastern/Western regional meeting of the Japanese Society of Nephrology during the 15 years following 2001. RESULTS: Forty-seven facilities completed the questionnaire, resulting in a collection rate of 34 %. The total numbers of renal biopsies in 2012 and 2013 were 3387 and 3591, respectively. Forty-seven of these cases (24 in 2012 and 23 in 2013) were diagnosed as IgG4-RKD. The frequency of development of IgG4-RKD per one million over 40-year-old individuals during these 15 years varied between 0.9 and 3.1, depending on Japanese geographic region of Japan. CONCLUSION: The results of the present survey indicate that the number of diagnosis for IgG4-RKD is approximately 130 cases per year throughout Japan, and no regional differences in disease frequency appear to exist.

Improvements in Out-of-Hospital Cardiac Arrest Survival from 1998 to 2013.

OBJECTIVES: Out-of-hospital cardiac arrest (OHCA) remains a major public health burden. Aggregate OHCA survival to hospital discharge has reportedly remained unchanged at 7.6% for almost 30 years from 1970 to 2008. We examined the trends in adult OHCA survival over a 16-year period from 1998 to 2013 within a single EMS agency. METHODS: Observational cohort study of adult OHCA patients treated by Tualatin Valley Fire & Rescue (TVF&R) from 1998 to 2013. This is an ALS first response fire agency that maintains an active Utstein style cardiac arrest registry and serves a population of approximately 450,000 in 9 incorporated cities in Oregon. Primary outcomes were survival to hospital discharge in all patients and in the subgroup with witnessed ventricular fibrillation/pulseless ventricular tachycardia (VF/VT). The impact of key covariates on survival was assessed using univariate logistic regression. These included patient factors (age and sex), event factors (location of arrest, witnessed status, and first recorded cardiac arrest rhythm), and EMS system factors (response time interval, bystander CPR, and non-EMS AED shock). We used multivariate logistic regression to examine the impact of year increment on survival after multiple imputation for missing data. Sensitivity analysis was performed with complete cases. RESULTS: During the study period, 2,528 adult OHCA had attempted field resuscitation. The survival rate for treated cases increased from 6.7% to 18.2%, with witnessed VF/VT cases increasing from 14.3% to 31.4% from 1998 to 2013. Univariate analysis showed that younger age, male sex, public location of arrest, bystander or EMS witnessed event, initial rhythm of pulseless electrical activity (PEA) or VF/VT, bystander CPR, non-EMS AED shock, and a shorter EMS response time were independently associated with survival. After adjustment for covariates, the odds of survival increased by 9% (OR 1.09, 95%CI: 1.05-1.12) per year in all treated cases, and by 6% (OR 1.06, 95% 1.01-1.10) per year in witnessed VF/VT subgroups. Findings remained consistent on sensitivity analysis. CONCLUSIONS: Overall survival from treated OHCA has increased over the last 16 years in this community. These survival increases demonstrate that OHCA is a treatable condition that warrants further investigation and investment of resources.

Unique proximal tubular cell injury and the development of acute kidney injury in adult patients with minimal change nephrotic syndrome.

BACKGROUND: Adult patients with minimal change nephrotic syndrome (MCNS) are often associated with acute kidney injury (AKI). To assess the mechanisms of AKI, we examined whether tubular cell injuries unique to MCNS patients exist. METHODS: We performed a retrospective analysis of clinical data and tubular cell changes using the immunohistochemical expression of vimentin as a marker of tubular injury and dedifferentiation at kidney biopsy in 37 adult MCNS patients. AKI was defined by the criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI. RESULTS: Thirteen patients (35.1%) were designated with AKI at kidney biopsy. No significant differences in age, history of hypertension, chronic kidney disease, diuretics use, proteinuria, and serum albumin were noted between the AKI and non-AKI groups. Urinary N-acetyl-ß-D-glucosaminidase (uNAG) and urinary alpha1-microglobulin (uA1MG) as markers of tubular injury were increased in both groups, but the levels were significantly increased in the AKI group compared with the non-AKI group. The incidence of vimentin-positive tubules was comparable between AKI (84.6%) and non-AKI (58.3%) groups, but vimentin-positive tubular area per interstitial area was significantly increased in the AKI group (19.8%) compared with the non-AKI group (6.8%) (p = 0.011). Vimentin-positive injured tubules with tubular simplification (loss of brush-border of the proximal tubule/dilated tubule with flattening of tubular epithelium) were observed in the vicinity of glomeruli in both groups, suggesting that the proximal convoluted tubules were specifically injured. Two patients exhibited relatively severe tubular injuries with vimentin positivity and required dialysis within 2 weeks after kidney biopsy. The percentage of the vimentin-positive tubular area was positively correlated with uNAG but not with uA1MG in the non-AKI group. CONCLUSIONS: Proximal tubular injuries with increased uNAG exist in MCNS patients without renal dysfunction and were more severe in the AKI group than they were in the non-AKI group. The unique tubular injuries probably due to massive proteinuria might be a predisposing factor for the development of severe AKI in adult MCNS patients.