Severe Leptospirosis with Acute Kidney Injury - A Case Description and Literature Review.

INTRODUCTION: Leptospirosis is a globally transmitted zoonotic disease caused by Leptospira spp., a highly mobile, obligate aerobic, spiral-shaped bacteria. Described first by Adolf Weil in 1886, leptospirosis in Germany is rare, leading to a delayed diagnosis due to diverse symptoms. Most cases are mild, but severe forms, like Weil's disease, cause life-threatening complications such as fever, jaundice, hemoptysis, and acute kidney injury (AKI). The aim of this work is to provide a literature review of leptospirosis with renal manifestation based on a case report. CASE PRESENTATION: We report the case of an 81-year-old male patient with initially unclear oliguric AKI, bilateral pulmonary infiltrates, and jaundice. After excluding common AKI causes, the expanded patient history suggested possible rat contact in his chicken coop. Finally, we serologically identified an infection with Leptospira spp. by positive IgM, proving that the illness was compatible with classical Weil`s disease. The patient underwent temporary hemodialysis and antibiotic treatment with intravenous penicillin G for 2 weeks. Under therapy, the AKI, hyperbilirubinemia, and clinical condition of the patient improved. The patient was discharged after 2 weeks. In the following controls, slightly impaired kidney function was observed, indicating a progress of his chronic kidney disease (CKD). CONCLUSION: Although leptospirosis is rare, there are some cases with a fulminant course. Impairment of renal function often correlates with severity of the disease requiring antibiotic treatment. In some cases, AKI progresses to CKD demonstrating the need to raise awareness for leptospirosis.

Target Values for 25-Hydroxy and 1,25-Dihydroxy Vitamin D Based on Their Associations with Inflammation and Calcium-Phosphate Metabolism.

Target values for 25-hydroxy vitamin D and 1,25(OH)2D or 1,25-dihydroxy vitamin D remain a topic of debate among clinicians. We analysed data collected from December 2012 to April 2020 from two cohorts. Cohort A, comprising 455,062 subjects, was used to investigate the relationship between inflammatory indicators (white blood cell [WBC] count and C-reactive protein [CRP]) and 25(OH)D/1,25(OH)2D. Cohort B, including 47,778 subjects, was used to investigate the connection between 25(OH)D/1,25(OH)2D and mineral metabolism markers (phosphate, calcium, and intact parathyroid hormone [iPTH]). Quadratic models fit best for all tested correlations, revealing U-shaped relationships between inflammatory indicators and 25(OH)D and 1,25(OH)2D. Minimal CRP and WBC counts were observed at 1,25(OH)2D levels of 60 pg/mL and at 25(OH)D levels of 32 ng/mL, as well as of 42 ng/mL, respectively. iPTH correlated inversely with both 1,25(OH)2D and 25(OH)D, while phosphate as well as calcium levels positively correlated with both vitamin D forms. Calcium-phosphate product increased sharply when 25(OH)D was more than 50 ng/mL, indicating a possible risk for vascular calcification. Multiple regression analyses confirmed that these correlations were independent of confounders. This study suggests target values for 25(OH)D between 30-50 ng/mL and for 1,25(OH)2D between 50-70 pg/mL, based particularly on their associations with inflammation but also with mineral metabolism markers. These findings contribute to the ongoing discussion around ideal levels of vitamin D but require support from independent studies with data on clinical endpoints.

Post-COVID-19 complement-mediated TMA: A case report.

Systemic COVID-19 disease is associated with a variety of organ involvement in infected patients. A rarely reported complication is the induction of complement-mediated thrombotic microangiopathy (TMA). TMA is an extremely rare pathological condition that results in thrombosis in capillaries and small arterioles, due to an endothelial injury. It is often combined with thrombocytopenia, Coombs-negative hemolytic anemia, and end-organ damage. This case involves a patient who was admitted to our hospital for the purpose of diagnosis and treatment of acute kidney injury (AKIN 3) with severe proteinuria after a preceding SARS-CoV-2 infection. A 77-year-old male patient had COVID-19 pneumonia in January 2021 with the need of high-flow oxygen therapy in the intensive care unit. In March 2021, he was hospitalized again due to elevated serum creatinine levels and proteinuria. The patient exhibited normal vital parameters. A renal biopsy showed severe TMA. A diagnosis of COVID-19-associated TMA was made, and treatment with high-dose glucocorticoid therapy and plasma exchange was initiated. Additionally, therapy with eculizumab was established. Unfortunately, the kidney failure was initially progressive, so that hemodialysis (HD) was temporarily necessary. In May 2021, kidney function recovered to an estimated glomerular filtration rate of ~ 30 mL/min/1.73m2 corresponding to chronic kidney disease stage 3bA3 - 4A3. COVID-19-associated TMA is an extremely rare disease. TMA may be a possible long-term complication with the risk of end-stage renal disease if not properly diagnosed and treated.

Periostin Predicts All-Cause Mortality in Male but Not Female End-Stage Renal Disease Patients on Hemodialysis.

INTRODUCTION: Periostin is a matricellular protein. Elevated serum concentrations of periostin have been reported in patients with various cardiovascular diseases, including heart failure. Patients with end-stage renal disease have a substantially increased risk for cardiovascular diseases. However, there is a lack of clinical studies to clarify the prognostic significance of systemic periostin on all-cause mortality in patients with end-stage renal disease on hemodialysis. METHODS: 313 stable end-stage renal disease patients were recruited and followed for 5 years concerning all-cause mortality. At baseline, we collected blood samples and clinical data. Serum periostin concentrations were measured using a certified ELISA. RESULTS: The optimal cut-off value for serum periostin regarding all-cause mortality, calculated through receiver operating characteristic analysis, was 777.5 pmol/L. Kaplan-Meier survival analysis using this cut-off value demonstrated that higher periostin concentrations are linked to higher all-cause mortality (log-rank test: p = 0.002). Subgroup analysis revealed that serum periostin concentrations only affected all-cause mortality in male but not in female patients (p = 0.002 in male patients and p = 0.474 in female patients). Multivariate Cox regression analyses, adjusted for confounding factors, likewise showed that elevated serum periostin concentrations were positively associated with all-cause mortality in male (p = 0.028) but not in female patients on hemodialysis (p = 0.313). CONCLUSION: Baseline serum periostin is an independent risk factor for all-cause mortality in male patients with chronic renal disease on hemodialysis.

Donor Conditioning and Organ Pre-Treatment Prior to Kidney Transplantation: Reappraisal of the Available Clinical Evidence.

Therapeutic measures aimed at optimising organ function prior to transplantation-whether by conditioning the donor after determination of brain death or by improving organ preservation after kidney removal-have the potential to enhance outcomes after transplantation. The particular advantage is that, unlike any optimised immunosuppressive therapy, a favourable effect can be achieved without side effects for the organ recipient. In recent years, several such measures have been tested in controlled clinical trials on large patient cohorts following kidney transplantation. Hypothermic pulsatile machine perfusion, in particular, has become the focus of interest, but interventions in the donor prior to organ removal, such as the administration of low-dose dopamine until the start of cold perfusion as an example of conditioning antioxidant therapy and therapeutic donor hypothermia in the intensive care unit after brain death confirmation, have also significantly reduced the frequency of dialysis after transplantation with far less effort and cost. With regard to benefits for graft survival, the database for all procedures is less clear and controversial. The aim of this review article is to re-evaluate the available clinical evidence from large multicentre controlled trials, which have also significantly influenced later meta-analyses, and to assess the significance for use in routine clinical practice.

Serum carnosinase 1, an early indicator for incident microalbuminuria in type 1 diabetes.

Aims: Carnosinase (CN1) polymorphisms have been linked to diabetic kidney disease (DKD), as CN1 degrades dipeptides which scavenge oxidative metabolites and prevent the formation of advanced glycation end-products. In this work, we studied the association between serum CN1, the systemic redox status and long-term renal outcome in type 1 diabetes. Methods: Serum CN1 was measured in a prospective type 1 diabetes cohort (n = 218) with a 16-year follow-up. A total of 218 patients treated at the Diabetes Outpatient Clinic of the Weezenlanden Hospital (nowadays Isala Hospital, Zwolle, The Netherlands) were included in this analysis. We assessed whether serum CN1 was associated with renal function and development of DKD as well as other diabetic complications. Results: At baseline, age, systemic redox status and N-terminal pro brain-natriuretic peptide (NT-proBNP) were associated with serum CN1 concentration (p < 0.05). During follow-up, CN1 concentration in the middle tertile was associated with less incident microalbuminuria (odds ratio = 0.194, 95% C.I.: 0.049-0.772, p = 0.02) after adjustment for age, systemic redox status, NT-proBNP and sex. Discussion: Serum CN1 could predict incident microalbuminuria and may be used as a novel parameter to identify patients at risk for DKD.

Long-Term Renal Function with Cardiac Contractility Modulation Therapy.

INTRODUCTION: Cardiac implantable electrical devices are able to affect kidney function through hemodynamic improvements. The cardiac contractility modulation (CCM) is a device-based therapy option for patients with symptomatic chronic heart failure (HF) despite optimized medical treatment. The long-term cardiorenal interactions for CCM treated patients are yet to be described. METHODS: CCM recipients (n = 187) from the Mannheim Cardiac Contractility Modulation Observational Study (MAINTAINED) were evaluated in the long-term (up to 60 months) for changes in serum creatinine, estimated glomerular filtration rate (eGFR), other surrogate markers of kidney function, and the chronic kidney disease (CKD) stage distribution. With regard to kidney function at baseline, the patients were furthermore grouped to either advanced CKD (aCKD, CKD stage ≥3, eGFR≤59 mL/min/1.73 m2, n = 107) or preserved kidney function and mild CKD (pCKD, CKD stages 1-2, eGFR≥60 mL/min/1.73 m2, n = 80). The groups were compared for differences regarding kidney function, New York Heart Association classification (NYHA), biventricular systolic function, HF hospitalizations and other parameters in the long-term (60 months). RESULTS: CKD stage distribution remained stable during the entire follow-up (p = 0.65). An increase in serum creatinine (1.47 ± 1 vs. 1.6±1 mg/dL) with a corresponding decline of eGFR (58.2 ± 23.4 vs. 54.2 ± 24.4 mL/min/1.73 m2, both p < 0.05) were seen after 60 months but not before for the total cohort, which was only significant in pCKD patients in terms of group comparison. Mean survival (54.3 ± 1.3 vs. 55.3 ± 1.2 months, p = 0.53) was comparable in both groups. Improvements in NYHA (3.11 ± 0.46 vs. 2.94 ± 0.41-2.28 ± 0.8 vs. 1.94 ± 0.6) and LVEF (24.8 ± 7.1 vs. 22.9 ± 6.6-31.1 ± 11.4 vs. 35.5 ± 11.1%) were likewise similar after 60 months (both p < 0.05). The aCKD patients suffered from more HF hospitalizations and ventricular tachycardias during the entire follow-up period (both p < 0.05). CONCLUSIONS: The kidney function parameters and CKD stage distribution might remain stable in CCM treated HF patients in the long-term, who experience improvements in LVEF and functional status, regardless of their kidney function before. An impaired kidney function might be associated with further cardiovascular comorbidities and more advanced HF before CCM, and could be an additional risk factor of HF complications afterward.

Diagnostic accuracy of Afirma gene expression classifier, Afirma gene sequencing classifier, ThyroSeq v2 and ThyroSeq v3 for indeterminate (Bethesda III and IV) thyroid nodules: a meta-analysis.

Objective: The management of thyroid nodules with indeterminate cytology (ITN) is still a challenge. To evaluate the performance of commercial molecular tests for ITN, we performed this comprehensive meta-analysis. Methods: We performed an electronic search using PubMed/Medline, Embase, and the Cochrane Library. Studies assessing the diagnostic accuracy of Afirma gene expression classifier (GEC), Afirma gene sequencing classifier (GSC), ThyroSeq v2 (TSv2), or ThyroSeq v3 (TSv3) in patients with ITN (only Bethesda category III or IV) were selected; Statistical analyses were performed by using Stata. Results: Seventy-one samples (GEC, n = 38; GSC, n = 16; TSv2, n = 9; TSv3, n = 8) in 53 studies, involving 6490 fine needle aspirations (FNAs) with ITN cytology with molecular diagnostics (GEC, GSC, TSv2, or TSv3), were included in the study. The meta-analysis showed the following pooled estimates: sensitivity 0.95 (95% CI: 0.94-0.97), specificity 0.35 (0.28-0.43), positive likelihood ratio (LR+) 1.5 (1.3-1.6), and negative likelihood ratio (LR-) 0.13 (0.09-0.19), with the best performance for TSv3 (area under the ROC curve 0.95 (0.93-0.96), followed by TSv2 (0.90 (0.87-0.92)), GSC (0.86 (0.82-0.88)), and GEC (0.82 (0.78-0.85)); the best rule-out property was observed for GSC (LR-, 0.07 (0.02-0.19)), followed by TSv3 (0.11 (0.05-0.24)) and GEC (0.16 (0.10-0.28), and the best rule-in was observed for TSv2 (LR+, 2,9 (1.4-4.6)), followed by GSC (1.9 (1.6-2.4)). A meta-regression analysis revealed that study design, Bethesda category, and type of molecular test were independent factors. Conclusion: We showed that in patients with ITN, TSv3 has the best molecular diagnostic performance, followed by TSv2, GSC, and GEC. As regards rule-out malignancy, GSC, and rule-in, TSV2 is superior to other tests.

Inverse association of prepregnancy systolic blood pressure and live birth rate in normotensive women undergoing in vitro fertilization/intracytoplasmic sperm injection.

OBJECTIVE: To explore whether maternal baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) affect pregnancy outcomes particularly in normotensive women (SBP, 90-139 mm Hg; DBP, 60-89 mm Hg) and hypertensive women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective cohort study. SETTING: Maximum care hospital for reproductive medicine. PATIENT(S): This study included 73,462 patients who underwent IVF/ICSI at the Reproductive and Genetic Hospital of CITIC-Xiangya between January 1, 2016, and November 30, 2020, selected on the basis of pre-established criteria. Analysis was limited to the first transfer cycle of the first stimulation cycle. INTERVENTION: Baseline SBP and DBP. MAIN OUTCOME MEASURE(S): The primary outcome focused on the live birth rate (LBR), with the secondary outcomes including clinical pregnancy rate, ectopic pregnancy rate, first-trimester miscarriage rate, second- or third-trimester fetal loss, and delivery/neonatal/maternal outcomes. Analytic methods included Poisson regression, linear regression, linear mixed-effect model, and restricted cubic spline analysis as appropriate. RESULT(S): For normotensive women, a 10-mm Hg increase in SBP was associated with an adjusted relative risk of 0.988 (95% confidence interval, 0.981-0.995) for live birth likelihood. However, DBP was not significantly associated with LBR after adjustments. The secondary outcomes indicated that increases in SBP and DBP were associated with higher risks of first-trimester miscarriage, gestational diabetes mellitus, and gestational hypertension in the normotensive subset. Sensitivity analyses confirmed these associations between SBP/DBP and LBR, consistent with the main findings even under stricter guidelines and after adjusting for multiple confounders. Subgroup analyses showed variation in the impact of blood pressure on LBR across different demographics and conditions. Consistent with earlier studies on blood pressure and birth outcomes, we found a 10-mm Hg increase in SBP was associated with a 5.4% (adjusted relative risk per 10 mm Hg, 0.946; 95% confidence interval, 0.907-0.986) reduction in LBR in the hypertensive subgroup. CONCLUSION(S): Systolic blood pressure impacted LBR outcomes in normotensive women who underwent IVF/ICSI, which suggests the need for reconsidering blood pressure management guidelines for reproductive-age women, focusing on reproductive health in addition to cardiovascular risk.

Both partial inactivation as well as activation of NF-κB signaling lead to hypertension and chronic kidney disease.

BACKGROUND AND HYPOTHESIS: Activation of NF-κB-signalling is key in the pathogenesis of chronic kidney diseases (CKD). However, a certain level of NF-κB activity is necessary to enable tissue repair. METHODS: To investigate the relationship between activated and inactivated NF-κB signaling on the pathogenesis of CKD using mouse models of NF-κB partial inactivation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into alanine) and activation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into serine). RESULTS: The density of CD3, CD8, CD68 positive cells, as well as the expression of IL-6, TRAF-1, and NAF-1 in the kidney tissues of NF-κBC59A mice were reduced, whereas an opposing pattern was observed in the NF-κBC59S mice. Blood pressure, kidney fibrosis (analyzed by PAS-, Masson trichrome-, and Sirius-Red-staining as well as α-SMA immunofluorescence), serum creatinine and urinary albumin-to-creatinine-ratio are markedly increased in NF-κB activated and inactivated mice compared to controls. Transmission electron microscopy indicated that the glomerular basement membrane was thicker in both NF-κBC59A and NF-κBC59S mice compared to wild-type mice. CONCLUSIONS: Using mice models with partially activated and inactivated NF-κB pathways suggests that there is an apparently U-shaped relationship between blood pressure, kidney function as well as morphology and the activation of the NF-κB pathway. A certain optimal activity of the NF-κB pathway seems to be important to maintain optimal kidney function and morphology.

Renal and cardiac effects of the PDE9 inhibitor BAY 73-6691 in 5/6 nephrectomized rats.

It has been suggested that the novel selective phosphodiesterase 9 (PDE9) inhibitor may improve cardiac and renal function by blocking 3',5'-cyclic guanosine monophosphate (cGMP) degradation. 5/6 nephrectomized (5/6Nx) rats were used to investigate the effects of the PDE9 inhibitor (BAY 73-6691) on the heart and kidney. Two doses of BAY 73-6691 (1 mg/kg/day and 5 mg/kg/day) were given for 95 days. The 5/6Nx rats developed albuminuria, a decrease in serum creatinine clearance (Ccr), and elevated serum troponin T levels. Echocardiographic data showed that 5/6 nephrectomy resulted in increased fractional shortening (FS), stroke volume (SV), and left ventricular ejection fraction (EF). However, 95 days of PDE9 inhibitor treatment did not improve any cardiac and renal functional parameter. Histopathologically, 5/6 nephrectomy resulted in severe kidney and heart damage, such as renal interstitial fibrosis, glomerulosclerosis, and enlarged cardiomyocytes. Telmisartan attenuated renal interstitial fibrosis and glomerulosclerosis as well as improved cardiomyocyte size. However, except for cardiomyocyte size and renal perivascular fibrosis, BAY 73-6691 had no effect on other cardiac and renal histologic parameters. Pathway enrichment analysis using RNA sequencing data of kidney and heart tissue identified chronic kidney disease pathways, such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, complement and coagulation cascades, and nuclear factor kappa B (NF-κB) signaling pathway. PDE9i did not affect any of these disease-related pathways. Two dosages of the PDE9 inhibitor BAY 73-6691 known to be effective in other rat models have only limited cardio-renal protective effects in 5/6 nephrectomized rats.

Only bioactive forms of PTH (n-oxPTH and Met18(ox)-PTH) inhibit synthesis of sclerostin - evidence from in vitro and human studies.

Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized. PTH oxidized at Met18 (Met18(ox)-PTH) continues to be bioactive, whereas PTH oxidized at Met8 (Met8(ox)-PTH) or PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-PTH) has minor bioactivity. How non-oxidized PTH (n-oxPTH) and oxidized forms of PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-PTH, Met18(ox)-PTH, and Met8, Met18(di-ox)-PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive PTH forms such as n-oxPTH and Met18(ox)-PTH, inhibit SOST synthesis.

Clinical and genetic diagnosis of familial hypercholesterolaemia in patients undergoing coronary angiography: the Ludwigshafen Risk and Cardiovascular Health Study.

AIMS: To investigate the prevalence of familial hypercholesterolaemia (FH) and compare the performance of clinical criteria and genetic testing in patients undergoing coronary angiography. METHODS: The prevalence of FH was determined with the Dutch Lipid Clinical Network (DLCN), US-MEDPED, Simon Broome (SB) criteria, the 'Familial Hypercholesterolaemia Case Ascertainment Tool' (FAMCAT), and a clinical algorithm. Genetic screening was conducted with a custom array from Affymetrix (CARRENAL array) harboring 944 FH mutations. RESULTS: The study cohort consisted of 3267 patients (78.6% with coronary artery disease [CAD]). FH was diagnosed in 2.8%, 2.2%, 3.9%, and 7.9% using the DLCN, US-MEDPED, SB criteria, and the FAMCAT. The clinical algorithm identified the same patients as the SB criteria. Pathogenic FH mutations were found in 1.2% (1.2% in patients with CAD, 1.0% in patients without CAD). FH was more frequently diagnosed in younger patients. With genetic testing as reference, the clinical criteria achieved areas under the ROC curve (AUCs) in the range of 0.56-0.68. Using only LDL-C corrected for statin intake, an AUC of 0.68 was achieved. CONCLUSION: FH is up to fourfold more prevalent in patients undergoing coronary angiography than in contemporary cohorts representing the general population. Different clinical criteria yield substantially different diagnosis rates, overestimating the prevalence of FH compared to genetic testing. LDL-C testing alone may be sufficient to raise the suspicion of FH, which then needs to be corroborated by genetic testing.

Rescue Allocation Modes in Eurotransplant Kidney Transplantation: Recipient Oriented Extended Allocation Versus Competitive Rescue Allocation-A Retrospective Multicenter Outcome Analysis.

BACKGROUND: Whenever the kidney standard allocation (SA) algorithms according to the Eurotransplant (ET) Kidney Allocation System or the Eurotransplant Senior Program fail, rescue allocation (RA) is initiated. There are 2 procedurally different modes of RA: recipient oriented extended allocation (REAL) and competitive rescue allocation (CRA). The objective of this study was to evaluate the association of patient survival and graft failure with RA mode and whether or not it varied across the different ET countries. METHODS: The ET database was retrospectively analyzed for donor and recipient clinical and demographic characteristics in association with graft outcomes of deceased donor renal transplantation (DDRT) across all ET countries and centers from 2014 to 2021 using Cox proportional hazards methods. RESULTS: Seventeen thousand six hundred seventy-nine renal transplantations were included (SA 15 658 [89%], REAL 860 [4.9%], and CRA 1161 [6.6%]). In CRA, donors were older, cold ischemia times were longer, and HLA matches were worse in comparison with REAL and especially SA. Multivariable analyses showed comparable graft and recipient survival between SA and REAL; however, CRA was associated with shorter graft survival. Germany performed 76% of all DDRTs after REAL and CRA and the latter mode reduced waiting times by up to 2.9 y. CONCLUSIONS: REAL and CRA are used differently in the ET countries according to national donor rates. Both RA schemes optimize graft utilization, lead to acceptable outcomes, and help to stabilize national DDRT programs, especially in Germany.

Hyperfiltration can be detected by transcutaneous assessment of glomerular filtration rate in diabetic obese mice.

We addressed if hyperfiltration can be assessed transcutaneously in male diabetic obese mice (BTBRob/ob) at 12 and 24 wk and how this relates to glomerular parameters indicative for hyperfiltration. Transcutaneous assessment of FITC-Sinistrin clearance [transcutaneous assessment of glomerular filtration rate (tGFR)] was compared against classical plasma clearance. Kidney from SV620C-01-PEI perfused mice were harvested at 24 wk and processed for tissue clearing and classical histology. Perfusion patterns of glomerular capillaries, glomerular size, and vasodilation of the afferent arterioles were assessed. Although at 12 wk FITC-Sinistrin half-life (t1/2) for both tGFR and plasma clearance suggested hyperfiltration, this was not significant anymore at 24 wk. In kidneys of diabetic mice the diameter of the afferent arteriole was significantly larger and positively correlated with glomerular size. Glomerular perfusion pattern in these mice was heterogeneous ranging from non- to well-perfused glomeruli. Nonperfused glomerular areas displayed a strong periodic acid-Schiff's (PAS) positive staining. Collectively our data demonstrate that tGFR is a valid method to detect hyperfiltration. Hyperfiltration occurs early in BTBRob/ob mice and disappears with disease progression as a consequence of a reduced filtration surface. It remains to be assessed if tGFR is also a valid method in diabetic mice with severely compromised renal function.NEW & NOTEWORTHY tGFR measurement is a relatively new method to assess kidney function in conscious rodents, which can be repeated multiple times in the same animal to track the course of the disease and/or the effect of potential treatments. Since the literature was inconclusive on the suitability of this technique in obese mice, we validated it for the first time against classical plasma clearance in the commonly used BTBRob/ob mouse model.

The Degree of Prepregnancy Vitamin D Deficiency Is Not Associated With Gestational Diabetes in Women Undergoing ART.

Context: Gestational diabetes mellitus (GDM) is a common pregnancy complication, particularly in women undergoing assisted reproductive technology (ART). An association of GDM with vitamin D in women conceiving naturally has been described; however, studies have yielded heterogeneous results. Objective: To analyze the association between prepregnancy total and free vitamin D and GDM incidence in women undergoing ART. Methods: Post hoc analysis of a prospective study at the Reproductive and Genetic Hospital of CITIC-Xiangya in Changsha, China. Total and free vitamin D were measured 1 day before embryo transfer. The patients were screened for GDM using the oral glucose tolerance test. Results: A total of 1593 women were included in the study, among whom 256 (16.1%) developed GDM. According to international guidelines for total 25-hydroxyvitamin D [25(OH)D], 47 (2.9%) patients had sufficient (≥30 ng/mL) levels, while 696 (43.7%) were insufficient (20 to <30 ng/mL) and 850 (54.4%) were deficient (<20 ng/mL). Comparing GDM and non-GDM patients, there was no significant difference in total nor free vitamin D levels (P = .340 and .849). Similarly, analysis of GDM rates by quintiles of total and free 25(OH)D showed no significant association in one-way ANOVA (P = .831 and .799). Multivariate logistic regression, considering age, BMI, and fasting glucose, also did not show a significant influence of the 2 vitamin D forms on GDM incidence (P = .266 and .123 respectively). Conclusion: In this relatively vitamin D deficient/insufficient ART cohort, the degree of neither total nor free vitamin D deficiency before pregnancy was associated with the occurrence of GDM.

Blood Pressure and Mortality in the 4D Study.

INTRODUCTION: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) are risk factors for cardiovascular mortality (CVM). Pulse pressure (PP) is an easily available parameter of vascular stiffness, but its impact on CVM in chronic dialysis patients with diabetes is unclear. METHODS: Therefore, we have examined the predictive value of baseline, predialytic PP, SBP, DBP, and MAP in the German Diabetes and Dialysis (4D) study, a prospective, randomized, double-blind trial enrolling 1,255 patients with type 2 diabetes on hemodialysis in 178 German dialysis centers. RESULTS: Mean age was 66.3 years, mean blood pressure 146/76 mm Hg, mean time suffering from diabetes 18.1 years, and mean time on maintenance dialysis 8.3 months. Considered as continuous variables, PP, MAP, SBP, and DBP could not provide a significant mortality prediction for either cardiovascular or all-cause mortality. After dividing the cohort into corresponding tertiles, we also did not detect any significant mortality prediction for PP, SBP, DBP, or MAP, both for all-cause mortality and CVM after adjusting for age and sex. Nevertheless, when comparing the HR plots of the corresponding blood pressure parameters, a pronounced U-curve was seen for PP for both all-cause mortality and CVM, with the trough range being 70-80 mm Hg. DISCUSSION: In patients with end-stage renal disease and long-lasting diabetes mellitus predialytic blood pressure parameters at study entry are not predictive for mortality, presumably because there is a very high rate of competing mortality risk factors, resulting in overall very high rates of all-cause and CVM that may no longer be significantly modulated by blood pressure control.

Gene regulation for inflammation and inflammation resolution differs between umbilical arterial and venous endothelial cells.

Systemic inflammation affects the whole vasculature, yet whether arterial and venous endothelial cells differ in their abilities to mediate inflammation and to return to homeostasis after an inflammatory stimulus has not been addressed thoroughly. We assessed gene-expression profiles in isolated endothelial cells from human umbilical arteries (HUAEC) or veins (HUVEC) under basal conditions, after TNF-α stimulation and various time points after TNF-α removal to allow reinstatement of homeostasis. TNF-α regulates the expression of different sets of transcripts that are significantly changed only in HUAEC, only in HUVEC or changed in both. We identified three types of gene regulation, i.e. genes that were significantly regulated after 24 h of TNF-α stimulation but no longer when TNF-α was removed (homeostatic regulation), genes that maintained significantly regulated after TNF-α removal (not homeostatic regulation) and genes that were only significantly regulated when TNF-α was removed (post-regulation). HUAEC and HUVEC quantitatively differed in these types of gene regulation, with relatively more genes being post-regulated in HUAEC. In conclusion our data demonstrate that HUAEC and HUVEC respond intrinsically different to an inflammatory insult. Whether this holds true for all endothelial cells and its relevance for inflammatory insults in different organs during systemic inflammation warrants further studies.

Fibroblast growth factor 23 is associated with the development of gestational diabetes mellitus.

BACKGROUND: Besides its established impact on bone and mineral metabolism, it was suggested that fibroblast growth factor 23 (FGF23) might play an important role in the pathogenesis of type 2 diabetes. The impact of FGF23 on gestational diabetes mellitus (GDM), however, is not well understood. iFGF23 ELISAs measure the intact FGF23 molecule, whereas cFGF23 assays measure intact FGF23 as well as degradation products of FGF23. OBJECTIVES: The aim of this study is to compare the association of maternal and foetal cFGF23 and iFGF23 with GDM in a German birth cohort. METHODS: cFGF23 and iFGF23 were analysed in 826 random mother/child pairs from the Berlin Birth Cohort. RESULTS: Mothers who developed GDM had higher concentrations of iFGF-23 compared to mothers who did not suffer from GDM (19.73 vs. 13.23 pg/mL, p < 0.0001), but not higher concentrations of cFGF-23. Multivariant regression analyses showed that gestational diabetes is associated with iFGF23 independently of confounding factors such as age, BMI, ethnic background, family history of diabetes, smoking during pregnancy, and recurrent pregnancy loss. This, however, was only seen when using an iFGF23 ELISA measuring just the full length FGF23 and not in addition FGF23 fragments. No differences in both iFGF23 and cFGF23 concentrations between the GDM and non-GDM groups were detected in cord blood samples of the offspring. CONCLUSIONS: This study of a representative German birth cohort showed that maternal but not foetal iFGF23 is independently associated with GDM.