Metanalyses on metformin's role in pancreatic cancer suffer from severe bias and low data quality - An umbrella review.

AIMS: Discrepancies in the preclinical evidence, retrospective studies, and randomized trials evaluating metformin's role in pancreatic cancer are difficult to disentangle. We aimed to critically and systematically examine the quality and sources of heterogeneity between meta-analyses investigating the association between metformin intake and the prognosis of patients with pancreatic cancer. MATERIALS AND METHODS: We performed a literature search on PubMed, MEDLINE, Embase, and Scopus on October 31, 2021 to identify meta-analyses investigating the impact of metformin treatment on the prognosis of patients with pancreatic cancer. Meta-analyses quality was assessed using according to the AMSTAR 2 criteria. We assessed bias in individual studies included in the meta-analyses, with particular attention to immortal time bias and quality of reporting. RESULTS: Eleven meta-analyses describing 24 individual studies were included. All meta-analyses were rated low (n = 5) or critically low (n = 6) quality. Only 4 followed PRISMA reporting guidelines and only in 5 presented data were sufficient to replicate the analyses. Most meta-analyses combined results from clinical trials and retrospective studies (n = 6); patients with different cancer stages (resectable vs advanced) and from studies with different control group definitions. Immortal time bias was present and not accounted for in most (65.2%) of the individual retrospective studies; almost all (n = 9) meta-analyses failed to identify and correct for this source of bias. CONCLUSIONS: Meta-analyses describing the association of metformin use in patients with pancreatic cancer are plagued by various types of bias inherent in retrospective studies. The quality of evidence linking metformin to decreased pancreatic cancer mortality is generally low.

Testosterone Replacement Therapy in Chronic Kidney Disease Patients.

(Background) The aim of our study was to evaluate the efficacy and safety of testosterone replacement therapy (TRT) in men with chronic kidney disease and hypogonadism on conservative and hemodialysis treatment. (Methods) The studied population consisted of 38 men on hemodialysis (HD), 46 men with CKD stages II-IV (predialysis group, PreD) and 35 men without kidney disease who were similar in age to others (control group). Serum total testosterone level (TT) was measured, and free testosterone level (fT) was calculated. Hypogonadism criteria according to the EAU definition were fulfilled by 26 men on HD (68.4%) and by 24 men from the PreD group (52%). Testosterone replacement therapy (TRT) with testosterone enanthate in intramuscular injections every 3 weeks was applied in 15 men from HD and in 14 men from PreD. The safety of TRT was monitored by measuring PSA and overhydration. (Results) A significant rise of TT and fT was observed after 3 months of TRT, but no significant changes were observed after 6 and 12 months in the HD and PreD group. An intensity of clinical symptoms of hypogonadism measured by ADAM (androgen deficiency in the ageing male) questionnaire gradually decreased, and the intensity of erectile dysfunction measured by the IIEF-5 (international index of erectile functioning) questionnaire also decreased after 3, 6 and 12 months of TRT in the HD and PreD group. (Conclusions) The applied model of TRT is effective in the correction of clinical signs of hypogonadism without a significant risk of overhydration or PSA changes.

Anti-Xa Activity of Enoxaparin for Prevention of Venous Thromboembolism in Severe Nephrotic Syndrome-A Single Center Prospective Study.

Severe nephrotic syndrome (NS) is associated with high risk of venous thromboembolic events (VTE), as well as presumably altered heparin pharmacokinetics and pharmacodynamics. Although prophylactic anticoagulation is recommended, the optimal dose is not established. The aim of the study was to test two co-primary hypotheses: of reduced enoxaparin effectiveness and of the need for dose-adjustment in NS. Forty two nephrotic patients with serum albumin ≤2.5 g/dL were alternately assigned to a standard fixed-dose of enoxaparin (NS-FD: 40 mg/day) or ideal body weight (IBW)-based adjusted-dose (NS-AD: 1 mg/kg/day). Twenty one matched non-proteinuric individuals (C-FD) also received fixed-dose. Co-primary outcomes were: the achievement of low- and high-VTE risk threshold of antifactor-Xa activity (anti-FXa) defined as 0.2 IU/mL and 0.3 IU/mL, respectively. Low-VTE-risk threshold was achieved less often in NS-FD than C-FD group (91 vs. 62%, p = 0.024), while the high-VTE-risk threshold more often in NS-AD than in NS-FD group (90 vs. 38%, p < 0.001). Two VTE were observed in NS during 12 months of follow-up (incidence: 5.88%/year). In both cases anti-FXa were 0.3 IU/mL implying the use of anti-FXa >0.3 IU/mL as a target for dose-adjustment logistic regression models. We determined the optimal dose/IBW cut-off value at 0.8 mg/kg and further developed bivariate model (termed the DoAT model) including dose/IBW and antithrombin activity that improved the diagnostic accuracy (AUC 0.85 ± 0.06 vs. AUC 0.75 ± 0.08). Enoxaparin efficacy is reduced in severe NS and the dose should be adjusted to ideal body weight to achieve target anti-FXa activity.

Free testosterone levels and their association with body composition in women with chronic kidney disease.

Data concerning the influence of sex hormones on body composition in women with chronic kidney disease (CKD) is limited. AIM: The aim of our study was to define free testosterone levels and their association with body composition, biochemical markers of nutrition in females with CKD. MATERIALS AND METHODS: 47 women were included into the study. 13 females treated with hemodialysis formed the hemodialysis group (HD), 24 females with CKD stage IV/V (eGFR < 30 ml/min/1,73 m2) formed the predialysis group (PreD), and 10 females without kidney disease formed the control group (C). Lean tissue mass (LTM) and fat mass (Fat) were measured using bioimpedance spectroscopy. Free testosterone levels were assessed using ELISA (IBL International). Statistical analysis was performed using Statistica v 13.1. RESULTS: The median free testosterone (fT) levels were 0.7, 0.6, 0.85 pg/ml respectively for HD, PreD and C group. The median fT did not differ significantly between the groups (p=0.24). The mean LTM was 28.5 ±5.6, 27.3 ±4.9, 30.6 ±4.3 kg, mean Fat mass was 22.7 ±8.5, 31.3 ±9.8, 31.6 ±8.5 kg for the HD, PreD and C groups respectively. Positive correlations were observed between fT and LTM (r=0.306, p=0.035) in the whole study group. A negative correlation was observed between fT and age (r=-0.284) but was on the border of statistical significance (p=0.052). CONCLUSIONS: In women with advanced CKD, median testosterone levels did not differ significantly from those observed in women without kidney failure. Free testosterone levels were associated with the amount of muscle mass in the whole study population.

Serum Osteoprotegerin Is an Independent Marker of Metabolic Complications in Non-DialysisDependent Chronic Kidney Disease Patients.

BACKGROUND: Osteoprotegerin (OPG) belongs to the tumour necrosis factor superfamily and is known to accelerate endothelial dysfunction and vascular calcification. OPG concentrations are elevated in patients with chronic kidney disease. The aim of this study was to investigate the association between OPG levels and frequent complications of chronic kidney disease (CKD) such as anaemia, protein energy wasting (PEW), inflammation, overhydration, hyperglycaemia and hypertension. METHODS: One hundred non-dialysis-dependent men with CKD stage 3-5 were included in the study. Bioimpedance spectroscopy (BIS) was used to measure overhydration, fat amount and lean body mass. We also measured the serum concentrations of haemoglobin, albumin, total cholesterol, C-reactive protein (CRP), fibrinogen and glycated haemoglobin (HgbA1c), as well as blood pressure. RESULTS: We observed a significant, positive correlation between OPG and age, serum creatinine, CRP, fibrinogen, HgbA1c concentrations, systolic blood pressure and overhydration. Negative correlations were observed between OPG and glomerular filtration rate (eGFR), serum albumin concentrations and serum haemoglobin level. Logistic regression models revealed that OPG is an independent marker of metabolic complications such as anaemia, PEW, inflammation and poor renal prognosis (including overhydration, uncontrolled diabetes and hypertension) in the studied population. CONCLUSION: Our results suggest that OPG can be an independent marker of PEW, inflammation and vascular metabolic disturbances in patients with chronic kidney disease.

Giant Intrathoracic Mass in a Young Woman With Acute Kidney Injury.

CASE PRESENTATION: A 35-year-old woman without past medical history sought treatment for fatigue and dry cough of 3 weeks' duration. Basic laboratory tests revealed severe anemia. She had no history of bleeding, hemoptysis, dyspnea, or fever. The patient was admitted for RBC transfusion and more extensive diagnostics.

Impaired Kidney Function Associated with Increased Risk of Side Effects in Patients with Small Vessel Vasculitis Treated with Rituximab as an Induction Therapy.

Rituximab (RTX), a monoclonal antibody against the CD20 molecule, is used as an induction therapy in the treatment of small vessel vasculitis (SVV). The aim of the study was to evaluate the efficacy and safety of RTX induction therapy for refractory SVV. A retrospective analysis of 20 patients treated with RTX for active SVV (BVAS/WG ≥ 3) was performed to assess the remission rate and the drug-related severe adverse events 6 months after therapy. The mean age of the studied population was 49 ± 13 years (50% female), 90% of which were PR3-ANCA positive. Complete remission was achieved in 85% of patients, and partial remission was achieved in a further 10% within 6 months after RTX infusions. The remission rate was not influenced by kidney function. Adverse events such as infections (25%), a late onset of neutropenia (10%) and severe hypogammaglobulinemia (5%) were noted. The patients who developed adverse events were older (42 ± 11 vs. 57 ± 12 years; p = 0.014) and had a higher serum creatinine level (1.3 mg/dL vs. 3.35 mg/dL; p = 0.044). Patients with a glomerular filtration rate (eGFR) lower than 30 mL/min/1.73 m2 had a nine-fold higher risk of side effects (OR 9.0, 95%CI: 1.14-71.0). In conclusion, RTX was highly effective as an induction therapy in patients with SVV. Advanced kidney failure with an eGFR lower than 30 mL/min/1.73 m2 was one of the risk factors for the occurrence of side effects.

Advanced Chronic Kidney Disease is a Strong Predictor of Hypogonadism and is Associated with Decreased Lean Tissue Mass.

PURPOSE: In patients with chronic kidney disease (CKD), hypogonadism is more frequent than in the general population and its prevalence ranges between 40% and 60%. The aim of the study was to investigate the prevalence of hypogonadism and its association with kidney function, body composition, inflammatory markers and lipid disorders in patients with CKD. MATERIALS AND METHODS: The study population consisted of 112 men aged ≥40 years in different stages of CKD: 33 participants with eGFR ≥60 mL/min/1.73 m2, 27 men with eGFR 30-59 mL/min/1.73 m2, 17 predialysis patients with eGFR <30 mL/min/1.73 m2, and 35 men on hemodialysis therapy three times a week for more than 3 months (G5D stage). Total testosterone (TT) levels were measured and free testosterone (FT) levels were calculated. Body composition was assessed using bioimpedance spectroscopy (Body Composition Monitor, FMC). Statistical analysis was performed using Statistica version 13.1. RESULTS: CKD stage was a strong predictor of hypogonadism (providing an information value of 0.83). The weight of evidence technique allowed us to differentiate the high-risk group, which was a group of patients with advanced CKD, defined as eGFR <30 mL/min/1.73 m2. In this group, the likelihood of hypogonadism was 69.23%. Another significant predictor of hypogonadism was lean tissue index (LTI). TT and FT levels were significantly lower in the advanced CKD group in comparison to the control group, whereas prolactin, luteinizing hormone and C-reactive protein levels were significantly higher in the advanced CKD group. The LTI was significantly lower in advanced CKD and was positively correlated with TT and FT. CONCLUSION: Decreased eGFR and decreased LTI are predictors of hypogonadism associated with CKD. The study results suggest that hypogonadism screening should be carried out when eGFR deceases below 30 mL/min/1.73 m2.

Protein energy-wasting associated with nephrotic syndrome - the comparison of metabolic pattern in severe nephrosis to different stages of chronic kidney disease.

BACKGROUND: Nephrotic syndrome (NS) is associated with a hypercatabolic state expressed as an exacerbated degradation of muscle mass. However, the clinical significance of this phenomenon has not yet been investigated. The aim of the study was to evaluate the nutritional status of patients with severe NS (defined as nephrotic range proteinuria with hypoalbuminemia ≤2.5 g/dL) and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 in comparison to patients in different stages of chronic kidney disease (CKD). METHODS: Twenty men with severe NS (NS group) and 40 men without proteinuria similar in term of serum creatinine (control group) were included into the study. A retrospective cohort of 40 men with CKD stage G4 (PreD group) and 20 haemodialysis men (HD group) were added to the analysis after matching for age, height and weight using propensity score matching. The bioimpedance spectroscopy and biochemical nutritional markers were evaluated. RESULTS: Nephrotic patients had a significantly lower lean tissue mass (LTM; p = 0.035) and index (a quotient of LTM over height squared, LTI; p = 0.068), with an expected deficiency of LTM by 3.2 kg, and LTI by 0.9 kg/m2 when compared to the control group. A significant lean tissue deficit (defined as LTI below the lower limit of the reference range by 1.0 kg/m2) was observed in 12.5% of patients in the control group in comparison to 31.7% with advanced CKD (PreD+HD; p = 0.032) and 50% with NS (p = 0.003). NS group presented with higher phosphorus (p = 0.029), uric acid (p = 0.002) and blood urea (p = 0.049) than the control group. Blood urea was strongly negatively correlated with LTM in NS (r = - 0.64, p = 0.002). Nine nephrotic patients (45%) were identified as hypercatabolic based on severe hyperphosphatemia (> 5.0 mg/dL) and/or hyperuricemia (> 8.0 mg/dL), and were characterized by higher blood urea and lower prealbumin, as well as LTM lower by 5.6 kg than in less catabolic individuals. CONCLUSIONS: In term of lean tissue amount, NS group was more similar to advanced CKD than to the control group. We concluded that specific metabolic pattern with elevated phosphorus, uric acid and blood urea, and lean tissue deficiency may be defined as protein-energy wasting associated with nephrotic syndrome (neph-PEW).

Lean Tissue Index and Body Cell Mass Can Be Predictors of Low Free Testosterone Levels in Men on Hemodialysis.

OBJECTIVE: Testosterone deficiency is a common disorder among men treated with hemodialysis. The aim of our study was to evaluate the relationship between free testosterone levels and body composition, biochemical markers of nutritional status, and inflammation in men on hemodialysis. DESIGN: Prospective analysis of men treated with hemodialysis for more than 3 months in one hemodialysis center. SUBJECTS: A total of 56 men-41 men undergoing hemodialysis treatment thrice-weekly over a period of at least 3 months (HD group) and 15 men without kidney disease, with estimated glomerular filtration rate >60 mL/min/1.73 m2 (C group)-were included. Serum levels of free testosterone, creatinine, protein, albumin, prealbumin, high-sensitivity C-reactive protein, and interleukin 6 and body composition by bioimpedance spectroscopy, waist-to-hip ratio, and waist-to-height ratio were measured. INTERVENTION: None, observational study. MAIN OUTCOME MEASURE: Free testosterone level. RESULTS: The mean free testosterone level was significantly lower in the HD group than that in the C group and positively correlated with lean tissue index (LTI, r = 0.51, P = .001) and body cell mass (BCM, r = 0.57, P < .001). Significant, negative correlations were observed between free testosterone level and age (r = -0.4, P = .004) as well as fat tissue index (r = -0.36, P = .018). In a subgroup of men on hemodialysis who have low testosterone levels (<9.4 pg/mL), we observed a lower LTI and BCM and higher age, fat tissue index, and loginterleukin-6. In our receiver operating characteristic curve analysis, LTI and BCM were shown to be good predictors of a low testosterone level with cutoff points of 13.3 kg/m2 and 22.3 kg, respectively, meaning that men on hemodialysis with LTI <13.3 kg/m2 were 26 times more likely to have free testosterone levels below 9.4 pg/mL (odds ratio, 26.7; 95% confidence interval: 3.0-236.6). CONCLUSION: Low lean tissue mass and BCM can be predictors of low testosterone level.

[Above-standard proceeding in nephrotic syndrome - case report]. / Ponadstandardowe postepowanie w zespole nerczycowym - opis przypadku.

The nephrotic syndrome is characterized by the loss of many proteins, via the urinary system. It exceeds the bodies compensatory abilities and results in abnormalities in blood clotting system, particularly due to antithrombin deficiency. It significantly increases the risk of thromboembolic complications. A loss of erythropoietin and transferrin leads to anemia. Polycythemia is a rarely reported phenomenon. The case describes a 20-years old patient with massive nephrotic syndrome and polycythemia, complicated by a pulmonary embolism. The patient had a steroid-dependent submicroscopic glomerulonephritis with a severe episode of nephrotic syndrome associated with centralization of circulation, proteinuria 40.9 g/day, deep hypoproteinemia (albumin=1.2 g/dl), hyperlipidemia, hypercoagulable state (antithrombin activity 29%), polycythemia (Hb=21.1 g/dl, HTC=60%). Kidney function parameters were normal. We started the immunosupression (glycocorticosteroids i.v., continuated p.o. and cyclosporine A) and intensive symptomatic treatment. To reverse hypovolemia and polycythemia, 20% albumin solutions, intravenous infusions and diuretics were used. There was no effect. Due to intensive polycythemia the erythroapheresis procedure was performed. It resulted in normalization of the red blood cell count (Hb=13.4 g/dl, HCT=37%) and the improvement of blood circulation. To prevent the patient from thromboembolism, the prophylactic dose of low molecular weight heparin (LMWH) was administered (dalteparin 5000 IU subcutaneously, once a day). Despite the prophylaxis, an episode of dyspnea with tachycardia occured. It was connected with elevated Ddimer and troponin levels and a right ventricle overload in echocardiographic imaging. The pulmonary embolism was suspected. Perfusion lung scintigraphy confirmed this diagnosis. We supposed that the heparin was ineffective due to an antithrombin deficiency. Therefore, apart from a therapeutic dose of LMWH, intravenous antithrombin concentrate was given to the patient (1500 IU twice). The dyspnea resolving was observed. The D-dimer and troponin level reversion to normal was noticed. Heparin injections, connected with antithrombin infusion, was an effective treatment of the pulmonary embolism. Due to the lack of antithrombin in nephrotic syndrome, using only heparin may be insufficient. The erythroapheresis is an effective treatment of polycythemia.