The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation.

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous glomerular filtration rate (GFR)-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by the identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterized by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules <1 kDa dominating the glomerular filtrate, for example water, urea and creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterized by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.

Prognostic potential of creatinine and Cystatin C in COVID-19 - a retrospective cohort study from Karolinska University Hospital.

Acute kidney injury (AKI) is common in COVID-19 and is diagnosed using relative serum creatinine increase. Estimated GFR (eGFR) is a more accurate measure of glomerular filtration due to compensation for age and sex. Serum Cystatin-C, less affected by non-renal factors than creatinine, may further improve renal function estimation and add prognostic information. Our aim is to investigate the importance of a calculated eGFR in relation to creatinine as well as the value of Cystatin-C in patients with severe COVID-19. This study is a retrospective cohort study investigating levels and trends of routine laboratory parameters combined with clinical data from 286 consecutive patients with severe COVID-19 from Karolinska University Hospital. AKI developed in 38% of the patients and 15% were treated with hemodialysis. Mortality in the AKI group was 42% compared to 5% in the non-AKI group. At admission, eGFR, but not creatinine, was significantly associated with AKI development, need of intubation and mortality. Moreover, discrepant results between eGFR creatinine (eGFRCR) and eGFR Cystatin-C (eGFRCYS) was common in the ICU patients compared to non-ICU patients and related to outcome. In addition, we found that daily median Cystatin-C levels during the hospital stay were correlated to neutrophil count. eGFRCR was found to be an overall better prognostic marker than creatinine regarding AKI development and prognosis in severe COVID-19. Fulfillment of Shrunken pore syndrome criteria indicated a higher mortality risk. Cystatin-C may be related to neutrophil count, which could be a clue to the discrepant eGFR results.

The Swedish Version of the eHealth Literacy Questionnaire: Translation, Cultural Adaptation, and Validation Study.

BACKGROUND: With the increasing digitalization in health care, an effective instrument is necessary to assess health care consumers' digital competencies-their "eHealth literacy." The 7-scale eHealth Literacy Questionnaire (eHLQ), based on the theoretically robust eHealth Literacy Framework, has shown strong psychometric properties in Denmark and Australia. OBJECTIVE: The aim of this study was to translate, culturally adapt, and evaluate the psychometric properties of the Swedish version of the eHLQ. METHODS: We followed the Translation Integrity Procedure guidelines to translate and culturally adapt the questionnaire to Swedish using forward and backward translations, review by an expert panel, and cognitive interviewing. The psychometric properties of the Swedish eHLQ were investigated by evaluating its internal consistency (Cronbach α) and a priori-defined factor structure (confirmatory factor analysis). RESULTS: A total of 236 primary health care patients and parents of hospitalized children were included in the validation analysis. The mean age was 48.5 years, and 129 (55%) were women. All 7 eHLQ scales showed good internal consistency, with the Cronbach α ranging from .82 to .92. Single-factor and 7-factor confirmatory factor analysis showed satisfactory model-fit values. With one exception, all items demonstrated satisfactory loadings on their respective factors. CONCLUSIONS: The Swedish eHLQ demonstrated strong psychometric properties. It has the potential as a useful tool for a variety of purposes, including population surveys, intervention evaluations, and eHealth service implementations.

Feline Heinz bodies interfering in standard bicarbonate analysis by the ABL90 FLEX.

Venous blood gases were analyzed with ABL90 FLEX in two cats with Heinz bodies in approximately 60% of the erythrocytes. The instrument demonstrated an inability to correctly report standard bicarbonate (stHCO3 - ), hematocrits, and hemoglobin concentrations by indicating an OXI spectrum mismatch alarm (ie, the spectrum of measured hemoglobin forms differed from the spectrum of calculated forms). Actual bicarbonate (aHCO3 - ) did not indicate any errors. The ABL90 FLEX uses spectrophotometry to measure hemoglobin, and the presence of Heinz bodies interfered with the measurement in these cases. Because hemoglobin is included in the formula for calculating stHCO3 - , the instrument gave an alarm for stHCO3 - . At follow-up, Heinz bodies were present in only 2%-3% of the erythrocytes, and the ABL90 FLEX did not indicate any alarm messages. To the authors' knowledge, these are the first cases reported that have interference in stHCO3 - measurements due to Heinz body formation using the ABL90 FLEX, a common blood gas instrument used in both veterinary and human critical care. The methodology used for evaluating acid-base status should be taken into consideration, and caution is needed when interpreting acid-base results in cats with Heinz bodies.

Copeptin in Growth Hormone-Treated Patients.

Growth hormone (GH) changes body composition, including increasing body water. GH is known to have an anti-natriuretic effect in the kidney, but little is known of its effect on arginine-vasopressin (AVP) release. We studied the effect of GH on AVP release by measurement of copeptin, a fragment from the same precursor protein, in GH-treated patients with GH deficiency. The study was designed as a retrospective cohort study of biobank samples from 34 patients substituted with GH between 1999 and 2004. Copeptin and insulin-like growth factor 1 (IGF-1) results were compared with previously obtained data. An increase in IGF-1 and copeptin was seen at 3 and 6 months' treatment compared to baseline. Between the 3 and 6 months follow up, copeptin levels were stable. There was a difference in HbA1c between 3 and 6 months (p < 0.01) and between baseline and 6 months (p = 0.042), with higher levels at 6 months. In addition, LDL levels were lower at the 6 months follow up (p = 0.046). The waist circumference at 3 months was lower (p = 0.02). To conclude, three months of GH treatment increased the levels of copeptin and the increase remained at 6 months. This could be a compensatory mechanism balancing the anti-natriuretic effect of GH treatment seen in previous studies.

Twenty Years of GH Treatment in Adults with Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder. In adults, the syndrome is characterised by muscular hypotonia, a different body composition with more body fat than muscle mass, hyperphagia, behavioural problems, and cognitive dysfunction. Endocrine deficiencies are common, including growth hormone (GH) deficiency. Here, we present data from a cross-sectional study in adults with PWS with a focus on the long-term safety of GH treatment. A total of 22 patients (14 men) were treated with GH for a median of 20 years. Data on body composition, hormones, and metabolic parameters were retrieved from the patients' medical records. The median age was 27 years. The median GH dose was 0.5 mg/day. Insulin-like growth factor 1 (IGF-I) and blood lipids were normal, while fasting glucose and HbA1c were slightly elevated in three men with diabetes. Fat mass was less than fat free mass in all, though this was less pronounced in women. GH treatment did not negatively affect the metabolic profile, and none developed cardiovascular diseases or cancer. All adults on long-term GH treatment had a normal body composition and our results indicate that treatment was safe. However, PWS is a complex, multisystemic disease and continuous, individual considerations are required during GH treatment, especially in patients with risk factors for adverse effects.

Electrolyte and acid-base imbalance in severe COVID-19.

Acute systemic diseases, such as severe infections, can lead to electrolyte and acid-base alterations. To study the presence of electrolyte imbalance in severe COVID-19, we investigated the frequency and consequences of changes in electrolyte and acid-base patterns over time. We performed a retrospective cohort study including 406 patients with severe COVID-19. Levels of electrolytes, base excess, pH, serum osmolality, and hematocrit, the first 2 weeks of hospitalization, were collected daily from the laboratory database and clinical data from patients' medical records. We found that hyponatremia was present in 57% of the patients at admission and 2% in hypernatremia. However, within 2 weeks of hospitalization 42% of the patients developed hypernatremia, more frequently in critically ill patients. Lower levels of sodium and potassium during admission were associated with the need for mechanical ventilation. Decreased pH at admission was associated with both death and the need for mechanical ventilation. Hypernatremia in the ICU was combined with rising base excess and a higher pH. In the group without intensive care, potassium levels were significantly lower in the patients with severe hypernatremia. Presence of hypernatremia during the first 2 weeks of hospitalization was associated with 3.942 (95% CI 2.269-6.851) times higher odds of death. In summary, hypernatremia was common and associated with longer hospital stay and a higher risk of death, suggesting that the dynamics of sodium are an important indicator of severity in COVID-19.

Simplified and improved fluid deprivation test for diagnosing diabetes insipidus.

OBJECTIVE: The challenge of finding patients with the rare conditon of diabetes insipidus in need of vasopressin treatment is demanding. The guidelines for performing the fluid deprivation test and interpreting the results are abundant. We evaluated the discriminative capacity of the fluid deprivation test in patients with polyuria to define a cut off for a more effective discrimination between diabetes insipidus and other polyuria syndromes. RESEARCH DESIGN AND METHODS: Retrospective review and data collection of all ambulatory fluid deprivation tests, of patients with mild polyuria and polydipsia (< 3 L/day), performed between 2000 and 2018. Serum osmolality, urine osmolality, urine volumes and clinical information of diagnosis were retrieved from the patient's medical records. RESULTS: The study group consisted of 153 patients, 123 were diagnosed with non-diabetes insipidus and 30 with diabetes insipidus. After 12 h fasting (baseline) median duration of the fluid deprivation test was 5 h (fasting range: 12-21 h). At baseline, there was a significant difference between median serum and urine osmolality between the groups (P < 0.05). The best cut-off for the diagnosis of diabetes insipidus, was the combination of < 400 mosmol/kg in urine and > 302 mosmol/kg in serum. With this cut-off a sensitivity of 90% and specificity of 98% was achieved. CONCLUSION: After 12 h fasting our proposed cut off clearly differentiated between diabetes insipidus, and non-diabetes insipidus suggesting a possibility to considerably reduce the duration of the fluid deprivation test.

Experiences of Online COVID-19 Information Acquisition among Persons with Type 2 Diabetes and Varying eHealth Literacy.

During the COVID-19 pandemic, the Internet has been a major source of information for people to keep updated with news and guidelines. However, concerns have been raised about the 'infodemic', which includes the overabundance of online information and the spread of misleading information. Adequate eHealth literacy skills among world citizens have therefore been emphasized as vital during the pandemic. Persons with type 2 diabetes have been at increased risk of severe outcomes of COVID-19 disease. This study aimed to explore online COVID-19 information acquisition experiences among persons with type 2 diabetes and varying eHealth literacy. Fifty-eight participants filled out the eHealth Literacy Scale (eHEALS), along with a qualitative questionnaire with free-text questions. Additionally, 10 participants were interviewed. Thematic analysis was applied to identify patterns in participants' experiences. Two domains were identified: perceived challenges with online information about COVID-19, and coping strategies to manage challenges. The perceived challenges were: being exposed to information overload, dealing with conflicting information, and being strongly emotionally affected. The related coping strategies were: protecting oneself, trusting authorities, taking command, and using common sense. These strategies often involved triangulation of the information obtained, including participants consulting their common sense, various sources, or family and friends. This paper highlights the crucial role of authorities in delivering online information, that according to health literacy principles, is easy to access, understand, and use. Furthermore, our results reinforce the importance of diabetes nurses, as well as healthcare professionals in general, in encouraging patients to share their Internet findings, promote information from reliable sources, and deliver tailored information that suits individual needs. Because our results underline the importance of social support in eHealth literacy and the assessment of online health information, the inclusion of family and friends needs to be increasingly considered in diabetes care. Due to the small homogenous sample, the results of this study cannot be generalized. However, the reader can assess the transferability to other situations and settings based on our contextual descriptions.

Hyperprolactinemia in Adults with Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder typically characterized by body composition abnormalities, hyperphagia, behavioural challenges, cognitive dysfunction, and hypogonadism. Psychotic illness is common, particularly in patients with maternal uniparental disomy (mUPD), and antipsychotic medications can result in hyperprolactinemia. Information about hyperprolactinemia and its potential clinical consequences in PWS is sparse. Here, we present data from an international, observational study of 45 adults with PWS and hyperprolactinemia. Estimated prevalence of hyperprolactinemia in a subset of centres with available data was 22%, with 66% of those related to medication and 55% due to antipsychotics. Thirty-three patients were men, 12 women. Median age was 29 years, median BMI 29.8 kg/m2, 13 had mUPD. Median prolactin was 680 mIU/L (range 329-5702). Prolactin levels were higher in women and patients with mUPD, with only 3 patients having severe hyperprolactinemia. Thyroid function tests were normal, 24 were treated with growth hormone, 29 with sex steroids, and 20 with antipsychotic medications. One patient had kidney insufficiency, and one a microprolactinoma. In conclusion, severe hyperprolactinemia was rare, and the most common aetiology of hyperprolactinemia was treatment with antipsychotic medications. Although significant clinical consequences could not be determined, potential negative long-term effects of moderate or severe hyperprolactinemia cannot be excluded. Our results suggest including measurements of prolactin in the follow-up of adults with PWS, especially in those on treatment with antipsychotics.

Platelet Count Rose While D-Dimer Levels Dropped as Deaths and Thrombosis Declined-An Observational Study on Anticoagulation Shift in COVID-19.

BACKGROUND: High levels of D-dimer and low platelet counts are associated with poor outcome in coronavirus disease 2019 (COVID-19). As anticoagulation appeared to improve survival, hospital-wide recommendations regarding higher doses of anticoagulation were implemented on April 9, 2020. OBJECTIVES: To investigate if trends in D-dimer levels and platelet counts were associated with death, thrombosis, and the shift in anticoagulation. METHODS: Retrospective cohort study of 429 patients with COVID-19 at Karolinska University Hospital. Information on D-dimer levels and platelet counts was obtained from laboratory databases and clinical data from medical records. RESULTS: Thirty-day mortality and thrombosis rates were 19% and 18%, respectively. Pulmonary embolism was common, 65/83 (78%). Increased D-dimer levels in the first week in hospital were significantly associated with death and thrombosis (odds ratio [OR]: 6.06; 95% confidence interval [CL]: 2.10-17.5 and 3.11; 95% CI: 1.20-8.10, respectively). If platelet count increased more than 35 × 109/L per day, the mortality and thrombotic risk decreased (OR: 0.16; 95% CI: 0.06-0.41, and OR: 0.36; 95% CI: 0.17-0.80). After implementation of updated hospital-wide recommendations, the daily mean significantly decreased regarding D-dimer levels while platelet counts rose; -1.93; 95% CI: -1.00-2.87 mg/L FEU (fibrinogen-equivalent unit) and 65; 95% CI: 54-76 ×109/L, and significant risk reductions for death and thrombosis were observed; OR: 0.48; 95% CI: 0.25-0.92 and 0.35; 95% CI: 0.17-0.72. CONCLUSION: In contrast to D-dimer levels, increase of platelet count over the first week in hospital was associated with improved survival and reduced thrombotic risk. The daily mean levels of D-dimer dropped while the platelet counts rose, coinciding with increased anticoagulation and a decline in thrombotic burden and mortality.

COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin-aldosterone system.

SARS-CoV-2 uses ACE2, an inhibitor of the Renin-Angiotensin-Aldosterone System (RAAS), for cellular entry. Studies indicate that RAAS imbalance worsens the prognosis in COVID-19. We present a consecutive retrospective COVID-19 cohort with findings of frequent pulmonary thromboembolism (17%), high pulmonary artery pressure (60%) and lung MRI perfusion disturbances. We demonstrate, in swine, that infusing angiotensin II or blocking ACE2 induces increased pulmonary artery pressure, reduces blood oxygenation, increases coagulation, disturbs lung perfusion, induces diffuse alveolar damage, and acute tubular necrosis compared to control animals. We further demonstrate that this imbalanced state can be ameliorated by infusion of an angiotensin receptor blocker and low-molecular-weight heparin. In this work, we show that a pathophysiological state in swine induced by RAAS imbalance shares several features with the clinical COVID-19 presentation. Therefore, we propose that severe COVID-19 could partially be driven by a RAAS imbalance.

Primary Health Care Nurses' Experiences of Consultations With Internet-Informed Patients: Qualitative Study.

BACKGROUND: Most people in modern societies now use the Internet to obtain health-related information. By giving patients knowledge, digital health information is considered to increase patient involvement and patient-centered interactions in health care. However, concerns are raised about the varying quality of health-related websites and low health literacy in the population. There is a gap in the current knowledge of nurses' experiences with Internet-informed patients. OBJECTIVE: The objective of this study was to explore primary health care nurses' experiences of consultations with patients who present health-related information from the Internet. METHODS: This is a qualitative study based on interviews with 9 primary health care nurses. Data were analyzed using qualitative content analysis. Results are reported according to the consolidated criteria for reporting qualitative research guidelines. RESULTS: The phenomenon of Internet-informed patients was considered to change the usual rules in health care, affecting attributes and actions of patients, patterns of interactions in consultations, and roles of nurses and patients. Three categories were identified: (1) Facing the downsides of Googling, (2) Patients as main actors, and (3) Nurse role challenged. Although the benefits of health-related Internet information were described, its negative consequences were emphasized overall. The problems were mainly ascribed to inaccurate Internet information and patients' inability to effectively manage the information. CONCLUSIONS: Our study suggests ambivalent attitudes among nurses toward health-related Internet information. In order to promote equitable care in the digital era, increased awareness in health care about useful strategies for overcoming the difficulties and embracing the benefits of conferring with Internet-informed patients seems to be a legitimate goal.

In vitro characterization of 211 At-labeled antibody A33--a potential therapeutic agent against metastatic colorectal carcinoma.

The humanized antibody A33 binds to the A33 antigen, expressed in 95% of primary and metastatic colorectal carcinomas. The restricted pattern of expression in normal tissue makes this antigen a possible target for radioimmunotherapy of colorectal micrometastases. In this study, the A33 antibody was labeled with the therapeutic nuclide (211)At using N-succinimidyl para-(tri-methylstannyl)benzoate (SPMB). The in vitro characteristics of the (211)At-benzoate-A33 conjugate ((211)At-A33) were investigated and found to be similar to those of (125)I-benzoate-A33 ((125)I-A33) in different assays. Both conjugates bound with high affinity to SW1222 cells (K(d) = 1.7 +/- 0.2 nM, and 1.8 +/- 0.1 nM for (211)At-A33 and (125)I-A33, respectively), and both showed good intracellular retention (70% of the radioactivity was still cell associated after 20 hours). The cytotoxic effect of (211)At-A33 was also confirmed. After incubation with (211)At-A33, SW1222 cells had a survival of approximately 0.3% when exposed to some 150 decays per cell (DPC). The cytotoxic effect was found to be dose-dependent, as cells exposed to only 56 DPC had a survival of approximately 5%. The (211)At-A33 conjugate shows promise as a potential radioimmunotherapy agent for treatment of micrometastases originating from colorectal carcinoma.

Targeting against epidermal growth factor receptors. Cellular processing of astatinated EGF after binding to cultured carcinoma cells.

BACKGROUND: The alpha-emitting nuclide 211At is of great interest for radionuclide therapy when coupled to a tumor-targeting biomolecule, e.g. epidermal growth factor (EGF) the receptors of which are overexpressed in many malignancies. However, almost no information concerning the cellular processing of astatinated targeting agents is available. MATERIALS AND METHODS: We indirectly astatinated EGF ([211At]-benzoate-EGF) and studied its cellular processing in A-431 carcinoma cells in comparison with data concerning [125I]-benzoate-EGF. RESULTS: The biological half-life of astatine (3.5 h) was longer than the half-life of the iodine label (1.5 h). The increase of the half-life was due to longer retention of the internalised astatine radioactivity. The maximum accumulation for the astatine label occurred later (4-6h) than that for the iodine label (2-4h), indicating a slower excretion of astatine that was confirmed in experiment with 211At/1251-benzoate-EGF. CONCLUSION: The long retention of astatine might be advantageous for radionuclide therapy.

Intra-individual variations and temporal trends in dioxin levels in human blood 1987-2002.

OBJECTIVES: In Sweden, an important source for exposure to persistent organochlorine pollutants, such as PCDD and PCDF, is through intake of fatty fish from the Baltic Sea off the Eastern coast of Sweden. The present study assesses temporal trends for human levels of PCDD/F between 1987 and 2002 among 26 men from Sweden. In addition, we investigate the impact of potential determinants (age, relative change in BMI and fish consumption) on the relatively change in individual PCDD/F congener levels between 1987 and 2002. METHODS: In 1987, nine of the men did not eat fatty fish from the Baltic Sea, eight had a moderate intake, and nine were high consumers. For the same individuals, blood samples were collected in 1987 as well as in 2002, and the concentrations of seven PCDD and 10 PCDF congeners were analyzed at the same laboratory. RESULTS: The WHO-TEQ levels for PCDD/F did not significantly change over the 15-year period. There were, however, some specific congeners that significantly had changed over time. None of the investigated determinants were associated with the change over time for the specific PCDD/F congeners. CONCLUSION: The present study may be of importance for risk assessment and setting standards for food contamination with PCDD/F, especially regarding intake of fatty fish from the Baltic Sea.

HER-2--a possible target for therapy of metastatic urinary bladder carcinoma.

Human epidermal growth factor receptor 2, HER-2, is overexpressed in various tumours, e.g. breast- and bladder tumours. The aim of this study was to predict the potential use of HER-2 receptors as targets in systemic treatment of disseminated bladder tumours. HER-2 expression was assessed in bladder carcinoma metastases and the corresponding primary tumours, and subsequently compared with the EGFR expression. HER-2 and EGFR expression was analysed by immunohistochemistry in formalin-fixed, paraffin-embedded tissues from 21 patients with metastatic bladder carcinoma. HER-2 was overexpressed in 81% of the primary tumours and in 67% of the metastases. All HER-2-positive metastases were from HER-2-positive primary tumours. The results for EGFR were 71% of both primary and metastases-positive tumours. In 90% of the primary tumours and 86% of the metastases, at least one of the receptors was overexpressed. These results suggest that HER-2 targeted therapy can be considered as an alternative or a complement to other modalities in the treatment of metastatic urinary bladder carcinoma.

The protean immune cell synapse: a supramolecular structure with many functions.

Heterogeneity in the supramolecular organization of immunological synapses arises from the involvement of different cells, distinct environmental stimuli, and varying levels of protein expression. There may also be heterogeneity in the types and amounts of cell surface proteins and lipids that transfer between lymphocytes during immune surveillance. In addition, immune cells can be involved in the assembly of a 'viral synapse', such that micrometer-scale organization of proteins at intercellular contacts occurs during transmission of a virus between T cells. Thus, while there may be unity in molecular mechanisms underlying the organization of cell surface receptors at immune cell synapses, there is diversity in their function.