A case report of severe calciphylaxis - suggested approach for diagnosis and treatment.

BACKGROUND: Calciphylaxis is a serious complication in patients with chronic kidney disease associated mineral and bone disorder. It can occur in conditions with low and high bone turnover. So far, there are no definite diagnostic and therapeutic guidelines which may prevent the devastating outcome in many calciphylaxis patients. We report a case which clearly illustrates that knowledge of the underlying bone disorder is essential for a directed treatment. Based on this experience we discuss a systematic diagnostic and therapeutic approach in patients with calciphylaxis. CASE PRESENTATION: We report a patient with severe calciphylaxis. Initial evaluation showed an elevated serum parathormone concentration and a bone-specific alkaline phosphatase activity in the upper normal range; however, the bone biopsy clearly showed adynamic bone disease. Extended dialysis with low calcium dialysate concentration and citrate anticoagulation, and administration of teriparatide led to a further increase in bone-specific alkaline phosphatase activity and most importantly, resulted in an activated bone turnover as confirmed by a second bone biopsy 11 weeks later. CONCLUSIONS: This case illustrates that laboratory tests cannot reliably differentiate between high and low bone turnover in calciphylaxis patients. More importantly, this case highlights the fact that specific therapies that alter bone metabolism cannot be applied without knowledge of the bone status. On this background, we suggest that bone biopsies should be an integral part in the diagnosis and therapeutic decision in these patients and should be evaluated in further studies.

Patient-reported non-adherence and immunosuppressant trough levels are associated with rejection after renal transplantation.

BACKGROUND: Different measures of non-adherence to immunosuppressant (IS) medication have been found to be associated with rejection episodes after successful transplantation. The aim of the current study was to investigate whether graft rejection after renal transplantation is associated with patient-reported IS medication non-adherence and IS trough level variables (IS trough level variability and percentage of sub-therapeutic IS trough levels). METHODS: Patient-reported non-adherence, IS trough level variability, percentage of sub-therapeutic IS trough levels, and acute biopsy-proven late allograft rejections were assessed in 267 adult renal transplant recipients who were ≥12 months post-transplantation. RESULTS: The rate of rejection was 13.5%. IS trough level variability, percentage of sub-therapeutic IS trough levels as well as patient-reported non-adherence were all significantly and positively associated with rejection, but not with each other. Logistic regression analyses revealed that only the percentage of sub-therapeutic IS trough levels and age at transplantation remained significantly associated with rejection. CONCLUSIONS: Particularly, the percentage of sub-therapeutic IS trough levels is associated with acute rejections after kidney transplantation whereas IS trough level variability and patient-reported non-adherence seem to be of subordinate importance. Patient-reported non-adherence and IS trough level variables were not correlated; thus, non-adherence should always be measured in a multi-methodological approach. Further research concerning the best combination of non-adherence measures is needed.

Monocyte chemoattractant protein-1 and the kidney.

PURPOSE OF REVIEW: Recently, initial studies have been carried out in patients using monocyte chemoattractant protein-1 (MCP-1) inhibitors. This review summarizes the known function of MCP-1 in regulating monocytes during inflammation and its role in inflammatory disease of the kidney. RECENT FINDINGS: MCP-1 is one of the first chemokines described and plays an important role in renal inflammatory disease. The function of MCP-1 has been investigated and analyzed in both animal models of renal disease and renal patients. MCP-1 mediates firstly the release of monocytes from the bone marrow, and then generates a gradient in the endothelial glycocalyx to direct monocytes to sites of inflammation, thereby alleviating the migration of blood leukocytes into the inflamed tissue. In addition, MCP-1 has direct signaling effects in monocytes and influences migration, proliferation, and differentiation of leukocytes. Blockade of MCP-1 in several models of renal disease has ameliorated the disease, suggesting that inhibition of MCP-1 is a promising and valid strategy to treat patients with renal inflammatory disease. SUMMARY: Understanding the role of MCP-1 in monocyte homeostasis and the implications of MCP-1 inhibition in renal disease will help in designing better diagnostic and therapeutic strategies in patients with inflammatory renal disease.

Finerenone: a New Mineralocorticoid Receptor Antagonist Without Hyperkalemia: an Opportunity in Patients with CKD?

Aldosterone binds to the mineralocorticoid receptor and has an important regulatory role in body fluid and electrolyte balance. It also influences a variety of different cell functions such as oxidative stress, inflammation and organ fibrosis. The important role of the tissue-specific mineralocorticoid receptors in cardiovascular and renal injury has been shown in knockout animals and in clinical studies Mineralocorticoid receptor antagonists seem to exert their beneficial effects via anti-oxidative, anti-inflammatory and anti-fibrotic effects. Spironolactone and eplerenone were the first steroidal mineralocorticoid receptor antagonist. The established steroidal mineralocorticoid receptor antagonists show important therapeutic effects but are hampered by a variety of side effects, most importantly clinically significant hyperkaliemia. Selective non-steroidal mineralocorticoid receptor antagonists have been recently developed and demonstrate effectiveness in early clinical trials. Finereroneholds promise for the future application of this new mineralocorticoid receptor antagonist class in patients with chronic kidney disease since it has shown a significant reduction in UACR combined with a safety profile similar to that in the placebo group. However, further long-term studies investigating relevant clinical end points like reduction in cardiovascular or renal event rate are warranted.

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis.

ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasma-derived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease.

Protein kinase C-θ is required for murine neutrophil recruitment and adhesion strengthening under flow.

Protein kinase C (PKC)-θ is involved in T cell activation via regulating the avidity of the ß(2) integrin LFA-1 in the immunological synapse. LFA-1 also mediates leukocyte adhesion. To investigate the role of PKC-θ in neutrophil adhesion, we performed intravital microscopy in cremaster venules of mice reconstituted with bone marrow from LysM-GFP(+) (wild-type [WT]) and PKC-θ gene-deficient (Prkcq(-/-)) mice. Following stimulation with CXCL1, both WT and Prkcq(-/-) cells became adherent. Although most WT neutrophils remained adherent for at least 180 s, 50% of Prkcq(-/-) neutrophils were detached after 105 s and most by 180 s. Upon CXCL1 injection, rolling of all WT neutrophils stopped for 90 s, but rolling of Prkcq(-/-) neutrophils started 30 s after CXCL1 stimulation. A similar neutrophil adhesion defect was seen in vitro, and spreading of Prkcq(-/-) neutrophils was delayed. Prkcq(-/-) neutrophil recruitment was impaired in fMLP-induced transmigration into the cremaster muscle, thioglycollate-induced peritonitis, and LPS-induced lung injury. We conclude that PKC-θ mediates integrin-dependent neutrophil functions and is required to sustain neutrophil adhesion in postcapillary venules in vivo. These findings suggest that the role of PKC-θ in outside-in signaling following engagement of neutrophil integrins is relevant for inflammation in vivo.

Linguistic features of suicidal thoughts and behaviors: A systematic review.

Language is a potential source of predictors for suicidal thoughts and behaviors (STBs), as changes in speech characteristics, communication habits, and word choice may be indicative of increased suicide risk. We reviewed the current literature on STBs that investigated linguistic features of spoken and written language. Specifically, we performed a search in linguistic, medical, engineering, and general databases for studies that investigated linguistic features as potential predictors of STBs published in peer-reviewed journals until the end of November 2021.We included 75 studies that investigated 279,032 individuals with STBs (age = 29.53 ± 10.29, 35% females). Of those, 34 (45%) focused on lexicon, 20 (27%) on prosody, 15 (20%) on lexicon and first-person singular, four (5%) on (morpho)syntax, and two (3%) were unspecified. Suicidal thoughts were predicted by more intensifiers and superlatives, while suicidal behaviors were predicted by greater usage of pronouns, changes in the amount of verb usage, more prepend and multifunctional words, more nouns and prepositions, and fewer modifiers and numerals. A diverse field of research currently investigates linguistic predictors of STBs, and more focus is needed on their specificity for either suicidal thoughts or behaviors.

Use of an electronic medication monitoring device to estimate medication adherence in kidney transplant patients.

Electronic medication monitoring devices (EMD) have been used as a gold standard for assessing medication adherence. We used a wireless EMD (SimpleMed+), assessed its usability in patients after kidney transplantation (KTx), evaluated adherence, and analyzed concordance with other adherence measures. Fifty-five patients (53% female, mean age 46 years) at least 6 months after KTx agreed to use the EMD over a period of 8 weeks. Self-reported adherence was measured with the BAASIS, and immunosuppressant trough level variability was assessed prior to and again during the study period. Fourteen patients stopped using the EMD or were low users (<70%). These non-completers reported that using the EMD would interfere with their daily activities. Taking-adherence of the completers was high with 98.3% (±1.9) over the entire study period. Timing-adherence was somewhat lower (94.6% ± 7.9) and decreased during the second half of the study. We found statistically significant correlations between EMD results and self-reported adherence with moderate effect sizes, but no significant association with trough level variability. The low usage of the EMD supports the need to assess the practicability of an EMD before applying it in research and clinical routine. Taking- and timing-adherence of KTx patients using the EMD was satisfactory. Self-reported adherence might be a good enough estimate of medication adherence.

Adherence is associated with a favorable outcome after lung transplantation.

Non-adherence to therapy is associated with impaired outcome in solid organ allograft recipients. Outcome data are limited after lung transplantation. In a single-center cohort study, adherence was assessed in 427 patients undergoing lung transplantation from 2010 to 2013. Objective criteria of adherence were judged by health care workers on every visit on a five item Likert scale including trough level monitoring, home spirometry and contact with an overall rating of adherence between 0 and 100%. Cut-off values for good vs. suboptimal adherence were defined retrospectively. Primary outcome was allograft survival, secondary outcomes were patient survival, prevalence of chronic lung allograft dysfunction, hospitalizations, renal function and quality of life. Follow-up ended on 31st December 2018. Median adherence was 86% on 6,623 visits, this cut-off was used as a discriminator between good and suboptimal adherers. Patients with good adherence within the first three years showed better 5-year allograft (74% vs. 60%, p = 0.003) and patient survival (79% vs. 64%, p<0.001) and lower prevalence of chronic allograft dysfunction (33% vs. 45%, p = 0.011) after 5 years compared to patients with suboptimal adherence. A multidimensional adherence score proved to be a simple tool to assess adherence in clinical practice. Suboptimal adherence was associated with impaired outcome in lung transplant patients.

Psychological processing of a kidney transplantation, perceived quality of life, and immunosuppressant medication adherence.

Introduction: Though psychosocial well-being and quality of life generally improve after transplantation, a relevant proportion of patients suffers from psychosocial problems. Further analysis of the psychological coping after kidney transplantation is needed to identify patients at risk. The aim of this study was to examine the psychological response after kidney transplantation and its associations with health-related quality of life and immunosuppressant medication adherence. Materials and methods: The coping process after kidney transplantation was investigated with the Transplant Effects Questionnaire (TxEQ; subscales: worry, guilt, disclosure, adherence, responsibility) in 267 adult kidney transplant recipients ≥12 months post-transplantation. Furthermore, perceived health-related quality of life, self-reported immunosuppressant medication adherence, and sub-therapeutic immunosuppressant trough levels as biological markers of adherence were assessed. Results: Patients showed moderate scores concerning the subscales "worry", "guilt", and "responsibility" as well as high scores concerning "disclosure". Except for "adherence", all TxEQ subscales were associated with mental, but not with physical health-related quality of life and self-reported adherence. Sub-therapeutic immunosuppressant trough levels were significantly associated only with the TxEQ subscale "worry". Conclusions: The present results suggest a conditional structure in which mental health-related quality of life is negatively associated with worries, guilt, and responsibility and positively with disclosure. Adherence seems to be a complex behavior, which is not necessarily directly associated with the psychological processing of organ transplantations. As mental health-related quality of life is related to this psychological processing, the TxEQ could be used as a screening tool for problematic psychological processing after kidney transplantation.

Psychosocial Variables Associated with Immunosuppressive Medication Non-Adherence after Renal Transplantation.

INTRODUCTION: Non-adherence to immunosuppressive medication is regarded as an important factor for graft rejection and loss after successful renal transplantation. Yet, results on prevalence and relationship with psychosocial parameters are heterogeneous. The main aim of this study was to investigate the association of immunosuppressive medication non-adherence and psychosocial factors. METHODS: In 330 adult renal transplant recipients (≥12 months posttransplantation), health-related quality of life, depression, anxiety, social support, and subjective medication experiences were assessed, and their associations with patient-reported non-adherence was evaluated. RESULTS: 33.6% of the patients admitted to be partially non-adherent. Non-adherence was associated with younger age, poorer social support, lower mental, but higher physical health-related quality of life. There was no association with depression and anxiety. However, high proportions of clinically relevant depression and anxiety symptoms were apparent in both adherent and non-adherent patients. CONCLUSION: In the posttransplant follow-up, kidney recipients with lower perceived social support, lower mental and higher physical health-related quality of life, and younger age can be regarded as a risk group for immunosuppressive medication non-adherence. In follow-up contacts with kidney transplant patients, physicians may pay attention to these factors. Furthermore, psychosocial interventions to optimize immunosuppressive medication adherence can be designed on the basis of this information, especially including subjectively perceived physical health-related quality of life and fostering social support seems to be of importance.

Molecular Mechanisms and Treatment Strategies in Diabetic Nephropathy: New Avenues for Calcium Dobesilate-Free Radical Scavenger and Growth Factor Inhibition.

Diabetic nephropathy is one of the most important microvascular complications of diabetes mellitus and is responsible for 40-50% of all cases of end stage renal disease. The therapeutic strategies in diabetic nephropathy need to be targeted towards the pathophysiology of the disease. The earlier these therapeutic strategies can bring about positive effects on vascular changes and prevent the vasculature in patients with diabetes from deteriorating, the better the renal function can be preserved. Studies evaluating anti-inflammatory and antioxidative strategies in diabetic nephropathy demonstrate the need and value of these novel treatment avenues. CaD is an established vasoactive and angioprotective drug that has shown a unique, multitarget mode of action in several experimental studies and in different animal models of diabetic microvascular complications. On the molecular level, CaD reduces oxidative stress and inhibits growth factors such as fibroblast growth factor and vascular endothelial growth factors. Recent findings have demonstrated a strong rationale for its use in reducing urine albumin excretion rate and markers of inflammation as well as improving endothelial function. Its beneficial effects make it an attractive therapeutic compound especially in the early stages of the disease. These findings, although promising, need further confirmation in prospective clinical trials with CaD.

Differences in emotional responses in living and deceased donor kidney transplant patients.

BACKGROUND: The psychological functioning of living donor (LD) and deceased donor (DD) recipients are important factors for emotional adjustment to transplantation. This study investigated differences in medical, sociodemographic and emotional factors between these two groups. METHODS: A total of 241 kidney transplant recipients (68 LD, 173 DD) completed questionnaires on emotional and behavioural responses to transplantation, including quality of life, anxiety and depression, social support and experience with immunosuppressive medication. RESULTS: Overall, LD recipients were younger, better educated, more often employed and had a shorter duration of dialysis prior to transplantation. Findings indicate that LD recipients expressed more guilt towards the donor than DD recipients. In addition, more LD recipients experienced clinically significant levels of anxiety. Both groups experienced high levels of negative effects of immunosuppressant medication. No differences between LD and DD recipients were found for gender, relationship status, time since transplantation or transplant rejection treatment during the last 12 months. In addition, perceived social support and quality of life were comparable between the two groups. CONCLUSIONS: Feelings of guilt and anxiety may be an important focus for interventions to improve emotional adjustment to transplantation, especially in LD recipients.

Physician reported adherence to immunosuppressants in renal transplant patients: Prevalence, agreement, and correlates.

OBJECTIVE: Adherence to immunosuppressants (IS) is crucial to prevent allograft rejection. Even though there is evidence that non-adherence to IS among kidney transplant recipients is common, it is rarely routinely assessed in clinical practice. Especially, little is known about how physicians estimate patients' adherence to IS medication. METHODS: In a single center, cross-sectional study adult patients at least 1 year after kidney transplantation were asked to complete measures of adherence (BAASIS©, Transplant Effect Questionnaire) and of general psychopathology (anxiety, depression, perceived social support). Also the physicians were asked to estimate their patients' adherence. Medical data (time since transplantation, treatment for rejection, IS serum trough levels and target levels) were taken from the patients' charts. RESULTS: Physicians rated 22 of 238 (9.2%) patients as non-adherent. Physicians' estimations of non-adherence were lower compared to the results of the self-ratings and biopsy-proven rejections. No association was found between physicians' estimates and the variability of IS through levels. Significantly more women and patients who reported that their native language was not German were rated as non-adherent by the physicians. Also, physician-rated non-adherent patients reported significantly higher depression and anxiety scores as well as less social support compared to adherent patients. CONCLUSION: Our results suggest that physicians tend to underestimate patient non-adherence to IS medication. They appear to use observable cues such as sex, language skills, and elevated anxiety and depression scores in particular, to make inferences about an individual patient's adherence. Underestimation of medication non-adherence may impede physicians' ability to provide high quality care.