Kidney transplantation in prostate cancer patients after local therapy with curative intent: a systematic review.

PURPOSE: It is still unclear whether kidney transplantation can be safely performed in patients with prostate cancer after local therapy with curative intent. METHODS: The protocol was registered in PROSPERO. We systematically searched Google, MEDLINE, the Cochrane Library, and the ICTRP for studies, official standards, clinical practice guidelines and organ transplant laws. Two review authors independently examined the full-text reports and identified relevant studies and one review author extracted the data. We assessed the overall certainty of the evidence for each outcome according to the GRADE approach. RESULTS: We identified 1346 references through electronic database searching and finally included 6 references for official standards, clinical practice guidelines, and organ transplant laws, and 6 references for retrospective studies with very low certainty of evidence. We identified no prospective or ongoing studies and reported all results narratively. CONCLUSION: We recommend that decisions on kidney transplantation in patients with prostate cancer after local therapy with curative intent should be made on a case-by-case basis. It is indispensable to consult with health care professionals or specialists at transplant centers to obtain individualized information regarding the waiting time requirements for renal transplantation in prostate cancer patients after local therapy with curative intent. No recommendation can be made regarding the waiting times after prostate cancer therapy with curative intent.

Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure.

BACKGROUND: Recent studies indicated that sodium glucose cotransporter (SGLT)2 inhibition increases levels of ketone bodies in the blood in patients with type 1 and 2 diabetes. Other studies suggested that in patients with chronic heart failure (CHF), increased myocardial oxygen demand can be provided by ketone bodies as a fuel substrate. Experimental studies reported that ketone bodies, specifically beta-hydroxybutyrate (ß-OHB) may increase blood pressure (BP) by impairing endothelium-dependant relaxation, thereby leading to increased vascular stiffness. In our study we assessed whether the SGLT 2 inhibition with empagliflozin increases ketone bodies in patients with stable CHF and whether such an increase impairs BP and vascular function. METHODS: In a prospective, double blind, placebo controlled, parallel-group single centre study 75 patients with CHF (left ventricular ejection fraction 39.0 ± 8.2%) were randomised (2:1) to the SGLT-2 inhibitor empagliflozin 10 mg orally once daily or to placebo, 72 patients completed the study. After a run-in phase we evaluated at baseline BP by 24 h ambulatory blood pressure (ABP) monitoring, vascular stiffness parameters by the SphygmoCor system (AtCor Medical, Sydney, NSW, Australia) and fasting metabolic parameters, including ß-OHB by an enzymatic assay (Beckman Coulter DxC 700 AU). The same measurements were repeated 12 weeks after treatment. In 19 of the 72 patients serum levels of ß-OHB were beneath the lower border of our assay (< 0.05 mmol/l) therefore being excluded from the subsequent analysis. RESULTS: In patients with stable CHF, treatment with empagliflozin (n = 36) was followed by an increase of ß-OHB by 33.39% (p = 0.017), reduction in 24 h systolic (p = 0.038) and diastolic (p = 0.085) ABP, weight loss (p = 0.003) and decrease of central systolic BP (p = 0.008) and central pulse pressure (p = 0.008). The increase in ß-OHB was related to an attenuated decrease of empagliflozin-induced 24 h systolic (r = 0.321, p = 0.069) and diastolic (r = 0.516, p = 0.002) ABP and less reduction of central systolic BP (r = 0.470, p = 0.009) and central pulse pressure (r = 0.391, p = 0.033). No significant changes were seen in any of these parameters after 12 weeks of treatment in the placebo group (n = 17). CONCLUSION: In patients with stable CHF ketone bodies as assessed by ß-OHB increased after treatment with empagliflozin. This increase led to an attenuation of the beneficial effects of empagliflozin on BP and vascular parameters. Trial registration The study was registered at http://www.clinicaltrials.gov (NCT03128528).

Fedratinib hydrochloride to treat intermediate-2 or high-risk primary or secondary myelofibrosis.

Fedratinib hydrochloride is a selective Janus kinase 2 (JAK2) inhibitor approved by the U.S. Food and Drug Administration (FDA) in August 2019 for intermediate- 2 or high-risk primary or secondary myelofibrosis. The approval of this novel oral agent was based on the phase II and III JAKARTA-2 and JAKARTA trials, which both showed significant reduction in splenomegaly and myelofibrosis symptom burden. The most common adverse effects associated with fedratinib include anemia, gastrointestinal symptoms and elevation in liver transaminases. Early clinical trial data was concerning for an increased incidence of Wernicke's encephalopathy (WE), which led the FDA to place a clinical hold on further drug development. However, upon further investigation it was determined that there was no clear evidence that fedratinib causes WE, and the clinical hold was lifted in 2017. This inclusive review provides insight into the pharmacology, safety and efficacy, and future direction of fedratinib use in myeloproliferative neoplasms.

Characterizing renal involvement in Hermansky-Pudlak Syndrome in a zebrafish model.

Hermansky-Pudlak Syndrome (HPS) is a rare disease caused by mutations in the genes coding for various HPS proteins. HPS proteins are part of multi-subunit complexes involved in the biogenesis of organelles from the lysosomal-endosomal-system. In humans, this syndrome is characterized by the presence of albinism, platelet dysfunction and pulmonary fibrosis. The renal component to the disease remains unstudied and untreated in patients with HPS. Here we demonstrate that in humans, HPS proteins have a high renal expression with active transcription of HPS1, 3, 4 and 5 in human podocyte cell culture, suggesting that impaired function of HPS proteins could directly impact renal function. Therefore, we developed a zebrafish model to study the renal involvement of HPS proteins in proteinuric kidney disease. Remarkably, knockdown of HPS genes in zebrafish causes glomerular injury with edema, proteinuria and structural changes of the glomerular filtration barrier. Moreover, reduced expression of HPS proteins in zebrafish recapitulates other important disease hallmarks, like hypopigmentation and accumulation of intracellular debris characteristic of lysosomal disorders. In conclusion, we present a valid zebrafish model that highlights the previously underestimated relevance of renal disease in HPS. This draws attention to the therapeutic options available to manage this component of the syndrome.

The nephrology eHealth-system of the metropolitan region of Hannover for digitalization of care, establishment of decision support systems and analysis of health care quality.

BACKGROUND: Even though a high demand for sector spanning communication exists, so far no eHealth platform for nephrology is established within Germany. This leads to insufficient communication between medical providers and therefore suboptimal nephrologic care. In addition, Clinical Decision Support Systems have not been used in Nephrology until now. METHODS: The aim of NEPHRO-DIGITAL is to create a eHealth platform in the Hannover region that facilitates integrated, cross-sectoral data exchange and includes teleconsultation between outpatient nephrology, primary care, pediatricians and nephrology clinics to reduce communication deficits and prevent data loss, and to enable the creation and implementation of an interoperable clinical decision support system. This system will be based on input data from multiple sources for early identification of patients with cardiovascular comorbidity and progression of renal insufficiency. Especially patients will be able to enter and access their own data. A transfer to a second nephrology center (metropolitan region of Erlangen-Nuremburg) is included in the study to prove feasibility and scalability of the approach. DISCUSSION: A decision support system should lead to earlier therapeutic interventions and thereby improve the prognosis of patients as well as their treatment satisfaction and quality of life. The system will be integrated in the data integration centres of two large German university medicine consortia (HiGHmed ( highmed.org ) and MIRACUM ( miracum.org )). TRIAL REGISTRATION: ISRCTN16755335 (09.07.2019).

Circulating factors cause proteinuria in parabiotic zebrafish.

Proteinuria can be induced by impairment of any component of the glomerular filtration barrier (GFB). To determine the role of circulating permeability factors on glomerular damage, we developed a parabiosis-based zebrafish model to generate a common circulation between zebrafish larvae. A morpholino-mediated knockdown of a podocyte specific gene (nephronectin) was induced in one zebrafish larva which was then fused to an un-manipulated fish. Notably, proteinuria and glomerular damage were present in the manipulated fish and in the parabiotically-fused partner. Thus, circulating permeability factors may be induced by proteinuria even when an induced podocyte gene dysregulation is the initiating cause.

[Minimal change disease and focal segmental glomerulosclerosis]. / Minimal-change-Glomerulonephritis und fokal-segmentale Glomerulosklerose.

Minimal change disease (MCD) or minimal change glomerulonephritis and focal segmental glomerulosclerosis (FSGS) are the two major causes of nephrotic syndrome in children and young adults. Both disease entities resemble each other and can sometimes only be discriminated on the basis of their clinical courses. MCD and FSGS display two classical examples that share a common pathophysiology in which the glomerular podocyte and the cytoskeleton of its foot processes play important roles. Therefore, the term "podocytopathy" was introduced for both diseases. In this article, we compare their differences and similarities, and summarized new data on pathophysiology and treatment. In adults, only a renal biopsy including electron microscopy allows for the discrimination of MCD and FSGS and other differential diagnoses. The identification of a primary or secondary form of the disease is based on the clinical course. Data from studies on the treatment are sparse; hence, treatment is still based on high-dose steroids followed by additional immunosuppressive agents. In secondary forms, treatment of the underlying disease is elementary.

Notch inhibition counteracts Paneth cell death in absence of caspase-8.

Opposing activities of Notch and Wnt signaling regulate mucosal barrier homeostasis and differentiation of intestinal epithelial cells. Specifically, Wnt activity is essential for differentiation of secretory cells including Wnt3-producing Paneth cells, whereas Notch signaling strongly promotes generation of absorptive cells. Loss of caspase-8 in intestinal epithelium (casp8∆int) is associated with fulminant epithelial necroptosis, severe Paneth cell death, secondary intestinal inflammation, and an increase in Notch activity. Here, we found that pharmacological Notch inhibition with dibenzazepine (DBZ) is able to essentially rescue the loss of Paneth cells, deescalate the inflammatory phenotype, and reduce intestinal permeability in casp8∆int mice. The secretory cell metaplasia in DBZ-treated casp8∆int animals is proliferative, indicating for Notch activities partially insensitive to gamma-secretase inhibition in a casp8∆int background. Our data suggest that casp8 acts in the intestinal Notch network.

FERMT2 links cortical actin structures, plasma membrane tension and focal adhesion function to stabilize podocyte morphology.

Simplification and retraction of podocyte protrusions, generally termed as foot process effacement, is a uniform pathological pattern observed in the majority of glomerular disease, including focal segmental glomerulosclerosis. However, it is still incompletely understood how the interaction of cortical actin structures, actomyosin contractility and focal adhesions, is being orchestrated to control foot process morphology in health and disease. By uncovering the functional role of fermitin family member 2 (FERMT2 or kindlin-2) in podocytes, we provide now evidence, how cell-extracellular matrix (ECM) interactions modulate membrane tension and actomyosin contractility. A genetic modeling approach was applied by deleting FERMT2 in a set of in vivo systems as well as in CRISPR/Cas9 modified human podocytes. Loss of FERMT2 results in altered cortical actin composition, cell cortex destabilization associated with plasma membrane blebbing and a remodeling of focal adhesions. We further show that FERMT2 knockout podocytes have high levels of RhoA activation and concomitantly increased actomyosin contractility. Inhibition of actomyosin tension reverses the membrane blebbing phenotype. Thus, our findings establish a direct link between cell-matrix adhesions, cortical actin structures and plasma membrane tension allowing to better explain cell morphological changes in foot process effacement.

The KTx360°-study: a multicenter, multisectoral, multimodal, telemedicine-based follow-up care model to improve care and reduce health-care costs after kidney transplantation in children and adults.

BACKGROUND: Follow-up care after kidney transplantation is performed in transplant centers as well as in local nephrologist's practices in Germany. However, organized integrated care of these different sectors of the German health care system is missing. This organizational deficit as well as non-adherence of kidney recipients and longterm cardiovascular complications are major reasons for an impaired patient and graft survival. METHODS: The KTx360° study is supported by a grant from the Federal Joint Committee of the Federal Republic of Germany. The study will include 448 (39 children) incident patients of all ages with KTx after study start in May 2017 and 963 (83 children) prevalent patients with KTx between 2010 and 2016. The collaboration between transplant centers and nephrologists in private local practices will be supported by internet-based case-files and scheduled virtual visits (patient consultation via video conferencing). At specified points of the care process patients will receive cardiovascular and adherence assessments and respective interventions. Care will be coordinated by an additional case management. The goals of the study will be evaluated by an independent institute using claims data from the statutory health insurances and data collected from patients and their caregivers during study participation. To model longitudinal changes after transplantation and differences in changes and levels of immunosuppresive therapy after transplantation between study participants and historical data as well as data from control patients who do not participate in KTx360°, adjusted regression analyses, such as mixed models with repeated measures, will be used. Relevant confounders will be controlled in all analyses. DISCUSSION: The study aims to prolong patient and graft survival, to reduce avoidable hospitalizations, co-morbidities and health care costs, and to enhance quality of life of patients after kidney transplantation. TRIAL REGISTRATION: ISRCTN29416382 (retrospectively registered on 05.05.2017).

A novel signal transduction protein: Combination of solute binding and tandem PAS-like sensor domains in one polypeptide chain.

We report the structural and biochemical characterization of a novel periplasmic ligand-binding protein, Dret_0059, from Desulfohalobium retbaense DSM 5692, an organism isolated from Lake Retba, in Senegal. The structure of the protein consists of a unique combination of a periplasmic solute binding protein (SBP) domain at the N-terminal and a tandem PAS-like sensor domain at the C-terminal region. SBP domains are found ubiquitously, and their best known function is in solute transport across membranes. PAS-like sensor domains are commonly found in signal transduction proteins. These domains are widely observed as parts of many protein architectures and complexes but have not been observed previously within the same polypeptide chain. In the structure of Dret_0059, a ketoleucine moiety is bound to the SBP, whereas a cytosine molecule is bound in the distal PAS-like domain of the tandem PAS-like domain. Differential scanning flourimetry support the binding of ligands observed in the crystal structure. There is significant interaction between the SBP and tandem PAS-like domains, and it is possible that the binding of one ligand could have an effect on the binding of the other. We uncovered three other proteins with this structural architecture in the non-redundant sequence data base, and predict that they too bind the same substrates. The genomic context of this protein did not offer any clues for its function. We did not find any biological process in which the two observed ligands are coupled. The protein Dret_0059 could be involved in either signal transduction or solute transport.

[Transplant Surgeon Meets Nephrologist: Important Nephrological Aspects Before and After Kidney or Liver Transplantation]. / Abdominalchirurgie trifft Nephrologie: Wichtige nephrologische Aspekte vor und nach Nieren- bzw. Lebertransplantation.

In cases of chronic renal insufficiency, successful kidney transplantation is the method of choice to restore patients' health, well-being and physical fitness. The interdisciplinary collaboration of nephrologists and transplant surgeons has always been a prerequisite for the successful pre-, peri- and post-transplant care of renal transplant patients. The same holds true for liver transplant patients. Here the nephrologist is often involved in cases requiring pre- or post-transplant dialysis as well as in decision making for combined liver-kidney transplantation. This review focuses on nephrological aspects in patient care before and after kidney and liver transplantation.

[Chronic rejection: Differences and similarities in various solid organ transplants]. / Chronische Abstoßung: Unterschiede und Ähnlichkeiten bei verschiedenen soliden Organtransplantationen.

In this paper, chronic rejections after transplantation of the lungs, heart, liver, and kidney are described. Chronic allograft dysfunction (CAD) plays an important role in all of these transplantations and has a significant influence on patient survival. The pathophysiological reasons for CAD varies greatly in the various organs.Chronic lung allograft dysfunction (CLAD) is the most important determinant of survival and quality of life after lung transplantation. Diagnosis is based on lung function, especially forced expiratory flow in 1 s (FEV1) decline. Prevention, early detection, and rapid treatment are extremely important. Azithromycin and extracorporeal photopheresis are commonly used for treatment because they usually positively influence the progression of lung remodeling.The expression for chronic rejection of the heart is cardiac allograft vasculopathy (CAV). Immunological and nonimmunological factors are important for its development. Due to limited therapeutic options, prevention is of utmost importance (administration of mTOR inhibitors and minimizing cardiovascular risk factors).The mid- and long-term survival rates after liver transplantation have hardly changed in recent decades, which is an indication of the difficulty in diagnosing chronic graft dysfunction. Chronic ductopenic rejection accounts for a small proportion of late graft dysfunction. Idiopathic posttransplant hepatitis and de novo autoimmune hepatitis are important in addition to recurrence of the underlying disease that led to transplantation.Chronic allograft nephropathy is the result of severe rejection which cumulates in increasing fibrosis with remodeling. The earliest possible diagnosis and therapy is currently the only option. Diagnosis is based on evidence of donor-specific antibodies and histological findings.

[Rehabilitation after kidney transplantation: Old problems and new structures]. / Rehabilitation nach Nierentransplantation: Alte Probleme und neue Strukturen.

Kidney transplantation is currently the best therapeutic option for patients with end stage renal disease. Alternative treatment with hemo- or peritoneal dialysis is associated with higher comorbidities, higher morbidity/mortality, and reduced quality of life. Thus, a major aim in posttransplant care is to develop strategies to increase transplant survival and reduce known risk factors and comorbidities. In this overview, we propose a concept to include rehabilitation clinics in all aspects of the transplant process. This concept includes pretransplant care on the waiting list to prepare the patient for the transplant, the direct postoperative treatment phase, and repeated and risk adapted stays in rehabilitation clinics during long-term follow-up to address specific and individual problems.

[Prehospital analgesia by paramedics in Rhineland-Palatinate : Feasability, analgesic effectiveness and safety of intravenous paracetamol]. / Prähospitale Analgesie durch Rettungsassistenten in Rheinland-Pfalz : Praktikabilität, analgetische Wirkung und Sicherheit bei i.v.-verabreichtem Paracetamol.

BACKGROUND: In contrast to the widespread practice in life-threatening emergencies, delegation of medical pain therapy to paramedics by the medical director  of Emergency Medical Services, EMS, are still the exception in Germany. This is due to the fact that in non-life-threatening situations, the expected benefit and potential side effects of drug therapy have to be carefully weighed. In addition, in Germany federal law generally restricts the administration of opiates to physicians. METHODS: In 2011 the medical directors of EMS in the German state of Rhineland- Palatinate (4 million inhabitants) developed and implemented a standard operating procedure (SOP) for paramedics related to the prehospital parenteral administration of paracetamol for patients with isolated limb trauma. After a 2 h training session and examination, paramedics were authorized to administer 1 g of paracetamol to patients with a pain score > 5 points on an 11-point numerical rating scale (NRS). For purposes of quality management, every administration of paracetamol had to be prospectively documented on a specific electronic mission form. RESULTS: A total of 416 mission forms could be analyzed. After administration of paracetamol the median NRS score decreased from 8 points (interquartile range: 6; 8) to 4 points (interquartile range: 3; 7). In 51.2 % of the patients the pain intensity was reduced by at least 3 NRS points and in 50.5 % of the patients the NRS was less than 5 points after treatment. The extent of pain reduction was positively correlated with the initial NRS value (r = 0.31, p < 0.0001). No serious side effects were noted. The percentage of patients with an initial heart rate > 100/min declined from 14.6 % to 5.2 % after the administration of paracetamol (p < 0.0001), 18.7 % of the patients received paracetamol for trauma not related to the extremities and 7 % of the patients for nontraumatic pain. An emergency physician was involved in 50 % of the EMS missions and 98.6 % of the patients were transported to a hospital for further diagnostics and treatment. CONCLUSION: The prehospital intravenous administration of paracetamol by paramedics to patients with limb trauma is simple, safe and in 50 % of the patients effective in achieving a NRS value < 5; however, further improvements in prehospital pain therapy initiated by paramedics are desirable, especially in patients with an initial NRS value > 7.

Control over spinal nociception as quantified by the nociceptive flexor reflex (RIII reflex) can be achieved under feedback of the RIII reflex.

BACKGROUND: Descending pain modulatory systems control transmission of nociceptive information at the spinal level, and their activity can be modified by cognitive and emotional processes. Thus, it may be possible to learn using cognitive-emotional strategies to specifically target descending pathways in order to achieve pain reduction. METHODS: The present study used visual feedback of the nociceptive flexor reflex (RIII reflex) to train healthy subjects over three sessions to reduce their spinal nociception (RIII reflex size) by self-selected cognitive-emotional strategies. The study included two feedback groups (fixed vs. random stimulation intervals) and a control group without feedback (15 subjects each). RESULTS: While all three groups successfully reduced their RIII reflexes (p < 0.01), reductions were larger in the feedback groups (p < 0.05). Success increased over training sessions in the feedback groups (p < 0.05). In the third session, RIII was reduced to 90 ± 15% of baseline in the control group, and to 72 ± 24 and 66 ± 22% in the feedback groups. Most subjects used mental imagery or relaxation to achieve RIII reduction. Pain reduction correlated with RIII reduction in the feedback groups, but was not significantly different between feedback and control groups. CONCLUSIONS: The present results suggest that healthy subjects are able to learn using cognitive and emotional strategies to reduce their spinal nociception under feedback of their RIII reflex size. However, future studies will have to include a sham feedback group to differentiate true learning effects from expectancy effects induced by the feedback procedure.

CXCL13 as a new biomarker of systemic lupus erythematosus and lupus nephritis - from bench to bedside?

Different studies over the last decade have linked the B cell-attracting chemokine CXC ligand 13 (CXCL13) to the autoimmune disease systemic lupus erythematosus (SLE). A pathogenetic role of this chemokine for disease manifestation in SLE was described initially in mouse models for SLE. Mechanisms of CXCL13 actions were also identified in SLE patients. Moreover, various clinical studies have identified CXCL13 serum levels as a useful biomarker in patients with SLE of different ethnicities for disease activity. In addition, CXCL13 seems to be a promising marker for the diagnosis of lupus nephritis, one of the most severe complications of SLE. However, its exact place within the mechanisms that lead to SLE remains to be defined. Further research is needed to resolve more details of the pathomechanism and the signalling pathway of CXCL13 in SLE. Blocking CXCL13 or the signal pathways of CXCL13 is seen as a promising therapeutic approach for SLE and will be addressed in the near future. This review summarizes all papers that linked CXCL13 to SLE and highlights its importance in the pathogenesis and diagnosis of SLE.

Pathogenetic role of glomerular CXCL13 expression in lupus nephritis.

Podocytes maintain the structure and function of the glomerular filtration barrier. However, podocytes have recently been implicated in the innate immune response, and their function as non-haematopoietic antigen-presenting cells was highlighted. We have shown previously that excessive expression of the chemokine CXCL13 is a distinctive early event for nephritis in a murine model of systemic lupus erythematosus (SLE). Furthermore, we found that CXCL13 is elevated significantly in the serum of patients with SLE-nephritis. In this study, we were able to show for the first time that (i) CXCL13 is expressed locally in glomeruli in a model for SLE-nephritis in mice and that (ii) incubation of human podocytes with CXCL13 induces receptor stimulation of CXCR5 with activation of signalling pathways, resulting in (iii) secretion of proinflammatory cytokines and chemokines in culture supernatant. This cytokine/chemokine cocktail can lead to (iv) a neutrophil respiratory burst in isolated human granulocytes. Taken together, our results provide further evidence that CXCL13 is involved in the pathogenesis of glomerulonephritis and that podocytes can play an active role in local proinflammatory immune responses. Thus, CXCL13 could be a direct target for the therapy of glomerulonephritis in general and for SLE-nephritis in particular.

Insight into the sporulation phosphorelay: crystal structure of the sensor domain of Bacillus subtilis histidine kinase, KinD.

The Bacillus subtilis KinD signal-transducing histidine kinase is a part of the sporulation phosphorelay known to regulate important developmental decisions such as sporulation and biofilm formation. We have determined crystal structures of the extracytoplasmic sensing domain of KinD, which was copurified and crystallized with a pyruvate ligand. The structure of a ligand-binding site mutant was also determined; it was copurified and crystallized with an acetate ligand. The structure of the KinD extracytoplasmic segment is similar to that of several other sensing domains of signal transduction proteins and is composed of tandem Per-Arnt-Sim (PAS)-like domains. The KinD ligand-binding site is located on the membrane distal PAS-like domain and appears to be highly selective; a single mutation, R131A, abolishes pyruvate binding and the mutant binds acetate instead. Differential scanning fluorimetry, using a variety of monocarboxylic and dicarboxylic acids, identified pyruvate, propionate, and butyrate but not lactate, acetate, or malate as KinD ligands. A recent report found that malate induces biofilm formation in a KinD-dependent manner. It was suggested that malate might induce a metabolic shift and increased secretion of the KinD ligand of unknown identity. The structure and binding assays now suggests that this ligand is pyruvate and/or other small monocarboxylic acids. In summary, this study gives a first insight into the identity of a molecular ligand for one of the five phosphorelay kinases of B. subtilis.