[Rare diseases in the differential diagnosis of myalgia]. / Seltene Erkrankungen in der Differenzialdiagnose bei Myalgien.

Myalgia describes pain in the skeletal muscles. According to the current German clinical guidelines from 2020 (AWMF register number: 030/051), the initial diagnostic assessment consists of the anamnesis, clinical examination, electrophysiological examination and standard laboratory tests. Additional special examinations, such as molecular genetic investigations, special laboratory tests, medical imaging and muscle biopsy are only needed in certain cases. This article focuses on rare neurological diseases that are classically associated with myalgia. In this context etiologically different diseases are considered, whereby some genetically linked diseases (fascioscapulohumeral dystrophy, FSHD, dystrophia myotonica, McArdle's disease, Pompe's disease, limb girdle muscular dystrophy) are contrasted with diseases with an (auto)immune-related pathogenesis (stiff-person syndrome, Isaacs syndrome). The aspects relevant for the diagnosis are particularly highlighted. The therapeutic aspects of the diseases are not part of this article.

[Rare diseases in the differential diagnosis of myalgia]. / Seltene Erkrankungen in der Differenzialdiagnose bei Myalgien.

Myalgia describes pain in the skeletal muscles. According to the current German clinical guidelines from 2020 (AWMF register number: 030/051), the initial diagnostic assessment consists of the anamnesis, clinical examination, electrophysiological examination and standard laboratory tests. Additional special examinations, such as molecular genetic investigations, special laboratory tests, medical imaging and muscle biopsy are only needed in certain cases. This article focuses on rare neurological diseases that are classically associated with myalgia. In this context etiologically different diseases are considered, whereby some genetically linked diseases (fascioscapulohumeral dystrophy, FSHD, dystrophia myotonica, McArdle's disease, Pompe's disease, limb girdle muscular dystrophy) are contrasted with diseases with an (auto)immune-related pathogenesis (stiff-person syndrome, Isaacs syndrome). The aspects relevant for the diagnosis are particularly highlighted. The therapeutic aspects of the diseases are not part of this article.

[Syncope, pain in the large joints, and painful swelling of the right eye in a 51-year-old patient : Pitfalls in the diagnosis and treatment of a rare disease]. / Synkope, Schmerzen der großen Gelenke und schmerzhafte Rötung des rechten Auges bei einer 51-jährigen Patientin : Fallstricke in Diagnostik und Therapie einer seltenen Erkrankung.

In the present case we report on a 51-year-old patient diagnosed with Cogan syndrome. This vasculitis of variable vessel size is a rare disease that poses a major challenge for the correct diagnostics and therapy. In the classic setting, it comprises a triad of non-syphilitic interstitial keratitis as well as hearing loss with vestibular dysfunction. A vascultis-related aortitis, an uncertain, more likely degenerative structure in combination with strongly elevated inflammation parameters was misinterpreted as infective endocarditis for a long time and treated with anti-infective medications. After diagnosis the patient recovered following treatment with high-dose steroids and in the further course cyclophosphamide and tumor necrosis factor­α blockers.

[Fever and renal failure in a 38-year-old woman]. / Fieber und Nierenversagen bei einer 38-jährigen Patientin.

Persistent fever and sepsis require a thorough anamnesis and examination especially in women of childbearing age to determine the presence of implanted devices. We report on a case of a severe septic shock with renal failure in a 38-year-old woman triggered by an infected intrauterine device (IUD). After a symptom-free period of 4 weeks after implantation of the pessary, acute and rapidly progressive nonspecific general symptoms and fever occurred. Vaginal smears detect Staphylococcus (S.) aureus. After removal of the pessary under broad antibiotic therapy and short-term continuous veno-venous hemofiltration in combination with CytoSorb®, the patient was quickly stabilized. Within 8 days she was free of symptoms and could be transferred to a normal ward. It should be specifically noted that after receipt of the antibiogram, there was no change of treatment to flucloxacillin, which would have been more sensitive for S. Aureus.

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).

Dysregulation of lysophosphatidic acids in multiple sclerosis and autoimmune encephalomyelitis.

Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR1640 mice, and EAE in Lpar2 -/- mice. Serum LPAs were reduced in MS and EAE whereas spinal cord LPAs in TCR1640 mice increased during the 'symptom-free' intervals, i.e. on resolution of inflammation during recovery hence possibly pointing to positive effects of brain LPAs during remyelination as suggested in previous studies. Peripheral LPAs mildly re-raised during relapses but further dropped in refractory relapses. The peripheral loss led to a redistribution of immune cells from the spleen to the spinal cord, suggesting defects of lymphocyte homing. In support, LPAR2 positive T-cells were reduced in EAE and the disease was intensified in Lpar2 deficient mice. Further, treatment with an LPAR2 agonist reduced clinical signs of relapsing-remitting EAE suggesting that the LPAR2 agonist partially compensated the endogenous loss of LPAs and implicating LPA signaling as a novel treatment approach. Graphical summary of lysophosphatidic signaling in multiple sclerosis.

Alterations of the Ceramide Metabolism in the Peri-Infarct Cortex Are Independent of the Sphingomyelinase Pathway and Not Influenced by the Acid Sphingomyelinase Inhibitor Fluoxetine.

Ceramides induce important intracellular signaling pathways, modulating proliferation, migration, apoptosis, and inflammation. However, the relevance of the ceramide metabolism in the reconvalescence phase after stroke is unclear. Besides its well-known property as a selective serotonin reuptake inhibitor, fluoxetine has been reported to inhibit the acid sphingomyelinase (ASM), a key regulator of ceramide levels which derives ceramide from sphingomyelin. Furthermore, fluoxetine has shown therapeutic potential in a randomized controlled rehabilitation trial in stroke patients. Our aim was to investigate and modulate ceramide concentrations in the peri-infarct cortex, whose morphological and functional properties correlate with long-term functional outcome in stroke. We show that certain ceramide species are modulated after experimental stroke and that these changes do not result from alterations of ASM activity, but rather from nontranscriptional induction of the ceramide de novo pathway. Unexpectedly, although reducing lesion size, fluoxetine did not improve functional outcome in our model and had no significant influence on ASM activity or the concentration of ceramides. The ceramide metabolism could emerge as a potential therapeutic target in the reconvalescence phase after stroke, as its accumulation in the peri-infarct cortex potentially influences membrane functions as well as signaling events in the tissue essential for neurological recovery.

[Glial fibrillary acidic protein in patients with symptoms of acute stroke: diagnostic marker of cerebral hemorrhage]. / Saures Gliafaserprotein beim Patienten mit akuten Schlaganfallsymptomen : Diagnostischer Marker einer Hirnblutung.

Glial fibrillary acidic protein (GFAP) is a highly brain-specific protein that is expressed in large quantities in astrocytes and has important functions in terms of maintaining and stabilizing the cytoskeleton. Acute intracerebral hemorrhage leads to an immediate mechanical destruction of astroglial cells with the subsequent release of GFAP into the extracellular space and the bloodstream. On the other hand, necrosis, cytolysis and GFAP release does not occur before 6-12 h after symptom onset in ischemic stroke. Thus, in the early hours after stroke increased GFAP values could indicate intracerebral hemorrhage. This review article describes the underlying pathophysiology of the test and guides the reader through the available data. Potential implications regarding the prehospital triage of acute stroke patients are discussed, including the possibility to initiate hyperacute treatment, such as blood pressure reduction in patients with intracerebral hemorrhage. Other areas of interest for a potential GFAP test include traumatic brain injury and malignant gliomas.

[Mineral and bone disorder in chronic kidney disease : Critical appraisal of pharmacotherapy]. / Störungen des Mineralstoffwechsels bei chronischer Nierenerkrankung : Kritische Würdigung der Arzneitherapie.

BACKGROUND: Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is associated with increased cardiovascular calcification and mortality. Pharmacological interventions for MBD in CKD are characterized by inconsistent data and a wide spectrum of (sometimes costly) treatment options. The objective of this article is a guideline-oriented overview of the differential indications for pharmacotherapy considering cost-effectiveness. CURRENT DATA: The serum phosphate concentration in patients with CKD stages 3-5 with a glomerular filtration rate (GFR) of < 45 ml/min should be kept within the normal range. Currently, under consideration of cost-effectiveness, calcium-containing phosphate binders and combinations of calcium acetate with magnesium carbonate are the preferred treatment options. Phosphate binders free of calcium are indicated in patients with high normal or elevated serum calcium levels. Low vitamin D concentrations in CKD stages 3-5 should be treated under consideration of serum calcium and parathyroid hormone (PTH) with calcidiol (25-cholecalciferol) and in dialysis patients (CKD 5D) with calcitriol (1,25 dihydroxycholecalciferol, activated vitamin D). In CKD the PTH levels should be kept in the range of 2-9-times the upper limit of normal levels. This is achieved by administration of phosphate binding drugs, activated vitamin D, calcimimetic compounds and parathyroidectomy. In CKD stages 3-5 patients metabolic acidosis with < 22 mmol/l serum bicarbonate should be treated with oral sodium bicarbonate. CONCLUSION: In MBD of CKD patients an individualized pharmacotherapy which is closely guideline-oriented is required in order to achieve cost-effectiveness.

[Dialysis and ultrafiltration therapy in patients with cardio-renal syndrome: recommendations of the working group "heart-kidney" of the German Cardiac Society and the German Society of Nephrology]. / Dialyse- und Ultrafiltrationsverfahren bei kardio-renalem Syndrom. Empfehlung der Arbeitsgemeinschaft "Herz--Niere" der Deutschen Gesellschaft für Kardiologie--Herz- und Kreislaufforschung e.V. und der Deutschen Gesellschaft für Nephrologie e.V.

Renal failure is common in patients with severe heart failure. This complex pathophysiological interaction has been classified as cardio-renal syndrome. In these patients hydropic decompensation is the main cause of hospitalization. In patients with refractory heart failure, characterized by diuretic resistance and congestion due to volume overload, ultrafiltration has to be considered. In acute decompensated heart failure with worsening of renal function, extracorporeal ultrafiltration is the preferred treatment modality. On the other hand, patients suffering from chronic decompensated heart failure, particularly patients with ascites, will profit from the treatment specific advantages of peritoneal ultrafiltration. Prerequisite for an optimized care of patients with cardio-renal syndrome is the close collaboration among intensive care doctors, cardiologists and nephrologists.

Hyperemesis and a high water bill.

A male patient aged 28 years was admitted with hyperemesis that did not cease in spite of different therapeutic approaches and had persisted for several days. A wide range of differential diagnoses was excluded and all tests remained without pathological findings. He reported regular cannabis use and showed abnormal bathing behavior taking hot showers several times a day for more than one hour each, which was the only measure to ease his nausea; on the basis of these clinical findings, the diagnosis of cannabinoid hyperemesis syndrome was made. After detoxification, he remained free of symptoms. Cannabinoid hyperemesis syndrome was first described in 2004 in Australia and is an underrecognized cause of hyperemesis and abnormal bathing behavior. To the best of our knowledge, this is the first reported case in Germany.

[Circulatory disorders of the renal and mesenteric arteries]. / Durchblutungsstörungen der Nieren- und Mesenterialarterien.

Symptomatic mesenteric circulatory disorders are potentially life-threatening diseases with an increasing frequency due to the demographic population development. Renal artery stenosis is a well accepted cause of hypertension or at least deterioration of blood pressure control as well as the cause of a progressive course of renal insufficiency if of an atherosclerotic nature. Further consequences of renal artery stenosis, such as left ventricle hypertrophy and hypertensive encephalopathy are topics of recent research. Due to progress in percutaneous techniques during the last decade interventional therapy has replaced surgery as the treatment method of choice for lesions located near the origin. The only randomized study comparing endovascular stent revascularization with best medical therapy (ASTRAL) failed to show a benefit of revascularization of renal artery stenoses.

Hypervolemia, arterial hypertension and cardiovascular disease: a largely neglected problem in peritoneal dialysis.

Here we review the existing data on hypertension, volume overload and volume control in peritoneal dialysis (PD) patients and comment on the impact of these factors on residual renal function and cardiovascular disease in PD patients.

Long-term comparison of a calcium-free phosphate binder and calcium carbonate--phosphorus metabolism and cardiovascular calcification.

BACKGROUND: Calcium carbonate used as a phosphate binder may contribute to cardiovascular calcification. Long-term comparisons of sevelamer, a non-calcium polymeric phosphate binder, and calcium carbonate (CC) are lacking. METHODS: 114 adult hemodialysis patients were randomly assigned to open label sevelamer or CC for 52 weeks. Study efficacy endpoints included changes in serum phosphorus, calcium, calcium-phosphorus product, and lipids. In addition, initial and sequential electron beam computerized tomography scans were performed to assess cardiovascular calcification status and change during follow-up. Safety endpoints were serum biochemistry, blood cell counts and adverse events. RESULTS: Patients receiving sevelamer had a similar reduction in serum phosphorus as patients receiving CC (sevelamer -0.58 +/- 0.68 mmol/l, CC -0.52 +/- 0.50 mmol/l; p = 0.62). Reductions in calcium-phosphorus product were not significantly different (sevelamer -1.4 +/- 1.7 mmol2/l2, CC -0.9 +/- 1.2 mmol2/l2; p = 0.12). CC produced significantly more hypercalcemia (> 2.8 mmol/l in 0% sevelamer and 19% CC patients, p < 0.01) and suppressed intact parathyroid hormone below 150 pg/ml in the majority of patients. Sevelamer patients experienced significant (p < 0.01) reductions in total (-1.2 +/- 0.9 mmol/l, -24%) and LDL cholesterol (-1.2 +/- 0.9 mmol/l, -30%). CC patients had significant increases in coronary artery (median +34%, p < 0.01) and aortic calcification (median +32%, p < 0.01) that were not observed in sevelamer-treated patients. Patients on sevelamer required more grams of binder (sevelamer 5.9 g vs. CC 3.9 g) and experienced more dyspepsia than patients on calcium carbonate. CONCLUSIONS: Sevelamer is an effective phosphate binder that unlike calcium carbonate is not associated with progressive cardiovascular calcification in hemodialysis patients.

Cardiovascular morbidity and mortality in patients with diabetes mellitus type I after kidney transplantation: a case-control study.

BACKGROUND: The proportion of diabetics among patients requiring renal replacement therapy continues to increase in most western countries. The acceptance rate for renal transplantation varies among transplant centers and is influenced by the current opinion on the outcome of transplantation in diabetics. Controlled data on patient and graft survival in type I diabetics, however, are scarce. METHODS: We performed a retrospective case-control analysis on patient and graft survival and the cardiovascular morbidity of patients with type I diabetes after renal transplantation versus carefully matched non-diabetic transplant recipients. Match criteria were duration of previous hemodialysis, age and date of renal transplantation. Moreover, risk factors for cardiovascular disease in uremic patients were evaluated at the time of registration for renal transplantation and at the end of the observation period. RESULTS: Seventy-seven matched pairs were enclosed. Patient survival was significantly worse in the diabetic patients, graft survival was comparable in both groups, when graft loss because of patient's death was censored. In the diabetic patients, risk of death (odds ratio: 4.38) as well as the prevalence of cardiovascular morbidity (odds ratio: 4.47) were significantly higher than in the matched nondiabetic controls. Cox regression analysis showed that diabetes mellitus was an independent risk factor for patient survival; no association was found with hypertension, hyperlipidemia, hyperparathyroidism, calcium x phosphate product, body mass index and HbA1c. Cardiovascular morbidity, however, was already significantly higher in the diabetic group at the time of registration. CONCLUSIONS: Diabetes mellitus type I has a dominant impact on morbidity and mortality after renal transplantation and is associated with an approximately 4-fold higher risk of death. Cardiovascular disease accounts for the significantly worse long-term outcome of diabetic patients after renal transplantation.

Endothelial tissue factor stimulation by proteinase 3 and elastase.

In ANCA-associated vasculitis the activation of primed leucocytes by autoantibodies with subsequent release of proteases such as myeloperoxidase (MPO), proteinase 3 (PR3) and elastase is thought to play an important pathogenetic role. Whether these proteases contribute to the vascular lesions by stimulating the procoagulant activity of these cells is unknown. Tissue factor (TF) expression and activity were investigated in human umbilical vein endothelial cells after stimulation with MPO, PR3 and elastase. TF activity was measured using a one-stage clotting assay. Polyclonal antibodies to TF were used to prove specificity. TF mRNA was detected by reverse transcriptase-polymerase chain reaction. PR3 and elastase led to a significant increase in TF mRNA expression and increased activity. The stimulation was not mediated by IL-1. The stimulatory effect of PR3 did not depend on its proteolytic activity (no inhibition by alpha-1-antitrypsin), whereas the effect of elastase was blocked by alpha-1-antitrypsin. MPO had no effect on TF activity. These results show that PR3 and elastase stimulate TF expression in human endothelial cells. In ANCA-associated vasculitis the increased release of proteases may contribute to the development of microthrombi and consecutive necrosis.

C-reactive protein and chronic Chlamydia pneumoniae infection--long-term predictors for cardiovascular disease and survival in patients on peritoneal dialysis.

BACKGROUND: Accelerated arteriosclerosis with cardiovascular disease is the main cause of death in end-stage renal disease patients. Increased, levels of C-reactive protein (CRP) and evidence of chronic Chlamydia pneumoniae infection have been identified as risk factors for cardiovascular disease in the general population. We tested the hypothesis that elevation of CRP, indicating chronic inflammation, and positive serum antibody titres for C. pneumoniae are associated with an increased cardiovascular mortality in patients on chronic peritoneal dialysis. METHODS: We measured CRP and antibodies to C. pneumoniae in 34 patients on peritoneal dialysis. CRP was measured by a sensitive ELISA and C. pneumoniae antibodies by microimmunofluorescence. In addition, risk factors such as lipids, smoking status and hypertension were assessed. Coronary artery disease (CAD) was defined by cardiac stress testing and/or angiography. Patients showing clinical evidence of systemic or peritoneal dialysis-associated infection during the investigation period of 6 months (between 1990 and 1991) were excluded. RESULTS: The incidence of CAD was significantly increased in patients with CRP values >1.5 mg/l (odds ratio 7.0, P<0.022) during 72 months of follow-up. In addition, in patients seropositive for IgA C. pneumoniae antibodies, the incidence of CAD was significantly increased (odds ratio 7.2, P<0.014). These findings resulted in an increased risk of death in patients with mean CRP values >1.5 mg/l at the start of the study (odds ratio 20.0, P<0.001). Furthermore, in patients seropositive for IgA C. pneumoniae antibodies, the risk of death (odds ratio 10.2, P<0.005) was significantly increased. There was a highly significant correlation between CRP and seropositivity for IgA C. pneumoniae antibodies (r=0.445, P<0.01). CONCLUSIONS: Increased circulating CRP and seropositivity for C. pneumoniae in patients on chronic peritoneal dialysis are associated with reduced survival due to cardiovascular complications. CRP and C. pneumoniae antibodies may indicate a chronic inflammatory process as an underlying cause and/or result of arteriosclerosis.

Native pyeloureterostomy after kidney transplantation: experience in 48 cases.

Necrosis and stenosis of the ureter are severe complications after kidney transplantation and occur with mean incidence of 2,9-13,4 %. Several surgical techniques like simple nephrostomy or complex urinary tract reconstruction have been applied for repair. In this study, our experience with native pyeloureterostomy (NPUS) using the native ureter is presented. Between March 1978 and June 1996, 2,592 kidney transplantations were performed in our institution. In 48 patients (1,9%), secondary urinary tract reconstruction by NPUS was necessary. These patients were evaluated retrospectively by review of the case notes. At the time of operation the mean age was 45 +/- 14 years. Indications for NPUS were distal ureteral stenosis (n = 29), necrosis (n = 17), bleeding (n = 1) or iatrogenic lesion of the ureter (n = 1). The mean time period between transplantation and urinary tract reconstruction was 20 +/- 23 days (range: 1-90 days) for necrosis and 404 +/- 637 days (range: 14-2,385 days) for stenosis. A pyeloureterostomy was technically feasible in all patients using the recipient's ipsilateral ureter. In 40 out of 48 patients the graft developed a normal function postoperatively (follow up: 39 +/- 48 months). A graft nephrectomy was necessary only in one patient, because of complete pyelonnecrosis 6 days after NPUS. Two grafts were lost due to acute rejection. Data of five patients were not available > 15 years after successful reconstruction. We can conclude that NPUS is a safe and simple rescue technique for the treatment of distal ureteral complications after kidney transplantation. Therefore, this technique should be the therapy of choice when secondary reconstruction by re-ureteroneocystostomy is not possible.