Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations.

BACKGROUND: Patients with autosomal or X-linked Alport syndrome (AS) with heterozygous mutations in type IV collagen genes have a 1-20 % risk of progressing to end-stage renal disease during their lifetime. We evaluated the long-term renal outcome of patients at risk of progressive disease (chronic kidney disease stages 1-4) with/without nephroprotective therapy. METHODS: This was a prospective, non-interventional, observational study which included data from a 4-year follow-up of AS patients with heterozygous mutations whose datasets had been included in an analysis of the 2010 database of the European Alport Registry. Using Kaplan-Meier estimates and logrank tests, we prospectively analyzed the updated datasets of 52 of these patients and 13 new datasets (patients added to the Registry after 2011). The effects of therapy, extrarenal symptoms and inheritance pattern on renal outcome were analyzed. RESULTS: The mean prospective follow-up was 46 ± 10 months, and the mean time on therapy was 8.4 ± 4.4 (median 7; range 2-18) years. The time from the appearance of the first symptom to diagnosis was 8.1 ± 14.2 (range 0-52) years. At the time of starting therapy, 5.4 % of patients had an estimated glomerular filtration rate of <60 ml/min, 67.6 % had proteinuria and 27.0 % had microalbuminuria. Therapeutic strategies included angiotensin-converting enzymer inhibitors (97.1 %), angiotensin receptor antagonists (1 patient), dual therapy (11.8 %) and statins (8.8 %). Among patients included in the prospective dataset, prevented the need for dialysis. Among new patients, no patient at risk for renal failure progressed to the next disease stage after 4 years follow-up; three patients even regressed to a lower stage during therapy. CONCLUSIONS: Treatment with blockers of the renin-angiotensin-aldosterone system prevents progressive renal failure in AS patients with heterozygous mutations in the genes causing AS. Considerable numbers of aging AS patients on dialysis may have heterozygous mutations in these genes (present in 1 % of total population) as underlying disease. Hence, greater alertness towards timely diagnosis and therapy has the potential to prevent progressive renal failure in most-if not all-AS patients with heterozygous mutations in the causal genes.

Influence of dietary amino acid level on chemical body composition and performance of growing-finishing boars of two sire lines.

There is only little information available concerning the chemical body composition of growing-finishing boars. For that reason, a total of 26 entire male pigs (boars) of two different Piétrain sire lines were fed with different levels of dietary essential amino acids (EAA) and the influence of this treatment on performance and chemical body composition was evaluated. In addition, an initial group of eight boars (n = 4 per sire line) was slaughtered at approximately 21 kg live weight (LW). The other 26 boars were fed three different diets containing 11.5, 13.2 and 14.9 g lysine/kg during the grower period and 9.0, 10.4, 11.7 g lysine/kg during the finisher period, respectively. Other EAA were added in relation to lysine (Lys: Met + Cys: Thr: Trp: Val = 1: 0.60: 0.65: 0.18: 0.75). At a LW of approximately 122 kg these 26 boars (six groups with three to seven animals each) were also slaughtered. The effects of EAA level and sire line on fattening and slaughter performance was recorded, and body and weight gain composition were analysed. There were no significant effects of EAA level on performance or on chemical body composition. Boars sired with Piétrain line 1 demonstrated increased lean meat content and protein body content (p < 0.05) as compared to Piétrain line 2-sired boars.

Stepwise Reduction of Dietary Phosphorus in Diets for Piglets and Fattening Pigs of Different Genetic Origin Housed under Various Station Environments-A Ringtest.

The reduction of emissions of nutrients from livestock is one of the main topics in areas with intensive animal husbandry. In order to minimize the loss of nutrients into the environment, it is common practice to feed animals as close as possible to metabolic demands. For phosphorus (P), there are various studies for swine and poultry, which showed that a reduction of dietary P levels is possible, if a sufficient level of phytase is added to the diet. The supplementation of a sufficient dosage of phytase to plant-based diets leads to an increase in digestible phosphorus (dP) upon the hydrolisation of phytate (InsP6) to P and lower inositol-phosphates. However, most of these studies were conducted under standardized experimental conditions. In terms of transfer to practical conditions with varying housing, management and genetics, there are concerns that have led to speculation by farmers and veterinarians whether the reduction of dietary P could negatively affect bone health and therefore animal welfare. In order to test whether a reduction of dietary P according to the recommendations for dP of the German Society of Nutrition Physiology (GfE) affects bone mineralization and growth performance, a ringtest was conducted where piglets and fattening pigs were fed at four experimental stations with three centrally produced diets from the same batches. The diets contained three different levels of P and were designed to reflect practical diets. The P level decreased from diet one to three, respectively. Diets one and two were calculated to contain P levels, which are typically fed under practical conditions in Germany. The third diet was optimized to fulfill the requirements of dP by the GfE. The animals were fed in two phases as post-weaning piglets (8-15 kg and 15-28 kg BW) followed by a three-phase fattening regime (28-60 kg, 60-90 kg and 90-120 kg BW). Individual body weight and feed consumption (pen basis or individually, depending on the experimental station) were recorded for every feeding phase. At the end of the experiment, animals were slaughtered. At one experimental station, additional blood serum, metatarsi of the left leg and kidney tissue were sampled to analyze serum P concentration, expression of P transporters in the kidney and bone traits. In two experimental stations, femur and vertebra were sampled, and bone ash was determined. Overall, animal performance and all other traits analyzed did not differ between the treatment with the highest and the treatment with the lowest dietary P concentration. The results demonstrate that it is possible to decrease dietary P according to the recommendations for dP of the GfE, without impairing the animals' performance or mineral homeostasis and health. A reduction of total P by reducing mineral P to the levels of the present study require the supplementation of phytase to achieve sufficient concentrations of dP.

Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations.

We studied here the clinical course of heterozygous carriers of X-linked Alport syndrome and a subgroup of patients with thin basement membrane disease due to heterozygous autosomal recessive Alport mutations whose prognosis may be worse than formerly thought. We analyzed 234 Alport carriers, including 29 with autosomal recessive mutations. Using Kaplan-Meier estimates and log-rank tests, autosomal and X-linked carriers were found to have similar incidences of renal replacement therapy, proteinuria, and impaired creatinine clearance. Further, age at onset of renal replacement therapy did not differ between X-chromosomal and autosomal carriers. Both groups showed an impaired life expectancy when reaching renal replacement therapy. RAAS inhibition significantly delayed the onset of end-stage renal failure. Not only carriers of X-linked Alport mutations but also heterozygous carriers of autosomal recessive mutations were found to have an increased risk for worse renal function. The risk of end-stage renal disease in both groups affected life expectancy, and this should cause a greater alertness toward patients presenting with what has been wrongly termed 'familial benign hematuria.' Timely therapy can help to delay onset of end-stage renal failure. Thus, yearly follow-up by a nephrologist is advised for X-linked Alport carriers and patients with thin basement membrane nephropathy, microalbuminuria, proteinuria, or hypertension.

Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Living donor kidney transplantation from relatives with mild urinary abnormalities in Alport syndrome: long-term risk, benefit and outcome.

BACKGROUND: Alport syndrome is a hereditary nephropathy leading to renal failure during adolescence. This study evaluates the outcome of living donor transplantation (Tx) from heterozygous mothers to their affected children. METHODS: Seven mothers were evaluated, and donation was refused in one because of proteinuria. RESULTS: All of the remaining six donors had microhaematuria, and one had proteinuria. Renal function was monitored after Tx (average 6.7 years in donors and 5.3 years in acceptors). Three of six donors developed new onset hypertension, and two new onset of proteinuria. Renal function declined significantly in four donors: (1) -35% after 2 years; (2) -25% after 3 years; (3) -30% after 4 years and (4) -60% after 14 years versus before Tx. However, creatinine clearance remained >40 ml/min in all donors. All transplanted kidneys worked well 1 and 5 years after Tx, and one failed after 10 years. One patient died from meningitis, and the remaining four remained stable. CONCLUSION: Living donor Tx from relatives in Alport families is an ambivalent option. Proteinuria should be an exclusion criterion. Yet, even in donors with isolated microhaematuria, families and their physicians should be aware of an increased risk of renal failure in donor and recipient. This risk might be minimized by careful donor evaluation including biopsy and nephroprotective strategies after Tx in both donor and recipient.

Cost effectiveness of enoxaparin as prophylaxis against venous thromboembolic complications in acutely ill medical inpatients: modelling study from the hospital perspective in Germany.

OBJECTIVE: To estimate, from the hospital perspective in Germany, the cost effectiveness of the low-molecular-weight heparin (LMWH) subcutaneous enoxaparin sodium 40 mg once daily (ENOX) relative to no pharmacological prophylaxis (NPP) and relative to subcutaneous unfractionated heparin (UFH) 5,000 IU three times daily (low-dose UFH [LDUFH]). Each is used in addition to elastic bandages/compression stockings and physiotherapy in the prevention of venous thromboembolic events (VTE) in immobilised acutely ill medical inpatients without impaired renal function or extremes of body weight. METHODS: The incremental cost-effectiveness ratios (ICERs) of the 'additional cost for ENOX per clinical VTE avoided versus NPP' and 'additional cost for ENOX per episode of major bleeding avoided versus LDUFH' were chosen as target variables. The target variables were quantified using a modelling approach based on the decision-tree technique. Resource use during thromboprophylaxis, diagnosis and treatment of VTEs, episode of major bleeding and secondary pneumonia after pulmonary embolism (PE) was collected from a hospital survey. Costs were exclusively those to hospitals incurred by staff expenses, drugs, devices, disposables, laboratory tests and equipment for diagnostic procedures. These costs were determined by multiplying utilised resource items by the price or tariff of each item as of the first quarter of 2003. Safety and efficacy values of the comparators were taken from the MEDENOX (prophylaxis in MEDical patients with ENOXaparin) and the THE-PRINCE (THromboEmbolism-PRevention IN Cardiac or respiratory disease with Enoxaparin) trials and from a meta-analysis. The evaluation encompassed 8 (6-14) days of thromboprophylaxis plus time to treat VTE and episode of major bleeding in hospital. Point estimates of all model parameters were applied exclusively in the base-case analysis. RESULTS: There were incremental costs of euro 1,106 for ENOX per clinical VTE avoided versus NPP (1 euro approximately equals 1.07 US dollars; average of the first quarter of 2003). ENOX dominated LDUFH: cost savings of euro 55,825 were obtained and 7.7 episodes of major bleeding were avoided by ENOX compared with LDUFH, each per 1000 patients. In comprehensive sensitivity analyses, the robustness of the model and its results was shown. CONCLUSIONS: Results of this evaluation suggest that, in immobilised acutely ill medical inpatients, ENOX may offer hospitals in Germany a very cost-effective option for thromboprophylaxis compared with NPP and a cost-saving alternative compared with LDUFH.

Rho/Rho kinase pathway regulates maintenance of the differentiated tubular epithelial cell phenotype on laminin-1.

BACKGROUND: Maintenance of a polarized tubular epithelium by appropriate intracellular signaling and extracellular matrix is critical both in normal renal function as well as in acute and chronic tubular injury. We examined the hypothesis that maintenance of a differentiated epithelial phenotype on the basement membrane glycoprotein laminin-1 is controlled by the Rho/Rho kinase pathway. METHODS: Using the tubular epithelial cell lines LLC-PK1 and MDCK which were cultured on laminin-1 vs. collagen IV, we analyzed cell morphology and motility (cohort migration assay) as well as expression of differentiation and dedifferentiation markers (immunofluorescence microscopy). RESULTS: Cohort migration of LLC-PK1 cells was significantly slowed down on laminin-1 (10.7 +/- 2.2 m.u. (migratory units)) compared with collagen IV (16.6 +/- 2.3 m.u.; BSA control: 2.8 +/- 2.5 m.u.). Inhibition of the Rho/Rho kinase pathway by C3 exotoxin (1 mug/ml) or the Rho kinase inhibitor Y27632 (10 microM) significantly augmented cohort migration on laminin-1 (14.5 +/- 1.4 and 16.0 +/- 1.8 m.u. vs. 10.7 +/- 2.2 m.u.). In parallel to the increased migratory activity, inhibition of the Rho/Rho kinase pathway resulted in a more mesenchymal phenotype of LLC-PK1 cells on laminin-1 with increased formation of lamellopodia and filopodia, distinct loss of focal contacts and stress fibers, upregulation of the dedifferentiation marker vimentin, and loss of cell-cell contacts with translocation of beta-catenin from the adherens junctions to the cytosol and nucleus. Similarly, cohort migration of MDCK cells was retarded on laminin-1 when compared with collagen IV, and addition of the Rho kinase inhibitor Y27632 resulted in enhanced motility and a change in cell morphology. CONCLUSION: The study demonstrates that the Rho/Rho kinase pathway is required to maintain a non-migratory epithelial phenotype of cultured renal tubular LLC-PK1 and MDCK cells on the basement membrane glycoprotein laminin-1.

[Characterization of proteinuria in patients with ulcerative colitis and therapy with aminosalicylates]. / Charakterisierung der Proteinurie bei Patienten mit Colitis ulcerosa unter der Behandlung mit Aminosalicylaten.

BACKGROUND AND PURPOSE: Patients with ulcerative colitis have a higher rate of tubular nephropathies. Data concerning the cause of these lesions is rare and inconsistent, the occurrence may be part of the disease itself or a side effect of 5-aminosalicylates (5-ASA). This study investigated proteinuria and eosinophiluria in patients with moderate ulcerative colitis under treatment with 5-ASA. PATIENTS AND METHODS: Urine specimens (microelectrophoresis and eosinophiluria) of 34 patients with acute onset of moderate ulcerative colitis who were treated only with 5-ASA as active drug were analyzed. RESULTS: Data of 27 patients could be evaluated. Twelve patients had tubular proteinuria previous to treatment. By the end of the study, urine specimens normalized in six, in further six the proteinuria remained unaltered, two patients developed proteinuria under treatment. In 14 patients, proteinuria was not detectable at any time. Eosinophiluria was found in none of the specimens. CONCLUSION: Under treatment with 5-ASA no toxic or allergic nephropathy developed. One initially pathologic urine specimen normalized under treatment coming along with remission of the intestinal symptoms and histological findings. This indicates an association between the activity of the ulcerative colitis and might be caused by renal excretion of pro-inflammatory cytokines.

Vasoactive Therapy in Systemic Sclerosis: Real-life Therapeutic Practice in More Than 3000 Patients.

OBJECTIVE: Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry. METHODS: The data of 3248 patients with SSc were analyzed. RESULTS: Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005. CONCLUSION: These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.

Differential regulation of smooth muscle markers in human bone marrow-derived mesenchymal stem cells.

OBJECTIVE: To study smooth-muscle differentiation and de-differentiation of human bone marrow-derived mesenchymal stem cells (MSCs), which have been shown to enter the circulation and to contribute to vascular repair and atherosclerosis. DESIGN: Human MSCs from bone marrow were cultured with 20% fetal calf serum (FCS) or with 10% FCS and various concentrations of dimethyl sulfoxide (DMSO). Expression of smooth muscle markers was determined by Western blot analysis and immunofluorescence. For signalling studies, involvement of the mammalian target of rapamycin (mTOR) pathway was tested by treatment with rapamycin. RESULTS: MSCs cultured with 20% FCS acquired a smooth muscle-like appearance and expressed the smooth muscle (sm) markers sm-alpha-actin, desmin, sm-calponin and myosin light chain kinase (MLCK). DMSO induced a spindle-like morphology with marked reduction of stress fibers. As judged by Western blot analysis, treatment with 2.5% DMSO strongly downregulated expression of sm-calponin (-85%), short MLCK (-98%) and sm-alpha-actin expression (-51%). Reduced calponin expression was detected by day 2 of treatment with 0.5-2.5% DMSO. After withdrawal of DMSO, MSCs regained high expression of sm-calponin. Treatment with 6 nmol/l rapamycin partly antagonized the effect of DMSO, indicating the involvement of mTOR in regulation of the smooth muscle phenotype of MSCs. CONCLUSIONS: DMSO strongly downregulates the smooth muscle markers sm-calponin, short MLCK and sm-alpha-actin in human MSCs, indicating a transition from a smooth muscle-like phenotype to an undifferentiated state by an mTOR-dependent mechanism. Regulating the phenotype of human MSCs may be of relevance for novel therapeutic approaches in atherosclerosis and intimal hyperplasia after vascular injury.

Identification of a new tumor suppressor gene located at chromosome 8p21.3-22.

Transformation of normal cells into malignant tumor cells, a process termed carcinogenesis, depends on progressive acquisition of genetic alterations. These result in activation of protooncogenes or inactivation of tumor suppressor genes responsible for the loss of proliferative control in tumor cells and the failure to undergo cellular differentiation. The aim of our study was the identification of molecular regulators of carcinogenesis by studying gene expression during induction of cellular differentiation and quiescence in a three-dimensional (3D) cell culture model. Here, we report the discovery of a tumor suppressor gene located at chromosome 8p21.3-22 near marker D8S254. It is ubiquitously expressed in normal tissue and transiently up-regulated during initiation of cellular differentiation and quiescence in 3D cell culture. In contrast, mRNA expression was not detectable in tissue from pancreatic tumor and the pancreatic tumor cell line MIA PaCa-2. Recombinant expression in the tumor cell line MIA PaCa-2 inhibited proliferation, as shown by a 30% reduction of BrdU uptake after recombinant expression. Immunocytochemistry and Western blot analysis of subcellular fractions demonstrated a mitochondrial localization for the mature protein. In conclusion, we identified a tumor suppressor gene at chromosome 8p21.3-22, encoding a mitochondrial protein, controlling cellular proliferation.

[From the molecular genetics of Alport's syndrome to principles of organo-protection in chronic renal diseases]. / Von der Molekulargenetik des Alport-Syndroms zu Prinzipien der Organprotektion bei chronischen Nierenerkrankungen.

BACKGROUND: Scarring is known to be the endpoint of most chronic kidney diseases. Therefore, prevention of renal fibrosis is a very important topic. The hereditary type IV collagen disease Alport's syndrome is a rare, but challenging cause of chronic renal fibrosis. PATHOGENESIS OF GLOMERULAR AND INTERSTITIAL RENAL FIBROSIS IN HUMANS: Increasing knowledge about the pathogenesis of Alport's syndrome may help to find principles of nephro-protection in chronic renal diseases. The defect gene in Alport's syndrome causes an altered assembly of extracellular matrix leading to a defect cell-matrix interaction and fibrosis. This scarring is regulated by comparable mechanisms as in diabetic nephropathy or chronic inflammatory renal diseases. NEPHRO-PROTECTION IN ANIMAL MODELS: By using an Alport animal model of chronic renal fibrosis, principles of nephro-protective therapies such as blockade of the renin-angiotensin system or the effect of HMG-CoA reductase inhibitors can be investigated. CURRENT AND FUTURE NEPHRO-PROTECTION IN HUMANS: The same model serves for evaluation of new organo-protective therapies such as vasopeptidase inhibitors, blockade of endothelin, chemokine and collagen receptors as well as stem cell therapy and their potential benefit for patients with chronic renal diseases.

[The Jo-1 Syndrome--immunological findings and clinical manifestations]. / Das Jo-1-Syndrom und seine klinischen Manifestationen.

El The Jo-1 syndrome is an autoimmune disease which is characterized by the presence of autoantibodies against the Jo-1 antigen. The designation Jo-1 is derived from the name of the first patient (John P.) who was tested positive for this antibody. This patient suffered from polymyositis and fibrosing alveolitis. The Jo-1 antigen was identified as histidyl-transfer-RNA synthetase present in the cytosol. The Jo-1 syndrome is a member of a family of autoimmune diseases, called anti-synthetase syndromes. These syndromes are characterized by autoantibodies directed against aminoacyl-transfer-RNA synthetases. The etiology of the Jo-1 syndrome is unknown. The most frequent clinical manifestation is myositis, which may present as polymyositis or dermatomyositis. In addition to muscle involvement, interstitial lung disease is frequently found and critical for the prognosis. Furthermore, symptoms of other autoimmune disorders such as polyarthritis may occur. Similar to polymyositis and dermatomyositis, the Jo-1 syndrome may present as myositis overlap syndrome. In these cases, antibodies against U1-RNP are detected. The Jo-1 syndrome responds to treatment with corticosteroids and, if necessary, azathioprine, methotrexate or cyclophosphamide. The clinical manifestations of the Jo-1 syndrome are illustrated by two clinical cases.

[Successful treatment of a severe case of idiopathic pulmonary fibrosis with rapamycin]. / Erfolgreiche Rapamycin--Therapie bei idiopathischer pulmonaler Fibrose (IPF) im Präfinalstadium.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder of the lower respiratory tract. The main clinical feature is a progressive shortness of breath, particularly on exercise. An overproduction and deposition of collagen and a proliferation of mesenchymal cells are the histopathologic characteristics. Rapamycin is an immunosuppressive agent with antiproliferative effects on mesenchymal cells including fibroblasts. It was this rationale that prompted the authors to administer rapamycin in a case of rapidly progressive IPF. CASE REPORT: In a 73-year-old female with a 2-month history of IPF, treatment with steroids and interferon gamma-1b did not improve the detrimental clinical course. Treatment with rapamycin was started; subsequently, clinical condition and objective findings improved markedly within weeks. She is now under treatment for 18 months. CONCLUSION: The authors presume that partial remission is related to rapamycin which may be effective in blocking the progressive fibrosis and increased collagen synthesis thought to be pathophysiologically relevant in this disease. Further studies have to show whether rapamycin may be a treatment option in idiopathic pulmonary fibrosis.

[Atypical headache and facial pain as a result of hypertrophic pachymeningitis in C-ANCA-positive Wegener's granulomatosis]. / Atypischer Kopf- und Gesichtsschmerz infolge hypertropher Pachymeningitis bei c-ANCA positivem Morbus Wegener.

BACKGROUND: Wegener's granulomatosis (WG) is a systemic vasculitis involving the nervous system in 20-54% of cases; lesions of peripheral nerves are commonest, while manifestation in the central nervous system (CNS) is rarer. Focal hypertrophic pachymeningitis is a very rare complication of WG. This inflammatory thickening and fibrosis of the dura mater is always associated with headaches, whereas cranial nerve lesions, cerebellar symptoms or epileptic seizures occur more rarely. CASE REPORT: A 67-year-old patient, in whom WG had been diagnosed 2 years earlier and who had been treated with immunosuppressants since then, complained of continuous severe, mainly left-sided headache and facial pain for weeks. Cranial MRI showed thickening of the left tentorium cerebelli with obvious contrast enhancement and led to the diagnosis of hypertrophic pachymeningitis. The inflammatory parameters and the C-ANCA (antineutrophil cytoplasmic antibodies) in the serum were raised and CANCA were detectable in the cerebrospinal fluid. The headaches subsided with several days of intravenous high-dose corticosteroids and a simultaneous increase in the immunosuppressive basic medication. On a follow-up MRI after 3 months, the magnetic resonance changes were less apparent, i. e., the hypertrophic pachymeningitis was resolving; C-ANCA were now no longer detectable in the cerebrospinal fluid. CONCLUSION: With newly occurring, unusually severe and persistent headaches in the presence of WG, the very rare complication of hypertrophic pachymeningitis should be considered.

[From acute to chronic rejection after kidney transplantation]. / Zusammenhang zwischen akuter und chronischer Abstossungsreaktion nach Nierentransplantation.

BACKGROUND: Increased frequency of acute rejection episodes is the best predictor for the development of an chonic rejection process in kidney transplantation. An effective antirejection therapy is critical to prevent transplant failure due to chronic rejection. OBJECTIVE: The relationship between acute and chronic rejection is determined by the number of rejection episodes, clinical and histological grading, timing, residual function and individual problems of donor and recipient. THERAPY: Standard immunosuppression with calcineurin inhibitors such as cyclosporine or tacrolimus and antiproliferative substances such as azathioprine or mycophenolatemofetile have to be intensified when an acute rejection episode occurs. For maximal immunosuppression antibody preparations such as ATG and OKT3 in combination with with a short course of steroid pulse therapy are available. CONCLUSION: In this review we summarize the clinical implications and therapeutic consequences of the relationship between acute and chronic rejection. The acute rejection episode has still a great impact on long-term graft outcome which may only be improved by a prompt treatment of initial acute rejection episodes.

[Glomerular-type proteinuria in hantavirus nephritis]. / Glomeruläre Proteinurie bei Hantavirus-Nephritis.

BACKGROUND: Infection with hantavirus of the Puumala type is known to cause severe illness, fever, loin pain and impaired vision. Tubulointerstitial nephritis leads to acute renal failure. CASE REPORTS: In four patients presenting with hantavirus infection and acute renal failure, proteinuria was analyzed by microelectrophoresis to explore possible causes of renal protein loss in hantavirus nephritis. The patients (three men, one woman) presented with a short history of fever, headache, loin pain and acute renal failure (enlarged kidneys in ultrasonography, serum creatinine 7.7/3.4/3.2/7.8 mg/dl, urinary protein excretion 1.7/0.5/1.5/9.0 g/l, IgM antibodies against hantavirus positive in all patients, subtype Puumala). Microelectrophoresis of the urine revealed a major fraction of higher molecular weight proteins such as transferrin and immunoglobulins indicating unselective glomerular-type proteinuria in all four patients. In three renal biopsy specimens obtained, morphology of glomeruli and vasculature was normal as judged by light microscopy. The tubulointerstitium exhibited interstitial hemorrhage and round-cell infiltrates. After 2 weeks, renal function had completely recovered in all patients and no persistent proteinuria developed. CONCLUSION: Hantavirus nephritis may lead to glomerular-type proteinuria. Glomerular morphology may be normal and proteinuria may cease within 2 weeks indicating a transient lesion of the glomerular filtration barrier. Transiently increased glomerular permeability may be caused by an immunologic response to virus infection.