The prognostic fingerprint of quality of life in older inpatients : Relationship to geriatric syndromes' and resources' profile.

BACKGROUND: The Comprehensive Geriatric Assessment (CGA) provides essential information about older hospitalized patients but is either not systematically adopted or not adopted at all in clinical routine. As a consequence, critical factors influencing patients' trajectories, like personal resources (geriatric resources, GR), geriatric syndromes (GS), health-related quality of life (HRQoL) and multidimensional prognosis often escape routine diagnostics. OBJECTIVE: To investigate the association between HRQoL and GR/GS as well as its prognostic signature. MATERIAL AND METHODS: In this study 165 inpatients older than 65 years admitted to an internal medicine department of a German large metropolitan hospital were assessed by a CGA-based calculation of the multidimensional prognostic index (MPI). Ten different GR and 17 GS, as well as HRQoL were collected. After 3, 6 and 12 months the patients were followed-up by telephone. RESULTS: The HRQoL was associated with MPI (p < 0.001), number of GS (p < 0.001) and survival days after discharge (p = 0.008). Additionally, significant associations were found between HRQoL and number of GR (p < 0.001). GS displaying risk for physical dependence like instability (p < 0.001) and chronic pain (p = 0.007) and single GR/GS that influence patient's confidence like isolation (p < 0.001), depression (p < 0.001) and emotional resources (p = 0.002) were also associated with HRQoL. CONCLUSION: The HRQoL is significantly associated to specific risk and protective factor profiles of GR and GS. To improve quality of life, targeted, patient-centered diagnostics and treatment of GS as well as stabilization of GR should be encouraged in the management of older, multimorbid patients outside geriatric settings.

Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53.

The tumor suppressor p53 is mainly involved in the transcriptional regulation of a large number of growth-arrest- and apoptosis-related genes. However, a clear understanding of which factor/s influences the choice between these two opposing p53-dependent outcomes remains largely elusive. We have previously described that in response to DNA damage, the RNA polymerase II-binding protein Che-1/AATF transcriptionally activates p53. Here, we show that Che-1 binds directly to p53. This interaction essentially occurs in the first hours of DNA damage, whereas it is lost when cells undergo apoptosis in response to posttranscriptional modifications. Moreover, Che-1 sits in a ternary complex with p53 and the oncosuppressor Brca1. Accordingly, our analysis of genome-wide chromatin occupancy by p53 revealed that p53/Che1 interaction results in preferential transactivation of growth arrest p53 target genes over its pro-apoptotic target genes. Notably, exposure of Che-1(+/-) mice to ionizing radiations resulted in enhanced apoptosis of thymocytes, compared with WT mice. These results confirm Che-1 as an important regulator of p53 activity and suggest Che-1 to be a promising yet attractive drug target for cancer therapy.

Proteinuria in systemic sclerosis: reversal by ACE inhibition.

In systemic sclerosis (SSc), kidney damage is a major clinical problem which can lead to a deleterious outcome. Recently, in diabetes mellitus, early detection of proteinuria and treatment with angiotensin-converting enzyme (ACE) inhibitors has been shown to slow progression of kidney disease and to improve prognosis. In this study, we investigated the spontaneous course of proteinuria in SSc and the effects of ACE inhibitor therapy. Proteinuria was determined in SSc patients with urine protein electrophoresis. SSc patients with proteinuria (n = 31) were followed over a median of 12 months. Of all 31 patients with pathologic urine protein electrophoresis investigated in this study, 9 patients (29 %) had additional microalbuminuria and 4 patients (12.9 %) showed increased total urinary protein. ACE inhibitor treatment was subsequently given to 23 patients. A total of 8 patients remained untreated for various reasons. Proteinuria resolved in 74 % of patients treated with ACE inhibitors, whereas in the untreated group, remission was observed only in 25 % (p = 0.014). Improvement of proteinuria was predominantly achieved in patients with recently diagnosed proteinuria and short disease duration. In patients with SSc and proteinuria, initiation of ACE inhibitor therapy resulted in a significant decrease in proteinuria.

[De novo sarcoidosis after kidney transplantation]. / Neu aufgetretene Sarkoidose nach Nierentransplantation.

HISTORY AND CLINICAL FINDINGS: A 39-year-old man complained of unspecific chest pains four years after kidney transplantation. INVESTIGATIONS: Laboratory tests revealed a slow increase of retentions values; the value of soluble IL-2 receptor was slightly elevated. Computed tomography of the chest confirmed mediastinal and bilateral hilar masses. The broncho-alveolar lavage (BAL) showed a marked increase of the CD4/CD8 T-lymphocyte ratio and the aspiration cytology of these lymphadenopathies revealed the cytopathological characteristics of sarcoidosis. TREATMENT AND CLINICAL COURSE: An asymptomatic stage I sarcoidosis was diagnosed, and the immunosuppressive treatment with cyclosporine, mycophenolatmofetil and prednisone was retained. The patient has remained asymptomatic for now six months. CONCLUSION: When bilateral hilar / mediastinal lymphadenopathies occur after organ transplantation with immunosuppression de novo sarcoidosis should be taken into account.

[Recent developments in genetic kidney diseases]. / Neue Entwicklungen auf dem Gebiet der genetischen Nierenerkrankungen.

The improved understanding of genetic kidney diseases has given rise to a more detailed understanding of kidney function within the last decade. Insights into the pathophysiological principles of frequent kidney diseases - partly inherited, partly acquired - have been obtained by the investigation of rare genetic disorders and can now serve as a starting point for the development of novel therapeutic strategies. In this way various clinical multicenter trials, which are based on the observations made in basic science have been established for the very common autosomal dominant polycystic kidney disease. Furthermore, the influence of genetic aspects on frequent kidney diseases, e. g. diabetic nephropathy, is becoming more obvious. This article aims to give an overview over essential recent development in the field of genetic kidney diseases.

[Treating the symptoms in nephrotic syndrome: which therapeutic strategies are evidence based in the treatment of proteinuria?]. / Symptomatische Therapie bei nephrotischem Syndrom: Was ist gesichert in der Therapie der Proteinurie?.

Glomerular diseases are among the most common renal pathologies leading frequently to end-stage renal disease. Clinical disease can be divided into five different groups the features of which are determined by the underlying pathophysiology. One of these five clinical syndromes is the nephrotic syndrome, which is characterized by proteinuria > 3.5 g/day accompanied by hypalbuminemia, hyperlipoproteinemia and pronounced edema. The nephrotic syndrome may be the clinical manifestation of a row of underlying diseases. The pathophysiological basics had remained elusive for decades, yet recently significant progress which allows for establishing new therapeutic strategies has been made. A major breakthrough in understanding the function of the glomerular filter unit has been possible in the last years through both genetic and cell biological studies, which have revealed a crucial role for the visceral epithelial cells of the glomerulus - the podocytes. By now various factors have been found causing podocyte damage, such as toxines, immunological phenomena or systemic disease like diabetes mellitus.

Leflunomide therapy for polyomavirus-induced allograft nephropathy: efficient BK virus elimination without increased risk of rejection.

BACKGROUND: Optimal treatment of polyomavirus-induced allograft nephropathy (PVAN) with immunosuppressive and antiviral therapy is uncertain at present. Reduced immunosuppression is accompanied by increased risk of rejection, and antiviral agents are nephrotoxic. Leflunomide has immunosuppressive and antiviral properties and may be an alternative treatment agent. We report a two-center experience with use of leflunomide for treatment of PVAN. PATIENTS AND METHODS: Thirteen renal allograft recipients were diagnosed with biopsy-proven PVAN. Treatment consisted of lowering the calcineurin-inhibitor trough level, discontinuing mycophenolate mofetil therapy, and initiating leflunomide therapy. In 8 of the 13 patients, the serum concentration of the leflunomide active metabolite A771726 was monitored. RESULTS: Exchange of mycophenolate mofetil with leflunomide in patients with PVAN was well tolerated and safe, with no serious adverse effects or episodes of graft rejection. Mean follow-up after transplantation was 717 days, and after initiation of leflunomide therapy was 465 days. With the modified therapy, 12 patients cleared the virus at a mean of 109 days. One graft was lost due to refractory rejection accompanied by a decreasing viral load. In the other 12 patients, graft function stabilized or improved (mean [median] creatinine concentration at diagnosis, 2.39 [2.5] mg/mL, vs 2.27 [2.0] mg/dL at follow-up). Leflunomide concentration did not correlate with treatment efficiency. CONCLUSIONS: Treatment of PVAN with leflunomide, a low-dose calcineurin inhibitor, and prednisone seems to reduce viral load and stabilize renal graft function without increasing the risk of rejection. Even low serum concentrations of leflunomide support viral elimination and prevention of graft rejection.

Atypical Alport syndrome associated with a novel COL4A5 mutation.

Alport syndrome is a progressive hereditary renal disease. Mutations in the genes encoding for three members of the type IV collagen protein family have been found to be the cause of the disease. Alport syndrome is often associated with sensorineural hearing loss and ocular abnormalities, and patients suffering from typical Alport syndrome usually develop end stage renal disease during adolescence or young adulthood. Here we report on a family with atypical Alport disease initially presenting as hereditary focal and segmental glomerulosclerosis. Genetic testing identified a previously undescribed COL4A5 mutation as cause of the disease.

Interaction with podocin facilitates nephrin signaling.

Mutations of NPHS1 or NPHS2, the genes encoding for the glomerular podocyte proteins nephrin and podocin, cause steroid-resistant proteinuria. In addition, mice lacking CD2-associated protein (CD2AP) develop a nephrotic syndrome that resembles NPHS mutations suggesting that all three proteins are essential for the integrity of glomerular podocytes. Although the precise glomerular function of either protein remains unknown, it has been suggested that nephrin forms zipper-like interactions to maintain the structure of podocyte foot processes. We demonstrate now that nephrin is a signaling molecule, which stimulates mitogen-activated protein kinases. Nephrin-induced signaling is greatly enhanced by podocin, which binds to the cytoplasmic tail of nephrin. Mutational analysis suggests that abnormal or inefficient signaling through the nephrin-podocin complex contributes to the development of podocyte dysfunction and proteinuria.

Nephrocystin interacts with Pyk2, p130(Cas), and tensin and triggers phosphorylation of Pyk2.

Juvenile nephronophthisis type 1 is caused by mutations of NPHP1, the gene encoding for nephrocystin. The function of nephrocystin is presently unknown, but the presence of a Src homology 3 domain and its recently described interaction with p130(Cas) suggest that nephrocystin is part of the focal adhesion signaling complex. We generated a nephrocystin-specific antiserum and analyzed the interaction of native nephrocystin with endogenous proteins. Immunoprecipitation of nephrocystin revealed that nephrocystin forms protein complexes with p130(Cas), proline-rich tyrosine kinase 2 (Pyk2), and tensin, indicating that these proteins participate in a common signaling pathway. Expression of nephrocystin resulted in phosphorylation of Pyk2 on tyrosine 402 as well as activation of downstream mitogen-activated protein kinases, such as ERK1 and ERK2. Our findings suggest that nephrocystin helps to recruit Pyk2 to cell matrix adhesions, thereby initiating phosphorylation of Pyk2 and Pyk2-dependent signaling. A lack of functional nephrocystin may compromise Pyk2 signaling in a subset of renal epithelial cells.

Control of the cystic fibrosis transmembrane conductance regulator by alphaG(i) and RGS proteins.

The cystic fibrosis transmembrane conductance regulator (CFTR) has been shown previously to be regulated by inhibitory G proteins. In the present study, we demonstrate inhibition of CFTR by alphaG(i2) and alphaG(i1), but not alphaG(0), in Xenopus oocytes. We further examined whether regulators of G protein signaling (RGS) proteins interfere with alphaG(i)-dependent inhibition of CFTR. Activation of CFTR by IBMX and forskolin was attenuated in the presence of alphaG(i2), indicating inhibition of CFTR by alphaG(i2) in Xenopus oocytes. Coexpression of the proteins RGS3 and RGS7 together with CFTR and alphaG(i2) partially recovered activation by IBMX/forskolin. 14-3-3, a protein that is known to interfere with RGS proteins, counteracted the effects of RGS3. These data demonstrate the regulation of CFTR by alphaG(i) in Xenopus oocytes. Because RGS proteins interfere with the G protein-dependent regulation of CFTR, this may offer new potential pathways for pharmacological intervention in cystic fibrosis.

14-3-3 interacts with regulator of G protein signaling proteins and modulates their activity.

Regulator of G protein signaling (RGS) proteins function as GTPase-activating proteins (GAPs) that stimulate the inactivation of heterotrimeric G proteins. We have recently shown that RGS proteins may be regulated on a post-translational level (Benzing, T., Brandes, R., Sellin, L., Schermer, B., Lecker, S., Walz, G., and Kim, E. (1999) Nat. Med. 5, 913-918). However, mechanisms controlling the GAP activity of RGS proteins are poorly understood. Here we show that 14-3-3 proteins associate with RGS7 and RGS3. Binding of 14-3-3 is mediated by a conserved phosphoserine located in the Galpha-interacting portion of the RGS domain; interaction with 14-3-3 inhibits the GAP activity of RGS7, depends upon phosphorylation of a conserved residue within the RGS domain, and results in inhibition of GAP function. Collectively, these data indicate that phosphorylation-dependent binding of 14-3-3 may act as molecular switch that controls the GAP activity keeping a substantial fraction of RGS proteins in a dormant state.

Upregulation of RGS7 may contribute to tumor necrosis factor-induced changes in central nervous function.

The central nervous dysfunctions of lethargy, fever and anorexia are manifestations of sepsis that seem to be mediated by increased cytokine production. Here we demonstrate that tumor necrosis factor (TNF)-alpha, an essential mediator of endotoxin-induced sepsis, prevents the proteasome-dependent degradation of RGS7, a regulator of G-protein signaling. The stabilization of RGS7 by TNF-alpha requires activation of the stress-activated protein kinase p38 and the presence of candidate mitogen-activated protein kinase phosphorylation sites. In vivo, RGS7 is rapidly upregulated in mouse brain after exposure to either endotoxin or TNF-alpha, a response that is nearly abrogated in mice lacking TNF receptor 1. Our findings indicate that TNF-mediated upregulation of RGS7 may contribute to sepsis-induced changes in central nervous function.

Interaction between RGS7 and polycystin.

Regulators of G protein signaling (RGS) proteins accelerate the intrinsic GTPase activity of certain Galpha subunits and thereby modulate a number of G protein-dependent signaling cascades. Currently, little is known about the regulation of RGS proteins themselves. We identified a short-lived RGS protein, RGS7, that is rapidly degraded through the proteasome pathway. The degradation of RGS7 is inhibited by interaction with a C-terminal domain of polycystin, the protein encoded by PKD1, a gene involved in autosomal-dominant polycystic kidney disease. Furthermore, membranous expression of C-terminal polycystin relocalized RGS7. Our results indicate that rapid degradation and interaction with integral membrane proteins are potential means of regulating RGS proteins.

Angiotensin-converting enzyme inhibitor ramiprilat interferes with the sequestration of the B2 kinin receptor within the plasma membrane of native endothelial cells.

BACKGROUND: ACE (kininase II) inhibitors have been shown to exert their beneficial cardiovascular effects via the inhibition of both angiotensin II formation and bradykinin breakdown. Because recent evidence suggests that ACE inhibitors may also interfere with B2 kinin receptor signaling and thus enhance the vascular response to bradykinin, we examined whether the distribution of B2 kinin receptors within the plasma membrane of native endothelial cells is affected by an ACE inhibitor. METHODS AND RESULTS: Localization of the B2 kinin receptor in membranes prepared from native porcine aortic endothelial cells was evaluated by means of specific [3H]bradykinin binding and immunoprecipitation of the B2 receptor from isolated membranes. Effects of bradykinin and ramiprilat on intracellular signaling were determined by monitoring the activation of the extracellularly regulated kinases Erk1 and Erk2 as well as [Ca2+]i increases in fura 2-loaded endothelial cells. Stimulation of native endothelial cells with bradykinin 100 nmol/L resulted in the time-dependent sequestration of the B2 receptor to caveolin-rich (CR) membranes, which was maximal after 5 minutes. Pretreatment with ramiprilat 100 nmol/L for 15 minutes significantly attenuated the recovery of B2 kinin receptors in CR membranes while increasing that from membranes lacking caveolin. This effect was not due to the inhibition of bradykinin degradation, because no effect was seen in the presence of an inhibitory concentration of the synthetic ACE substrate hippuryl-L-histidyl-L-leucine. Ramiprilat also decreased [3H]bradykinin binding to CR membranes when applied either before or after bradykinin stimulation. Moreover, ramiprilat resulted in reactivation of the B2 receptor in bradykinin-stimulated cells and induced a second peak in [Ca2+]i and reactivation of Erk1/2. CONCLUSIONS: The ACE inhibitor ramiprilat interferes with the targeting of the B2 kinin receptor to CR membrane domains in native endothelial cells. Therefore, effects other than the inhibition of kininase II may account for the effects of ramiprilat and other ACE inhibitors on the vascular system.

Cellular activation triggered by the autosomal dominant polycystic kidney disease gene product PKD2.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by germ line mutations in at least three ADPKD genes. Two recently isolated ADPKD genes, PKD1 and PKD2, encode integral membrane proteins of unknown function. We found that PKD2 upregulated AP-1-dependent transcription in human embryonic kidney 293T cells. The PKD2-mediated AP-1 activity was dependent upon activation of the mitogen-activated protein kinases p38 and JNK1 and protein kinase C (PKC) epsilon, a calcium-independent PKC isozyme. Staurosporine, but not the calcium chelator BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N', N'-tetraacetate], inhibited PKD2-mediated signaling, consistent with the involvement of a calcium-independent PKC isozyme. Coexpression of PKD2 with the interacting C terminus of PKD1 dramatically augmented PKD2-mediated AP-1 activation. The synergistic signaling between PKD1 and PKD2 involved the activation of two distinct PKC isozymes, PKC alpha and PKC epsilon, respectively. Our findings are consistent with others that support a functional connection between PKD1 and PKD2 involving multiple signaling pathways that converge to induce AP-1 activity, a transcription factor that regulates different cellular programs such as proliferation, differentiation, and apoptosis. Activation of these signaling cascades may promote the full maturation of developing tubular epithelial cells, while inactivation of these signaling cascades may impair terminal differentiation and facilitate the development of renal tubular cysts.

The polycystic kidney disease 1 gene product modulates Wnt signaling.

Two distinct signaling pathways, involving Wnt signaling and polycystin, have been found to be critical for normal kidney development. Renal tubulogenesis requires the presence of certain Wnt proteins, whereas mutations in polycystin impede the terminal differentiation of renal tubular epithelial cells, causing the development of large cystic kidneys that characterize autosomal dominant polycystic kidney disease. Polycystin is an integral membrane protein, consisting of several extracellular motifs indicative of cell-cell and cell-matrix interactions, coupled through multiple transmembrane domains to a functionally active cytoplasmic domain. We report here that expression of the C-terminal cytoplasmic domain of polycystin stabilizes soluble endogenous beta-catenin and stimulates TCF-dependent gene transcription in human embryonic kidney cells. Microinjection of the polycystin C-terminal cytoplasmic domain induces dorsalization in zebrafish. Our findings suggest that polycystin has the capacity to modulate Wnt signaling during renal development.

Occurrence and management of hepatitis B virus reactivation following kidney transplantation.

A 28-year-old woman was kidney transplanted. She had an inapparent hepatitis B virus (HBV) infection 2 years previously. At the time of transplantation she was hepatitis B surface antigen (HBsAg) negative, anti-HBs, anti-HBc, anti-HBe and anti-HCV antibody positive and her transaminase activities were within the normal range. The donor of the kidney allograft was HBV negative. Twelve weeks after transplantation a life-threatening liver failure occurred with a rapid rise of alanine aminotransferase (ALT) to 1427 U/l and a decrease of the prothrombin time to 25% of normal value. Anti-HBs had become negative, anti-HBc and anti-HBe titers had decreased. HBsAg became positive, associated with a HBV DNA of 3 x 10(8) genome equivalents/ml. Azathioprine and prednisone were withdrawn and foscarnet therapy was started. This therapy led to a decrease of ALT activity associated with an elimination of HBsAg and HBV DNA. Eight months after transplantation liver function tests were within the normal range. Graft rejection did not occur despite low or intermittent cessation of immunosuppressive therapy.

[Paraneoplastic cerebellar degeneration in Hodgkin's disease]. / Paraneoplastische Kleinhirndegeneration bei Morbus Hodgkin.

HISTORY AND CLINICAL FINDINGS: A 30-year-old previously healthy man suddenly developed double vision, unsteady gait and some difficulty in speech articulation. Within 4 weeks he had become markedly ataxic, unable to walk, stand or sit down unaided. Neurological examination indicated a severe cerebellar syndrome. There were no other abnormal findings on physical examination. INVESTIGATIONS: There was no pleocytosis and no oligoclonal bands in cerebrospinal fluid (CSF). A test for anti-Purkinje cell antibodies was negative in both CSF and serum. Computed tomography and nuclear magnetic imaging (NMI) of the brain were normal. TREATMENT AND COURSE: As a para- or postinfectious or paraneoplastic process was suspected. I.v. immunoglobulin and oral corticosteroids were administered, but without improvement. 13 month later, a mediastinal mass was noted on a chest radiogram. This led to the diagnosis of a stage IA Hodgkin's disease. Retrospectively the cerebellar degeneration was most likely a paraneoplastic change related to the Hodgkin's disease. However, an independent second disease cannot be excluded. While the treatment of Hodgkin's disease was successful, the neurological symptoms remained unchanged. Severe cerebellar atrophy was demonstrated on NMI. CONCLUSION: In case of cerebellar atrophy of undetermined aetiology a paraneoplastic cause should be considered and an underlying malignant disease looked for.