[Prognosis and therapy of inflammatory rheumatic diseases : Impact of renal manifestations]. / Prognose und Therapie von entzündlich-rheumatischen Erkrankungen : Einfluss der Nierenbeteiligung.

BACKGROUND: Inflammatory rheumatic diseases and their treatment cause various renal manifestations requiring modification of treatment. OBJECTIVES: Discussion of renal manifestations in selected rheumatic diseases, including their impact on general prognosis and therapy. MATERIALS AND METHODS: Basic literature and expert opinions are analyzed and discussed. RESULTS: Inflammatory rheumatic diseases and their treatment cause various renal manifestations, including glomerular, tubular, interstitial, and vascular damage. The type of damage determines both, associated clinical symptoms (i.e. hematuria, proteinuria, loss of kidney function) and the renal and overall survival as will be discussed here for rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjögrens syndrome, cryoglobulinemia and ANCA-associated vasculitis. CONCLUSION: Renal manifestations are generally indicators of high disease activity and usually require more intensive treatment of the underlying rheumatic disease. Early and rigorous treatment, which has to be adapted to renal function, is capable of improving renal and overall survival in many of the affected patients.

[Anti-RNA polymerase III antibodies in scleroderma renal crisis]. / Anti-RNA-Polymerase-III-Antikörper bei renaler Krise der systemischen Sklerose.

HISTORY AND CLINICAL FINDINGS: A 67-year old patient underwent a kidney biopsy because of newly diagnosed hypertension, haemolytic anemia with fragmentocytes and acute kidney failure requiring dialysis therapy. The biopsy showed thrombotic microangiopathy. Since last winter Raynaud's phenomenon and changes of hands and lips were recognised. INVESTIGATIONS: Initial immunological tests revealed anti-nuclear antibodies (ANA) but neither anti-centromere nor anti-Scl70 antibodies. The positive analysis of anti-RNA polymerase III antibodies confirmed the clinical suspicion of scleroderma renal crisis in the setting of first diagnosis of systemic sclerosis. TREATMENT AND COURSE: After diagnosis therapy with lisinopril, candesartan and amlodipin was established. Four months after discharge dialysis dependency persisted. CONCLUSION: Scleroderma renal crisis is an important differential diagnosis in the setting of acute kidney failure. Medical history, clinical examination and immunological test confirm the diagnosis. The mainstay of therapy is aggressive blood pressure control with ACE-inhibitors (or angiotensin receptor blocking agents).

Wnt pathway regulation in chronic renal allograft damage.

The Wnt signaling pathway, linked to development, has been proposed to be recapitulated during the progressive damage associated with chronic organ failure. Chronic allograft damage following kidney transplantation is characterized by progressive fibrosis and a smoldering inflammatory infiltrate. A modified, Fischer 344 (RT1(lvl)) to Lewis (RT1(l)) rat renal allograft model that reiterates many of the major pathophysiologic processes seen in patients with chronic allograft failure was used to study the progressive disease phenotype and specific gene product expression by immunohistochemistry and transcriptomic profiling. Central components of the Tgfb, canonical Wnt and Wnt-Ca2+ signaling pathways were significantly altered with the development of chronic damage. In the canonical Wnt pathway, Wnt3, Lef1 and Tcf1 showed differential regulation. Target genes Fn1, Cd44, Mmp7 and Nos2 were upregulated and associated with the progression of renal damage. Changes in the Wnt-Ca2+ pathway were evidenced by increased expression of Wnt6, Wnt7a, protein kinase C, Cam Kinase II and Nfat transcription factors and the target gene vimentin. No evidence for alterations in the Wnt planar cell polarity (PCP) pathway was detected. Overall results suggest cross talk between the Wnt and Tgfb signaling pathways during allograft inflammatory damage and present potential targets for therapeutic intervention.

[Acute or rapidly progressive renal failure in elderly patients]. / Das akute oder rasch fortschreitende Nierenversagen im Alter.

Elderly patients are at increased risk to develop an acute or rapidly progressive renal failure. The acute renal injury (ARF) is mainly a problem of in-patients whereas out-patients often present with rapidly progressive kidney failure. The main cause for ARF is acute tubular necrosis, which has to be distinguished from prerenal or postrenal causes. The differential diagnosis of a rapid decline includes crescentic glomerulonephritis and acute interstitial nephritis. Diagnostic approaches and additional causes of renal failure in the elderly population are discussed in the article.

Aliskiren-associated acute renal failure with hyperkalemia.

We report the first case of acute renal failure with hyperkalemia associated with the recently marketed direct renin inhibitor aliskiren. To optimize blood pressure control, the antihypertensive medication of a 76-year-old hypertensive female patient was changed from the angiotensin II receptor antagonist irbesartan to aliskiren. Spironolactone was continued, as serum creatinine and potassium levels were initially normal. Two weeks later the patient presented with acute oliguric renal failure, symptomatic hyperkalemia and metabolic acidosis, necessitating emergency dialytic treatment. Unrecognized pre-existing renal insufficiency (CKD Stage 2 - 3) and the continuation of spironolactone were identified as predisposing risk factors.

Safety and tolerability of ferric carboxymaltose (FCM) for treatment of iron deficiency in patients with chronic kidney disease and in kidney transplant recipients.

BACKGROUND: Iron deficiency is common in patients with chronic kidney disease and in kidney transplant recipients. PATIENTS AND METHODS: We analyzed the safety and tolerability of the new intravenous iron preparation ferric carboxymaltose (FCM) in these two patient groups. Adverse events after administration of the drug were assessed by using a questionnaire. Vital signs and laboratory data were collected before and after the application of FCM. A total of 46 FCM doses were applied to 44 patients (17 with chronic kidney disease and 27 kidney transplant recipients) either as single injection of 100 or 200 mg (n = 42) or as short infusion with up to 500 mg (n = 4). RESULTS: Mild and transient adverse events (metallic taste, headache, dizziness) occurred in six patients. The estimated glomerular filtration rate remained unchanged by the FCM administration. CONCLUSION: We conclude that safety and tolerability of FCM were excellent. Compared with other intravenous iron preparations the considerably shorter administration time of FCM allows to save time and to reduce costs.

[Gene expression analyses of kidney biopsies: the European renal cDNA bank--Kröner-Fresenius biopsy bank]. / Genexpressionsanalysen an Nierenbiopsien: Die Europäische Renale cDNA Bank--Kröner-Fresenius Biopsiebank.

Histological analysis of kidney biopsies is an essential part of our current diagnostic workup of patients with renal disease. Besides the already established diagnostic tools, new methods allow extensive analysis of the sample tissue's gene expression. Using results from a European multicenter study on gene expression analysis of renal biopsies, in this review we demonstrate that this novel approach not only expands the scope of so-called basic research but also might supplement future biopsy diagnostics. The goals are improved diagnosis and more specific therapy choice and prognosis estimates.

Compartment specific expression of dendritic cell markers in human glomerulonephritis.

Macrophages and dendritic cells are heterogenous and highly plastic bone marrow-derived cells that play major roles in renal diseases. We characterized these cells using immunohistochemistry in 55 renal biopsies from control patients or patients with glomerulonephritis as an initial step towards postulating specific roles for these cells in kidney disease. In proliferative glomerulonephritis numerous CD68 positive (pan monocyte, macrophage and dendritic marker) cells were found in both glomeruli and the tubulointerstitial space, however, a myeloid dendritic cell marker (DC-SIGN) was identified only in the tubulointerstitium. A significant number of plasmacytoid dendritic cells (identified as BDCA-2 positive cells) were seen at sites of interstitial inflammation, including follicular aggregates of inflammatory cells. Langerin positive cells (a marker of Langerhans' cells) were detectable but rare. The area of either CD68 or DC-SIGN positive interstitial cells correlated with serum creatinine. Low levels of DC-SIGN, DC-LAMP and MHC class II mRNA were present in the tubulointerstitial space in controls and increased only in that region in proliferative glomerulonephritis. We demonstrate that the CD68 positive cells infiltrating the glomerulus lack dendritic cell markers (reflecting macrophages), whereas in the tubulointerstitial space the majority of CD68 positive cells are also DC-SIGN positive (reflecting myeloid dendritic cells). Their number correlated with serum creatinine, which further emphasizes the significance of interstitial DCs in progressive glomerular diseases.

Collagen type VIII expression in human diabetic nephropathy.

BACKGROUND: Collagen type VIII is a non-fibrillar short-chain collagen that may modulate migration, proliferation and adherence of various cells. Only very sparse information exists on collagen type VIII expression in human diabetic nephropathy. MATERIAL AND METHODS: We retrospectively studied mRNA expression for the two collagen type VIII chains (COL8A1 and COL8A2) in 20 biopsies with histologically confirmed diabetic nephropathy by real-time PCR, and compared glomerular and tubular expression with normal kidney [pre-transplant biopsies (n = 10)]. Expression of collagen type VIII was also studied in biopsies from patients with benign nephrosclerosis (BNS; n = 16) and focal-segmental glomerulosclerosis (FSGS; n = 9). RESULTS: A strong specific induction of COL8A1 mRNA was found in diabetic nephropathy in both glomerular and tubular compartments. There was also a robust induction of COL8A2 in diabetic nephropathy, but overall expression was lower than that of COL8A1 transcripts. No significant increase in COL8A1 and COL8A2 mRNAs expression was found in biopsies from patients with BNS and FSGS compared with normal kidneys. The cross-reactivity of the used anti-alpha1(VIII) antibody with human tissue was confirmed by Western blots. Immunohistological analysis revealed only little staining for collagen type VIII in the normal kidney, localized to vessels. There was an up-regulation of collagen type VIII protein expression as shown by immunohistochemistry in the diabetic nephropathy biopsies mainly localized to mesangial cells, tubules and the interstitium. Proteinuria and serum creatinine did not correlate with glomerular or tubular COL8A1 and COL8A2 mRNA expression in diabetic patients. CONCLUSION: Our study systemically investigates collagen type VIII expression in human biopsies. Induction of collagen type VIII was specific for diabetic nephropathy and did not occur in the other renal diseases studied. More specific factors of the diabetic environment are likely involved in the stimulated expression because there was no correlation of collagen type VIII mRNA expression with proteinuria. Since collagen type VIII may influence proliferation and migration of cells, it is possible that an increase in renal expression of collagen type VIII initiates other pathophysiological processes (e.g. proliferation of renal fibroblasts) involved in diabetic nephropathy.

Potential role of fractalkine receptor expression in human renal fibrogenesis.

The inhibition of several chemokine/chemokine receptors has been shown to reduce progressive renal interstitial fibrosis. In this study, we examined the expression of the CX(3)C receptor in human renal biopsies with interstitial fibrosis and from normal kidneys by real-time polymerase chain reaction (PCR) and immunohistochemistry. The CX(3)C receptor was not only detected in mononuclear, tubular epithelial, and dendritic cells but also in alpha-smooth muscle actin and vimentin-positive interstitial myofibroblasts in fibrotic kidneys. Real-time PCR indicated a significant upregulation of CX(3)C receptor mRNA in fibrotic kidneys compared with non-fibrotic nephropathies or donor biopsies. In renal fibroblasts in vitro, hydrogen peroxide increased the expression of the CX(3)C receptor, an increase that was inhibited by N-acetylcysteine and catalase. However, neither proinflammatory nor profibrotic cytokines resulted in this upregulation. Stimulation of fibroblasts by CX(3)C ligand led to a significant enhancement of migration, which was abrogated by pre-incubation with a blocking anti-CX(3)C receptor antibody. Our studies indicate that renal fibrosis is associated with the expression of CX(3)C receptors on human renal fibroblasts. The expression is induced by reactive oxygen species suggesting a role of oxidative stress.

AIDS, multicentric Castleman's disease, and plasmablastic leukemia: report of a long-term survival.

Plasmablastic leukemia (PL) as a complication of human herpes virus 8 (HHV8)-associated Castleman's disease is marked by a rapid and fatal outcome. In patients with AIDS, survival of 7 to 14 days after diagnosis has been reported. Prompt splenectomy and chemotherapy might lead to a significant survival benefit. Here we report a case of long-term survival in a patient with AIDS and multicentric Castleman's disease (MCD) complicated by PL.

[Gene expression profiling in prostatic cancer]. / Genexpressions-Analyse des Prostatakarzinoms.

Basic aspects of the biology and molecular alterations in prostate carcinoma remain poorly understood. New diagnostic and prognostic markers for prostate carcinoma may add additional information to current histopathological diagnosis. In order to achieve these goals, a comprehensive gene expression analysis was performed on non-metastasizing, untreated prostate cancer tissues. RNA expression profiles of approximately 12,600 sequences from 26 human prostate tissues (17 adenocarcinomas and 9 normal adjacent to cancer tissues) were investigated using high-density oligonucleotide microarray technology (Affymetrix). We identified 63 genes which were significantly increased (at least 2.5-fold) and 153 genes which were decreased (at least 2.5-fold). Upregulated genes included several which had not yet been described, such as the genes encoding the specific granule protein (SGP28), several members of the histone family, and the alpha-methylacyl-CoA racemase, but also previously reported ones such as hepsin, LIM domain kinase 2, and carcinoma-associated antigen GA733-2. Laser capture-microdissection of epithelial and stromal compartments from cancer and histologically normal specimens followed by an amplification protocol for low amounts of RNA (< 0.1 microgram) allowed us to distinguish between gene expression profiles characteristic of epithelial cells and those typical of stroma. Most of the genes identified in bulk tumor material as upregulated were indeed overexpressed in cancerous epithelium rather than in the stromal compartment. DNA microarray data for up- and downregulated genes were confirmed by quantitative RT-PCR. We demonstrated that development of prostate cancer is associated with downregulation as well as upregulation of genes that show complex differential regulation in epithelia and stroma. Some of the alterations in gene expression identified in this study may prove useful in development of novel diagnostic and therapeutic strategies. Gene expression profiling of microdissected tumor cells in prostate biopsies may supplement histopathologic diagnosis.

Chemokine-Induced secretion of gelatinase B in primary human monocytes.

Chemokines help control normal leukocyte trafficking as well as their infiltration into tissues during acute and chronic inflammation. Matrix metalloproteinases (MMPs) help support the extravasation and infiltration of leukocytes through limited proteolysis of basement membranes and matrix material. The effect of the chemokines RANTES/CCL5, MCP-1/CCL and SDF-1/CXCL12 on secretion of the matrix metalloproteinase B and its endogenous inhibitor TIMP-1 was studied. RANTES/CCL5 and SDF-1/CXCL12 were found to induce MMP-9 secretion in primary human monocytes while TIMP-1 secretion was not affected. RANTES/CCL5 effects were mediated through CCR1 because the CCR1 antagonist BX471 was found to effectively block RANTES/CCL5-induced MMP-9 secretion.

Altering glomerular epithelial function in vitro using transient and stable transfection.

Damage of the glomerular filtration barrier leads to proteinuria and progressive renal failure. Several independent lines of research have implicated the glomerular epithelial cell (GEC) as a key player in initiation and propagation of pathways leading to glomerulosclerosis. A growing number of molecules activated in this process have been identified. To further define their cellular function, manipulation of these molecules using pharmacological or genetic approaches in tissue culture systems are required. In this study, strategies for altering GEC gene expression by transient and stable transfection of fluorescence labeled proteins will be presented and discussed. The insight gained through these and comparable systems should allow a detailed dissection of the molecular pathways active in GEC function and failure.

Hyponatraemia as a complication of colonoscopy.

A case of colonoscopy-induced hyponatraemic encephalopathy led us to study the risk of hyponatraemia after gastrointestinal endoscopy. We assessed 40 patients before and after colonoscopy. 20 gastroscopy patients served as controls. Our findings show a high incidence (7.5%) of hyponatraemia after colonoscopy, in association with raised serum concentrations of arginine vasopressin. Physicians should be aware of this complication, since it may contribute to psychological and neurological symptoms after colonoscopy.

K+ currents of human T-lymphocytes are unaffected by Alzheimer's disease and amyloid beta protein.

Alterations of Ca2+ homeostasis have been reported for both fibroblasts and T-lymphocytes of patients with Alzheimer's disease (AD). Considering the importance of K+ conductances for the cellular Ca2+ regulation and the recently reported absence of a K+ channel in Alzheimer fibroblasts, we investigated K+ currents in T-lymphocytes of patients with AD. In addition, the finding that amyloid beta protein affects the Ca2+ signal of T-lymphocytes and the function of K+ channels in fibroblasts prompted us to study a possible influence of amyloid beta protein fragments on K+ channels of T-lymphocytes. Our data, obtained by means of the whole-cell patch-clamp configuration on freshly isolated T-lymphocytes, indicate that K+ channels of these cells do not present any functional deficit in AD, and amyloid beta protein does not mediate an alteration of their currents.