Biomedical subjects
Publications and source records attributed to M Ketteler.
Previously, uremic toxins were sometimes regarded as a large, mysterious, but also anonymous group of factors potentially contributing to morbidity and mortality in end-stage renal disease. By identifying the protein-bound solute p-cresol as a risk factor for mortality in dialysis patients, Bammens and colleagues for the first time present evidence of a clinically relevant uremic toxin in relation to clinical outcome.
Bisphosphonates are inhibitors of bone resorption that are widely used to treat osteoporosis. Price and colleagues demonstrate that ibandronate suppressed the development of uremia-related vascular calcification in rats. These findings extend the link between bone remodeling and vascular calcification to the context of chronic renal failure, opening perspectives toward novel therapeutic strategies.
Vascular calcification is not just a hallmark of uremic arterio- and atherosclerosis, but also a significant cardiovascular risk factor in patients with chronic kidney disease. In contrast to the previous assumption that vascular calcification predominantly occurs by passive precipitation of calcium and phosphate ions, recent research led to the insight that extraosseous calcification is a highly regulated process. High serum phosphate and calcium levels may induce a process of osteogenic 'bone-like' differentiation of vascular smooth muscle cells, while deficiencies of calcification inhibitors or a disturbed balance towards calcification inducers may have a relevant pathophysiological influence on the initiation and progression of calcified lesions. This overview summarizes some of the best explored novel risk factors for disturbances of calcium and phosphate homeostasis and points to the integral role of hyperphosphatemia as a modifiable key trigger in calcification processes.
The present review attempts to summarize recent developments in the field of beta2-microglobulin-derived amyloidosis (A(beta2)m amyloidosis) in patients on chronic dialysis therapy. A key factor in the pathogenesis is the uremic retention of the precursor molecule, beta2-microglobulin (beta2m). However, secondary modifications of the molecule such as limited proteolysis, conformational changes, and the formation of advanced glycation end products have also been described. Finally, in order to explain the striking predilection of the disease for synovial and periarticular structures, a role of local predisposing factors within the synovial membrane (for example, of the particular constituents of the extracellular matrix) must also be postulated. With respect to clinical symptomatology, recent data have confirmed that clinically manifest signs of the amyloidosis represent only the tip of the iceberg, since histologically amyloid deposition is much more widespread. Noninvasive diagnosing of the disease has been advanced by technical changes of the beta2m scintigraphy. Finally, there is accumulating evidence that prevention of the disease not only includes the usage of high-flux synthetic membranes for hemodialysis or hemodiafiltration, but that other factors contribute to the clinical manifestations of amyloidosis such as the dialysate composition and its microbacteriological quality. Such factors, which have changed over the last years as part of general improvements in dialysis care, may explain why the prevalence of the amyloidosis appears to decrease.
PURPOSE: A new hemodialysis access port system was implanted. METHODS: The Dialock consists of a port-like double-valve, implanted subcutaneously below the clavicle, which is attached to two catheters, placed in the right atrium via the jugular vein. The device has been implanted in 5 patients (4 female, 1 male). RESULTS: In all 5 patients the implantation of the catheters and the port was technically successful. Total average duration of dialysis was 3.6 months. Two patients developed a port pocket hematoma 10-14 days post implantation, one of them required surgical revision. One port was explanted due to septicemia, whereas a port infection was not confirmed. One patient showed a thrombotic occlusion of both catheter tips 8 days after implantation, fixed by catheter exchange. Another patient presented with slight migration of the port catheters, which was managed by refixation of the port within the pocket. Beside these complications, the devices were working well. CONCLUSION: The Dialock system offers an interesting alternative to external catheters for hemodialysis. With respect to the complications it deserves further studies to determine its future role in the field of vascular access.
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BACKGROUND: Pathways of L-arginine metabolism including nitric oxide, agmatine and polyamine synthesis are upregulated during glomerular inflammation in experimental glomerulonephritis. In anti-Thy-1-glomerulonephritis L-arginine-deficient diets ameliorate the disease course in this model. However, it is unclear which metabolic pathway is affected by this substrate depletion. Since polyamines are important proproliferative molecules, we studied the effect of specific polyamine synthesis blockade in vivo on mesangial cell proliferation and glomerular fibrosis in this model. METHODS: Anti-Thy-1-glomerulonephritis was induced in male Sprague-Dawley rats by single-bolus injection of monoclonal ER4-antibodies. Rats were treated with difluoromethylornithine (0.5-2% in the drinking water), a selective inhibitor of the rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC). Mesangial cell proliferation and matrix expansion were evaluated in PAS-stained kidney tissues. Glomerular TGF-beta and biglycan-mRNA-expression were determined by Northern blot analysis and albuminuria was measured using a competitive ELISA. Data were compared to untreated controls. RESULTS: Though complete inhibition of ODC activity was achieved at any time point, difluoromethlornithine treatment had no significant effect on albuminuria, glomerular matrix protein expression and mesangial cell count in this model. CONCLUSIONS: The acute upregulation of glomerular ODC activity above baseline in anti-Thy1-glomerulonephritis is not pathophysiologically important for disease development however, biological effects of available polyamine pools cannot be excluded by our study.
OBJECTIVE: An inherited reduction in nephron number has been implicated in the development of salt-sensitive hypertension and end stage renal disease. The Munich Wistar Frömter (MWF) rat represents a genetic model with a 30-50% reduction of nephrons compared with normal rats. MWF rats develop spontaneous hypertension and increased urinary albumin excretion (UAE). We addressed the question whether the inherited defect in this model leads to salt-sensitive hypertension. METHODS: At the age of 6 weeks, we started male and female MWF/Fub rats and salt-resistant Lewis (Lew) reference rats on either a normal NaCl (0.2%) or a high NaCl (8%) diet (n = 8, each group). Systolic blood pressure (SBP) and UAE were measured at 14 weeks. RESULTS: Under a normal diet, MWF/Fub rats demonstrated significantly elevated SBP compared to Lew rats both in male (165 +/- 2 versus 133 +/- 3 mmHg, P < 0.0001) and female (156 +/- 3 versus 134 +/- 3 mmHg, P < 0.0001) rats. After high NaCl treatment, SBP was significantly higher in both male and female MWF/Fub rats (+55 mmHg and +36 mmHg, P < 0.0001, respectively) compared with MWF/ Fub under a normal diet UAE was also significantly higher in male and female MWF/Fub rats after high NaCl excess (P < 0.0005, respectively). In contrast, both SBP and UAE remained unchanged in response to high NaCl in Lew rats. CONCLUSIONS: Our findings demonstrate that both the hypertension and UAE are sensitive to high NaCl loading in female and male MWF/Fub rats. Thus, an inborn nephron deficit may lead to salt-sensitive hypertension and renal dysfunction.
Primary mesangial cells (rat) from monolayer cultures of the 6th to 12th passage and permanent SV40 Mes13 cells were grown at high density in organoid culture at the medium/air interphase. After adaptation to the in vitro conditions, both mesangial cell types developed after 7 days a synthesis apparatus (endoplasmic reticulum, Golgi apparatus) and produced matrix which consisted of Lamina densa-like material, collagenous fibrils and filaments. Unspecific contacts, gap junctions and adhesion belts could be demonstrated in the contact areas. Additionally, some cells exhibited thick bundles of actin filaments. A close resemblance of the mesangial cells in high density culture to those in vivo can, therefore, be stated. Hence, they differentiated with regard to their matrix formation, contraction and contact behaviour and can therefore be used for experimental studies within a short culture period of 7 days. Cell aggregates in monolayer culture and in cultures in collagen gels had not differentiated at this stage.
Cytomegalovirus (CMV) infections occur with an incidence of up to 70% in renal transplant patients and mortality is low due to effective antiviral drugs. We report here the case of a patient who suffered from an uncommonly severe and therapy-resistant pulmonary CMV infection. During the disease course, CMV-PCR from alveolar cells and lung biopsy material was repeatedly negative despite high CMV pp65 antigenemia. CMV pneumonia was finally diagnosed from a biopsy obtained by open thoracotomy revealing positive CMV immunostaining of lung tissue. The patient died of respiratory failure though double-treatment using both ganciclovir and foscavir was administered. Post mortem, the clinically suspected resistance to both antiviral drugs, but not to cidofovir, could be proven by bioassay testing of in vitro growth responses using viral cultures. CMV pneumonia may thus not be diagnosed by standard PCR techniques in rare cases and may be resistant to the available antiviral therapy. Severe CMV pneumonia may benefit from novel antiviral drugs such as cidofovir, which is currently used in the treatment of CMV retinitis in HIV patients.
In essential hypertension, stroke and kidney damage may result from an impaired interaction of vasoregulatory systems. Stroke-prone spontaneously hypertensive rats (SHRSP) were studied to analyze the effects of a low-dose treatment of the angiotensin II type 1 receptor (AT1) blocker candesartan cilexetil on the expression of nitric oxide synthases (NOS) and on vascular structure. Both treated and untreated SHRSP were kept on a stroke-promoting dietary regimen, and compared with Wistar Kyoto rats (WKY). Early mortality of untreated SHRSP was prevented by the treatment. In untreated SHRSP, cerebral intraparenchymal vessels of the parietal lobe showed lesions of the vascular wall and its periphery, such as proteinaceous deposits, perivascular dilated spaces, increase in phagocytic cells, and decreased actin immunostaining. Renal lesions were more pronounced comprising arteriolar occlusion, extensive loss of actin, increased alpha1(IV) collagen expression, and glomerular sclerotic as well as tubulointerstitial lesions. Beneficial effects of the AT1 blockade were more pronounced in brain than in kidney. Activity profile of NOS showed increased NADPH diaphorase staining in media and endothelium of SHRSP; endothelial NOS3 immunoreactivity was decreased, but instead, inducible NOS2 increased in untreated SHRSP. These changes were largely prevented in the treated group. NOS activity in macula densa cells was unchanged, whereas afferent arteriolar renin levels were increased in untreated SHRSP. Results demonstrate an effective reduction of hypertensive vascular changes with a nonpressor dose of candesartan. A "role switch" of vascular NOS in hypertension from physiologic NOS3 toward deleterious NOS2 is suggested, and its prevention by the AT1 blocker points to an angiotensin II-dependent, nitric oxide-mediated pathway that may impair endothelial function and aggravate defects of the blood-brain barrier and kidney structures.
BACKGROUND: Nitric oxide (NO) is a small gaseous molecule with multiple biological effects. NO is produced from the semi-essential amino acid L-arginine by NO synthases (NOS). In the kidney, neuronal NOS (bNOS), which is localized in the macula densa, and endothelial NOS (ecNOS) are involved in the regulation of glomerular hemodynamics. Dysfunction of these enzymes may cause glomerular hypertension and increased intraglomerular platelet aggregation. NO production in high tissue concentrations can be achieved by activation of an inducible NOS isoform (iNOS) and may act as a potent mediator of inflammation in immune-mediated renal diseases. Selective inhibition of iNOS may, therefore, become a novel anti-inflammatory approach in the treatment of glomerulonephritis. Based on experimental data, the potential importance of NO and other metabolites of L-arginine in the pathophysiology and therapy of renal diseases is summarized in this article. CONCLUSION: Modulation of the renal L-arginine/NO-system represents a promising therapeutic target in the treatment of acute an chronic kidney diseases.
Nitric oxide (NO) is an effector molecule with multiple effects on various organ systems. The most prominent physiological actions of NO as a biological mediator include cGMP-dependent vasodilation and cytotoxicity against pathogens in the unspecific immune defense. Sepsis syndrome is a complex disease entity mostly caused by overwhelming bacterial infections. It has a high mortality rate of 40 to 60%. Catecholamine-resistant hypotension and myocardial depression are regarded as major factors contributing to death in septic patients. In septic shock, a pathophysiologically increased NO production occurs due to an excessive induction of the inducible NO synthase (iNOS). Inducible nitric oxide synthase up-regulation is probably caused by bacterial endo- and exotoxins as well as by an increase of circulating pro-inflammatory cytokines. It may be a key factor leading to pronounced vasodilation and myocardial toxicity. Experimental studies have confirmed that NO overproduction causes severe hypotension in septic animals. Treatment with competitive NOS-inhibitors abolishes this hypotension in animals as well as in septic patients. However, their use is complicated by concomitant decreases in cardiac index and oxygen delivery. Conclusive data on mortality in animals and patients with sepsis-syndrome treated by NOS antagonists are not available. This article discusses current concepts concerning the L-arginine/NO system in the pathophysiology of and as a potential therapeutic target in septic shock.
Low-protein diets slow the progression of some renal diseases. We recently found that dietary restriction of L-arginine markedly ameliorates disease in antithymocyte serum-induced glomerulonephritis in the rat, suggesting that L-arginine may play a key role in the beneficial effects of low-protein diets. L-arginine is metabolized by nitric oxide synthases to nitric oxide and L-citrulline or by arginase to urea and L-ornithine. L-ornithine is a precursor for polyamines, which are required for cell proliferation and for proline, an essential component of collagen. In a time course of disease, we found that inducible nitric oxide synthase gene expression and nitric oxide production were increased very early. Arginase activity was significantly increased until 5 days of disease. Ornithine decarboxylase, the rate-limiting step for polyamine synthesis, was increased at 3 days coincident with the onset of cell proliferation. Gene expression of ornithine aminotransferase, a proline synthetic enzyme, was increased from day 1, paralleling increased collagen synthesis. Thus, the three pathways of L-arginine metabolism are upregulated in a manner consistent with their possible roles in the cell lysis, cell proliferation, and collagen deposition, which characterize this model of glomerulonephritis.
In recent years, nitric oxide (NO) has been identified as an effector molecule with multiple biological functions. NO production is physiologically involved in the regulation of vascular tone, platelet aggregation and hormone release, in neurotransmission, and in immune defense against several pathogens. However, uncontrolled up-regulation of NO release by cytokine-inducible NO synthases (iNOSs) may cause tissue damage in immune-mediated diseases. In experimental glomerulonephritis, there is now good evidence that glomerular induction of NO synthesis mediates glomerular cell injury. In contrast, an intact constitutive NO release within the glomerular vasculature may be protective by decreasing glomerular capillary pressure. This review discusses the pathophysiological role of NO in glomerulonephritis based on experimental data and provides a perspective for potential anti-inflammatory treatment approaches selectively targeting iNOS overexpression.
We have previously shown beneficial effects of dietary protein restriction on transforming growth factor beta (TGF-beta) expression and glomerular matrix accumulation in experimental glomerulonephritis. We hypothesized that these effects result from restriction of dietary L-arginine intake. Arginine is a precursor for three pathways, the products of which are involved in tissue injury and repair: nitric oxide, an effector molecule in inflammatory and immunological tissue injury; polyamines, which are required for DNA synthesis and cell growth; and proline, which is required for collagen production. Rats were fed six isocaloric diets differing in L-arginine and/or total protein content, starting immediately after induction of glomerulonephritis by injection of an antibody reactive to glomerular mesangial cells. Mesangial cell lysis and monocyte/macrophage infiltration did not differ with diet. However, restriction of dietary L-arginine intake, even when total protein intake was normal, resulted in decreased proteinuria, decreased expression of TGF-beta 1 mRNA and TGF-beta 1 protein, and decreased production and deposition of matrix components. L-Arginine, but not D-arginine, supplementation to low protein diets reversed these effects. These results implicate arginine as a key component in the beneficial effects of low protein diet.
Both angiotensin II and TGF-beta are key mediators of glomerular and tubulointerstitial injury and fibrosis in progressive kidney diseases. It was thought that angiotensin II damages the kidney by increasing glomerular filtration pressure, whereas autocrine TGF-beta overexpression occurs from unidentified mechanisms. Recent studies reveal that angiotensin II is a potent inducer of TGF-beta synthesis in a variety of cells and that this mechanism exerts important biological effects including extracellular matrix accumulation, cell proliferation, and hypertrophy. Because these studies were performed in vitro, there is clear evidence that the biological effects were observed independently of the vasoconstrictive properties of angiotensin II. Although it is difficult to study angiotensin II-mediated effects in vivo without influencing systemic and glomerular blood pressure, further studies are needed to evaluate the ability of ACE-inhibitors and angiotensin II receptor blockers to suppress TGF-beta overexpression in selected models of chronic progressive kidney disease.
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