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Markus Ketteler

Publications and source records attributed to Markus Ketteler.

At least 37 records · Page 2Linked to original sources
PubMed2005

Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD).

BACKGROUND: The majority of patients with chronic kidney disease (CKD) have excessive vascular calcification; however, most studies demonstrate that a subset of CKD patients do not have, nor develop, vascular calcification despite similar exposure to the uremic environment. This suggests protective mechanisms, or naturally occurring inhibitors, of calcification may be important. METHODS: In order to determine the role of three inhibitors, fetuin-A, matrix gla protein (MGP), and osteoprotegerin (OPG) in the vascular calcification observed in patients with CKD-5, we (1) measured serum levels of these inhibitors and compared the levels to calcification assessed by computed tomography (CT); (2) examined arteries from CKD-5 patients by immunostaining for these inhibitors; and (3) examined the expression and effect of these inhibitors in cultured bovine vascular smooth muscle cells (BVSMCs) incubated in serum pooled from uremic patients compared to healthy controls. RESULTS: There was a negative correlation of coronary artery calcification scores with serum fetuin-A levels (r=-0.30, P= 0.034) and a positive association with OPG levels (r= 0.29, P= 0.045). There was increasing immunostaining for both fetuin-A and MGP in arteries with increasing calcification graded semiquantitatively (P < 0.003). In vitro, fetuin-A added to mineralizing BVSMCs inhibited mineralization (P < 0.001). Compared to normal serum, BVSMCs incubated with uremic serum had a progressive increase in MGP expression with mineralization (P < 0.001) and increased expression of OPG in BVSMCs (P < 0.04). CONCLUSION: These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.

Animals↗
PubMed2005

Calcification and cardiovascular problems in renal failure.

Extraosseus calcification has plagued management of renal failure since the beginning of hemodialysis, but the issue has largely been neglected because the impact on survival was thought to be limited. The recent recognition that hyperphosphatemia is a strong predictor of all-cause mortality, and particularly of cardiac mortality, has transformed the situation. Relatively stringent, though difficult to implement, guidelines have been proposed for the management of hyperphosphatemia. Important recent insights document that, for different reasons, both high and low turnover of bone disease increase the risk of vascular calcifications. Vascular calcification impacts cardiac death not only by complicating coronary atherosclerosis, but also by increasing the stiffness of central arteries, impacting on heart function (increased impedance, reduced coronary perfusion). While in the past extraosseous calcification, including vascular calcification, was thought to be a passive process resulting from transgression of a critical Ca x P product, recent studies show that the adverse effect of hyperphosphatemia is also mediated by active processes (e.g., induction of "osteogenic" genetic programs), and is modulated by calcification inhibitors.

Calcinosis↗
PubMed2004

"Missing" inhibitors of calcification: general aspects and implications in renal failure.

In the recent past, it has become increasingly clear that extracellular calcium and phosphate homeostasis is a tightly regulated process. Since the physiological serum concentrations of calcium and phosphate are several orders of magnitude above their solubility product, mechanisms inhibiting precipitation must be operative to prevent extraosseous calcification. A number of local and systemic calcification inhibitors, including fetuin-A, matrix Gla protein, and osteoprotegerin, have been identified in recent years. Deficiency and dysregulation of such factors may contribute to morbidity and even mortality. Extraosseous calcifications occur with high prevalence in patients with end-stage renal disease. In particular, vascular manifestations are clearly associated with cardiovascular events and decreased survival. In addition to the well-established roles of hyperphosphatemia and an increased calcium x phosphate product, the biological and potential clinical roles of disturbances in calcification inhibition in uremia are discussed in this overview.

Blood Proteins↗
PubMed2004

Early rapid loss followed by long-term consolidation characterizes the development of lumbar bone mineral density after kidney transplantation.

BACKGROUND: Bone mineral density (BMD) decreases significantly early after renal transplantation. This prospective study was designed to evaluate the long-term lumbar BMD development. METHODS: Sixty-three renal-transplant recipients (mean age 44 +/- 12 years, 37 [59%] male) underwent serial yearly posttransplant laboratory parameter and BMD measurements of the lumbar spine (dual energy x-ray absorptiometry). Combined maintenance immunosuppression included prednisolone in 95% of patients. The minimum number of consecutive scans was three; the maximum number seven (n = 15). Examinations were performed between 3 +/- 2 and 68 +/- 4 months posttransplant. RESULTS: BMD was significantly lower compared with healthy controls at all times after transplantation. t scores were below -1. BMD development revealed a biphasic pattern: between 3 +/- 2 and 10 +/- 2 months, a significant BMD decrease of -0.016 +/- 0.055 g/cm2 (-1.6%, P = 0.024) occurred. Later, a moderate increase resulting in BMD stability until the sixth year posttransplant was detected. Within the first year, posttransplant osteocalcin (from 19 +/- 15 to 32 +/- 23 microg/L) and calcitriol (from 24 +/- 15 to 43 +/- 24 ng/L) displayed a significant increase. Compared with patients with a pronounced decrease, patients with a substantial increase in early posttransplant BMD had a lower baseline BMD (0.989 +/- 0.131 vs. 1.149 +/- 0.202 g/cm2 [P = 0.0122]) and lower creatinine levels (105 +/- 23 vs. 141 +/- 53 mmol/L [P = 0.0227]). CONCLUSION: Our study confirms a significant decrease of lumbar BMD early after renal transplantation. Bone loss was less pronounced than previously described. The longitudinal follow-up verifies a previously assumed biphasic lumbar BMD development: after the first year, no further significant bone loss occurred, and bone density remained relatively stable at significantly lower levels compared with healthy controls.

Absorptiometry, Photon↗
PubMed2004

Vascular calcification in patients with end-stage renal disease.

Vascular calcification is the most common type of extra-osseous calcification in end-stage renal disease (ESRD), manifesting as both medial and intimal calcification of large arteries. It is highly prevalent, often progressive and is associated with reduced arterial elasticity and increased mortality. Risk factors for calcification in ESRD include age, duration of dialysis, diabetes mellitus, most probably an elevated calcium-phosphorus product (Ca x P) level, the dose of calcium-containing phosphate binders and the induction of the systemic inflammatory response. Uraemic calcification was thought to be a largely physico-chemical process facilitated by elevated Ca x P (i.e. "metastatic" calcification). It is now well established, however, that vascular smooth muscle cells actively take up phosphate to form bioapatite. This process is associated with a phenotypic transformation of vascular smooth muscle cells during which they express osteoblast markers. In addition to phosphate, various other factors are likely to increase bioapatite formation, e.g. lipids and inflammatory cytokines. There have also been relatively new insights relating to the role of endogenous inhibitors of calcification [i.e. matrix Gla protein and fetuin-A (alpha(2)-Heremans-Schmid glycoprotein)], in particular the downregulation of fetuin-A in systemic inflammation. Decreased serum fetuin-A has been shown to be associated with a reduced capacity to inhibit calcium phosphate precipitation in vitro and is predictive of mortality in dialysis patients. These new insights into pathogenesis may lead to better prevention and treatment of calcification (e.g. with calcimimetics, anti-cytokines, etc.). However, the only preventive approach to have been established prospectively to date is the replacement of calcium-containing phosphate binders with sevelamer HCl, a non-calcaemic phosphate binder. Yet, it remains unclear whether sevelamer HCl reduces vascular calcification by preventing episodes of hypercalcaemia and/or by reducing low-density lipoprotein (LDL)-cholesterol levels.

Blood Proteins↗
PubMed2004

Inducible nitric oxide synthase-derived nitric oxide promotes glomerular angiogenesis via upregulation of vascular endothelial growth factor receptors.

The vascular endothelial growth factor (VEGF) system is of major importance for glomerular endothelial repair in glomerulonephritis (GN) and is significantly affected by nitric oxide (NO) release. For investigating whether glomerular upregulation of inducible NO synthase (iNOS) in GN might affect VEGF-mediated repair, a selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysin (L-NIL), was administered to rats with anti-Thy 1.1 GN from day -2 until day 5 after GN induction. Compared with untreated nephritic rats, L-NIL-treated nephritic rats showed similar mean arterial BP, significantly decreased de novo peak nitrate production, and increased albuminuria on day 6. This was preceded by a significant decrease of glomerular endothelial cell proliferation and endothelial area on day 2 in L-NIL-treated nephritic rats. Upregulation of glomerular VEGF mRNA and protein expression, in particular of the VEGF(164) splicing variant, occurred similarly in L-NIL-treated and untreated nephritic rats on days 2 and 7. However, the upregulation of glomerular VEGF receptor 1 and 2 mRNA expression on day 2 was reduced by 77 and 67%, respectively, in L-NIL-treated nephritic rats as compared with untreated nephritic rats. In parallel, glomerular VEGF(165) binding was reduced by 34% in L-NIL-treated nephritic rats on day 2. Glomerular upregulation of the VEGF(164) co-receptor neuropilin-1 mRNA in nephritic rats was reduced by L-NIL treatment only on day 7. Healthy untreated or L-NIL-treated controls showed no significant differences in any parameter analyzed. In conclusion, impaired repair of glomerular endothelium and downregulation of glomerular VEGF receptor expression was observed after selective iNOS inhibition in experimental GN. These data identify iNOS-derived NO production as the first in vivo regulator of the glomerular VEGF system and as an important mechanism promoting glomerular healing.

Animals↗
PubMed2003

Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study.

BACKGROUND: Vascular calcification is the most prominent underlying pathological finding in patients with uraemia, and is a predictor of mortality in this population. Fetuin-A (alpha2-Heremans Schmid glycoprotein; AHSG) is an important circulating inhibitor of calcification in vivo, and is downregulated during the acute-phase response. We aimed to investigate the hypothesis that AHSG deficiency is directly related to uraemic vascular calcification. METHODS: We did a cross-sectional study in 312 stable patients on haemodialysis to analyse the inter-relation of AHSG and C-reactive protein (CRP) and their predictive effect on all-cause and cardiovascular mortality, over a period of 32 months. Subsequently, we tested the capacity of serum to inhibit CaxPO4 precipitation in patients on long-term dialysis (n=17) with apparent soft-tissue calcifications, and in those on short-term dialysis (n=8) without evidence of calcifications and cardiovascular disease. FINDINGS: AHSG concentrations in serum were significantly lower in patients on haemodialysis (mean 0.66 g/L [SD 0.28]) than in healthy controls (0.72 [0.19]). Low concentrations of the glycoprotein were associated with raised amounts of CRP and with enhanced cardiovascular (p=0.031) and all-cause mortality (p=0.0013). Sera from patients on long-term dialysis with low AHSG concentrations showed impaired ex-vivo capacity to inhibit CaxPO4 precipitation (mean IC50: 9.0 microL serum [SD 3.1] vs 7.5 [0.8] in short-term patients and 6.4 [2.6] in controls). Reconstitution of sera with purified AHSG returned this impairment to normal. Interpretation AHSG deficiency is associated with inflammation and links vascular calcification to mortality in patients on dialysis. Activated acute-phase response and AHSG deficiency might account for accelerated atherosclerosis in uraemia.

Blood Proteins↗
PubMed2003

Deficiencies of calcium-regulatory proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia.

Dialysis patients suffer a manifold increase in cardiovascular mortality when compared to a nonuremic population, while this phenomenon is not sufficiently explained by an increased prevalence of traditional risk factors, such as hypercholesterolemia and hypertension. The presence of hyperphosphatemia, of an increased calcium x phosphate product, as well as the magnitude of vascular and valvular calcifications, were recently identified as specific major risk factors of cardiovascular mortality in the uremic population. Furthermore, hyperphosphatemia and an increased calcium x phosphate product could be quantitatively linked to the burden of coronary artery calcification in young dialysis patients, suggesting the correction of hyperphosphatemia as the central target for preventive therapeutic intervention. Recent studies in knockout mice, however, point to the alternative possibility that deficiencies in calcium-regulatory proteins may represent important pathomechanisms leading to extraosseous calcifications. alpha 2-Heremans Schmid glycoprotein (Ahsg/fetuin) and matrix Gla protein (MGP) are strong inhibitors of calcification in vivo. Novel evidence that deficiencies of such proteins may be involved in the pathogenesis of cardiovascular calcifications in dialysis patients will be discussed.

Animals↗
PubMed2003

Angiotensin-converting enzyme inhibition but not beta-adrenergic blockade limits transforming growth factor-beta overexpression in acute normotensive anti-thy1 glomerulonephritis.

OBJECTIVE: Recent experimental studies in chronic kidney disease have suggested that sympathicolytic drugs, similar to angiotensin II antagonism, limit renal fibrosis independent of blood pressure control. Using the model of acute and normotensive anti-thy1 glomerulonephritis, we analysed the action of beta-adrenergic blockade (as compared with angiotensin-converting enzyme inhibition) on renal overexpression of the profibrotic cytokine transforming growth factor (TGF)-beta. METHODS: One day after induction of anti-thy1 glomerulonephritis, rats were given increasing doses of the beta-blockers metoprolol or nebivolol (0.1-fold, one-fold, 10-fold and 20-fold of the known blood pressure dose) until day 6 and the 20-fold dose until day 12. Additional animals were treated with a high dose of the angiotensin-converting enzyme inhibitor enalapril. At the end of each experiment, blood pressure and heart rate were recorded, glomerular matrix expansion was scored histologically, and protein expression of TGF-beta(1), fibronectin and plasminogen activator inhibitor-1 was determined in the supernatant of cultured glomeruli. RESULTS: Metoprolol and nebivolol reduced heart rate in a dose-dependent manner. Blood pressure was normal in untreated animals and not significantly affected by either treatment. Compared with untreated nephritic rats, TGF-beta(1) overexpression was not significantly changed by metoprolol or nebivolol in any dose or treatment period. In contrast, TGF-beta(1) levels were significantly reduced by enalapril both 6 and 12 days after disease induction (-52 and -63%, respectively). The changes in glomerular matrix score, fibronectin and plasminogen activator inhibitor-1 production closely followed expression of TGF-beta(1). CONCLUSIONS: In a model of acute and normotensive glomerular fibrosis, beta-adrenergic antagonism does not reduce TGF-beta overexpression, suggesting that its pressure-independent antifibrotic action may be limited to chronic renal diseases. The beneficial effect of angiotensin II inhibition even on acute matrix expansion may be a relevant mechanism as to the explanation of its superiority in treating fibrotic renal diseases.

Adrenergic beta-Antagonists↗
PubMed2003

The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification.

Ectopic calcification is a frequent complication of many degenerative diseases. Here we identify the serum protein alpha2-Heremans-Schmid glycoprotein (Ahsg, also known as fetuin-A) as an important inhibitor of ectopic calcification acting on the systemic level. Ahsg-deficient mice are phenotypically normal, but develop severe calcification of various organs on a mineral and vitamin D-rich diet and on a normal diet when the deficiency is combined with a DBA/2 genetic background. This phenotype is not associated with apparent changes in calcium and phosphate homeostasis, but with a decreased inhibitory activity of the Ahsg-deficient extracellular fluid on mineral formation. The same underlying principle may contribute to many calcifying disorders including calciphylaxis, a syndrome of severe systemic calcification in patients with chronic renal failure. Taken together, our data demonstrate a critical role of Ahsg as an inhibitor of unwanted mineralization and provide a novel therapeutic concept to prevent ectopic calcification accompanying various diseases.

Animals↗
PubMed2002

Nitric oxide synthase isoform expression in acute versus chronic anti-Thy 1 nephritis.

BACKGROUND: Two inbred Lewis rat substrains (LEW/Moe, LEW/Maa) were identified responding differently to induction of anti-Thy 1 glomerulonephritis (aThy 1-GN). LEW/Moe rats show an acute mesangioproliferative glomerulonephritis with rapid healing of glomerular lesions within four weeks, while LEW/Maa rats develop severe glomerular injury followed by chronic glomerular sclerosis and persistent albuminuria. We investigated whether the glomerular expression pattern of nitric oxide synthase (NOS) isoforms could explain these substrain-related differences. METHODS: Rats (N = 5 to 7 per group) were investigated in a time course experiment. Severity of aThy 1-GN was determined by albuminuria measurements, glomerular matrix score and microaneurysm formation. Glomerular gene expression of NOS isoforms was determined by semiquantitative RT-PCR. Inducible NOS (iNOS) activity was determined in cultured glomeruli and peritoneal macrophages. Neuronal NOS (nNOS) protein expression was detected by Western blotting and enzyme histochemistry. Plasma renin activity (PRA) was measured by RIA. RESULTS: Induction of iNOS expression and activity was found significantly increased and sustained in LEW/Maa vs. LEW/Moe rats associated with an increased number of infiltrating macrophages and with an increased capacity of iNOS-expression and iNOS-activation by isolated macrophages in LEW/Maa rats. Glomerular nNOS mRNA and nNOS protein expression were constitutively increased in LEW/Maa rats. Renal nNOS localization was restricted to the macula densa region in both substrains and associated with increased PRA in LEW/Maa rats. No difference in glomerular endothelial NOS-mRNA expression between the substrains was observed. CONCLUSIONS: Increased glomerular iNOS and nNOS expression were associated with chronic anti-Thy 1 glomerulonephritis in LEW/Maa rats and may contribute to glomerular damage by separate mechanisms.

Acute Disease↗
PubMed2002

Selective inhibition of inducible nitric oxide synthase enhances intraglomerular coagulation in chronic anti-Thy 1 nephritis.

BACKGROUND: A particular Lewis rat substrain (LEW/Maa) develops chronic glomerulonephritis in the anti-Thy 1 model (aThy 1-GN) characterized by increased microaneurysm formation, chronic glomerular sclerosis and persistent albuminuria. This phenotype is accompanied by increased and prolonged glomerular induction of inducible nitric oxide synthase (iNOS) when compared to the LEW/Moe substrain, in which aThy 1-GN resolves quickly. We investigated the effect of selective iNOS inhibition by l-N6-(1-iminoethyl)-lysine (L-NIL) administration on aThy 1-GN in LEW/Maa rats. METHODS: Nephritic rats were studied over a period of 7 days. L-NIL-treated animals received 20 mg/day L-NIL in the drinking water starting two days prior to disease induction. iNOS activity was determined in cultured glomeruli and in urine samples, respectively. Severity of aThy 1-GN was determined by scoring glomerular matrix expansion and microaneurysm formation, and by albuminuria measurements (ELISA). Immunohistochemical evaluation was performed including staining for macrophages (ED-1), platelets (PL-1) and fibrin deposition. RESULTS: L-NIL treated rats (+NIL) showed a significant decrease in peak nitrate production by ex vivo cultured glomeruli, and in urinary nitrate excretion versus untreated nephritic rats (-NIL). Mean arterial pressure remained unchanged in both +NIL and -NIL rats. +NIL rats developed significantly increased albuminuria (+44%) associated with a significant increase in glomerular platelet (+45%) and fibrin deposition (+48%). CONCLUSIONS: Selective inhibition of iNOS aggravated albuminuria in chronic aThy 1-GN in LEW/Maa rats. Induction of iNOS during the inflammatory phase of this model may be a partially protective mechanism by interfering with intraglomerular coagulation processes.

Albuminuria↗
PubMed2002

Development of lumbar bone mineral density in the late course after kidney transplantation.

BACKGROUND: Rapid bone loss is a frequent finding early after kidney transplantation. Only limited data are available on the bone mineral density (BMD) in long-term kidney transplant recipients. METHODS: In 26 kidney transplant recipients (13 men and 13 women, age 45.3 +/- 12.3 years), serum biochemical markers of bone metabolism and BMD at the lumbar vertebrae L2-4 were evaluated prospectively in three serial examinations (E1, E2, E3; method: dual-energy X-ray absorptiometry). Examinations were performed at 47 +/- 2 months, 59 +/- 2 months, and 71 +/- 2 months after transplantation. All patients received standard dual or triple immunosuppression including prednisolone. RESULTS: The mean BMD was significantly lower (P < 0.001) than in sex-matched young controls: T-score was -1.43 +/- 1.49 (E1), -1.39 +/- 1.40 (E2), and -1.44 +/- 1.30 (E3). The BMD did not change significantly (Delta BMD, -0.5 +/- 5.9%) from E1 to E3. Regression analysis did not show significant associations between Delta BMD and biochemical parameters or prednisolone dosage. No clinically apparent new lumbar vertebral fracture occurred. The mean intact parathyroid hormone was 110.1 +/- 97.5 pg/mL (E1), 121 +/- 102.7 pg/mL (E2), and 134.5 +/- 128.6 pg/mL (E3). Serum creatinine was 1.44 +/- 0.45 (128 +/- 40) mg/dL (micromol/L) (E1), 1.44 +/- 0.47 (127 +/- 42) mg/dL (micromol/L) (E2), and 1.45 +/- 0.70 (128 +/- 62) mg/dL (micromol/L) (E3). Ten patients (38.5%) showed an increase of BMD (+5.7 +/- 3.2%) and 15 patients (57.7%) showed a decrease of -4.7 +/- 3.2% (P < 0.0001). Both groups were different in T-scores at E1 (-2.29 +/- 1 versus -0.88 +/- 1.5); intact parathyroid hormone, creatinine, vitamin D levels, and prednisolone dosage were not significantly different. CONCLUSION: This study shows that lumbar BMD is reduced in long-term kidney transplant recipients. During our 24-month observation period, overall lumbar BMD remained stable.

Absorptiometry, Photon↗