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M Ketteler

Publications and source records attributed to M Ketteler.

30 records · Page 2Linked to original sources
PubMed1995

Nitric oxide mediates immunologic injury to kidney mesangium in experimental glomerulonephritis.

BACKGROUND: Nitric oxide (NO), produced from L-arginine by an inducible NO synthase, is an important effector molecule in inflammatory and immunologic tissue injury. The role of NO generation in immunologic injury to glomerular mesangial cells and the effect of dietary restriction of L-arginine on this injury was investigated. EXPERIMENTAL DESIGN: Acute glomerulonephritis was induced by injection of anti-thymocyte serum (ATS) which binds to an antigen on the glomerular mesangial cell. Complement-mediated mesangial cell lysis follows. The effect of blocking NO production in vivo by administration of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) 60 minutes before ATS injection on mesangial cell lysis, and on the severity of disease was assessed. The effect of dietary restriction of L-arginine on mesangial cell lysis in response to ATS injection was also determined. RESULTS: We report here that blocking NO production in vivo with L-NMMA prevented mesangial cell lysis by 90%. Injection of L-NMMA caused transiently elevated systolic blood pressure, but did not diminish ATS binding to mesangial cells or recruitment of monocyte/macrophages into glomeruli indicating that L-NMMA pretreatment did not limit injury by insufficient glomerular perfusion. ATS-induced proteinuria and increases in urinary nitrite excretion were prevented. Glomerular expression of transforming growth factor-beta and accumulation of extracellular matrix were suppressed by the L-NMMA treatment. Low protein diet (6%), but also selective dietary L-arginine restriction, given for 7 days before induction of the disease mimicked L-NMMA treatment, significantly decreasing mesangial cell lysis. The effect of a low protein diet was abolished by dietary L-arginine supplementation. CONCLUSIONS: This study strongly implicates NO as a mediator in immune-mediated mesangial cell lysis. The data suggest that limiting NO production by limiting arginine intake might decrease glomerular injury and subsequent glomerulosclerosis.

Animals↗
PubMed1994

Increased expression of transforming growth factor-beta in renal disease.

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine and a major regulator of tissue repair and extracellular matrix. Recent studies show that TGF-beta overexpression in experimental and human kidney diseases leads to progressive glomerular and tubulointerstitial scarring and renal failure. New evidence suggests that angiotensin-converting enzyme inhibitors and a low-protein diet may slow the progression of chronic kidney diseases in part by suppressing TGF-beta overexpression. New therapies may prevent progressive fibrosis in chronic kidney disease by suppressing the action of TGF-beta.

Acute Disease↗
PubMed1994

Cytokines and L-arginine in renal injury and repair.

Advances in molecular biology have identified cytokines as mediators of pathophysiological changes in chronic renal disease. Transforming growth factor-beta (TGF-beta) plays an important role in the pathogenesis of glomerular and interstitial fibrosis, whereas platelet-derived growth factor (PDGF) is involved in proliferative changes in chronic progressive renal diseases. Tumor necrosis factor-alpha and interleukins are expressed in experimental models of renal disease and are causes of inflammation and cell migration. Cytokines act by many different mechanisms, and one target of their action may be L-arginine metabolism. Since the discovery of the effector molecule nitric oxide (NO), generated from L-arginine, knowledge of this pathway has increased dramatically. It became evident that the L-arginine/NO pathway is of major importance in the regulation of hemodynamics and neurotransmission, in host defense against intracellular microorganisms, and in immunologic tissue injury. This pathway is induced by proinflammatory cytokines and possibly regulated by TGF-beta and PDGF. L-Arginine is also metabolized to L-ornithine, which can be processed to polyamines or to L-proline. As polyamines are important mediators of cell growth and L-proline is a substrate for collagen synthesis, both pathways, once activated, may be important in repair processes. It is likely that cytokines and L-arginine metabolism are interconnected and that both are involved in the inflammation, tissue repair, and fibrogenesis processes in the kidney. Dietary protein restriction in progressive renal diseases may substantially affect both systems. This review summarizes current knowledge about interactions of cytokines and L-arginine metabolism and the relevance to renal diseases.

Animals↗
PubMed1991

[Significance of hyponatremia in patients with oropharyngeal tumors].

We observed 29 patients with hyponatremia associated with oropharyngeal carcinoma. In 19/29 the hyponatremia was attributable to a decreased effective arterial blood volume whereas in the remainder (10/29) the presence of SIADH could be demonstrated. These etiologies of hyponatremia were best differentiated by the plasma urea concentration (less than 30 mg/dl in SIADH), urate concentration (less than 4,0 mg/dl in SIADH) and creatinine concentration (less than 0,9 mg/dl in SIADH). Furthermore, SIADH patients had a spontaneous natriuresis. The mainstay of therapy in either form of hyponatremia is fluid restriction (less than 1 l/d).

Carcinoma, Squamous Cell↗
PubMed1989

[Kidney function in heart failure].

Congestive cardiac failure is a syndrome in which a decrease of cardiac output triggers a series of neuro-humoral compensatory mechanisms in part involving the kidney. In this response, dysfunction of atrial volume receptors as well as disturbances of the autonomic nervous system have recently been demonstrated and are held responsible for excessive stimulation of angiotensin II, followed by adverse regulatory effects. Renal hemodynamic compensation for heart failure primarily involves constriction of efferent arterioles thereby defending glomerular filtration. In this setting, the occurrence of prerenal insufficiency is indicative of a far advanced reduction in renal blood flow. Apparent diuretic resistance in the treatment of heart failure is usually caused by iatrogenic vascular compromise or by the use of a single diuretic rather than an appropriate combination. Hyponatremia, vasopressin stimulation and elevation of plasma N-epinephrine concentration have been found to be the most reliable indicators of a poor prognosis of heart failure. Atrial natriuretic peptide is stimulated in proportion to the degree of atrial distension in heart failure, however its intrarenal effects are markedly blunted or may even be absent in this particular disease.

Atrial Natriuretic Factor↗
PubMed1989

Natriuretic factors and lithium clearance in patients with the syndrome of inappropriate antidiuretic hormone (SIADH)

Because the syndrome of inappropriate antidiuretic hormone (SIADH) is a state of disturbed body fluid volume regulation and altered sodium balance we sought to determine if recently described volume regulatory factors were stimulated in SIADH. We measured atrial natriuretic peptide (ANP), endogenous digitalis-like natriuretic factor (EDNF) and urinary free dopamine in SIADH (n = 27). We also determined fractional clearance of lithium (FCLi). The data obtained in SIADH were compared with similar measurements performed in sodium retaining hyponatremias, such as those of heart failure (n = 26), liver cirrhosis (n = 19) and volume contraction (n = 28). We observed: ANP was 19.5 +/- 2.7 fM/ml in SIADH; it was significantly lower than ANP in cardiac failure, but no different from ANP in volume contraction. Urinary free dopamine was 2.2 +/- 0.8 microM/24 h in SIADH; this was significantly higher than in volume contraction and liver cirrhosis. EDNF (259 +/- 42 nM/24 h) and FCLi (21.4 +/- 2%) were both numerically higher in SIADH than in other hyponatremic disorders; however, the differences did not achieve significance. In conclusion, our observations did not establish a specific role of ANP in chronic stable SIADH. As to the importance of EDNF, dopamine and proximal tubular fluid reabsorption (FCLi) additional work using acute volume changes may demonstrate their participation in the renal sodium handling of SIADH more clearly than our study did.

Aged↗
PubMed1988

Role of diuretics, hormonal derangements, and clinical setting of hyponatremia in medical patients.

Because hyponatremia is frequently associated with preceding diuretic treatment and unrestricted fluid intake--conditions which have not been addressed sufficiently in published literature--we studied the pathophysiology and the clinical setting of such hyponatremia in a large group of internal medicine patients. We observed: a) Of an initial 310 patients with chemical hyponatremia only 204 (64%) had an associated plasma hypoosmolality. Since a normal plasma osmolality excludes a disturbance of water metabolism only the 204 patients with hypoosmolar hyponatremia were included in the study. This data shows that plasma osmolality is an essential measurement in any evaluation of hyponatremia. b) In 204 consecutive patients with hypoosmolar hyponatremia the electrolyte disturbance was related to advanced congestive cardiac failure in 25%, decompensated liver cirrhosis in 18%, volume contraction in 28%, syndrome of inappropriate antidiuretic hormone secretion in 19% and renal insufficiency in 4%. c) Plasma vasopressin was measurable in 90% of the 204 patients. It is known that radioimmunoassays to measure vasopressin fail to reliably detect low concentrations of circulating vasopressin (less than 0.5 pg/ml). It may therefore be stated that hypoosmolar hyponatremia was generally characterized by a failure of antidiuretic hormone suppression. d) Mean daily fluid intake of hyponatremic patients was 2.35 +/- 0.15 l. In the presence of stimulated vasopressin this large a fluid intake is bound to worsen the severity of hyponatremia. e) Of 204 patients 126 were treated with diuretics at the time of study. In these patients hyponatremia worsened during such treatments and was associated with evidence of prerenal azotemia. However there were no significant differences between diuretic-treated and -untreated patients with respect to plasma vasopressin stimulation and amount of fluid intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1988

Ionic conductances of cultured principal cell epithelium of renal collecting duct.

The ionic conductive properties were studied of epithelia of collecting duct principal cells which had been grown in primary tissue culture from renal cortex/capsule explants. When pretreated with aldosterone (10(-6) mol/l) and bathed on either surface with isotonic HCO3(-)-free Ringer's solution, the transepithelial voltage, Vte, varied between -21 and -72 mV (apical surface negative) while the transepithelial resistance, Rte, ranged from 0.4 to 1.5 k omega cm2. By 10:1 step-changes in Na+ concentration the apical cell membrane was shown to have a high conductivity for sodium, inhibitable by amiloride, 10(-6) mol/l. However, contrary to observations in natural collecting duct under control conditions, amiloride never reversed the polarity of Vte even at 10(-4) mol/l. Both the apical and the basolateral cell membranes were conductive for potassium and both conductivities were inhibitable by Ba2+ (5 mmol/l). 10:1 reduction of apical Cl- concentration strongly hyperpolarized Vte with a monophasic time course suggesting the presence of a paracellular shunt conductance for Cl-. In addition there may be a small Cl- conductance present in the apical cell membrane since apical application of the chloride channel blocker 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPAB) at 10(-7) mol/l produced a minute but significant hyperpolarization. On the other hand, 10:1 reduction of basolateral Cl- concentration caused a biphasic change in Vte (initial depolarization, followed by repolarization) which indicates the presence of a large Cl- conductance in the basolateral cell membrane. The latter was not inhibitable by 10(-7) mol/l NPPAB. Higher concentrations of this and of an other Cl-channel blocker produced non-specific effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

The charted and the uncharted waters of hyponatremia.

It was observed that hyponatremia has been evaluated by many studies of patients and laboratory animals. In virtually all of these the presence of nonosmotic ADH has been shown, but several details of this relationship remain controversial at this time. The role of specific receptor areas for ADH stimulation requires further study, particularly in the hyponatremia of a decreased effective arterial blood volume. In addition, it will be important to define the suspected vascular effects of nonosmotic ADH more specifically. Other areas of uncertainty include: the degree to which the tubular effect of ADH in hyponatremia may be modified by a decreased delivery of fluid to the loops of Henle; the potential stimulation of ADH by stress in clinical hyponatremia; and the meaning of very low or non-measurable concentrations of ADH in hyponatremia. New experimental tools such as vasopressin antagonists and agonists, measurements of baroreceptor input, and tests of proximal fluid reabsorption can be expected to clarify some of these questions in the near future.

Animals↗
PubMedDate not supplied

Imaging techniques in the diagnosis of dialysis-related amyloidosis.

beta(2)-microglobulin amyloidosis (A beta(2)M) is a major determinant of morbidity in patients on dialysis treatment. Symptoms of A beta(2)M amyloid are mainly related to (peri-)articular amyloid deposition. Imaging techniques [i.e., joint ultrasonography, X-ray, computed tomography (CT), or magnetic resonance imaging (MRI) findings], as well as conventional bone scans, are helpful in the screening of local lesions but are relatively nonspecific and/or not sensitive enough. Scintigraphic techniques using radiolabeled serum amyloid P component (SAP) or the radiolabeled A beta(2)M precursor protein, beta(2)M, generate more specific results. A beta(2)M deposits have been visualized in several long-term hemodialysis patients by using (123)I-labeled SAP. However, this scan did not show tracer accumulation in some frequently involved sites such as hips or shoulders, and frequently labeled the spleen, which is usually spared from A beta(2)M deposits. Improvements in technical sensitivity and specificity could be achieved by scanning with (131)I-labeled beta(2)M: this technique detected tracer accumulations corresponding to the typical distribution pattern of A beta(2)M. Further, both the radiation exposure and the optical resolution of this latter scan have been refined by substituting (111)In for (131)I. In a final step we generated recombinant human beta(2)M (rh beta(2)M). While (111)In rh beta(2)M again failed to show significant tracer accumulation over joint regions in patients on short-term hemodialysis without evidence of A beta(2)M, local tracer accumulations similar to those observed with natural, (111)In-labeled beta(2)M could be demonstrated in long-term hemodialysis patients with evidence of A beta(2)M. In conclusion, scintigraphy for A beta(2)M with (111)In-labeled rh beta(2)M provides a homogeneous and safe recombinant protein source and represents a suitable detection method of beta(2)M amyloid deposits in dialysis patients.

Amyloidosis↗