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Biomedical subjects

R Krapf

Publications and source records attributed to R Krapf.

At least 37 records · Page 2Linked to original sources
PubMed1996

Familial glomerulopathy with giant fibrillar (fibronectin-positive) deposits: 15-year follow-up in a large kindred.

A 15-year clinical follow-up is reported for a familial glomerulopathy characterized on light microscopy by the glomerular deposition of giant fibrillary deposits (Virchows Arch A Pathol Anat Histol 388:313-326, 1980). On electron microscopy, the deposits consist of randomly oriented fibrils (12 to 16 nm in width and 120 to 170 nm in length). These deposits show positive immunoreactivity for fibronectin. One hundred fifty-seven of 197 family members within five generations were investigated. The disease is characterized by the occurrence of albuminuria in the third to fourth decades of life and slow progression to end-stage renal disease over a period of 15 to 20 years with the occurrence of generalized distal tubular acidosis (renal tubular acidosis type IV), hypertension, and the nephrotic syndrome. The frequent occurrence of otherwise unexplained microalbuminuria in young individuals of generations IV and V could be indicative of incipient glomerular disease. In one affected male individual and in his unaffected sister, renal cell carcinoma was diagnosed, raising the possibility that this familial glomerulopathy might be associated with an increased risk to develop renal cell cancer by direct or indirect (associated genetic predisposition) mechanisms. The disease relapsed in one renal transplant, raising the possibility of the presence of a transferable factor that could be part of the deposited fibrillar material or, alternatively, interfere with the glomerular handling of the deposited material.

Acidosis, Renal Tubular↗
PubMed1995

Plasma potassium response to acute respiratory alkalosis.

Acute respiratory alkalosis (hyperventilation) occurs in clinical settings associated with electrolyte-induced complications such as cardiac arrhythmias (such as myocardial infarction, sepsis, hypoxemia, cocaine abuse). To evaluate the direction, magnitude and mechanisms of plasma potassium changes, acute respiratory alkalosis was induced by voluntary hyperventilation for 20 (18 and 36 liter/min) and 35 minutes (18 liter/min). The plasma potassium response to acute respiratory alkalosis was compared to time control, isocapnic and isobicarbonatemic (hypocapnic) hyperventilation as well as beta- and alpha-adrenergic receptor blockade by timolol and phentolamine. Hypocapnic hypobicarbonatemic hyperventilation (standard acute respiratory alkalosis) at 18 or 36 liter/min (delta PCO2-16 and -22.5 mm Hg, respectively) resulted in significant increases in plasma potassium (ca + 0.3 mmol/liter) and catecholamine concentrations. During recovery (post-hyperventilation), a ventilation-rate-dependent hypokalemic overshoot was observed. Alpha-adrenoreceptor blockade obliterated, and beta-adrenoreceptor blockade enhanced the hyperkalemic response. The hyperkalemic response was prevented under isocapnic and isobicarbonatemic hypocapnic hyperventilation. During these conditions, plasma catecholamine concentrations did not change. In conclusion, acute respiratory alkalosis results in a clinically significant increase in plasma potassium. The hyperkalemic response is mediated by enhanced alpha-adrenergic activity and counterregulated partly by beta-adrenergic stimulation. The increased catecholamine concentrations are accounted for by the decrease in plasma bicarbonate.

Acute Disease↗
PubMed1995

Glomerulopathy associated with predominant fibronectin deposits: a newly recognized hereditary disease.

A newly recognized type of familial glomerulopathy observed in patients of both sexes in six families is reported. Proteinuria, often within the nephrotic range, microscopic hematuria, hypertension and a slowly decreasing renal function over several years were common. No underlying systemic diseases were identified. Generally, light microscopy showed enlarged glomeruli with minimal hypercellularity and with extensive deposits in the mesangium and subendothelial space. By electron microscopy, granular deposits with some admixture of fibrils were most common. In one family, the deposits were predominantly fibrillary. Immunoglobulins and complement factors were inconstant or lacking. A main finding was a strong immune reactivity to fibronectin, corresponding to the distribution of the deposits. In one patient, the deposits recurred in a renal transplant. There was no indication of systemic deposition. Abnormalities in the metabolism of circulating fibronectin may play a pathogenetic role in this disease of probably autosomal dominant inheritance.

Adolescent↗
PubMed1995

Neutral phosphate administration generates and maintains renal metabolic alkalosis and hyperparathyroidism.

We examined the effects of chronic intravenous neutral phosphate administration on systemic acid-base equilibrium and parathyroid function in six normal, NaCl-replete male human subjects under metabolic balance conditions. The subjects received 4.35 mmol of neutral sodium phosphate.kg body wt-1.day-1 intravenously and continuously for 7 days and the same amount of sodium as NaCl during control and recovery. Blood pH increased from 7.388 to 7.411 (P < 0.001) and plasma bicarbonate from 23.5 to 26.0 mmol/l (P < 0.001). Urinary pH increased from 6.58 to 6.79 (P < 0.001). Net acid excretion increased from 59 to 100 mmol/24 h (P < 0.001). Plasma ionized calcium concentration decreased and plasma phosphate concentration increased transiently. Serum intact parathyroid hormone increased from 24 to 62 pg/ml (P < 0.001). Chronic phosphate administration also resulted in a significant increase in renal phosphate clearance (35 to 229 ml/min) and decrease in the fractional excretion of calcium (1.8 to 0.9%). Thus chronic intravenous phosphate administration generates and maintains renal metabolic alkalosis in salt-replete humans and induces hyperparathyroidism. The severity of metabolic alkalosis is mitigated by an apparent increase in effective endogenous acid production as evidenced by the significant increase in steady-state net acid excretion.

Acid-Base Equilibrium↗
PubMed1995

Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans.

Chronic metabolic acidosis has been previously shown to stimulate protein degradation. To evaluate the effects of chronic metabolic acidosis on nitrogen balance and protein synthesis we measured albumin synthesis rates and urinary nitrogen excretion in eight male subjects on a constant metabolic diet before and during two different degrees of chronic metabolic acidosis (NH4Cl 2.1 mmol/kg body weight, low dose group, and 4.2 mmol/kg body weight, high dose group, orally for 7 d). Albumin synthesis rates were measured by intravenous injection of [2H5ring]phenylalanine (43 mg/kg body weight, 7.5 atom percent and 15 atom percent, respectively) after an overnight fast. In the low dose group, fractional synthesis rates of albumin decreased from 9.9 +/- 1.0% per day in the control period to 8.4 +/- 0.7 (n.s.) in the acidosis period, and from 8.3 +/- 1.3% per day to 6.3 +/- 1.1 (P < 0.001) in the high dose group. Urinary nitrogen excretion increased significantly in the acidosis period (sigma delta 634 mmol in the low dose group, 2,554 mmol in the high dose group). Plasma concentrations of insulin-like growth factor-I, free thyroxine and tri-iodothyronine were significantly lower during acidosis. In conclusion, chronic metabolic acidosis causes negative nitrogen balance and decreases albumin synthesis in humans. The effect on albumin synthesis may be mediated, at least in part, by a suppression of insulin-like growth factor-I, free thyroxine and tri-iodothyronine.

Acidosis↗
PubMed1994

Induction of the putative copper ATPases, CopA and CopB, of Enterococcus hirae by Ag+ and Cu2+, and Ag+ extrusion by CopB.

The two P-type ATPases CopA and CopB are effecting regulation of cellular copper activity in Enterococcus hirae. With antibodies against these ATPases, we showed on Western blots the simultaneous induction of CopA and CopB by copper or silver ions. Copper contents of wild type and mutant cells lacking either CopA, CopB or both enzymes were measured by atomic absorption. Strains disrupted in copB showed clearly enhanced copper contents. Mutants lacking CopB also lost the ability of energy dependent efflux of silver ions. Our results demonstrate that CopA and CopB are under the same genetic control and support the proposal that CopB is a copper and silver exporting ATPase.

Adenosine Triphosphatases↗
PubMed1994

Copper pumping ATPases: common concepts in bacteria and man.

Recently, four genes encoding putative copper pumping ATPases have been cloned from widely different sources: two genes from Enterococcus hirae that are involved in copper metabolism and two human genes that are defective in the copper-related Wilson and Menkes disease. The predicted gene products are P-type ATPases. They exhibit extensive sequence similarity and appear to be members of a new class of ATP driven copper pumps involved in the regulation of cellular copper.

Adenosine Triphosphatases↗
PubMed1994

Functional adaptation to high PCO2 of apically and basolaterally located Na+/H+ exchange activities in cultured renal cell lines.

Cultured renal epithelial cells grown on filter support were examined for functional adaptation of Na+/H+ exchange activities to "respiratory" acidaemia, which was mimicked by increasing PCO2 from 5% to 10% during 24 h or 48 h of cell culture. We have selected proximal tubular cell lines with either dual location of Na+/H+ exchange activities (MCT cells, RKPC-2 cells), apical location of Na+/H+ exchange activity (OK/WOK cells) or a basolateral location of Na+/H+ exchange activities (LLC-PK1/clone 4 cells, MDCK cells). Na+/H+ exchange activity was determined microspectrofluorometrically (using BCECF) in the absence of CO2/HCO3-. Respiratory acidaemia specifically increased apical Na+/H+ exchange activity (previously classified as amiloride-resistant) in MCT cells, in RKPC-2 cells and in WOK cells; it stimulated basolateral Na+/H+ exchange activity (previously shown to be amiloride-sensitive) in RKPC-2 cells, in LLC-PK1/clone 4 cells and in MDCK cells, but did not affect basolateral Na+/H+ exchange activity in MCT cells. In MCT and in RKPC-2 cells the effect of high PCO2 on apical Na+/H+ exchange was prevented by inhibition of protein kinase C. In RKPC-2 cells, activation of basolateral Na+/H+ exchange by high PCO2 occurred also when protein kinase C was inhibited. In conclusion, these studies demonstrate stimulation of apical Na+/H+ exchange, but differential regulation of basolateral Na+/H+ exchange activities in response to a high-PCO2-induced acid environment. Protein kinase C activation might be involved in mediating the effect of acidaemia on stimulation of apical Na+/H+ exchange activity (MCT and RKPC-2 cells).

Adaptation, Physiological↗
PubMed1994

Analysis and pharmacokinetics of glycyrrhizic acid and glycyrrhetinic acid in humans and experimental animals.

Glycyrrhizic acid (GZA) and glycyrrhetinic acid (GRA) can be determined rapidly and precisely by high-performance liquid chromatography (HPLC) in biological fluids and tissues from experimental animals and humans. From plasma and tissues, GZA and GRA are extracted by organic solvents and the extracts can directly be used for HPLC. From bile or urine, extraction and determination of GZA and GRA are more difficult due to interfering endogenous compounds and conjugation of GRA with glucuronides or sulfates. Extraction of GZA and GRA from urine or bile can be performed by ion-pairing followed by extraction with organic solvents or by solid phase extraction. GRA conjugates can be determined by chromatographic separation or by pretreatment with beta-glucuronidase. The pharmacokinetics of GRA and GZA can be described by a biphasic elimination from the central compartment with a dose-dependent second elimination phase. Depending on the dose, the second elimination phase in humans has a half-life of 3.5 hours for GZA and between 10-30 hours for GRA. The major part of both GRA or GZA is eliminated by the bile. While GZA can be eliminated unmetabolized and undergoes enterohepatic cycling, GRA is conjugated to GRA glucuronide or sulfate prior to biliary excretion. Orally administered GZA is almost completely hydrolyzed by intestinal bacteria and reaches the systemic circulation as GRA.

Animals↗
PubMed1994

Azathioprine hypersensitivity mimicking Goodpasture's syndrome.

Side effects due to azathioprine (the nitroimidazole derivative of 6-mercaptopurine) can be classified as toxic (myelosuppression, hepatotoxicity) and idiosyncratic (fever, rigors, arthralgias, pneumonitis, and gastrointestinal symptoms). While the toxic effects are due to 6-mercaptopurine, the hypersensitivity reactions are believed to be caused by the nitroimidazole moiety. A 21-year-old male patient developed end-stage renal failure due to antiglomerular basement membrane (AGBM) disease (rapidly progressive glomerulonephritis with linear immunoglobulin G deposits and positive circulating AGBM antibodies). The patient became dependent on continuous ambulatory peritoneal dialysis and, later, hemodialysis, and received two renal allografts at the ages of 23 and 27 years. He received three courses of azathioprine treatment: one course for AGBM glomerulonephritis and two courses for rejection episodes. Each course was followed within 4 to 7 days by symptoms compatible with Goodpasture's syndrome, ie, high fever, rigors, arthralgias, diarrhea, myalgias, and pulmonary infiltrates with hemoptysis. All signs and symptoms always resolved completely on discontinuation of azathioprine. During the treatment for rejections, AGBM antibodies were not elevated, and during one episode AGBM disease in the lung (Goodpasture's syndrome) was excluded by open lung biopsy. Treatment of a subsequent rejection episode with 6-mercaptopurine was well tolerated. We conclude that azathioprine hypersensitivity can mimic the pulmonary manifestations of Goodpasture's syndrome. Hypersensitivity probably is due to the nitroimidazole moiety of azathioprine. Thus, differential diagnosis of Goodpasture's syndrome (and probably of any "pulmonary renal syndrome") should include azathioprine hypersensitivity.

Adult↗
PubMed1994

Kinetics and dynamics of orally administered 18 beta-glycyrrhetinic acid in humans.

18 beta-Glycyrrhetinic acid (GRA) represents a major metabolite of glycyrrhizic acid (glycyrrhizin), an important constituent of licorice and licorice root, and is a potent inhibitor of 11 beta-hydroxysteroid dehydrogenase (11 beta OHSD). Different oral doses of GRA (500, 1000, or 1500 mg) were administered to healthy volunteers in order to study its kinetics and dynamics. In agreement with the lipophilic nature of GRA, with a biphasic decay of the plasma concentration-time curve at doses greater than 500 mg. The mean (+/-SEM) half-life of the second elimination phase was 11.5 +/- 1.2 h after 1000 mg GRA and 38.7 +/- 10.5 h after 1500 mg GRA (P < 0.05). The peak plasma concentration and the area under the plasma concentration-time curve (AUC) increased with increasing GRA doses. Urinary elimination of GRA and GRA glucuronides over 24 h was less than 1% of the dose administered. The dynamics of GRA were assessed by measuring the activity of the 11 beta OHSD in vivo, as reflected by the cortisol and cortisone concentrations in plasma. With increasing doses of GRA, the cortisone concentration declined, and the cortisol/cortisone ratio increased. Both peak plasma concentration and AUCs of GRA correlated with changes in the AUC values of cortisone. Based on the single dose kinetics, the kinetic/dynamic analysis of the data revealed that after multiple doses of 1.5. g GRA/day, the 11 beta OHSD might be constantly inhibited, whereas at daily doses of 500 mg or less, such an inhibition might occur only transiently.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1994

[Vitamin D: clinical aspects and therapy].

This short review summarizes the metabolism and regulation of vitamin D3 with special emphasis on the regulation of renal 25-hydroxy-vitamin D3 1-alpha-hydroxylase. Vitamin D3 is of documented therapeutic utility in the following entities: Vitamin-D3 deficiency, involutional osteoporosis, glucocorticoid-induced osteoporosis and renal osteodystrophy. A therapeutic benefit of vitamin D3 is not yet established for hematological as well as for other neoplasias and for psoriasis. The introduction of noncalcemic vitamin-D3 analogs may lead to an increased use in these indications and will hopefully improve prevention and treatment of renal osteodystrophy.

Calcitriol↗
PubMed1993

Determination of 18 beta-glycyrrhetinic acid in biological fluids from humans and rats by solid-phase extraction and high-performance liquid chromatography.

Methods have been developed and characterized allowing rapid isolation and quantification of 18 beta-glycyrrhetinic acid (GRA) in biological fluids from both humans and rats. Sample preparation includes extraction with urea-methanol for plasma samples, and solid-phase extraction (SPE) for urine and bile samples. Hydrolysis of GRA glucuronides in urine and bile was performed by treatment with beta-glucuronidase. MGRA, the 3-O-methyl derivative of GRA was synthesized as an internal standard resistant to hydrolysis. High-performance liquid chromatography (HPLC) was performed with an isocratic system using methanol-water-acetic acid (83:16.8:0.2, v/v/v) as solvent on a Lichrocart RP-18 column at 30 degrees C with ultraviolet detection. The methods allowed base line separation of GRA and MGRA from all biological fluids tested, with a detection limit of 0.15 mg/l. Validation of the methods included determination of recovery, accuracy and precision in plasma, bile and urine from humans and rats. The methods were further evaluated by investigating the pharmacokinetics of GRA in normal rats and in rats with a bile fistula. Following an intravenous dose of 10 mg/kg, the plasma concentration-time curve of GRA could be fitted to a one compartment model both in control and bile fistula rats. The elimination half life averaged 15.0 +/- 2.2 versus 16.8 +/- 2.4 min in control and bile fistula rats (difference not significant). Within 90 min following administration of GRA, urinary elimination of GRA and GRA glucuronides was less than 1% in both groups whereas biliary elimination averaged 51.3 +/- 3.1%. The results show that the methods developed allow pharmacokinetic studies of GRA in humans and rats.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Primary structure of two P-type ATPases involved in copper homeostasis in Enterococcus hirae.

We cloned an operon, copAB, from Enterococcus hirae encoding two P-type ATPases of 727 and 745 amino acids, respectively. Both enzymes display heavy metal ion binding motifs in their polar N-terminal region. With an antibody against CopB, we showed on Western blots that expression of the operon is induced by either low or high ambient copper concentrations. Disruption of the copA gene renders the cells dependent, whereas copper disruption of copB results in a copper-sensitive phenotype. CopA exhibits 35% sequence similarity to CopB and 43% similarity to the ATPase encoded by the recently cloned human Mc1 gene, a gene responsible for the Menkes inborn error of copper metabolism. Our results imply that CopA and CopB are heavy metal ion ATPases that regulate the cytoplasmic copper activity, with CopA serving in the uptake and CopB in the extrusion of copper.

Adenosine Triphosphatases↗
PubMed1993

[3 dangerous electrolyte disturbances: hyponatremia, hyperkalemia and hypomagnesemia].

Three cases of acute and potentially dangerous electrolyte disturbances provide a basis for discussion of selected aspects of pathogenesis, clinical manifestation and correction of certain electrolyte disorders (hyponatremia, hyperkalemia, hypomagnesemia). A case of diuretic-induced hyponatremia illustrates the controversy surrounding correction of this disorder. The regulatory mechanisms of transcellular potassium equilibrium are discussed with the help of a case of exercise-induced hyperkalemia. A separate case is dedicated to the discussion of the multiple causes and symptoms of magnesium depletion.

Acute Disease↗