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Biomedical subjects

H G Preuss

Publications and source records attributed to H G Preuss.

At least 73 records · Page 4Linked to original sources
PubMed1989

Does renotropin have a role in the pathogenesis of hypertension?

The existence of an organ-specific, circulating renal growth factor, renotropin, has been established through various bioassays. However, renotropin may be more than a growth factor. The pathogenesis of essential hypertension is unknown, although a humoral agent related to renal metabolism is believed to be responsible, at least in part. In parallel with the development of a renotropin assay, we have measured vasomotor and natriuretic serum activities. Our data suggest that renotropin possesses vasomotor and natriuretic properties. Through one or both properties, renotropin may play an important role in essential hypertension. This possibility is strengthened by observations that: a) many methods to produce experimental hypertension involve elevations of renotropin--a reduction of renal mass and/or prevention of compensatory growth; b) high renotropin activity has been demonstrated in genetically hypertensive rats (SHR); and c) sera containing high renotropic activity stimulate contraction of isolated rat aortic rings and influence organic anion and cation transport.

Animals↗
PubMed1989

Evolution of ciclosporin nephrotoxicity in patients treated for autoimmune uveitis.

Among 73 patients treated with ciclosporin (CS) for autoimmune uveitis, a 50% elevation of serum creatinine was observed in 37% within 3 months of starting CS and in 25% after more than 6 months of relatively uncomplicated therapy. Sequential renal function and histologic evaluations were performed in 17 patients to further characterize the nephrotoxic effects of long-term CS therapy. Inulin clearance remained essentially unchanged in 12 patients despite CS dosage reductions in the majority. In 2 such patients, repeat renal biopsy specimens revealed evidence of progressive irreversible kidney injury even though renal function was stable. Inulin clearance decreased substantially in 3 patients; in 1 case a follow-up renal biopsy showed increased severity of chronic histologic change. For 2 patients, the inulin clearance more than doubled after CS dosage reduction; and in 1 of those cases, repeat renal biopsy showed no evidence of progressive renal scarring. Overall, the morphologic attributes of irreversible kidney injury (designated by a chronicity index including glomerular sclerosis, tubular atrophy and interstitial fibrosis) were increased in 3 of 6 follow-up renal biopsy specimens. Histologic alterations of renal arterioles, including hyaline change, were observed in all CS-treated patients. The hyaline change of arterioles was either extensive in the first renal biopsy specimen or became extensive in the second biopsy in the 3 cases manifesting an increased chronicity index on the follow-up renal biopsy. Thus, parenchymal injury can progress in some cases despite CS dosage reduction and stable renal function; renal arteriolar histologic change is a prominent finding in these patients. Patients that exhibit a substantial improvement in renal function after dosage reduction may experience a more favorable course.

Autoimmune Diseases↗
PubMed1989

Effects of malonate administration on renal ammoniagenesis in intact dogs.

In the dog kidney in vivo, malonate augmented ammoniagenesis from both amide and nonamide nitrogen sources, similar to previous in vitro investigations using incubating canine renal tubules. This was highly significant in alkalotic dogs, where it was accompanied by decreased renal tissue concentrations of glutamate. Changes in renal ammonia metabolism were less evident in acidotic dogs where a markedly decreased glomerular filtration rate was noted following malonate administration. Under conditions of complete ureteric obstruction which effectively abolished glomerular filtration, malonate significantly augmented ammoniagenesis above baseline in acidotic dogs. These in vivo results with malonate have similarities to those seen in dogs subjected to an acid challenge alone and suggest that the adaptation in renal ammoniagenesis under both circumstances occurs via enhanced deamination of glutamate pools.

Acidosis↗
PubMed1988

Cyclosporin A in severe, treatment-refractory rheumatoid arthritis. A randomized study.

STUDY OBJECTIVE: To assess the efficacy and toxicity of cyclosporin A in patients with severe, treatment-refractory rheumatoid arthritis. DESIGN: Prospective randomized, double-blind 6-month trial. PATIENTS: Thirty-one patients who had classic seropositive rheumatoid arthritis with active synovitis unresponsive to conventional therapy. INTERVENTIONS: Patients were randomly assigned to high-dose (10 mg/kg body weight.d) or low-dose (1 mg/kg.d) cyclosporin A therapy. A reduction in the dose was permitted for adverse side effects. After 6 months of therapy, patients who showed clinically relevant improvement, defined as a 40% or greater reduction in their total joint activity score, were given the option to continue receiving the therapy for an additional 6 months. MEASUREMENTS AND MAIN RESULTS: At 6 months, clinically relevant improvement occurred in 10 of 15 patients (95% CI, 38 to 88) receiving high-dose therapy and in 4 of 16 patients (CI, 7 to 52) receiving low-dose therapy (P = 0.02). Statistically significant improvements in individual measures were shown only in the high-dose group. Improvements were noted in the number of tender joints (-18.8; CI, -24.5 to -13.1) and swollen joints (-12.1; CI, -15.4 to -8.6), as well as in physician's global scores (-1.5; CI, -2.1 to -0.9) and patient's global scores (-1.1; CI, -1.9 to -0.5). Improvement in disease activity was maintained through 12 months in the high-dose group. The clinical responses to cyclosporin A were most evident in patients with depressed in-vitro proliferative responses of peripheral blood mononuclear lymphocytes to soluble recall antigens. Toxicities, such as fatigue, gastrointestinal and neurologic complaints, and hypertrichosis were frequent but often reversible with a reduction in the dose. Nephrotoxicity, with a 20% increase in the serum creatinine level, was seen in 27 of 31 patients (CI, 71 to 97). CONCLUSIONS: Cyclosporin A is an effective therapy for severe, treatment-refractory rheumatoid arthritis. Side effects, particularly nephrotoxicity, are common.

Adult↗
PubMed1988

Renotropic stimulation in rat kidney cell culture.

A circulating renotropic factor specific for renal cells has been described in rats. The addition of sera obtained from unilaterally nephrectomized (uni) rats 24h after operation compared to sham-operated (sham) rats augments 3H-thymidine incorporation into the DNA of incubating kidney slices approximately 10%-30%. Attempting to amplify the sensitivity of the assay for this renotropic agent, we replaced slices with primary rat kidney cultures. The assay system was based on one previously used for rabbits. The cultured cells were synchronized in their growth phase by a period of protein-free starvation. Compared to sera from sham rats, sera from uni rats showed significant stimulation of thymidine incorporation into DNA, 35.5% +/- 9.3 (SEM), p less than .0001, at 16 h; 63.3% +/- 10.0 (SEM), p less than .001, at 24 h; and 19.5% +/- 6.5 (SEM), p less than .01, at 48 h post operation. Accordingly, the maximal stimulation at 24 h was greater than that previously found using the kidney slice assay. Measurable renotropic activity occurred earlier and over a shorter duration than in rabbits. Stimulation was similar when a D-valine medium, relatively specific for renal epithelial cells, replaced DME medium. We conclude that growth synchronized, primary rat renal cells in culture verify the presence of a circulating renotropin arising 24 h post uni.

Animals↗
PubMed1988

The rabbit renotropic system.

Elevated levels of a specific renal growth factor, renotropin, have been associated with spontaneous hypertension. To examine this association more closely, we have undertaken the development of a better assay system to characterize and purify renotropin. Sera from rabbits prior to operation (control) and at a specified time after unilateral nephrectomy (uni) were examined for renotropic activity. Comparing the effects of uni to control sera in the same rabbit, significant stimulation of 3H-thymidine incorporation into the DNA of primary rabbit kidney cultures incubated in D-valine medium to eliminate fibroblast growth was noted: at 3 days postoperatively 73% (n = 13), at 7 days 103% (n = 39), at 10 days 130% (n = 31), at 21 days 101% (n = 24), at 42 days 89% (n = 13). All values were at least P less than 0.01. The stimulatory properties were dose-dependent but reached a plateau at high serum concentrations. Comparing CPM/mg protein in uni/control in different concentrations of sera 7 days postoperatively, uni versus control were 67/44 at 5% v/v, 139/72 at 10% v/v, 261/161 at 20% v/v, and 243/136 at 40% v/v. The renotropic effect of uni sera remained after dialysis in incubation medium and after sera were heated in boiling water for 5 minutes. Renal extracts obtained from growing kidneys 7 days postnephrectomy augmented renotropic activity. Atrial natriuretic factor, ouabain, PGF2 alpha, PGE1, and cAMP did not possess renotropic activity. We conclude that the primary rabbit kidney culture assay for renotropin is highly sensitive and will be an important tool to comprehend the role of renotropin in the pathogenesis of hypertension.

Animals↗
PubMed1988

Presence of a serum vasoconstrictive factor following unilateral nephrectomy.

Experimental hypertension is often associated with decreased renal mass and/or impediments to normal renal compensatory growth. This has led to the hypothesis that the renal growth factor (renotropin) is also a vasoconstrictor responsible for elevated blood pressure. Unilateral nephrectomy (uni) is the most popular mechanism to investigate compensatory renal growth. Accordingly, we examined the vasoconstrictive potential of rat sera following uni in order to compare it with serum renotropic activity. Compared to sham-operated (sham) rat sera, uni sera obtained at 24 hours after operation, a point in time when renotropic activity is highest, stimulated the constriction of isolated rat aortic rings significantly more than sham sera, and in a dose-dependent fashion. By paired analysis, the differences in constriction between uni and sham sera were significant at all doses examined. Unlike those obtained at 24 hours, uni sera did not show this response 48 hours, 1 week and 2 weeks after operation, simulating the temporal course of renotropin found in sera after uni. The uni serum factor was not influenced by dialysis suggesting that its molecular weight exceeds 6,000 daltons and that the vasoconstrictive response was not due to electrolyte differences between uni and sham sera. Vasoconstrictive activity was retained after serum passage through Affi-gel blue to remove albumin and after serum was heated in boiling water for 5 minutes. We conclude that a heat resistant serum vasoconstrictive factor with a molecular weight greater than 6,000 daltons arises shortly after uni but disappears once the remaining kidney begins to undergo a physiological compensatory growth response.

Animals↗
PubMed1988

Colorimetry of p-aminohippurate in the presence of sulfamethoxazole.

Colorimetric quantification of p-aminohippurate (PAH), which is helpful in assessment of renal function, is subject to interference from sulfa compounds such as sulfamethoxazole. We were unable to measure serum PAH in two patients receiving a trimethoprim-sulfamethoxazole combination because of interference by the latter with the colorimetric estimation. We found that isoamyl acetate removes sulfamethoxazole from the samples without influencing PAH. The extraction is simple, inexpensive, and reproducible.

Aminohippuric Acids↗
PubMed1987

Acidotic alterations in oxidative metabolism influencing rat renal slice ammoniagenesis.

We believe that two findings are interconnected and help to comprehend a major mechanism behind the regulation of renal ammonia production during acidosis. First, slices from acidotic compared to control and alkalotic rats produce more ammonia from glutamine. Second, inhibition of renal oxidative metabolism at various points by metabolic inhibitors augments slice ammoniagenesis. Based on this, our purpose was to determine whether enhanced renal ammoniagenesis during acidosis could occur through the same mechanism as the metabolic inhibitors. However, metabolic inhibitors (malonate; arsenite; 2,4-dinitrophenol) usually decrease while acidosis increases slice gluconeogenesis. There is one known exception. Fluorocitrate, which blocks citrate metabolism, simulates the acidotic condition by enhancing both ammonia and glucose production. Accordingly, a block of oxidative metabolism if located prior to citrate oxidation in the tricarboxylic acid cycle could theoretically augment ammoniagenesis during acidosis. Lactate, is a major renal fuel whose oxidative metabolism would be blocked by fluorocitrate. There, we concentrated on the effects of acidosis on lactate as well as glutamine metabolism. Lactate decarboxylation decreases in the face of increased glucose production during acidosis, and lactate inhibition of glutamine decarboxylation decreases in slices from acidotic rats. Also, we found lesser oxygen consumption in the presence of lactate by kidney slices from acidotic rats compared to control and alkalotic rats. We postulate that relatively less incorporation of lactate into the TCA cycle, causing decreased citrate formation and citrate oxidation during acidosis, contributes, at least in part, to acidotic adaptation of ammoniagenesis.

Acidosis↗
PubMed1987

Renal ammoniagenesis following glutamine loading in intact dogs during acute metabolic acid-base perturbations.

Adaptation of renal ammoniagenesis during acute metabolic acidosis in intact dogs may be nonexistent or, at least, markedly less than in chronic acidosis. This contrasts to adaptation in acute respiratory acidosis, where levels similar to those attained in chronic acidosis occur within hours. Accordingly, the inability to discern marked changes in acute metabolic acidosis compared with acute respiratory acidosis has been attributed to decreased glomerular filtration rate and renal blood flow seen frequently in the former. In our studies, we found early changes in ammoniagenesis and glutamine metabolism during acute metabolic acidosis, but not of the magnitude seen in chronic acidosis, even considering the changes in renal blood flow (RBF) and glomerular filtration rate (GFR). Exogenous glutamine loading allowed us to discover that the qualitative changes in glutamine metabolism during acute metabolic acidosis differed from control but fell short of those seen in chronic metabolic a acidosis. We also examined glutamine metabolism when renal ammoniagenic adaptation was acutely inhibited in chronically acidotic dogs. Infusing NaHCO3 into chronically acidotic dogs decreased renal ammonia production significantly (247 mumol min-1 100 ml-1 GFR vs 148 mumol min-1 100 ml-1 GFR: P less than 0.001) and glutamine extraction (111.8 mumol min-1 100 ml-1 GFR vs 90.9 mumol min-1 100 ml-1 GFR: P less than 0.02). The qualitative changes in renal glutamine metabolism in both studies suggest that alterations in deamination of glutamate formed from glutamine are responsible, at least in part, for adaptation to acute acid-base perturbations. Compared with respiratory acidosis, adaptation to metabolic acidosis is progressive and prolonged.

Acid-Base Imbalance↗
PubMed1987

Effects of sera from uninephrectomized rats on renal slices: PAH and TEA uptake and QO2.

We followed the effects of sera from unilaterally nephrectomized (uninephectomized) rats compared to sham-operated rats on 3H-p-aminohippurate (3H-PAH) and 14C-tetraethylammonium (14C-TEA) uptake and oxygen consumption (QO2) in incubating rat kidney slices. These studies were based on the assumption that a circulating renotropic substance might also influence various transport mechanisms. Sera were obtained at various times postoperation; the height of renotropic activity occurs 17-24 h after kidney extirpation. Sera removed 17-24 h postuninephrectomy significantly decreased both 3H-PAH and 14C-TEA uptake in incubating kidney slices. Similar to the inability to show significant renotropic activity after 36 h, sera obtained 48, 96, and 168 h postuninephrectomy had no significant influence on 3H-PAH and 14C-TEA uptake. Addition of sera (10% v/v) generally depressed QO2. However, sera obtained from uninephrectomized rats compared to sera from sham-operated rats had relatively more depressive effects on QO2 in renal tissue after 30 min of incubation (p less than 0.01). No significant differences in QO2 were seen when the uninephrectomized and sham-operated sera were added to the tissue immediately or after 60 min of incubation in the sera. These serum studies on 3H-PAH and 14C-TEA uptake simulate in many respects ones performed previously with serum from spontaneously hypertensive and salt-loaded rats and suggest the presence of a common circulating factor.

Aminohippuric Acids↗
PubMed1987

Renal ammonia production from the nitrogens of glutamine in intact acidotic dogs before and after bicarbonate infusions.

Renal ammonia is produced from the amide nitrogen of glutamine, approximately 33-50%. The remainder derives from the amino nitrogen of glutamine and other non amide sources, probably the amino nitrogens of other amino acids. We investigated the acute effects of acid-base perturbations on ammonia production from amide and non amide nitrogen sources to determine how they interrelate. Infusions of glutamine were given to some intact dogs to vary the renal load. Following an acute alkali challenge to dogs in metabolic acidosis, ammoniagenesis from the amide nitrogens decreased significantly when the presentation of glutamine to the kidney was normal or relatively low, but changed less or even increased when the glutamine load was relatively high. In contrast, ammonia from the non amide sources consistently decreased during acute alkalotic challenge at any glutamine load-high or low. Since decreased glutamine deamination leading to glutamate accumulation is generally associated with decreased deamidation in dogs with normal plasma glutamine concentrations, we explain the discrepancy of deamidation at high glutamine loads to an unmasking of a separate effect on the glutaminase (phosphate-dependent) pathway by the acute acid-base changes. Accordingly, our results indicate more than one influence from acute acid-base changes in vivo on renal ammonia formation, one stimulatory and other inhibitory. Nevertheless, the influence of glutamate removal predominates over the other effect on the phosphate-dependent glutaminase pathway at physiological concentrations of glutamine in the intact dog.

Acidosis↗
PubMed1987

Substrate oxidation in kidney slices from acidotic and alkalotic rats: role in ammoniagenic adaptation.

The enhanced renal ammoniagenesis that occurs during acidosis may depend on oxidative processes. To determine this, oxygen consumption (Qo2) of renal slices from acidotic rats (medium pH 7.0) and alkalotic rats (medium pH 7.8) in the presence of 4 different substrates (glutamine, lactate, acetate and 2-oxoglutarate) was investigated. Incremental addition of any oxidizable substrate tested to the incubation medium increased Qo2 until a maximal rate was approached (approximately 17-58% above baseline). Comparing acidotic to alkalotic slices, Qo2 was significantly less at low concentrations of lactate and acetate before maximal Qo2 occurred. In contrast, Qo2 was relatively higher at low concentrations of 2-oxoglutarate and glutamine with acidotic compared to alkalotic slices. Accordingly, acid-base perturbations produce different patterns of Qo2 depending on the substrate and its concentration. These observations coupled with others are consistent with the hypothesis that a relative block in the oxidation of lactate and acetate during acidosis provides more NAD+ for glutamine oxidation and participates in acidotic regulation of renal glutamine metabolism.

Acetates↗
PubMed1986

Renal histopathologic alterations in patients treated with cyclosporine for uveitis.

To evaluate abnormalities of renal morphology associated with long-term cyclosporine therapy, we obtained percutaneous renal biopsy specimens from 17 patients who had been treated for autoimmune uveitis with cyclosporine for an average of two years. For comparison, we also analyzed renal biopsy specimens from patients with idiopathic hematuria who had not received cyclosporine. The atrophic and sclerosing glomerular and tubulointerstitial lesions in the specimens were assessed to derive a chronicity index. The specimens from the patients treated with cyclosporine showed a significantly higher chronicity index than those from the controls (P less than 0.00005). All patients who had received cyclosporine had interstitial fibrosis, tubular atrophy, or both. A good functional predictor of the abnormalities in renal morphology was the length of time that a patient's serum creatinine had exceeded the base-line value by more than 50 percent. Chronic pathologic alterations were seen even in patients who had normal renal function at the time of the biopsy. In conjunction with sequential measurements of renal function, renal biopsy may have an important role in defining the type and degree of nephrotoxicity that can develop in patients receiving long-term cyclosporine therapy for autoimmune disease.

Adolescent↗
PubMed1986

Effects of diets high in refined carbohydrates on renal ammonium excretion in rats.

Ammonium excretion was investigated in spontaneously hypertensive rats (SHR) and normotensive control rats (WKY) ingesting different diets. SHR and WKY on low protein-high sucrose diets surprisingly showed the same ammonium excretion as rats ingesting a higher protein-lower sucrose diet. This was unexpected, because ammonium excretion correlates positively with protein intake. The relatively high ammonium excretion despite low protein intake (approximately 40% of control) was not associated with acidosis, hypokalemia, hypocalcemia, and/or hypomagnesemia. In a follow-up study, where diets were high in refined carbohydrates (sucrose, glucose, and starch) but more equal in protein content compared with a diet high in carbohydrates of a more complex form (grains), ammonium excretion increased significantly. When we examined the factors known to influence ammonium excretion, the only significant positive correlations found were between norepinephrine, epinephrine, dopamine, and ammonium excretion. These correlations still remained significant when only the data from the rats on the diets high in refined carbohydrates, i.e., rats on the same dietary intake of minerals and proteins, were compared. In vitro, we corroborated that catecholamines significantly increased ammoniagenesis from kidney slices. Our data show that diets high in refined carbohydrates augment both ammonium and catecholamine excretion and suggest that these two events may be interrelated.

Ammonia↗