Cyclosporine A for treatment of nephrotic syndromes.
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Adrenal Cortex Hormones↗
Biomedical subjects
U Helmchen
Publications and source records attributed to U Helmchen.
Short-term perfusion and "equilibration" of canine kidneys with protective solutions.
Kidneys were perfused either with Euro-Collins-solution or with HTK-solution of Bretschneider. The perfusion pressure as well as the perfusion flow were measured during a six-minute perfusion. The perfusion resistance was higher in Euro-Collins-kidneys than during HTK-perfusion. The venous outflow of the kidney as well as the ureteral outflow was measured during each minute of the perfusion and has analysed for osmolality, and for sodium and potassium concentrations. In Euro-Collins-kidneys a complete "equilibration" of the extracellular space was not achieved, while during HTK-perfusion concentrations in the venous as in the tubular outflow, similar to those in the HTK-solution itself, could be reached. At the end of the different perfusions, tissue was analysed for biochemical parameters such as ATP, ADP, AMP and lactate as well as for morphological features. Lactate had increased and ATP had decreased during perfusion with Euro-Collins-solution, while ATP had not changed and lactate had decreased during perfusion with HTK-solution. Normal glomerular, tubular and dilated vascular structures can be seen after HTK-perfusion, while a glomerular and vascular contraction takes place during Euro-Collins-perfusion.
Adenine Nucleotides↗
Effects of glucose in protected ischemic kidneys.
Energy reserves (TAN) and anaerobic substrates (glucose, glycogen) are lower in renal than in myocardial tissue. Euro-Collins-solution contains nearly 200 mmol/l glucose, while the HTK-solution of Bretschneider contains none. Therefore the influence of glucose on kidney lactate production, on energy reserves (TAN), intrarenal pH and on morphology during the protection of ischemic kidneys was analysed using either Euro-Collins-solution, or modified "Euro-Collins-solution", containing mannitol instead of glucose, or HTK-solution with and without the addition of 5, 10 and 20 mmol/l glucose. Glucose content changed during kidney perfusion with Euro-Collins-solution from about 60 to 800 mumol/gdw. While intrarenal pH decreased from 7.1 to 5.1 in Euro-Collins-kidneys during 420 min of ischemia at 25 degrees C, pH decreased to 6.7 with the modified, mannitol containing "Euro-Collins-solution". In HTK-protected kidneys intrarenal pH decreased with increasing glucose addition to the solution. Although Total Adenine Nucleotides are highest at the end of ischemia with Euro-Collins-solution, structural protection after the same ischemic stress was best in HTK-protected kidneys without glucose addition. We conclude that glucose stimulated lactate production, reduced interstitial pH in the kidney even in combination with a highly buffered solution and that it might cause greater membrane permeability leading to a structural deterioration. Mannitol seemed more appropriate than glucose in this respect, although other substances, which provide energy substrate and prevent structural damage, may exist.
Acidosis↗
High protein intake stimulates glomerular prostaglandin formation in remnant kidneys.
Reduction of renal mass in the rat results in an increased glomerular prostaglandin (PG) and thromboxane (TX) formation that modulates renal hemodynamics. To evaluate whether dietary protein intake could exert effects on renal PG and TX formation after reduction of approximately 70% of renal mass, rats with remnant kidneys were placed on either a high-protein (HP) or a low-protein (LP) diet. After 2 wk on the diet, proteinuria, glomerular filtration rate (GFR), urinary PGE2 excretion, and glomerular PGE2, 6-keto PGF1 alpha, and TxB2 biosynthesis were significantly greater in the rats on HP diets. Two-wk administration of the thromboxane synthesis inhibitor UK 38485 reduced renal TxB2 formation by approximately 70%. In addition, chronic UK 38485 treatment significantly inhibited papillary PGE2 production. Neither chronic nor bolus administration of UK 38485 had an effect on proteinuria or GFR in rats on HP diets. Chronic UK 38485 treatment, however, reduced GFR and proteinuria in rats on LP diets. The bolus administration of UK 38485 did not alter GFR in animals receiving a LP diet. The cyclooxygenase inhibitor indomethacin reduced GFR only in rats on HP diets. The data demonstrate that HP intake stimulates renal prostanoid formation. The increased prostaglandin formation on HP intake modulates GFR in these rats.
6-Ketoprostaglandin F1 alpha↗
Coexpression of keratin and vimentin in damaged and regenerating tubular epithelia of the kidney.
Most renal cell carcinomas coexpress vimentin and keratin, while renal tubular epithelia express only keratin. Investigation of the intermediate filament composition of tubular epithelia in diseased rat and human kidneys now shows that altered tubular epithelia unequivocally coexpress keratin and vimentin. In rats, pronounced coexpression of vimentin and keratin was observed in chronic nephrosis induced by daunomycin, and the extent of coexpression seemed to increase with the incidence of altered collapsed and cystically dilated tubules and with the degree of tubular epithelial proliferation. It was also seen during tubular regeneration after acute tubulotoxic injury induced by mercury chloride poisoning, with vimentin expression being lost in fully regenerated tubular epithelium. In man, expression was seen in chronically and irreversibly damaged kidneys. Thus, vimentin can be expressed temporarily in acutely and reversibly damaged kidneys and chronically in irreversibly damaged kidneys. Vimentin could perhaps be regarded as an indicator of the regenerating and proliferating activity of tubular lesions.
Animals↗
[Kidney function parameters following ischemia stress using the Euro-Collins solution or the Bretschneider cardioplegic HTK solution].
Protection-methods, for an improvement of ischemic tolerance of the kidney, can be investigated by intraischemic analysis of metabolism and structure. A definite proof for the effectiveness of a protection method is only postischemic function in combination with postischemic structure-regeneration. For this reason postischemic function was chosen for examination of the protective ability of the Euro-Collins-solution and the HTK-solution during a two-hour reperfusion period. We perfused 57 dog kidneys either with the Euro-Collins- or with the HTK-solution prior to ischemia. Ischemia was 7, 60, 90 and 120 min after Euro-Collins-perfusion and 7, 120, 150 and 180 min after HTK-protection. The protected and ischemic kidneys were left in-situ; the mean ischemic temperature was therefore 20-25 degrees C for the shorter ischemic times and 30-34 degrees C for the longer ischemic times. We compared the protected and ischemic kidneys with 14 untreated kidneys (control). Postischemic renal blood flow (RBF) was measured by an electromagnetic flow probe; renal oxygen consumption (V02/min) was calculated by arterio-venous oxygen content difference and the renal blood flow. If urine could be collected, the glomerular filtration rate (GFR) was measured by an endogenous creatinine clearance. In Euro-Collins-protected kidneys after 60-120 min ischemia the RBF was after 15 min of reperfusion between 20 and 100 ml/min/100 g. After 30 min we got values of 100-200 ml/min/100 g. The V02/min, which was in the control kidneys between 5-6 ml/min/100 g, was about 2 ml/min/100 g.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Pathology of renal ischemia and acute renal failure].
The morphological consequences of acute or chronic renal ischemia may consist of an anemic kidney infarction, bilateral cortical necrosis, acute tubular lesions in circulatory renal failure, so-called subinfarction, as well as arteriosclerotic endstage kidney. In renal biopsies obtained from patients with acute renal failure, renal dysfunction can be morphologically explained by acute intra- and extracapillary necrotizing glomerulonephritis in 50% of cases, and by solely acute tubular lesions in 30% of cases. It is suggested that the development of acute tubular lesions during circulatory insufficiency might be favoured by an angiotensin II-dependent vas efferens constriction, leading to a reduction of peritubular blood flow in the presence of preserved glomerular filtration. The balance between demand and supply of oxygen within the tubular epithelial cells might thereby be critically disturbed.
Acute Kidney Injury↗
Post-ischemic renal function after kidney protection with the HTK-solution of Bretschneider.
The cardioplegic solution HTK of Bretschneider was used for canine kidney protection. The kidneys were perfused with this solution for 6-10 min prior to the induction of ischemia. The kidneys were left in-situ for 60, 90, 120 and 135 min ischemia time at a temperature of 25-34 degrees C (n = 13). As a control group we used unilateral nephrectomized dogs (n = 9). After unilateral nephrectomy an elevated plasma creatinine in comparison to preoperative values was observed. After 60 and 90 min under HTK-protection the postoperative plasma creatinine was not elevated compared to the control group. After 120 min of ischemia creatinine level was slightly increased to an average of 2.1 mg% on the first and second postoperative day. These experiments indicate the protective effect of the cardioplegic solution for canine kidney preservation in situ.
Animals↗
Ultrastructure, renin status, contractile and electrophysiological properties of the afferent glomerular arteriole in the rat hydronephrotic kidney.
Histological, ultrastructural, immunohistochemical, intravital microscopic and electrophysiological techniques have been applied to study experimental hydronephrosis in rats in order to assess its value as a preparation for the investigation of renal microcirculation and of the electrophysiological properties of the renin-containing juxtaglomerular (JG) cells of the afferent glomerular arteriole. As hydronephrosis develops, the kidney parenchyma becomes progressively thinner owing to tubular atrophy. Twelve weeks after ureteral ligature, this process results in a transparent tissue sheet of about 150-200 microns in thickness. In this preparation, the renal arterial tree as well as the glomeruli can be easily visualized for intravital microscopic studies, e.g. the determination of kidney vessel diameters, or the identification of JG cells for penetration with an intracellular microelectrode. In contrast to the tubular atrophy, the vascular system is well preserved, and the JG cells and the sympathetic axon terminals are ultrastructurally intact. This is also true for the glomeruli, except for a certain confluence of the podocyte foot processes and a thickening of the basal laminae. Renin immunostaining and kidney renin content in the hydronephrotic organ correspond to those in control kidneys. In addition, there are no differences in the plasma renin levels of hydronephrotic and control rats. Intravital microscopic observations reveal that the renal vascular tree reacts in a typical, concentration dependent manner to the vasoconstrictor agent angiotensin II, mainly at the level of the resistance vessels. Electrophysiological recordings from juxtaglomerular granulated cells show a high membrane potential (-60 mV), and spontaneous depolarizing junction potentials, owing to random transmitter release from the nerve terminals. Angiotensin II, an inhibitor of renin release, depolarizes JG cells reversibly. Hence, we may infer that the hydronephrotic rat kidney is a suitable model for in vivo studies of the renal microcirculation as well as for in vitro investigations of the electrophysiological properties of the media cells of the afferent glomerular arteriole.
Angiotensin II↗
Impairment and recovery of the clipped kidney in two kidney, one clip hypertensive rats during and after antihypertensive therapy.
Earlier experiments have shown that in sodium depleted hypertensive rats with bilaterally constricted renal arteries the arterial pressure normalized after blockade of the renin-angiotensin system; simultaneously acute renal failure occurred. In hypertensive rats with unilateral renal artery stenosis an impaired excretory function of the clipped kidney can be expected, but may not be detectable by conventional tests of renal function. Male Wistar rats with chronic two kidney, one clip hypertension were fed a low sodium diet. After 7 days the rats were treated with vehicle, with the vasodilator dihydralazine, or with the angiotension converting enzyme inhibitor MK 421 for 2 weeks. During the 14-day treatment period a continuous blood pressure reduction was achieved in dihydralazine and MK 421 treated rats. Overall excretory kidney function (plasma creatinine concentration) was well maintained in all three groups until the end of the antihypertensive drug treatment. At the end of drug therapy mean glomerular filtration rates of the left clipped kidneys were significantly lower in both treated groups compared to hypertensive controls, and mean glomerular filtration rate of the left clipped kidneys of dihydralazine treated rats was significantly higher than in MK 421 treated rats: controls (N = 6) 1.03 +/- 0.03, dihydralazine-group (N = 10) 0.28 +/- 0.07, MK 421-group (N = 9) 0.03 +/- 0.01 ml/min. Renal blood flows were comparable in both treated groups. Only the left kidneys of rats treated with MK 421 showed a prominent tubular atrophy. Seven days after declipping of the left renal artery and right nephrectomy a considerable restitution of the tubular structure had occurred in the MK 421-group. The recovery of tubular epithelial cells was paralleled by a rise in glomerular filtration rate: MK 421 group (N = 7) 1.25 +/- 0.08 ml/min. Thus, the clipped kidney in two kidney, one clip hypertensive rats showed functional and morphological signs of impairment when systemic arterial pressure was reduced to the normal range. The alterations of the clipped kidney were most pronounced in rats with renin-angiotensin system-blockade.
Angiotensin-Converting Enzyme Inhibitors↗
The hydronephrotic kidney of the mouse as a tool for intravital microscopy and in vitro electrophysiological studies of renin-containing cells.
Experimental hydronephrosis in mice has been studied with histological, ultrastructural, immunohistochemical, biochemical, and electrophysiological techniques to establish its value as a preparation for the investigation of glomerular microcirculation as well as the electrophysiological and biochemical properties of the renin-containing juxtaglomerular (JG) and vascular smooth muscle (VSM) cells of the afferent glomerular arteriole. During developing hydronephrosis the kidney parenchyma becomes progressively thinner as a result of tubular atrophy, being, after 12 weeks, a tissue sheet of about 200 micron in thickness. In this preparation, the renal arterial tree, in particular the glomerular arterioles, and also the glomeruli can be easily visualized. This permits intravital microscopic studies or direct visual identification of JG and VSM cells for microelectrode impalement. In spite of complete tubular atrophy, the vascular system is well preserved. Ultrastructurally, JG and VSM cells as well as the axon terminals innervating the vessels are intact. The same holds for the glomeruli except for a certain confluence of the podocyte foot processes and a thickening of the basal lamina. Renin immunostaining and kidney renin content in the hydronephrotic organ correspond to those in control kidneys. In addition, renin release from this preparation can be stimulated in a typical manner by isoproterenol and inhibited by angiotensin II, indicating that the receptors controling renin release and the secretory mechanism itself are still intact. Electrophysiological recordings from JG and VSM cells show a high membrane potential (-75 mv), and spontaneous depolarizing junction potentials, owing to transmitter release from the nerve terminals. Inhibitors of renin secretion, e.g. angiotensin II, depolarize both cell types, whereas stimulators such as isoproterenol do not change the membrane potential. We conclude that the hydronephrotic mouse kidney is a suitable model for in vitro studies of the electrophysiology and biochemistry of the media cells of the afferent arteriole, as well as for in vivo studies of glomerular microcirculation.
Animals↗
Age-dependent glomerulosclerosis and proteinuria occurring in rats of the Milan normotensive strain and not in rats of the Milan hypertensive strain.
The development of an age-dependent glomerulosclerosis and proteinuria was investigated in two strains of rats in a model of moderate hypertension comparing rats of the Milan Hypertensive Strain (MHS) with rats of the Milan Normotensive Strain (MNS). Serum creatinine, urinary protein excretion, renal morphology (light- and electronmicroscopy) and morphometry of the media thickness of the intrarenal arteries and of the thickness of the glomerular basement membrane were studied in 2- to 16-month-old MHS and MNS rats. Serum creatinine did not differ between MNS and MHS rats in any age group. MNS rats developed a significant proteinuria which coincided with a glomerulosclerosis in about 22% of the glomeruli at 13 to 16 months. In contrast, urinary protein excretion in MHS rats remained stable during the entire observation period; glomerulosclerosis occurred only in 3% of the glomeruli at 13 to 16 months. As a consequence of hypertension media thickness of intrarenal arteries of MHS rats significantly exceeded that of MNS rats, in the interlobular arteries already at 2 months and in the arcuate arteries at 13 to 16 months. In contrast, thickness of the glomerular basement membrane of MHS rats never exceeded that of MNS rats. From these data we conclude, that glomeruli of MHS rats may be protected against the development of an age-dependent glomerulosclerosis and proteinuria. Further support for this conclusion may also be derived from recent experiments showing that the tubuloglomerular feedback sensitivity is significantly higher in MHS than in MNS rats (41).
Aging↗
Villin--a marker of brush border differentiation and cellular origin in human renal cell carcinoma.
Expression of villin, a 95-kd F-actin bundling and severing protein, is restricted in animal tissues to epithelial cells with a brush border. Thus, the enterocytes of the intestine and epithelial cells of proximal but not distal tubules of the kidney are strongly positive. Here we report a similar staining pattern for human intestine and kidney. In four human colon adenocarcinomas villin expression was seen in tubular and glandular structures but not in the undifferentiated parts. Fourteen human renal carcinomas (9-Grade I and 5 Grade II) were villin-positive, and 2 sarcomatous renal carcinomas (Grade III) were villin-negative. The percentage of tumor cells that were villin-positive varied from 10-90% for the Grade I and II types. Our results indicate that villin may be a grading marker that deserves further study in renal carcinoma. They also raise the question whether the majority of renal carcinomas are derived from the proximal tubular epithelium rather than from the distal epithelium.
Adenocarcinoma↗
[Drug treatment of chronic glomerulonephritis: pro].
This paper sets out the arguments for drug treatment of chronic glomerulonephritides (GN). Although the pathogenesis and mechanism of progression of chronic GN remained to be clarified, on the basis of controlled studies performed to date, there is a strong case to be made for an aggressive treatment approach to this disease spectrum. For instance, in patients with idiopathic membranous glomerulonephritis a six months treatment with chlorambucil (0.2 mg/KG/day) or prednisone (0.6 mg/KG/day) each given once a day over a period of three months has recently been shown to improve the outcome of the renal functional parameters after three years follow up. In another controlled trial a daily dose of 225 mg dipyridamole and 975 mg aspirin given over 12 months in patients with membrano-proliferative GN type I has been reported to normalize the increased platelet consumption rate and to stabilize the glomerular filtration rate. A third trial has demonstrated that the combined use of cyclophosphamide (100 mg/day) and prednisone (30 mg/day) over several months was superior to the use of prednisone alone (40 mg/day) in improving the long-term prognosis of diffuse-proliferative lupus nephritis (type IV, WHO). In some entities, however, as in IgA-nephritis there is still no evidence for a specific treatment improving the course of the chronic glomerular disease. Other therapeutic problems have to be solved: thus, in patients with minimal change nephropathy with a steroid dependent nephrotic syndrome the benefit of cyclophosphamide (given over three months) or of cyclosporin A is still being investigated. Furthermore, there is some evidence that progression of chronic GN, particularly that of glomerular sclerosing, can be prevented by a low protein diet. The role of eicosanoides and their inhibitors in this context has not yet been fully investigated. The different drug trials and new therapeutic concepts indicate a rapid development of chronic GN treatment. Therefore, a failure to treat actively is difficult to understand.
Chlorambucil↗
Construction and experimental application of a catheter for selective arterial kidney perfusion in situ.
In order to improve dog kidney perfusion in situ with a protective solution, a perfusion catheter was constructed which allowed continuous pressure measurement in the center of the catheter tip during perfusion. Using this catheter, the equilibration of the extracellular space with a protective solution (HTK solution) was found to be pressure dependent. Continuous pressure and resistance control is therefore a prerequisite for reliable organ protection.
Animals↗
Bilateral virilizing adrenal tumor in a 17 year old woman.
We report on a 17 year old female patient with amenorrhea, hirsutism and slight acne. Hormonal blood analyses showed markedly increased levels for dehydroepiandrosteronesulfate, testosterone and androstenedione. Ultrasound investigation revealed a large tumor above the left kidney and a small area above the right kidney, suspicious for a tumor on the contralateral side. This was confirmed by angiography. During surgery, bilateral tumors were removed. Pathological diagnosis was made as bilateral adenomas of the adrenal cortex. Postoperatively, an impressive normalization was observed, accompanied by a rapid decrease of the elevated hormone concentrations. This case is the first report of a bilateral occurrence of a virilizing tumor of the adrenal cortex.
Adenoma↗
Morphological and functional changes of pancreatic B cells in cyclosporin A-treated rats.
Cyclosporin A (50 mg/kg orally for 7 days) produced severe degranulation and hydropic degeneration of islet B cells in rats. These changes were accompanied by hyperglycaemia and hypoinsulinaemia, while the pancreatic insulin content decreased by 75%.
Animals↗
Adaptation and decompensation of intrarenal small arteries in experimental hypertension.
In the presence of hypertension, the arterial and arteriolar vessel walls may undergo adaptive, destructive, and reparative changes. These different types of hypertensive alterations were studied simultaneously in the intrarenal vascular bed of two-kidney, one-clip hypertensive rats. After constriction of one renal artery, focal medial necrosis of the interlobular arteries developed in the untouched kidneys after the first 24 h. These earliest signs of vascular decompensation could be explained by short-lasting hypertensive episodes that were only detectable by continuous blood pressure recording in conscious animals. Two weeks after the experiment was started, owing to a widening of the media, a substantial increase in the wall-to-lumen ratio was observed in the interlobular arteries. At the same time, the frequency of focal medial necrosis began to fall significantly. Therefore we concluded that the structural vascular adaptation might be responsible for the disappearance of focal medial necrosis in spite of still rising blood pressure values. This assumption was confirmed by an additional experiment in previously chronically two-kidney, one-clip hypertensive rats: 24 h after removing the renal artery clip, a short, severely hypertensive period, induced by infusions of angiotensin II, caused hypertensive vascular lesions almost exclusively in the primarily clipped kidneys with a nonadapted vascular bed. Early intimal changes, which are known to lead to malignant nephrosclerosis, were not only absent in the beginning of two-kidney, one-clip hypertension, but also did not occur during the angiotensin-induced accelerated hypertension. Thus, even extremely high blood-pressure values per se may not be enough to initiate this crucial renal vascular disease.
Adaptation, Physiological↗