J. F. E. Mann

Multicystic Transformation of Kidneys in Chronic Renal Failure

With real-time sonography, 120 nondialyzed uremic patients prior to hemodialysis, 108 patients on maintenance hemodialysis and 9 patients postdialysis after successful homotransplantation were examined for the presence of renal cysts. Even in incipient renal failure, multiple cysts were demonstrable in some patients (at a serum creatinine of 3 mg/dl in 22% of patients), particularly in patients with analgesic nephropathy. When hemodialysis was started (serum creatinine approximately 10 mg/dl), 35% of the patients had multiple cysts. On hemodialysis, the prevalence, number and size of cysts rose progressively with time. After 8 years of hemodialysis, 92% of the patients had multiple cysts. However, enlargement of the kidneys was observed in only 2/108 patients. No major clinical complications were noted with the possible exception of 1 case of renal cell carcinoma. No correlation was noted between hematocrit and presence or extent of cystic transformation, but the 2 patients with cystic enlargement of the kidneys were polyglobulic. In 8/9 patients after transplantation, cysts were demonstrable in the patients own kidneys after a median follow-up of 16 months. On light microscopy, cysts were lined by cuboidal or columnar epithelial cells with frequent papillary or adenomatous proliferations. The cyst lumen was filled with amorphous or lamellated organic material, which exhibited microfibrillar structure on electron microscopy. One kidney examined after ex vivo perfusion fixation showed multiple interconnected cavities on scanning electron microscopy. Ultrastructural studies showed epithelia with either the characteristics of proximal tubular cells (i.e. numerous microvilli, interdigitations and abundant lysosomes or mitochondria) or distal tubular cells (i.e. highly interdigitating processes) or finally collecting duct cells (i.e. no interdigitations and few microvilli).

Effects of parathyroidectomy on blood pressure in spontaneously hypertensive rats

The long-term effects of parathyroidectomy (PTX) on blood pressure, intravascular volume, pressor hormones, and on acute vascular effects of intravenous parathyroid hormone (PTH) were evaluated in spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WK) rats. PTX or sham operation (CO) were done at 4-5 weeks of age, and a high calcium diet was offered to PTX rats to study them at eucalcemic calcium levels. The cardiovascular effects of PTX, determined after 11-13 weeks, were qualitatively similar in SH and WK rats: mean arterial blood pressure (conscious unrestrained rats) was lower, intravascular volume was higher, total body sodium was slightly higher, and plasma angiotensin II or norepinephrine levels were not different from CO groups. The acute hypotensive and chronotrophic effect of intravenous PTH was unchanged in PTX groups. When parathyroid intact SH rats and PTX SH rats were both examined on an 1.6% Ca diet, blood pressure was significantly lower in PTX than in parathyroid-intact SH rats. The results are compatible with the hypothesis that PTH has a permissive action on blood pressure maintenance in eucalcemic SH and WK rats by mechanisms unrelated to volume status or circulating pressor hormone concentrations.

Sympathetic vascular tone in spontaneous hypertension of rats

ZusammenfassungUnterschiede des sympathischen Gefäßtonus zwischen spontan hypertonen Ratten (spSHR) und Wistar Kyoto Ratten (WKR) wurden an Hand folgender Größen erfaßt:Die sympathische Aktivität wurde ermittelt durch die Bestimmung der Plasmakatecholamine (Noradrenalin, Adrenalin und Dopamin) bei gleichzeitiger Messung der neuronalen und extraneuronalen Wiederaufnahme von Noradrenalin im isolierten Präparat (Langendorff Herz). Die Ansprechbarkeit glatter Gefäßmuskulatur auf vasopressorische Substanzen wurde in der isoliert perfundierten Hinterextremität der Ratte gemessen.Die sympathische Aktivität war bei spSHR im Alter von 5, 12, 15 und 28 Wochen gesteigert, da die Konzentration von Noradrenalin im Plasma um 50% bei unveränderter neuronaler und extraneuronaler Wiederaufnahme erhöht war. Die Ansprechbarkeit der glatten Gefäßmuskulatur gegenüber Noradrenalin war bei spSHR verstärkt.Neben einer stärkeren maximalen Vasokonstriktion nach supramaximalen Dosen von Noradrenalin (10−3 mol/l) oder BaCl2 (20 mmol/l) fand sich eine spezifische Überempfindlichkeit der einzelnen glatten Muskelzelle gegenüber Noradrenalin bei 5 Wochen alten spontan hypertonen Ratten. Während nach Kaliumdepolarisation keine Unterschiede in der Schwellendosis oder der ED50 auftraten, waren diese bei spSHR für die Noradrenalin-induzierten Widerstandserhöhungen um 25% vermindert.Die stimulierte sympathische Aktivität sowie die erhöhte Ansprechbarkeit der Widerstandsgefäße gegenüber Noradrenalin bei spSHR sind Ursache des gesteigerten sympathischen Gefäßtonus, der über eine Erhöhung des peripheren Widerstandes die Entwicklung des hohen Blutdrucks bei der genetischen Hypertonie der Ratte verursacht.SummaryDifferences in sympathetic vascular tone between Wistar Kyoto rats (WKR) and stroke prone spontaneously hypertensive rats (spSHR) were determined by comparing the following parameters: sympathetic activity was evaluated by determinations of plasma catecholamines (noradrenaline, adrenaline, dopamine) combined with the measurement of the neuronal and extraneuronal uptake of noradrenaline using an isolated rat heart preparation. The responsiveness of vascular smooth muscle to vasopressor agents was tested in the isolated perfused hindlimb preparation.At the age of 5, 12, 15, and 28 weeks sympathetic nervous activity was significantly higher in spSHR than in WKR since plasma noradrenaline was elevated by almost 50% in the presence of an unaltered activity of the uptake mechanisms. The responsiveness of vascular smooth muscle to noradrenaline was markedly enhanced in spSHR. Besides increased maximal vasoconstriction in response to BaCl2 (20 mmol/l) after potassium chloride depolarization or supramaximal doses of noradrenaline (10−3 mol/l), a supersensitivity of vascular smooth muscle to noradrenaline could also be detected in spSHR (age 5 weeks). The threshold dose and the ED50 were reduced by 25% in spSHR in response to noradrenaline infusions. No changes in threshold or ED50 were found in response to potassium chloride depolarization.The stimulated sympathetic activity in spSHR and the increased responsiveness of resistance vessels to noradrenaline, both contribute to the rise in sympathetic vascular tone. The finding of an increased sympathetic vascular tone in very early stages of hypertension suggest that this factor, producing a primary increase in total peripheral resistance underlies the development of high blood pressure in spSHR.

The Spectrum of Renal Involvement in Epidermolysis Bullosa Dystrophica Hereditaria: Report of Two Cases

Epidermolysis bullosa dystrophica Hallopeau-Siemens (EBDH) is one of the most severe inherited epidermolyses, a group of mechanobullous dermatological disorders. We observed two patients presenting with a severely multilating type of EBDH who developed biopsy-proven renal disease, which substantially altered the evolution and pathogenesis of their disease. In a boy, chronic postinfectious glomerulonephritis developed, most probably due to recurring superinfections of bullous skin lesions. He also experienced acute oliguric renal failure due to severe diarrhea during exacerbation of EBDH. A female patient developed a nephrotic syndrome due to secondary amyloidosis. Hypoalbuminemia caused further fluid losses through bullous skin lesions, aggravating intravascular hypovolemia and leading to rapid renal failure secondary to bilateral renal vein thrombosis. The study shows that, although rare, renal complications may alter the natural course of EBDH.

Vascular Effects of Parathyroid Hormone (PTH)

PTH causes dose dependent transient vasodilatation in various vascular beds, specifically renal, coeliac, coronary, but not osseous. It has an acute dose-dependent hypotensive effect in the intact animal which is not mediated by alpha- or beta-adrenergic, cholinergic or histaminergic mechanisms. Aortic medial smooth muscle cells respond to PTH with an increase of cAMP, cGMP and, presumably via protein kinase, with activation of phosphorylase B kinase. The acute vasodilatory effect of PTH is antagonised by indomethacin and diclofenac as well as by ouabain, suggesting that the membrane Na-K pump and prostaglandins are involved in PTH-induced vasodilatation. Parathyroidectomy and a high calcium diet attenuate the rise of arterial pressure in experimental hypertension, pointing to some permissive effect of PTH for development hypertension. This is most likely due to long term effects of PTH on vessel wall calcium content and exchange. This chronic effect of PTH may explain the high prevalence of hypertension in patients with primary hyperparathyroidism.

Synergistic effects of diabetes mellitus and renovascular hypertension on the rat heart - stereological investigations on papillary muscles

The effects of combined renovascular hypertension and diabetes mellitus on the rat heart were investigated in order to detect possible synergistic effects of the two conditions. Hypertensive diabetic and hypertensive nondiabetic young male Wistar rats were compared with diabetic and nondiabetic controls. Since the normal body weight increase of the diabetic animals was markedly suppressed a weight-matched nondiabetic control group was introduced in addition. Hypertension was established for eight weeks by a surgical stenosis of the left renal artery, diabetes mellitus was maintained for four weeks after a single intraperitoneal injection of 75 mg/kg streptozotocin. Light and electron microscopic stereological parameters were obtained for the left ventricular papillary muscles. The whole hearts were also investigated histologically. Qualitative morphology failed to substantiate synergistic effects in the hypertensive diabetic rats. Vascular abnormalities were not observed. The stereological parameters, however, revealed microstructural reactions which were observed exclusively in the hypertensive diabetic group: the volume ratio of mitochondria-to-myofibrils was decreased, the surface-to-volume ratio of mitochondria was increased (reduction of mitochondrial size) and the mean cross sectional area of capillaries was decreased. Similar quantitative mitochondrial changes have been frequently described in long-standing hypertension, but in the present investigation, they were not found in the nondiabetic hypertensive group. It is therefore concluded that diabetes mellitus potentiates the effects of chronic pressure overload on myocardial cells. However, the myocardial fibrosis which has been found by other groups at later stages of hypertension and/or diabetes mellitus was not detected in the present study. The reduced mean cross sectional area of capillaries in hypertensive-diabetic rats may be correlated with early molecular changes of the myocardial interstitium or with early abnormalities of small arteries. Thus our stereological results support the hypothesis that a non-coronary hypertensive diabetic cardiomyopathy occurs in mammalian hearts.

Increased blood pressure responses to central angiotensin II in spontaneously hypertensive rats.

ZusammenfassungAngiotensin II (ANG II) wurde spontan hypertensiven (SH) Ratten und normotensiven Wistar Kyoto (WK) Ratten in den lateralen Hirnventrikel (i.v.t.) infundiert. Der mittlere arterielle Blutdruck stieg bei den SH Ratten signifikant höher an als bei den normotensiven WK Ratten. Propranolol-Vorbehandlung reduzierte die Blutdruckanstiege nach i.v.t. ANG II Infusionen bei WK Ratten, nicht aber bei SH Ratten. Die höhere ANG II Empfindlichkeit der SH Raten bestätigt frühere Ergebnisse, die darauf hinweisen, daß zentrales ANG III an der Aufrechterhaltung des hohen Blutdruckes von SH Ratten beteiligt sein kann.SummaryThe blood pressure responses following infusions of angiotensin II (ANG II) into the brain ventricles (i.v.t.) have been tested in spontaneously hypertensive (SH) rats and in normotensive Wistar Kyoto (WK) rats. The mean arterial blood pressure increases were significantly higher in SH rats than in WK rats. Propranolol treatment reduced blood pressure increases to i.v.t. ANG II in WK, but not in SH rats. The higher sensitivity to i.v.t. ANG II in SH rats supports a role of central ANG II in the maintenance of high blood pressure in SH rats.

The Role of the Renal Renin-Angiotensin System in Thirst

Drinking is a homeostatic behavior that can correct body fluid deficits. Water deprivation produces dehydration of both the cellular and extracellular fluid compartments of the body. Cellular dehydration is caused by osmosis whenever the osmolality of the extracellular fluid is increased by solutes to which the cell membrane is not freely permeable. It is well established that this cellular dehydration is a potent stimulus to thirst and antidiuresis1. Likewise, Fitzsimons2 and others3,4 have shown that isotonic depletion of the extracellular fluid compartment by the subcutaneous or intraperitoneal injection of a hypertonic colloid solution such as polyethylene glycol (PEG) also causes drinking.

Vasoconstriction and increased blood pressure in the development of accelerated vascular disease

The pathogenesis of acute vascular lesions has been studied in two types of accelerated vascular disease. Firstly, vascular lesions were induced by a short-term (2 h) infusion of angiotensin II. Low doses of angiotensin II caused only a slight increase in blood pressure and non-destructive lesions. High doses caused a significant elevation of blood pressure and destructive vascular lesions. Secondly, in renovascular hypertension, renal vascular disease was induced by the removal of the stenosing clip from the renal artery. Incidence and severity of destructive vascular lesions were correlated with the calculated gradient between the pressure before and beyond the stenosis. Anaesthesia had a protective effect on the development of destructive vascular lesions in both models. Obviously, this effect is not related to a reduction of the systemic pressure, but rather to the suppression of abnormal vascular tone, characterized by focal constriction alternating with overdilation. Vasomotor changes, which cause a local overdilation, may be responsible for destructive vascular lesions even at normal to subnormal blood-pressure values. Destructive vascular lesions occur as a result of the exceeding of a critical wall tension. The necrosis of medial smooth-muscle cells in non-destructive lesions may be explained by an excessive contraction, which “surpasses” the metabolic capacity of the cells.

Thirst in the rat after ligation of the inferior vena cava: Role of angiotensin II

The role of angiotensin II in thirst states after ligation of the inferior vena cava above (CLA) or below (CLB) the origin of the renal veins as compared to sham operated controls was evaluated 24 hrs after ligation. Water intake was enhanced in CLB rats and even more so in CLA rats. Plasma angiotensin II and urea concentrations and serum osmolality were increased in CLA rats. Plasma sodium concentration and hematocrit were reduced in CLA rats, and hematocrit in CLB rats as well. Water intake in CLA rats was retarded by IV infusions of saralasin. Saralasin infusions in CLA rats resulted in a dramatic increase of plasma angiotensin II concentrations. Ligation of the inferior vena cava induces major changes in body fluid homeostasis, which are more pronounced in CLA than in CLB rats. The increase in water intake in CLA rats appears to be partly mediated by angiotensin II.