Spreading and flattening of glomerular podocyte cell bodies and major processes and an apparent lack of foot processes were observed by scanning electron microscopy in a reversible pedicle-clamping model of acute renal failure in ADH-treated rabbits and in biopsy specimens taken 1 hour after transplantation from patients who later showed clinical signs of "acute tubular necrosis." Glomerular changes were quantified by morphometry in A) normal rabbit kidneys, B) rabbit kidneys obtained 2 hours after 1 hour of left pedicle clamping and right nephrectomy, C) kidneys similar to Group B except that the animals were treated with an agent that reliably lessens the eventual severity of renal failure (clonidine, 30 microgram/kg given intravenously 1/2 hour before unclamping), D) 1-hour-posttransplantation biopsy specimens from human kidneys that functioned well after transplantation (recipient serum creatinine less than 2.5 mg/dl on Day 3), and E) 1-hour-posttransplant biopsy specimens from kidneys that later manifested posttransplantation ischemic acute renal failure (recipient serum creatinine greater than or equal to 2.5 mg/dl on Day 3). The fraction of glomerular capillary surface covered only by podocyte processes smaller than 1 mu (and not by cell bodies and wider processes) was .65 +/- .02 (SEM) in A; .48 +/- .03 in B; .64 +/-.03 in C; .57 +/- .01 in D; and .38 +/- .04 in E (A vs B, P less than .01; B vs C, P less than .02; D vs E, P less than .01). In Groups D and E there was a significant negative correlation between the fraction of glomerular capillary surface covered only by podocyte processes less than 1 mu in width and serum creatinine on the third posttransplantation day (r = --.86, P less than .01 by the Spearman rank test). It is concluded that podocyte changes are seen by scanning electron microscopy early in clinical and experimental postischemic acute renal failure and are more pronounced in those groups that eventually develop more severe renal failure. It is unclear whether these changes reflect a decrease in glomerular hydraulic permeability or an increase in glomerular permeability to protein.

Animals↗

PubMed1981

Clonal characteristics of cutaneous scars and implications for atherogenesis.

Atherosclerotic plaques in man have monoclonal characteristics. One possible explanation for this observation is that clonal selection occurs as cells proliferate at sites of intimal injury. To test whether such clonal selection could occur during the formation of an intimal "scar", the clonal characteristics of human cutaneous scars were studied with the use of glucose-6-phosphate dehydrogenase (G-6-PD) as a cellular marker. Scars from 7 black women heterozygous for the A and B isoenzymes of G-6-PD were divided into 870 portions consisting of contiguous normal skin, scar margin, outer scar, and inner scar. Portions were further divided into surface and deeper portions of scar. In 4 of the 7 cases, significant differences were observed between the mean percentage of total activity in the B isoenzyme band in portions of scar and portions of skin. Significant differences between surface and deeper portions of both skin and scar were also observed in 5 cases. The variance of isoenzyme values from portions of scars was not significantly greater than that within portions of skin. It is concluded that the results are consistent with clonal selection occurring during the healing of skin wounds. However, the magnitude of the difference (no greater than a 5.7% B isoenzyme difference) is far too small to even partially explain the marked differences in isoenzyme patterns observed between atherosclerotic plaques and uninvolved aortic wall. The results do not support the idea that the monoclonality of human atherosclerotic plaques is due to clonal selection following the healing of an intimal injury.

Adult↗

PubMed1981

The effects of heparin treatment on hypertension and vascular lesions in stroke-prone spontaneously hypertensive rats.

Stroke-prone spontaneously hypertensive rats (SPSHRs) were used to test the theory that heparin treatment may prevent the development of "malignant" hypertension and fibrinoid vascular lesions in the kidney. Subcutaneous injections of heparin (100 units/100 g body weight) were given every 8 hours over a 5-week period to 12 young (10-week-old) SPSHRs. A control group of 12 SPSHRs was injected with saline. Both heparin-treated and control animals showed an incremental rise in mean systolic pressure, but the pressure was significantly lower (P less than 0.05) in the heparin-treated animals during weeks 1-4 of treatment. There were significantly fewer fibrinoid vascular lesions (P less than 0.03) in the heparin-treated group. In 7 additional heparin-treated and 7 control SPSHRs plasma and blood volumes were determined for assessment of the effects of heparin treatment. There was no significant difference in total blood volume or plasma volume between the two groups, but heparin-treated animals had lower hematocrit levels. In 8 SPSHRs direct arterial pressures were recorded for 1 hour after a single heparin injection, and no acute changes in blood pressure were observed. The results suggest that heparin treatment prevents the development of severe fibrinoid vascular lesions and also attenuates the rate of the rise in systolic blood pressure; moreover, this reduction in blood pressure is not caused by a significant reduction in blood volume or an acute hypotensive effect of heparin.

Animals↗

PubMed1980

Evidence for two populations of fatty streaks with different roles in the atherogenic process.

Isoenzymes of glucose-6-phosphate dehydrogenase, used as cellular markers, showed that a minority of fatty streaks have clonal characteristics intermediate between those of normal arterial wall and those of fibrous plaques, suggesting that such streaks are evolving into fibrous plaques. "Intermediate" fatty streaks are found to cluster in patients in the middle-age years, suggesting that few fatty streaks evolve into plaques in the advanced years. It is suggested that two populations of fatty streaks exist: one destined, perhaps by its location or risk factors, to develop into fibrous plaques; and a second which remains as fatty streaks and never goes on to become fibrous plaques. This hypothesis helps to explain some of the evidence disclaiming the fatty streak as a forerunner of the atherosclerotic plaque.

Adult↗

PubMed1980

Clonidine after renal ischemia to lessen acute renal failure and microvascular damage.

Clonidine, an antihypertensive drug that inhibits renin release and causes a water diuresis in normal animals, was tested for its ability to reduce the severity of post-ischemic acute renal failure produced in rabbits by clamping the left renal pedicle for 1 hour and removing the opposite kidney. Clonidine significantly lessened renal failure when given during, or 1 hours after, the ischemic insult in dehydrated rabbits. It was also effective when given during the ischemic insult in vasopressin-treated water-drinking rabbits but not in control water-drinking rabbits. In vasopressin-treated rabbits, clonidine lessened renal failure observed 2 days after the ischemic insult despite the fact that in the immediate postischemic period it lowered total renal blood flow, produced hypotension, and did not bring about lower plasma renin levels. Clonidine treatment resulted in less outer medullary microvascular damage (demonstrated by colloidal carbon staining), higher outer medullary blood flow 1 to 2 hours after unclamping, fewer casts, and higher creatinine clearance and free water clearance/creatinine clearance 4 to 6 hours after unclamping compared with controls. The effect of clonidine was unrelated to plasma renin activity. Clonidine did not alter plasma vasopressin concentration. Demeclocycline and lithium, two agents that blunt renal responsiveness to vasopressin, had a beneficial effect in dehydrated animals similar to that of clonidine, but the angiotensin II antagonist saralasin and the angiotensin converting enzyme inhibitor SQ20881 did not. Normal rabbits given a large dose of vasopressin in oil plus clonidine had significantly greater urine output and free water clearance and lower urine osmolality than did rabbits given vasopressin in oil alone. These results suggest that clonidine may be beneficial because it prevents ischemic microvascular injury in the renal outer medulla, an effect that may decrease tubular obstruction by lessening desquamation of damaged tubular cells or cell constituents into the tubular lumen. Clonidine may also decrease formation of obstructive hyaline casts in collecting ducts by blunting the kidney's response to vasopressin and increasing tubular fluid flow rate.

Acute Kidney Injury↗

PubMed1980

The effect of clonidine on tubular obstruction in postischemic acute renal failure in the rabbit demonstrated by microradiography and microdissection.

Acute renal failure was produced in vasopression-pretreated rabbits by clamping the left renal pedicle for one hour and removing the opposite kidney. Treatment with clonidine, as antihypertensive drug that blunts the kidney's response to vasopressin, resulted in significantly higher creatinine clearance and urine flow rate in the first 6 hours after unclamping. Clonidine (30 microgram/kg given intravenously 30 minutes before unclamping) also significantly lessened the number of hyaline casts in outer medullary tubules and inner medullary loops of Henle 6 hours after unclamping and reduced the number of abnormal tubular contours in microadiograms produced by infusing barium sulfate into the renal artery at sufficient pressure to rupture glomerular capillaries, causing an escape of contrast material into the tubules. The spaces consistently observed between the ends of barium columns and hyaline casts in microdissection studies and the great lengths of the hyaline casts suggest that hyaline casts obstruct the flow of tubular fluid. Clonidine treatment resulted in fewer, shorter, and thinner hyaline casts. These results indicate that tubular obstruction by hyaline casts plays an important role in early postischemic acute renal failure, and that clonidine's beneficial effect is due in part to a reduction in cast formation.

Acute Kidney Injury↗

PubMed1980

The failure of furosemide-induced salt and water loss to convert benign to malignant hypertension in the rat.

The concept has been advanced that malignant hypertension is precipitated in the rat with renal hypertension by a sudden loss of sodium in the urine. In order to test this hypothesis modest degrees of hypertension were produced in Holtzman rats by the application of a silver clip to one renal artery, not touching the opposite kidney. When the systolic blood pressure reached a level between 160 and 180 mm Hg, loss of sodium and water was induced by the administration of furosemide, given either orally over a 7-day period, or by 3 intramuscular injections over a 24-hour period. Sodium and water balance studies, blood pressure determinations, histologic assessment of blood vessels in the nonclipped kidney, and measurement of activity of the juxtaglomerular apparatus were carried out in these 2 groups and appropriate control animals. It was found that in spite of a considerable natriuresis and diuresis in furosemide-treated animals, there was neither a significant increase in the blood pressure nor development of more severe vascular lesions in the nonclipped kidney than in the kidneys of control animals.

Animals↗

PubMed1979

Clonal characteristics of experimentally induced "atherosclerotic" lesions in the hybrid hare.

The female hybrid hare (Lepus timidus x Lepus europaeus) is heterozygous for electrophoretically separable, X-linked isoenzymes of glucose-6-phosphate dehydrogenase. The isoenzymes of this animal have been used as cellular markers in the study of the clonal origins of experimentally induced atherosclerotic lesions. Aortic lesions produced in the hybrid hare by feeding cholesterol and injuring the aortic wall with a catheter have been shown to have polyclonal characteristics and in this way are fundamentally different from atherosclerotic fibrous plaques in man.

Animals↗

PubMed1979

Monoclonal characteristics of organising arterial thrombi: Significance in the origin and growth of human atherosclerotic plaques.

The clonal characteristics of 26 arterial thrombi at different stages of organisation were determined using the X-linked enzyme, glucose-6-phosphate dehydrogenase (G.-6-P.D.), as a clonal marker in 13 women heterozygous for electrophoretically separable G.-6-P.D. isoenzymes. A gradation of increasing monoclonality was observed with increasing organisation of the thrombi, such that only 21% of poorly organised (red) thrombi displayed monoclonal characteristics similar to those of atherosclerotic plaques, whereas 78% of moderately organised (pink) thrombi and 91% of well-organised (white) thrombi showed such characteristics. These results provide objective evidence for the role of thrombosis in the formation of human atherosclerotic plaques.

Aorta, Thoracic↗

PubMed1979

Prognostic importance of vascular lesions in acute renal failure with microangiopathic hemolytic anemia (hemolytic-uremic syndrome): clinicopathologic study in 20 adults.

Renal biopsies obtained from 20 adult patients within 30 days after onset of acute renal failure with microangiopathic hemolytic anemia ("the hemolytic-uremic syndrome") were studied. Lesions were graded independently by two observers without knowledge of the clinical history. All patients who did not have refractory hypertension were treated with heparin. Ten of the patients died, and four developed end-stage renal failure requiring chronic dialysis. Six patients, however, had a relatively good outcome: two recovered completely and four developed mild-to-moderate chronic renal failure not requiring dialysis. The six patients with a good outcome had significantly less severe arterial intimal thickening on biopsy compared with the remaining patients with a poor outcome. The patients with a good outcome and those with a poor outcome did not differ in the severity of glomerular lesions. The clinical features did not allow a prediction of late outcome. These results suggest that early renal biopsies may be helpful in predicting prognosis in the "hemolytic-uremic syndrome." This clinical syndrome may occur either in apparently healthy people, or may complicate the course of a chronic essential hypertension.

Acute Kidney Injury↗

PubMed1979

Urinary deposits in veins and interstitium of the kidney: their possible role in causing renal damage.

Explore the source record for details and available documents.

Cicatrix↗

PubMed1979

Malignant melanoma with renal dense deposits containing tumor antigens.

A patient with disseminated malignant melanoma developed mild renal failure with proteinuria four months following the diagnosis of his neoplasm. Renal biopsy showed a membranoproliferative glomerulonephritis. Electron microscopy revealed intramembranous dense deposits in the glomeruli as well as in tubular basement membranes and Bowman's capsule. Immunofluorescence microscopy demonstrated granular staining for C3 in these same locations and granular deposits of immunoglobulins in the glomerular capillary loops. Light and electron microscopy of the autopsy kidney obtained 5 months later revealed progression of the number, size and density of the deposits. Eluates from both autopsy and biopsy kidney contained melanoma antigen and anti-melanoma antibodies. This case illustrates the association between the dense deposits and neoplasia with the dense deposits representing immune complexes with the tumor as antigen.

Antigen-Antibody Complex↗

PubMed1979

A morphometric study of arterial intimal thickening in kidneys of dialyzed patients.

Arterial intimal thickening is common in the end-stage kidneys of patients maintained on hemodialysis. We measured the intimal thickening in patients dialyzed for varying periods and in patients with the malignant phase of essential hypertension and with scleroderma-associated renal failure. The ratio of intimal area to medical area in intrarenal arteries was used as a measure of intimal thickening. In the dialysis groups, intimal thickening was relatively constant in arteries of all sizes and correlated with duration of dialysis, particularly in larger arteries. In the malignant hypertension and scleroderma groups, the intimal thickening was greatest in arteries less than 200 mu in diameter and least in those over 500 mu in diameter. There was much less intimal thickening in arteries of all sizes in kidneys of patients with end-stage polycystic disease than in other end-stage kidneys from patients with a similar diastolic blood pressure and similar duration of dialysis. We believe that the intimal thickening in dialyzed patients is probably a disuse type of change and may be related to reduction in the area of the renal microvascular bed.

Adolescent↗

PubMed1979

The morphology of "acute tubular necrosis" in man: analysis of 57 renal biopsies and a comparison with the glycerol model.

Renal biopsies from 24 patients with oliguric "acute tubular necrosis" (ATN) and 26 patients with non-oliguric ATN were compared with biopsies from 7 patients who had recently recovered from ATN and 20 control patients. Many morphologic changes were present in the biopsies of patients with ATN and absent in controls, but only two lesions were significantly more severe in patients who had ATN at the time of the biopsy compared with patients who had recently recovered from ATN. These two lesions, necrosis of individual tubular epithelial cells and loss of brush border in proximal tubules, may play a role in the pathogenesis of renal functional failure in ATN. Necrosis of individual tubular epithelial cells appeared to be a continuing process. In the patients with non-oliguric acute renal failure there was a positive correlation between duration of renal failure and severity of tubular necrosis. This was not observed in the patients with oliguric acute renal failure, but otherwise there were no identifiable morphologic differences between the two groups. The glycerol model of acute renal failure in the rabbit was found to differ in several significant ways from ATN in man. Despite the fact that the rabbits had significantly less severe renal failure, their kidneys showed much more severe tubular necrosis and much more prominent presence of tubular casts than was the case in biopsies from patients with ATN. Loss of brush border in proximal tubules was not an important feature of the glycerol model of acute renal failure in the rabbit. We suggest that the glycerol model is not analogous to human ATN and may have an entirely different pathogenesis.

Acute Kidney Injury↗