Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules?
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Aging↗
Biomedical subjects
T Bertani
Publications and source records attributed to T Bertani.
Three-dimensional morphometric analysis of segmental glomerulosclerosis in the rat.
In idiopathic nephrotic syndrome, and in experimental models of nephrosis, changes of visceral epithelial cells involve the entire glomerular population while segmental sclerotic changes are reported to affect only a certain number of glomeruli. Because conventional determination of the percentage of glomeruli affected by sclerotic lesions is usually based on the examination of randomly selected sections, we wondered whether glomeruli appearing normal in a given section could be affected by sclerosis in other regions of the capillary tuft (CT). To assess the real incidence and the spatial extension of sclerotic changes at the level of single glomerulus, we used serial-section morphological analysis to measure the volume of the glomerulus and that of sclerosis lesions. In glomeruli from control rats and in glomeruli from adriamycin (ADR) treated rats surface area of Bowman's capsule (BC), CT and sclerotic regions were measured using stereology techniques in all the consecutive sections containing each individual glomerulus, and corresponding volumes were then calculated. Mean volume of BC and CT were not significantly different between control and ADR rats (0.71 +/- 0.03 and 0.53 +/- 0.03 vs. 0.76 +/- 0.04 and 0.53 +/- 0.02 microns 3 x 10(-6), respectively). The distribution of glomerular volume parameters in the ADR rats were more spread out than in control animals, indicating that some glomeruli became smaller while other became larger. No sclerotic changes were found in control rats, while in the three ADR rats 94, 90 and 92% of glomeruli, respectively, were affected by sclerotic lesions.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Ticlopidine prevents renal disease progression in rats with reduced renal mass.
Functional and morphological studies were done in three groups of male Sprague-Dawley rats after removal of the right kidney and infarction of approximately five-sixths of the left. Group 1 received no specific therapy. Group 2 was treated with ticlopidine, 150 mg/kg per os, for 50 days starting 10 days after surgical ablation. Group 3 was given the thromboxane antagonist, GR 32191, 3 mg/kg b.i.d. orally for 50 days, like ticlopidine. Untreated Group 1 rats developed renal insufficiency, systemic hypertension, progressive proteinuria and glomerulosclerosis. In Group 2 treatment with ticlopidine was associated with less severe impairment of renal function. Proteinuria was significantly lower and animals were partially protected from the development of glomerulosclerosis. These animals had significantly prolonged skin bleeding time. In vitro ADP and arachidonic acid (AA)-induced platelet aggregation was inhibited. Systemic blood pressure was significantly lower than in controls. In Group 3 rats GR 32191 failed to influence progressive proteinuria and severity of glomerulosclerosis which were comparable to those in Group 1. Bleeding time was not prolonged, and in vitro platelet aggregation was inhibited only when AA was used as aggregating agent. Systemic blood pressure was not influenced. These studies suggest that a drug like ticlopidine, which has a broad spectrum of pharmacological actions on platelets and platelet-cell interactions, does retard the development of progressive renal injury when nephron number is reduced. Specific blocking of thromboxane A2 (TxA2) biological activity does not influence progressive renal disease in rats with remnant kidney.
Animals↗
Association of NK-cell lymphoproliferative disease and nephrotic syndrome.
A 56-year-old white man with a seven-year history of lymphocytosis of large granular lymphocytes (LGL) developed mild renal insufficiency (serum creatinine 150 mumol/L (1.7 mg/dL) with proteinuria (3.4 g/day). Laboratory investigations confirmed a proliferative disease of non-T lineage cytotoxic LGL/natural killer (NK) cells, and the renal biopsy documented focal and segmental glomerulosclerosis associated with interstitial inflammation and tubular atrophy. These findings could be explained by production and release of humoral mediators by pathologic LGL/NK cells. The renal function must be carefully monitored in patients with LGL/NK proliferative disorders, and the role of the NK cell system in renal diseases should be investigated.
Biopsy↗
HIV-associated nephropathy: a new entity. A study of 12 cases.
The existence of an HIV-related nephropathy as a distinct disease entity is controversial. Twelve patients affected by HIV infection (eight drug-abusers, three homosexuals and one black heterosexual) who showed nephrotic syndrome (five patients) or urinary abnormalities (seven patients), four with renal insufficiency, were submitted to renal biopsy. Six patients were in pre-AIDS, six had AIDS. Light microscopy, performed in all cases, showed focal segmental glomerular sclerosis in nine patients, a moderate hypercellularity in six, vacuolisation of visceral epithelium in ten, focal collapsed tuft in seven, and tubular microcystic dilatation with large dense protein casts in lumina in seven. Immunofluorescence, available in 11 patients, showed small deposits in mesangium or mesangial and subendothelial spaces. IgG, IgM, and C3 were more frequently found, while three cases were negative. Electron-microscopy (five patients), besides confirming light-microscopy changes, showed several tubuloreticular inclusions (four patients), nuclear bodies (mainly complex) in nuclei of tubular cells (three patients), and nuclear granulofibrillary transformation of tubular cells. Various histological aspects and clinical data confirm the hypothesis that HIV nephropathy can be considered as a separate entity, different from heroin nephropathy and idiopathic focal glomerulosclerosis.
Adult↗
Pattern of double glomerulopathies. A clinicopathologic study in nine nondiabetic patients.
Nine new cases of double glomerulopathies (GP) were found among 1,715 renal biopsies. Immunofluorescence and electron microscopy were needed to achieve a correct diagnosis and the prevailing relevance of these techniques in single cases was stressed. IgA nephropathy was the most commonly found GP, being associated with membranous glomerulonephritis (GN) (2 patients), minimal change disease (3 patients), and focal segmental glomerulosclerosis (1 patient). In addition, single cases of membranous GN plus crescentic GN and acute GN plus cryoglobulinemic GN were recorded. Possible factors involved in the pathogenesis and clinical significance of double glomerulopathies are discussed.
Adult↗
Effect of ticlopidine on the evolution of renal disease in rats with reduced renal mass.
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Adenosine Diphosphate↗
Angiotensin converting enzyme inhibition ameliorates glomerular filtration of macromolecules and water and lessens glomerular injury in the rat.
The effect of enalapril on glomerular hemodynamics and permselectivity and on subsequent sclerosis was studied in male MWF/Ztm rats which spontaneously develop proteinuria and glomerular structural damage. Untreated group 1 and enalapril-treated group 2 (50 mg/liter, in the drinking water) underwent micropuncture studies after 2 mo of observation. After the same period of treatment, group 3 (untreated) and group 4 (enalapril treated) were used for determination of whole-kidney function and neutral dextran clearances. Group 5 (untreated) and group 6 (enalapril treated) were followed for an additional 4 mo and used for kidney function and morphological studies. Enalapril significantly lowered systolic blood pressure, which was elevated in untreated groups, and significantly reduced proteinuria (295 +/- 64 vs. 128 +/- 24 mg/24 h by the end of the study). Despite the reduced renal perfusion pressure, whole-kidney glomerular filtration rate was higher in enalapril-treated than in untreated rats (0.96 +/- 0.14 vs. 0.81 +/- 0.10 ml/min, P less than 0.05) as was the single nephron glomerular filtration rate (54 +/- 7.1 vs. 46 +/- 4.0 nl/min, P less than 0.05). The single glomerular afferent plasma flow was comparable in both groups. Enalapril reduced mean glomerular capillary hydraulic pressure from the normal value of 51 +/- 1 mmHg (untreated rats) to a value lower than normal (44 +/- 1 mmHg, P less than 0.001). These hemodynamic changes were associated with a significant reduction in afferent (approximately 23%) and efferent (approximately 26%) arteriolar resistance. The mean ultrafiltration coefficient was two times higher in the enalapril (0.126 +/- 0.027 nl/s per mmHg) than in the untreated group (0.061 +/- 0.023 nl/s per mmHg). The clearance of dextran macromolecules relative to that of inulin was significantly reduced for all molecular sizes studied (26-64 A) in enalapril-treated vs. untreated rats. Theoretical analysis of dextran fractional clearances using a heteroporous model of neutral solute transport across the glomerular capillary wall indicated that enalapril affected glomerular membrane size selective properties, reducing uniformly the radius of hypothetical membrane pores. Enalapril treatment also significantly limited (P less than 0.01) the development of glomerular structural lesions (mean percentage of sclerotic glomeruli was 4.2 +/- 3.5% [treated] vs. 28 +/- 15% [untreated] rats at the end of the study) as well as tubulo-interstitial damage. These results suggest that the protective effect of enalapril on the development of proteinuria and glomerular sclerosis in this model is due to its property of ameliorating size selectivity and hydraulic permeability of the glomerular capillaries.
Animals↗
Thromboxane synthesis inhibition increases renal prostacyclin and prevents renal disease progression in rats with remnant kidney.
Previous studies have demonstrated that inhibition of thromboxane A2-dependent platelet aggregation by the thromboxane A2 synthase inhibitor, OKY 1581, ameliorated the progressive kidney disease of rats with subtotal renal ablation. OKY 1581 also decreased the excessive renal thromboxane A2 synthesis and lowered systemic blood pressure. In the same model, a low dose aspirin and a specific thromboxane A2 receptor antagonist failed to influence proteinuria, glomerulosclerosis, and hypertension, thus excluding a role for either platelet or renal thromboxane A2 in renal disease progression. The aims of this study were to establish (1) whether a thromboxane A2 synthase inhibitor different from OKY 1581 could retard the progression of glomerular disease in rats with remnant kidney and (2) whether this effect was associated with an increase in renal synthesis of the vasodilatory prostacyclin. Treatment of rats with renal mass ablation with FCE 22178 (100 mg/kg by gavage and 200 mg/kg in the drinking water) for 35 days starting 10 days after surgical ablation was associated with an improvement in renal function in comparison with rats receiving the vehicle alone. Proteinuria was significantly lower, and rats were partially protected from the development of glomerulosclerosis. Systolic blood pressure was significantly lower than in animals given the vehicle. Urinary thromboxane B2 excretion was significantly decreased, and urinary 6-keto-prostaglandin F1 alpha increased in respect to vehicle-treated rats. We conclude that FCE 22178 limits glomerular injury in rats with remnant kidney.
6-Ketoprostaglandin F1 alpha↗
Tissue plasminogen activator therapy of rabbit nephrotoxic nephritis.
To study the efficacy of tissue plasminogen activator (PA) therapy to prevent deteriorating renal function in experimental proliferative glomerulonephritis we used a model of nephrotoxic nephritis induced in rabbits by injection of antiglomerular basement membrane antiserum. Saline or recombinant tissue plasminogen activator (rt-PA, 1.3 mg/kg body weight) was infused daily for 7 days starting from day 7 after the injection of antiglomerular basement membrane antiserum when the disease had been already triggered. Animals were killed on day 14. Rabbits given saline had abundant deposits of fibrin and crescents in about 67% of glomeruli. rt-PA significantly protected animals from glomerular fibrin deposition and crescent formation with respect to saline-treated animals. Renal function measured as creatinine clearance was dramatically impaired in rabbits given saline. Treatment with rt-PA ameliorated the renal function impairment of nephrotoxic nephritis. rt-PA did not produce a systemic fibrinolytic state as indicated by alpha 2-antiplasmin level measurement. These results suggest that tissue PA may have important implications in preventing renal function deterioration in humans with crescentic glomerulonephritis and fibrin depositions.
Animals↗
Renal vascular and thrombotic effects of cyclosporine.
Cyclosporine A (CyA) given to prevent xenograft rejection induces renal function impairment. In the last few years many studies have been devoted to understanding the mechanism(s) of CyA-induced renal insufficiency. In humans, several specific findings--interstitial fibrosis, toxic tubulopathy, peritubular capillary congestion, arteriolopathy--have been associated with CyA administration. It is now recognized that CyA renal toxicity mainly manifests under three different syndromes: (1) acute reversible decrease in glomerular filtration rate (GFR), (2) acute microvascular disease with the pattern of thrombotic microangiopathy, and (3) chronic irreversible renal damage. This review analyzes the available evidence that the clinical syndromes of CyA nephrotoxicity are related to changes induced by CyA on renal vessels. Experimental studies have failed to document that the activation of renin-angiotensin axis or sympathetic nervous system plays a relevant role in the development of CyA-associated renal vasoconstriction, which is the main causal factor of acute reversible decrease in GFR, whereas it is possible that changes in arachidonic acid metabolites with vasoactive properties contribute to this CyA-induced phenomenon. In this context, findings of increased urinary TxB2 and protective effect of TxA2 receptor blocking are of particular interest. Since the introduction of CyA in clinical practice, a syndrome of thrombotic microangiopathy resembling hemolytic uremic syndrome/thrombotic thrombocytopenic purpura has been recognized in humans and reproduced in experimental animals. This is a rare form of vascular toxicity attributed to CyA which may have a poor prognosis and possibly results from a direct toxic effect of CyA on vascular endothelium. The syndrome of chronic progressive deterioration of renal function associated with CyA was first recognized in humans. Until recently the possibility of reproducing this syndrome in animals in order to better understand its nature was not addressed. As in humans, when animals are given CyA for greater than 2 months they may develop chronic renal insufficiency with tubular arteriopathy and interstitial fibrosis. A peculiar form of tubulointerstitial damage has been recognized in association with CyA, and called striped interstitial fibrosis, that is probably due to tubular collapse induced by afferent vasoconstriction. This lesion may be improved by withdrawal of CyA, but renal function usually does not normalize.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Kidney Injury↗
Sequence of glomerular changes in experimental endotoxemia: a possible model of hemolytic uremic syndrome.
Glomerular morphological changes produced by 5-hour intravenous infusion of endotoxin (40 micrograms/kg/h) were studied in 57 rabbits. During endotoxin infusion all animals developed signs of endotoxemia, anemia, and transient leukopenia and thrombocytopenia. Acute renal failure also developed in all animals. By light microscopy a marked polymorphonuclear cell infiltration was the prominent finding within 1 h from the beginning of the infusion. At hour 5 fibrin deposits and thrombi were detected in most animals. The abnormalities were reversible. By electron microscopy endothelial damage was detected few minutes after the beginning of endotoxin infusion followed by leukocyte and platelet infiltration in glomerular capillaries. Fibrin appeared at hour 5 as free strands into the lumens or in large clumps along the luminal surface of endothelial layer. Occasionally, occlusive fibrin thrombi were seen. At hour 48 only mild endothelial damage was seen, associated with few polymorphonuclear cells in the glomerular capillary lumens. These results document the sequence of renal changes in the best available animal model of hemolytic uremic syndrome. Beside endothelial damage, leukocyte infiltration in glomerular capillaries is a prominent finding suggesting a role of inflammatory cells in the development of microvascular thrombosis.
Animals↗
Selective inhibition of platelet thromboxane generation with low-dose aspirin does not protect rats with reduced renal mass from the development of progressive disease.
Rats with extensive renal mass reduction develop hypertension, proteinuria and progressive glomerulosclerosis. Previous studies have demonstrated that these changes are associated with an increased urinary excretion of thromboxane compared with normal rats and that the administration of a thromboxane synthetase inhibitor prevents glomerulosclerosis and progressive renal function deterioration. On this basis it has been speculated that the thromboxane synthetase inhibitor, by inhibiting platelet thromboxane, reduces platelet aggregation and prevents the generation of substances that can influence glomerular functional properties. Because the thromboxane synthetase inhibitor also inhibits thromboxane synthesis by resident glomerular cells and lowers blood pressure in these animals, the question of whether platelet thromboxane is indeed the factor implicated in the development of renal disease after renal ablation remains unanswered. To address this issue the authors administered at different time intervals from the surgical procedure a low-dose of oral aspirin (ASA) to rats with remnant kidney. This approach resulted in selective inhibition of platelet cyclooxygenase leading to an almost complete prevention of platelet thromboxane generation. Low-dose ASA spared renal cyclooxygenase as documented by a lack of significant inhibition of glomerular and urinary 6-keto-PGF1 alpha and did not lower blood pressure. Renal function studies showed that low-dose ASA, despite inhibiting platelet aggregation, had no effect on proteinuria and progressive renal insufficiency irrespectively if administered late (ie, 80 days after surgery) and given daily for all the observation period (ie, 20 days) or earlier in the course of the disease (ie, 40 and 10 days after surgery). Histologic data showed that the degree of glomerulosclerosis and tubulo-interstitial damage was not significantly different in rats with reduction of renal mass alone compared with rats with remnant kidney given low-dose ASA. In conclusion, the present findings indicate that inhibition of platelet aggregation and thromboxane formation does not prevent the progressive glomerulosclerosis that develops in rats with surgical reduction of renal mass. It is suggested that the beneficial results obtained previously in the same model by the use of a thromboxane synthesis inhibitor must be attributed either to an effect on resident glomerular cell thromboxane synthesis or to lowering systemic blood pressure.
Animals↗
Enhanced glomerular thromboxane A2 mediates some pathophysiologic effect of platelet-activating factor in rabbit nephrotoxic nephritis: evidence from biochemical measurements and inhibitor trials.
Previous studies have shown that platelet-activating factor (PAF) receptor blocking has a protective effect on rabbit nephrotoxic nephritis (NTN). We examined whether arachidonic acid (AA) metabolism is altered in NTN and whether a PAF receptor antagonist has any influence on such changes. Rabbits injected with anti-glomerular basement membrane antiserum in the heterologous phase had a markedly increased glomerular thromboxane B2 (TxB2) production level, whereas no changes have been detected in glomerular 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2). During the autologous phase of the disease, the glomerular TxB2 level was even higher than in the heterologous phase. The level of 6-keto-PGF1 alpha was significantly lower than normal, and the level of PGE2 was unchanged in respect to the basal values. The use of L-652,731 (a specific PAF receptor antagonist) reversed the abnormal generation of AA metabolites at glomerular level both in the heterologous and autologous phase of the disease. The effect of L-652,731 on AA metabolism is likely to be an indirect result of the PAF receptor blocking, because L-652,731 given to normal rabbits had no direct effect on glomerular AA metabolism. To assess whether the beneficial effect of L-652,731 in NTN is at least in part mediated by its capability of suppressing the excessive intrarenal synthesis of thromboxane A2 (TxA2), we compared the effect of L-652,731 with that of a selective TxA2-synthase inhibitor (FCE-22178). FCE-22178 ameliorated the morphologic expression of rabbit NTN and reduced function deterioration. The protective effect of L-652,731 on proteinuria in the autologous phase and on glomerular filtration rate in both phases was superior to that of FCE-22178. We conclude that an excessive intraglomerular synthesis of TxA2 occurs in rabbit NTN that can play a role in renal function deterioration. Both a specific PAF receptor antagonist and a TxA2-synthase inhibitor reduced the exaggerated TxA2 synthesis and favorably influenced the evolution of the disease.
Animals↗
Pattern of double glomerulopathies: a clinicopathologic study of superimposed glomerulonephritis on diabetic glomerulosclerosis.
Among 1715 renal biopsies investigated by means of light microscopy, immunofluorescence, and/or electron microscopy, 20 cases of various glomerulopathies (GP) were found to be superimposed on diabetic glomerulosclerosis (DGS). The most frequently superimposed GPs were acute GN (nine cases) and cryoglobulinemic GN (six cases). Although the former association is known to occur, the latter has not so far been reported. In the other patients DGS was associated with crescentic GN (two cases), membranoproliferative GN, membranous GN, and IgA nephropathy (one case each). Morphologic clues allowing the identification of the superimposed GP and the diagnostic relevance of the available morphologic methods were stressed. In particular, light microscopy was sufficient to identify the superimposed crescentic GN, whereas immunofluorescence and/or electron microscopy were needed in the other cases in order to show the composition and the seat of the deposits, respectively. In addition, electron microscopy was useful in identifying some peculiar features such as humps, mesangial cell interposition, and organized deposits in cryoglobulinemic GN. The actual frequency of superimposed GPs is difficult to assess: either under or overestimation is possible. Pathologists must be aware that this miscalculation is not an episodic event and that the estimation must be carefully sought whenever clinical data are equivocal and not fully fitting with DGS alone. The duration of the diabetes seems to favor the superimposition of GN on DGS. In these patients the prognosis is poor, not only when it could be expected to be, as in the cases with superimposition of crescentic or membranoproliferative GN, but also when DGS is associated with acute GN, whose prognosis is generally favorable.
Adult↗
Age-related nephropathy and proteinuria in rats with intact kidneys exposed to diets with different protein content.
Tubulointerstitial damage and glomerular sclerosis are findings commonly observed in the experimental models of adriamycin and puromycin aminonucleoside nephrosis. It has been suggested that in such models proteinuria might be an important mediator of tubulo-interstitial damage which in turn may determine the progression of the disease favoring the development of glomerulosclerosis. The objective of the present investigation was to establish the temporal relationship between proteinuria, tubulo-interstitial damage and glomerulosclerosis in aging rats with intact kidneys exposed to diets with different protein content. There were six groups of rats studied. Animals of groups 1, 5, and 6 (N = 10) were fed diets containing 20, 35, and 6% protein, respectively, for 20 months and sacrificed at the end of the experimental period. Rats in groups 3 and 4 (N = 6) exhibited marked and mild proteinuria, respectively, after 14 months of maintenance on standard diet, and followed for two additional months after the onset of proteinuria with the aim of evaluating the pattern of renal damage after a relatively short period of proteinuria. Rats in group 2 (N = 10) were fed standard diet and sacrificed before (5 months) and at the onset of proteinuria (10 months). Protein excretion and plasma creatinine were measured for each animal every month. Pathologic examination was performed by light and electron microscopy. At the onset of proteinuria neither renal structural nor functional abnormalities were detected. After 20 months, rats fed standard diet developed tubulo-interstitial damage (score: 1.29 +/- 1.05) and focal glomerular sclerosis (percentage of glomeruli with focal segmental glomerular sclerosis: 16.70 +/- 16.40). A significant correlation was found between the degree of tubulo-interstitial damage and the percentage of glomeruli with focal glomerular sclerosis (r = 0.99, p less than 0.01). Development of tubulo-interstitial damage and focal glomerular sclerosis were correlated with heavy and sustained proteinuria. The high protein diet significantly worsened proteinuria (at month 20: 247.08 +/- 101.73 mg/day), tubulo-interstitial changes (score: 1.99 +/- 0.70), focal glomerular sclerosis (percentage of glomeruli with focal segmental glomerular sclerosis: 21.50 +/- 9.44) and was associated with deteriorating renal function (at month 20, plasma creatinine: 1.20 +/- 0.50 mg/dl).(ABSTRACT TRUNCATED AT 400 WORDS)
Aging↗
Tumor necrosis factor induces glomerular damage in the rabbit.
Tumor necrosis factor (TNF) is a polypeptide hormone produced by activated macrophages detectable in the circulation of experimental animals given endotoxin. Recent evidence strongly suggests that many of the deleterious effects of endotoxin in experimental animals are mediated by TNF. Because endotoxemia in experimental animals and humans is associated with glomerular damage the present investigation was designed to establish whether TNF directly induces glomerular functional and structural changes. Twenty-three rabbits were given human recombinant TNF at the doses of 0.08, 0.8, and 8.0 micrograms/kg/h as a continuous 5-hour intravenous infusion. Animals were killed at the end of the infusion. All rabbits given 0.8 and 8.0 micrograms/kg/h TNF developed anemia (Ht value decrease at 5 hours: 0.8 microgram/kg/h, 15%; 8.0 micrograms/kg/h, 16%); leukopenia (leukocyte count decrease at 5 hours: 0.8 micrograms/kg/h, 47%; 8.0 micrograms/kg/h, 59%); thrombocytopenia (platelet count decrease at 5 hours; 0.8 micrograms/kg/h, 45%; 8.0 micrograms/kg/h, 57%). Rabbits given 8.0 micrograms/kg/h also had renal failure (serum creatinine from 1.02 +/- 0.15 to 1.64 +/- 0.34 mg/dl). By light microscopy only occasional polymorphonuclear leukocytes in the glomerular capillaries were detectable in rabbits infused with 0.08 micrograms/kg/h TNF, whereas with 0.8 micrograms/kg/h TNF the presence of inflammatory cells in the glomerular capillaries was the prominent finding. With 8.0 micrograms/kg/h TNF beside leukocyte accumulation, fibrin was detected in the glomerular capillary lumens of two of eight animals. Electron microscopy found dose-dependent glomerular endothelial cell damage in animals given TNF with fibrinlike material in the capillary lumens. Glomerular changes induced by TNF were remarkably similar to those previously found in animals given endotoxin. Thus, TNF is likely to be the mediator of endotoxin-induced glomerular damage and can be regarded as a new mediator of macrophage-dependent damage in glomerulonephritis.
6-Ketoprostaglandin F1 alpha↗
Increased urinary excretion of thromboxane B2 and 2,3-dinor-TxB2 in cyclosporin A nephrotoxicity.
Cyclosporin A (CsA) administration to rats is associated with a selective increase in urinary excretion of immunoreactive thromboxane B2 (i-TxB2), the stable breakdown product of TxA2. The exaggerated synthesis of TxA2 may play a role in the reduction of glomerular filtration rate (GFR) observed both in animals and humans undergoing CsA treatment. The present study was designed to get further insight into the origin of the abnormal i-TxB2 urinary excretion. Rats given orally CsA (50 mg/kg/day) for 30 days had a significant increase in the urinary excretion of both 2,3-dinor-TxB2 and TxB2 measured by technique of capillary column gas chromatography-negative ion chemical ionization mass spectrometry (HRGC-NICIMS). Urinary TxB2 is more likely to reflect the renal synthesis of the parent compound, whereas 2,3-dinor-TxB2 is considered to reflect the amount of TxB2 formed in the circulation. Experiments in isolated perfused kidney (IPK) taken from animals given CsA for 30 days showed a lower percentage increase in urinary TxB2 over vehicle treated animals. Moreover in IPK the ratio 2,3-dinor-TxB2/TxB2 was lower than in vivo. The amount of i-TxB2 detectable in serum of animals given CsA was not different from that of control animals. In contrast, isolated glomeruli taken from rats given CsA had an increase in their TxA2 synthesis measured as i-TxB2 in the supernatants. Ultrastructural studies on kidney specimens from animals given CsA showed a focal glomerular endothelial damage together with a marked infiltration of blood borne cells of monocyte-macrophage type in the glomerular tuft. In contrast, kidney specimens taken from IPK preparations were devoid of inflammatory cells. In vitro CsA did not interfere with platelet arachidonic acid (AA) metabolism as shown by a normal i-TxB2 generation in vitro by rat platelet-rich plasma (PRP) exposed to CsA and then challenged with AA or ADP. Similarly isolated glomeruli and isolated proximal tubules from normal rats when challenged with CsA in vitro converted AA into TxA2 normally. It is suggested that the cause of the increased urinary excretion of 2,3-dinor-TxB2 is the consequence of intrarenal platelet and macrophage activation, probably triggered by the endothelial damage. The parallel increase in the urinary excretion of unmetabolized TxB2 is likely to reflect a concomitant activation of resident renal cell AA metabolism induced by CsA.
Animals↗