RESUMO
BACKGROUND: The intractable and unexplained loin pain of severe 'loin pain haematuria syndrome' (LPHS) causes great psychosocial distress and disability. AIM: To examine the psychological factors in LPHS patients who had failed to respond to non-opiate analgesia, and explore the feasibility of conservative management. DESIGN: Retrospective review of case notes, medical and GP records, with follow up. METHODS: We studied 21 consecutive patients referred from specialist renal centres to a regional pain clinic. All records were reviewed, and patients received a comprehensive psychiatric and social assessment. Medication with pain-coping strategies was emphasized, and surgical solutions were discouraged. RESULTS: Patients' median age was 43 years (range 21-64) and duration of symptoms 11 (1-34) years. Sixteen were receiving opiates, and none had enduring benefit from surgery. Patients were divisible into three groups: twelve (57%) gave a history of recurrent, unexplained symptoms involving other parts of the body (somatoform disorder); seven had chronic loin pain; dissimulation was suspected in two. At follow-up (median 42 months), eight (38%) rated their pain absent or improved. Of the 11 whose pain was the same or worse, all were on opiates and seven had a somatoform disorder. A further two patients had developed 'other' medical problems. Despite our advice, three patients underwent major surgery for pain. DISCUSSION: We recommend that patients be managed in a regional pain clinic, where a multidisciplinary approach promotes self-management of pain. Patients who were able to accept conservative treatment, and taper or withdraw opiate analgesia, had a better prognosis.
Assuntos
Dor no Flanco/etiologia , Hematúria/complicações , Dor Intratável/etiologia , Transtornos Somatoformes/psicologia , Adolescente , Adulto , Estudos de Viabilidade , Feminino , Dor no Flanco/terapia , Seguimentos , Hematúria/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Dor Intratável/terapia , Equipe de Assistência ao Paciente , Escalas de Graduação Psiquiátrica , Psicologia , Estresse Psicológico/psicologia , Resultado do TratamentoRESUMO
High field 1H-NMR spectra of fluid collected from the cysts of six renal transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) have been measured and the major metabolite signals assigned. Quantitative NMR measurements have revealed a combination of unusual biochemical features of the cystic fluids that shows them to be distinct from both blood plasma and urine. Isoleucine, lysine, threonine and valine were present at mM concentrations, in cyst fluid and in some cases levels up to 2 orders of magnitude higher than normal plasma or urine were recorded. Mean glucose concentrations in the cyst fluids ranged from 3.4-9.6 mM and a number of organic acids and bases, including acetate, lactate, succinate, creatinine and dimethylamine were also present at high concentration and in different ratios to those found in either plasma or urine. The majority of cyst fluids examined also contained significant quantities of glycoproteins with characteristic 1H-NMR signals from N-acetyl groups of amino-sugar and sialic acid side chains which had a high degree of molecular mobility (as indicated by their relatively long T2 relaxation times, greater than 120 ms). High levels of ethanol (0.5-12.6 mM/l) were found in all fluid samples from the six transplanted patients (confirmed by conventional analysis). In general there was little variation in the 1H-NMR spectral patterns of either the intra- or interpatient cyst fluids, although the contribution of the protein macromolecules to individual spectra was lower in a few cysts. This constancy of biochemical composition probably reflects the chronic nature of the accumulation of cyst fluid and a long turnover of the cystic fluid components which has the effect of averaging composition. These findings suggest that the dynamic composition of cyst fluid from ADPKD patients is unique among the other body fluids and that the unusual composition may be related to epithelial polarity reversal of the cystic epithelium which could also contribute to the growth of the cysts.
Assuntos
Rim Policístico Autossômico Dominante/química , Aminoácidos/análise , Transporte Biológico , Humanos , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Concentração OsmolarRESUMO
Ifosfamide is an oxazophosphorine widely used in the treatment of cancer in children and adults. Nephrotoxicity and neurotoxicity are major side effects. The aim of this study was to use high-resolution proton nuclear magnetic resonance (1H NMR) spectroscopy of urine to identify novel biochemical markers of ifosfamide-induced toxicity. Urine samples were collected from 10 nonencephalopathic patients (who had not previously received nephrotoxic chemotherapy) immediately prior to the first ifosfamide dose and at timed intervals for up to four treatment cycles. The findings were compared with those for urine samples collected from five patients during acute encephalopathic episodes. 1H NMR urinalysis identified a series of characteristic time-related changes in the excretion profiles of low molecular weight endogenous metabolites during ifosfamide therapy. These changes included a decreased excretion of hippurate and an increased excretion of glycine, histidine, glucose, lactate, and trimethylamine-N-oxide. Two nonencephalopathic patients had marked but transient glutaric or adipic aciduria during the second cycle of ifosfamide treatment. Urinary retinol-binding protein rose acutely after each treatment cycle but usually returned to baseline levels. Maximum renal toxicity was observed by the fourth treatment cycle. The ratio of the urinary excretion of the uroprotectant mesna (active form) to dimesna (inactive form) correlated with the degree of renal toxicity. For the encephalopathic patients, the ifosfamide-induced changes in the urinary low molecular weight metabolite profile were similar to those for the nonencephalopathic group. In contrast to previous reports, none of the encephalopathic group developed glutaric aciduria, and i.v. methylene blue did not reverse neurotoxicity in the two patients who received it. The results suggest that ifosfamide nephrotoxicity involves both cortical and medullary regions of the nephron and that the urinary mesna:dimesna ratio may be important in assessing the degree of cytoprotection. This study demonstrates that 1H NMR can provide novel biochemical information on ifosfamide-induced toxicity and will be of value in the optimization of ifosfamide therapy.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Encefalopatias/induzido quimicamente , Encefalopatias/urina , Ifosfamida/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/urina , Espectroscopia de Ressonância Magnética/métodos , Urinálise/métodos , Adulto , Aminoácidos/urina , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Encefalopatias/diagnóstico , Encefalopatias/tratamento farmacológico , Ácidos Dicarboxílicos/urina , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/farmacologia , Córtex Renal/efeitos dos fármacos , Nefropatias/diagnóstico , Testes de Função Renal , Medula Renal/efeitos dos fármacos , Mesna/administração & dosagem , Mesna/efeitos adversos , Azul de Metileno/uso terapêutico , Peso Molecular , Neoplasias/tratamento farmacológico , Neoplasias/urina , Prótons , Proteínas de Ligação ao Retinol/urinaRESUMO
Renal allograft recipients treated with cyclosporine (CsA) have increased renal vascular resistance that falls when CsA is stopped. With the aim of identifying whether CsA-treated patients with excellent renal function also have an alteration in renal vascular tone and to investigate which vessels are affected, we have studied the response of GFR and effective renal plasma flow (ERPF) to an infusion of an amino acid solution in a group of 9 CsA-treated renal transplant recipients with a normal plasma creatinine concentration (104 +/- 3.8 mumol/L [mean +/- SEM]). A similar group of 9 azathioprine-treated patients with good renal function (91 +/- 3.6 mumol/L) were used as controls. The azathioprine group had significant increases in both GFR (22%, P less than 0.05) and ERPF (19%, P less than 0.05) following a protein load, whereas there was no increase in either function in the CsA group. Amino acid infusions increase GFR and ERPF in normal kidneys--at least in part by producing afferent glomerular arteriolar dilatation. The difference we found between the two groups indicates a direct effect of cyclosporine on intrarenal vascular tone, even when renal function is considered to be normal.
Assuntos
Aminoácidos/farmacologia , Ciclosporinas/farmacologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Transplante de Rim , Adulto , Ciclosporinas/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Rim/irrigação sanguínea , Fluxo Sanguíneo Regional/efeitos dos fármacosRESUMO
Very high plasma concentrations of factor-VIII-related antigen (RAG) (VIII-RAG) were found in renal allograft recipients during periods of nephrotoxicity induced by cyclosporine. In eight recipients, who were investigated at weekly intervals, levels of factor-VIII-RAG fell toward normal as the dose of cyclosporine was reduced. Plasma levels of C-reactive protein, an acute phase reactant protein, were never raised in these recipients. These findings are further evidence that toxic doses of cyclosporine are associated with vascular injury.
Assuntos
Antígenos/análise , Ciclosporinas/toxicidade , Fator VIII/imunologia , Rim/efeitos dos fármacos , Artéria Renal/lesões , Veias Renais/lesões , Ensaio de Imunoadsorção Enzimática , Fator VIII/análise , Humanos , Imunoeletroforese/métodos , Transplante de Rim , Transplante Homólogo , Fator de von WillebrandRESUMO
Scintigraphic findings in acute renal failure secondary to scleroderma are reported. In three patients, we have demonstrated severe reduction of renal perfusion with little or no parenchymal uptake of tracer and absent excretion. These findings are compatible with the known histological process of occlusive vasculopathy, and such scintigraphic findings at presentation may reflect a poor prognosis for renal recovery.
Assuntos
Injúria Renal Aguda/etiologia , Rim/diagnóstico por imagem , Escleroderma Sistêmico/complicações , Injúria Renal Aguda/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cintilografia , Escleroderma Sistêmico/diagnóstico por imagem , Agregado de Albumina Marcado com Tecnécio Tc 99m , Pentetato de Tecnécio Tc 99mRESUMO
Bleeding time and platelet function tests were performed on 31 patients with progressive chronic renal failure (CRF) due to non-immunological (urological) causes, and compared with 22 healthy controls. Patients were classified as mild (plasma creatinine less than 300 mumol/l), moderate (300-600 mumol/l) or severe renal failure (greater than 600 mumol/l). Bleeding time was rarely prolonged in mild and moderate CRF and mean bleeding time significantly elevated only in severe CRF (p less than 0.005). Haematocrit was the only index which correlated with bleeding time (r = -0.40). Platelet counts, collagen stimulated thromboxane generation, and platelet aggregation responses to ADP, collagen and ristocetin were all either normal or increased in all three CRF groups, but thromboxane production in clotting blood was reduced. Plasma fibrinogen, C reactive protein and von Willebrand factor (vWF) were elevated in proportion to CRF. We found no evidence that defects in platelet aggregation or platelet interaction with vWF prolong the bleeding time in patients with progressive CRF.
Assuntos
Tempo de Sangramento , Plaquetas/fisiologia , Falência Renal Crônica/sangue , Testes de Função Plaquetária , Humanos , Tromboxano B2/sangueRESUMO
D dimer and other large fragments produced during the breakdown of crosslinked fibrin may be measured by enzyme immunoassay using monoclonal antibodies. In 91 patients with renal disease and varying degrees of renal dysfunction, plasma D dimer showed no correlation with renal function, whereas FgE antigen, a fibrinogen derivative which is known to be cleared in part by the kidney, showed a significant negative correlation with creatinine clearance. Plasma concentrations of D dimer were, however, increased in patients with chronic renal failure (244 +/- 31 ng/ml) (mean +/- SEM) and diabetic nephropathy (308 +/- 74 ng/ml), when compared with healthy controls (96 +/- 13 ng/ml), and grossly elevated in patients with acute renal failure (2,451 +/- 1,007 ng/ml). The results indicate an increase in fibrin formation and lysis, and not simply reduced elimination of D dimer by the kidneys, and are further evidence of activated coagulation in renal disease. D dimer appears to be a useful marker of fibrin breakdown in renal failure.
Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Nefropatias/sangue , Biomarcadores/sangue , Creatinina/sangue , Creatinina/urina , Humanos , Nefropatias/fisiopatologia , Falência Renal Crônica/sangue , Falência Renal Crônica/fisiopatologia , Testes de Função Renal , Peso Molecular , Fator Plaquetário 4/análiseRESUMO
1. The endothelium releases a number of vasoactive compounds, including the vasodilator prostaglandins, prostacyclin (PGI2) and prostaglandin E2 (PGE2) and endothelium-derived relaxing factor (EDRF), which play an important role in the regulation of vascular tone in the microcirculation. Nephrotoxicity is the major complication of cyclosporin (CS) therapy and is related to an increase in intrarenal vascular tone. Endothelial cell generation of PGI2 is inhibited by CS although this cannot fully explain the changes in vascular tone observed. We have investigated the possibility that EDRF-dependent vasodilatation is also affected by CS therapy in vivo. 2. CS nephrotoxicity was induced in rabbits with CS (15 mg kg-1 per day s.c. for 20 days (n = 6]; 6 rabbits were given CS vehicle (Veh) and 9 animals were studied without any treatment. Creatinine clearance fell significantly during treatment in the CS-treated rabbits (11.78 +/- 1.5 ml min-1, mean +/- s.e. mean, to 7.79 +/- 1.2 after 20 days treatment) but did not change in the vehicle-treated animals. 3. The responses to the endothelium-dependent (acetylcholine (ACh] and endothelium-independent (nitroprusside (NP) and PGI2) vasodilators were assessed in indomethacin-treated isolated perfused kidneys (IPKs) from untreated, CS- and Veh-treated animals. Vascular tone was induced with a constant infusion of noradrenaline 150 nM and the perfusion rate adjusted to produce a perfusion pressure of 90 mmHg. Perfusate flow rate (22.3 +/- 4.6 vs 20.4 +/- 3.1 ml min-1) and glomerular filtration rate (2.04 +/- 0.37 vs 1.88 +/- 0.16 nl min-1) did not differ between IPKs from CS- and Veh-treated animals. 4. The vasodilator response to ACh was reduced in the kidneys from CS-treated animals compared with those from untreated and Veh-treated animals (mean reduction 35.3 + 2.3% compared with Veh) as were the responses to both NP (42.8 + 3.6%) and PGI2 (27.7 + 7.4%). 5. This suggests that CS nephrotoxicity is not mediated via an effect on endothelium-dependent responses and that it is more likely that CS has a direct effect on vascular smooth muscle.
Assuntos
Ciclosporinas/farmacologia , Circulação Renal/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Creatinina/metabolismo , Epoprostenol/farmacologia , Técnicas In Vitro , Nefropatias/induzido quimicamente , Nefropatias/fisiopatologia , Tono Muscular/efeitos dos fármacos , Óxido Nítrico/farmacologia , Coelhos , Resistência Vascular/efeitos dos fármacosRESUMO
1. Endothelin-1 infusion (5-40 pmol kg-1 min-1) in the normal anaesthetized rabbit, produced a dose-dependent increase in mean arterial blood pressure (MAP) and reduced renal blood flow (RBF) and glomerular filtration rate (GFR), when compared with an equivalent infusion of physiological saline. 2. Endothelin, 20 pmol kg-1 min-1, was also assessed in animals pretreated with either indomethacin (2 mg kg-1), methylene blue (1.6 mg kg-1 h-1) or NG-monomethyl L-arginine (L-NMMA, 10 mg kg-1 h-1). 3. The effect of endothelin on MAP and RBF was enhanced (P = 0.05 and < 0.01 respectively) by the cyclo-oxygenase inhibitor, indomethacin, without any significant change in the effect on GFR. 4. Methylene blue and L-NMMA, inhibitors of endothelium-derived relaxant factor (EDRF), enhanced the effect of endothelin on each of the parameters measured (P < 0.01). 5. Our results are consistent with endothelin having a predominant effect on pre-glomerular vascular resistance to reduce GFR. Endothelin appears to stimulate the release of vasodilator prostanoids and EDRF which oppose its effects. Thus endothelin may have an important role in the complex control of GFR in the rabbit.
Assuntos
Aminoácido Oxirredutases/antagonistas & inibidores , Inibidores de Ciclo-Oxigenase/farmacologia , Endotelinas/farmacologia , Circulação Renal/efeitos dos fármacos , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Indometacina/farmacologia , Masculino , Azul de Metileno/farmacologia , Óxido Nítrico/farmacologia , Óxido Nítrico Sintase , Pulso Arterial/efeitos dos fármacos , Coelhos , ômega-N-MetilargininaRESUMO
1. The effects of endothelin infusion on renal vascular resistance (RVR), glomerular filtration rate (GFR) and the interaction with locally generated endothelium-derived relaxant factor (EDRF) were studied in the rabbit isolated perfused kidney (IPK). For comparison the effects of infusions of angiotensin II (AII) and noradrenaline (NA) were also assessed. 2. Each kidney was perfused at a constant rate of 10 ml min-1 and alterations in RVR determined by measuring changes in perfusion pressure. GFR was determined by the clearance of [51Cr]-EDTA, using timed urine collections. 3. Endothelin (10(-11)-10(-9) M) produced a dose-related increase in RVR. Endothelin was approximately 30 times more potent in molar terms than AII and 500 times more than NA at inducing a 50 mmHg increase in perfusion pressure. 4. Endothelin appeared to be a weak inducer of EDRF release in the IPK as EDRF inhibitors methylene blue (10 microM) or haemoglobin (10 microM) only slightly augmented the increase in RVR at a given concentration of endothelin. In contrast the effect of NA on RVR was significantly increased by methylene blue (10 microM) whereas that induced by AII was not affected. 5. Endothelin infusion produced a significant, dose-dependent decrease in GFR of the IPK, contrasting with an increase in GFR during AII infusion and a minimal effect of NA on GFR. This supports evidence that AII is predominantly a constrictor of effernt glomerular arterioles and that NA constricts both afferent and efferent glomerular vessels. We suggest that the vasoconstrictive effect of endothelin in the kidney is predominantly preglomerular, which explains its effect on GFR.
Assuntos
Taxa de Filtração Glomerular/efeitos dos fármacos , Peptídeos/farmacologia , Circulação Renal/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Endotelinas , Hemoglobinas/fisiologia , Técnicas In Vitro , Azul de Metileno/farmacologia , Óxido Nítrico/farmacologia , Norepinefrina/farmacologia , CoelhosRESUMO
1. S-nitrosoglutathione (GSNO) is a potent and selective anti-platelet agent, despite the fact that its spontaneous rate of release of nitric oxide (NO) is very slow. Our aim was to investigate the mechanism of the anti-aggregatory action of GSNO. 2. The biological action of GSNO could be mediated by NO released from S-nitrosocystylglycine, following enzymatic cleavage of GSNO by gamma-glutamyl transpeptidase. The anti-aggregatory potency of GSNO was not, however, altered by treatment of target platelets with the gamma-glutamyl transpeptidase inhibitor acivicin (1 mM). gamma-Glutamyl transpeptidase is not, therefore, involved in mediating the action of GSNO. 3. The rate of breakdown of S-nitrosoalbumin was increased from 0.19 +/- 0.086 nmol min-1 to 1.52 +/- 0.24 nmol min-1 (mean +/- s.e.mean) in the presence of cysteine (P < 0.05, n = 4). Inhibition of platelet aggregation by S-nitrosoalbumin was also significantly increased by cysteine (P < 0.05, n = 4), suggesting that the biological activity of S-nitrosoalbumin is mediated by exchange of NO from the protein carrier to form the unstable compound cysNO. Breakdown of GSNO showed a non-significant acceleration in the presence of cysteine, from 0.56 +/- 0.22 to 1.77 +/- 0.27 nmol min-1 (mean +/- s.e.mean) (P = 0.064, n = 4), and its ability to inhibit platelet aggregation was not enhanced by cysteine. This indicates that the anti-platelet action of GSNO is not dependent upon transnitrosation to form cysNO. 4. Platelets pretreated with the copper (I)-specific chelator bathocuproine disulphonic acid (BCS), then resuspended in BCS-free buffer, showed resistance to the inhibitory effect of GSNO. These findings suggest that BCS impedes the action of GSNO by binding to structures on the platelet, rather than by chelating free copper in solution. 5. Release of NO from GSNO was catalysed enzymatically by ultrasonicated platelet suspensions. This enzyme had an apparent K(m) for GSNO of 12.4 +/- 2.64 microM and a Vmax of 0.21 +/- 0.03 nmol min-1 per 10(8) platelets (mean +/- s.e.mean, n = 5). It was inhibited by BCS, but not by the iron chelator bathophenathroline disulphonic acid, nor by acivicin. 6. We conclude that the stable S-nitrosothiol compound GSNO may exert its anti-platelet action via enzymatic, rather than spontaneous release of NO. This is mediated by a copper-dependent mechanism. The potency and platelet-selectivity of GSNO may result from targeted NO release at the platelet surface.
Assuntos
Plaquetas/efeitos dos fármacos , Glutationa/análogos & derivados , Compostos Nitrosos/farmacologia , Fenantrolinas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Soroalbumina Bovina/metabolismo , Análise de Variância , Animais , Plaquetas/metabolismo , Bovinos , Cobre/sangue , Cisteína/farmacologia , Glutationa/farmacologia , Humanos , Óxido Nítrico/metabolismo , S-Nitrosoglutationa , Soroalbumina Bovina/antagonistas & inibidoresRESUMO
1. The effect of copper on the activity of the S-nitrosothiol compounds S-nitrosocysteine (cysNO) and S-nitrosoglutathione (GSNO) was investigated, using the specific copper chelator bathocuproine sulphonate (BCS), and human washed platelets as target cells. 2. Chelation of trace copper with BCS (10 microM) in washed platelet suspensions reduced the inhibition of thrombin-induced platelet aggregation by GSNO; however, BCS had no significant effect on the anti-aggregatory action of cysNO. BCS inhibited cyclic GMP generation in response to both cysNO and GSNO. 3. The effect of BCS was rapid (within 30 s), and could be abolished by increasing the platelet concentration to 500 x 10(9) l-1. 4. In BCS-treated platelet suspensions, the addition of Cu2+ ions (0.37-2.37 microM) led to a restoration of both guanylate cyclase activation and platelet aggregation inhibition by GSNO. 5. The anti-aggregatory activity of GSNO was reduced in a concentration-dependent manner by the copper (I)-specific chelators BCS and neocuproine, and to a smaller extent by desferal. No effect was observed with the copper (II) specific chelator, cuprizone, the iron-specific chelator, bathophenanthroline sulphonate, or the broader-specificity copper chelator, D-penicillamine. 6. In both BCS-treated and -untreated platelet suspensions, cys NO was more potent than GSNO as a stimulator of guanylate cyclase. In BCS-treated platelet suspensions there was no significant difference between the anti-aggregatory potency of cysNO and GSNO; however, in untreated suspensions, GSNO was significantly more potent than cysNO. Thus, when copper was available, GSNO produced a greater inhibition of aggregation than cysNO, despite being a less potent activator of guanylate cyclase. 7. The breakdown of cysNO and GSNO was measured spectrophotometrically by decrease in absorbance at 334 nm. In Tyrode buffer, cysNO (10 microM) broke down at a rate of 3.3 microM min-1. BCS (10 microM)reduced this to 0.5 microM min-1. GSNO, however, was stable, showing no fall in absorbance over a period of 7 min even in the absence of BCS.8. We conclude that copper is required for the activity of both cysNO and GSNO, although its influence on anti-aggregatory activity is only evident with GSNO. The stimulatory effect of copper is unlikely to be explained solely by catalysis of S-nitrosothiol breakdown. The enhancement by copper of the anti-aggregatory activity of GSNO, relative to cysNO, suggests that copper may be required for biological activity of GSNO which is independent of guanylate cyclase stimulation.
Assuntos
Plaquetas/efeitos dos fármacos , Quelantes/farmacologia , Cobre/fisiologia , Cisteína/análogos & derivados , Glutationa/análogos & derivados , Compostos Nitrosos/antagonistas & inibidores , Inibidores da Agregação Plaquetária/farmacologia , S-Nitrosotióis , Plaquetas/metabolismo , Cobre/sangue , Cobre/farmacologia , GMP Cíclico/biossíntese , Cisteína/antagonistas & inibidores , Cisteína/farmacologia , Glutationa/antagonistas & inibidores , Glutationa/farmacologia , Humanos , Técnicas In Vitro , Ferro/sangue , Compostos Nitrosos/farmacologia , Fenantrolinas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , S-NitrosoglutationaRESUMO
Our studies have shown that CS inhibits PGI2 production in HUVEC, that this inhibition is not overcome when exogenous AA is supplied, that the inhibitory action of CS is proximal to PGI2 synthetase and finally that there is abundant free AA available in membrane phospholipids of CS treated HUVEC [4,5]. In conclusion, CS does not appear to inhibit PGI2 synthesis by reducing the availability of free AA in the endothelial cell membrane. Although CS appears to inhibit cyclo-oxygenase, we can not exclude an additional effect on acyltransferase.
Assuntos
Ácidos Araquidônicos/metabolismo , Ciclosporinas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Epoprostenol/biossíntese , Lipídeos de Membrana/metabolismo , Fosfolipídeos/metabolismo , 6-Cetoprostaglandina F1 alfa/biossíntese , Ácido Araquidônico , Células Cultivadas , Depressão Química , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , HumanosRESUMO
We have found glomerular capillary thrombi or afferent arteriolar thrombosis in eight renal biopsy specimens from seven renal allograft recipients. All patients were receiving cyclosporin and prednisolone. Biopsies were performed either routinely one and four weeks after transplantation or during periods of renal dysfunction. None of the patients whose biopsy material contained glomerular thrombi was considered, in retrospect, to have been undergoing rejection at the time of biopsy. Thrombi consisted of finely granular material partially obstructing glomerular capillaries. By light microscopy the staining characteristics of the thrombi were compatible with platelet-fibrin aggregates, and this was confirmed by immunoperoxidase examination. Such thrombi have not previously been seen in biopsy material from patients treated with prednisolone and azathioprine, except rarely associated with acute vascular injection. In none of these patients was there haematological evidence of the haemolytic uraemic syndrome as has been reported in bone marrow recipients treated with cyclosporin.
Assuntos
Ciclosporinas/efeitos adversos , Glomérulos Renais/patologia , Transplante de Rim , Trombose/induzido quimicamente , Adulto , Plaquetas/patologia , Feminino , Fibrina , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/patologia , Prednisolona/uso terapêutico , Trombose/patologiaRESUMO
In a prospective study of renal dysfunction in 60 consecutive allograft recipients treated with cyclosporin and prednisolone routine renal biopsies at one week and one month after transplantation, as well as for all episodes of renal dysfunction, were performed. The one year graft survival of this group was 88%. In a retrospective clinical analysis of these patients 35 episodes of dysfunction due to rejection, defined by a response to antirejection treatment alone, and 30 episodes due to cyclosporin nephrotoxicity, defined by a response to reduction in cyclosporin dose alone, were identified. The morphological findings from these biopsies were compared with 20 samples from routine biopsies taken from patients with stable renal function. All patients diagnosed as having rejection had a diffuse, interstitial mononuclear cell infiltrate (32 of 35) or arteritis (19 of 35), or both. In contrast, focal mononuclear cell infiltrates were common in both patients with nephrotoxicity and those with stable function (17 of 30 and 14 of 20, respectively). There were no important differences between biopsies from those with nephrotoxicity and those with stable function, except that arteriolar hyalinosis was considerably more common in the nephrotoxic patients than in those with stable function. Many patients with stable function were, in retrospect, in a state of stable mild nephrotoxicity. In our experience rejection should only be diagnosed when there is at least a diffuse interstitial infiltrate or an arteritis. Focal mononuclear cell infiltrates do not denote rejection. The development of arteriolar lesions in the absence of rejection is indicative of nephrotoxicity.
Assuntos
Ciclosporinas/efeitos adversos , Rejeição de Enxerto , Nefropatias/induzido quimicamente , Transplante de Rim , Adolescente , Adulto , Idoso , Artérias/patologia , Arteríolas/patologia , Creatinina/sangue , Diagnóstico Diferencial , Humanos , Rim/irrigação sanguínea , Rim/patologia , Nefropatias/diagnóstico , Nefropatias/patologia , Glomérulos Renais/patologia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/patologiaRESUMO
BACKGROUND: In uremia, diminished reactive oxygen intermediate (ROI) production is an important consequence of impaired neutrophil function. We have studied the effect of guanidino compounds, known uremic toxins, on neutrophil ROI production in vitro. METHODS: Neutrophils from healthy volunteers were exposed for three hours to individual or mixed guanidino compounds (GCmix) at concentrations encountered in uremic plasma. After removal of guanidino compounds, neutrophils were activated by adhesion, N-formyl-methionyl-leucyl-phenyalanine (fMLP), phorbol 12-myristate 13-acetate (PMA), or opsonized zymosan, and superoxide production was measured by lucigenin chemiluminescence (CL). The direct effect of guanidino compounds on superoxide production in activated neutrophils was also measured. The energy status (ATP and creatine phosphate), antioxidant status (total glutathione), and glycolytic flux (lactate production) were measured. RESULTS: The GCmix pretreatment decreased the superoxide production in activated neutrophils (fMLP or zymosan) by 50% (P < 0.01) and the ATP concentration by 60% (P < 0.05), and it inhibited glycolytic flux (lactate production) by 45% (P < 0.01), but did not alter glutathione concentration. Simultaneous exposure to GCmix and activation did not inhibit nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in cell lysates, but inhibited superoxide formation in zymosan-activated intact neutrophils, and this inhibition was reversed following removal of the guanidino compounds. CONCLUSION: Guanidino-succinate, -propionate, and -butyrate were individually as potent as the GCmix. Inhibition of neutrophil superoxide generation by guanidino compounds results from a depressed energy status. Uremic concentrations of guanidino compounds significantly inhibit neutrophil metabolism, and this has serious implications for their function in host defense.
Assuntos
Guanidinas/sangue , Guanidinas/toxicidade , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Superóxidos/sangue , Uremia/sangue , Trifosfato de Adenosina/sangue , Metabolismo Energético/efeitos dos fármacos , Humanos , Técnicas In Vitro , Ácido Láctico/sangue , Fosfocreatina/sangue , Espécies Reativas de Oxigênio/metabolismoRESUMO
Some features of the vascular and glomerular pathology of primary antiphospholipid syndrome (APS) are well recognized, but we describe novel glomerular ultrastructural changes that we consider to be pathognomonic of APS. Renal biopsies from eight patients with APS were examined by light and electron microscopy. All had anti-cardiolipin antibodies, and the clinical presentation ranged from fulminant multi-system disease to isolated proteinuria. By light microscopy, the hexamine silver stain showed a combination of glomerular basement membrane wrinkling and reduplication. By electron microscopy, redundant, wrinkled segments of basement membrane were accompanied by a 'new' straighter thin basement membrane adjacent to the endothelium. In two cases the presence of these antibodies was not suspected clinically, and there was no clinical history or evidence of a thrombotic microangiopathy. We describe a distinctive glomerular lesion that represents an unexplained form of endothelial injury in this syndrome.
Assuntos
Síndrome Antifosfolipídica/patologia , Glomérulos Renais/patologia , Adulto , Idoso , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Arteríolas/patologia , Membrana Basal/patologia , Biópsia , Endotélio/imunologia , Endotélio/patologia , Feminino , Humanos , Glomérulos Renais/irrigação sanguínea , Túbulos Renais/patologia , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Artéria Renal/patologia , Estudos RetrospectivosRESUMO
Fifteen patients with the loin pain and haematuria syndrome (LPH) were compared with 10 patients with complicated renal stone disease referred to the same tertiary centre and matched for age, sex and duration of illness. LPH patients had a history of three times more medically unexplained somatic symptoms other than loin pain (p < 0.01) and a higher proportion took analgesics regularly (p < 0.01). The onset of pain was associated with an adverse psychologically important life-event in eight of the LPH patients but in none of the controls (p < 0.02). LPH patients more frequently recalled serious parental illness and disability in childhood (p < 0.001) than controls, and a higher proportion felt responsible for causing or alleviating parental illness or distress (p < 0.05). LPH subjects scored higher in the 'paternal care' dimension of the Parental Bonding Instrument (p < 0.05). No difference was found between LPH patients and controls in terms of current depression and anxiety but both groups exhibited high rates of lifetime depression. LPH patients expressed lower levels of anger and hostility (p < 0.002) than did controls. Our observations suggest that psychological factors are of major importance in the aetiology of LPH, which may represent a type of somatoform pain disorder.
Assuntos
Dor nas Costas/psicologia , Hematúria/psicologia , Transtornos Somatoformes/psicologia , Adulto , Ansiedade , Depressão , Relações Pai-Filho , Feminino , Humanos , Acontecimentos que Mudam a Vida , Masculino , Pessoa de Meia-Idade , Relações Mãe-Filho , Estresse PsicológicoRESUMO
Twenty-two patients with heart, lung or heart and lung transplants maintained on cyclosporin for periods ranging from 3 months to 10 years developed renal insufficiency which was investigated by renal biopsy. The histopathological changes were: (i) severe vascular and glomerular damage due to thrombotic microangiopathy (TM); (ii) a form of focal segmental glomerulosclerosis (FSGS); (iii) glomerular ischaemia. Rather than being separate entities, these changes appeared to represent a spectrum of pathology, some biopsies showing all three forms of glomerular injury. In all cases the glomerular changes were accompanied by arteriolar and arterial pathology, and we identified novel ultrastructural changes in the arteriolar endothelial basal lamina. Tubular atrophy was a consistent feature, the severity of which reflected the severity of the glomerular sclerosis, and which appeared to be a consequence of glomerular loss. Our findings are consistent with the nephrotoxic effects of cyclosporin being mediated chiefly via damage to preglomerular vessels and glomerular capillary endothelium. From an analysis of the clinical aspects of these cases, the effects of cyclosporin appear to be to some extent idiosyncratic, and therefore not entirely preventable, but strict monitoring of blood cyclosporin levels is essential to minimize the risk of permanent renal damage. Monitoring urinary protein in addition to plasma creatinine may detect the onset of FSGS, as proteinuria precedes creatinine elevation.