Renal amyloidosis in intravenous drug users.

BACKGROUND: Intravenous drug abuse is associated with a wide variety of acute and chronic medical complications. The increased longevity of drug users has seen the emergence of new diseases as a result of chronic bacterial and viral infection. We recently observed an increase in the number of cases of renal amyloidosis among intravenous drug users in central London. AIM: To describe here the demographic and clinical characteristics of such patients. METHODS: Patients were identified retrospectively from computerized patient renal biopsy records at University College London and Royal Free Hospitals from 1990-2005. Clinical information was collected from patient hospital records. RESULTS: We identified 20 cases of AA amyloidosis; 65% occurred between January 2000 and September 2005. All were proteinuric (mean 7.3 g/l, range 0.5-14.8 g/l) and 13 required dialysis within 1 month of diagnosis. Of the remaining seven, four developed end-stage renal failure after mean follow-up of 16 months (range 6-30). Nine died, with median survival of 19 months (range 1-62); all deaths were due to sepsis. DISCUSSION: Secondary AA amyloidosis is a serious complication of chronic soft tissue infection in intravenous drug users in central London. Affected individuals invariably presented with nephrotic range proteinuria and advanced renal failure. Treatment options are limited and the outcome for such patients on renal replacement was poor. Cross-disciplinary strategies are needed to prevent this serious complication of long-term intravenous drug abuse.

Pre-conditioning with adenosine leads to concentration-dependent infarct size reduction in the isolated rabbit heart.

Adenosine (ADO) has a cardioprotective effect in ischemia-reperfusion injury when administered both prior to ischemia and during reperfusion. ADO has also been implicated in the mechanism of ischemic pre-conditioning. The aim of this study was to investigate whether there was a concentration-response between the administration of ADO prior to ischemia-reperfusion and reduction in subsequent infarct size. Rabbit isolated perfused hearts were subjected to 45 min ischemia and 180 min reperfusion following pre-treatment with either Krebs Henseleit buffer alone or buffer containing ADO at a range of concentrations (3 micro M-100 micro M) for 5 min followed by 5 min perfusion with buffer. Infarct/risk ratios were significantly reduced in hearts pre-perfused with higher (> 3 micro M) concentrations of ADO (Control, 58.5 +/- 1.5%; 3 micro M ADO, 51.6 +/- 3.0% ; 6 micro M ADO, 44.1% +/- 2.0%; 10 micro M ADO, 33.3 +/- 1.9%; 20 micro M ADO, 26.6 +/- 0.9%; 50 micro M ADO, 21.6 +/- 3.5%; 100 micro M ADO, 23.0 +/- 0.6%). We conclude that pre-treatment with ADO leads to a concentration-dependent reduction in infarct size.

Effect of ouabain on endothelium-dependent relaxation of human resistance arteries.

Inhibition of active sodium transport by ouabain was found to cause concentration- and time-dependent impairment of acetylcholine-induced relaxation in human resistance arteries with a significant effect at 100 pM. The reduced acetylcholine response was attributable to inhibition of the NG-monomethyl L-arginine-sensitive but not the indomethacin-sensitive component of relaxation. Relaxation by sodium nitroprusside was not affected by ouabain, suggesting that inhibition of sodium transport, directly or indirectly, must affect synthesis or release of endothelium-derived relaxing factor rather than its effector pathway. These results do not support the existence of an additional endothelium-derived relaxing factor other than endothelium-derived relaxing factor, which is dependent on sodium pump activity. The finding that inhibition of sodium transport has a profound effect on vascular relaxation may have implications in the pathogenesis of certain forms of hypertension.

Effects of ouabain and low sodium on contractility of human resistance arteries.

Earlier work with rat arteries has resulted in a widely held assumption that resistance artery smooth muscle will not contract on exposure to a reduced transplasmalemmal sodium gradient. In view of the well-recognized low sensitivity of rat tissue to cardiac glycosides, we have investigated the effects of altering the transplasmalemmal sodium gradient on vascular smooth muscle tone by using human resistance arteries. Incubation of arteries in low sodium or in ouabain to inhibit active sodium efflux for 1 hour increased the contractile response to caffeine stimulation; this finding indicated enhanced calcium buffering by the sarcoplasmic reticulum. Prolonged incubation in ouabain in the presence of phentolamine or diltiazem resulted in a concentration-dependent increase in the tone of resting human resistance arteries. Reduction of the transplasmalemmal sodium gradient by incubation in low sodium buffer effected an increase in tone similar to that obtained in the presence of ouabain. These results suggest that alteration of the transplasmalemmal sodium gradient may increase the vascular smooth muscle tone of human resistance arteries by altering intracellular calcium handling. This is a new finding in human resistance arteries and may involve inhibition and, indeed, reversal of sodium-dependent calcium efflux. A concentration-dependent potentiation of tone was found after the addition of ouabain to submaximally activated arteries. Sodium-calcium exchange may also play a pivotal role in this mechanism.

Renal scintigraphy in acute scleroderma: report of three cases.

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.

Management of bowel obstruction in patients with abdominal cancer.

OBJECTIVE: To determine the value of operation in patients with bowel obstruction caused by recurrent abdominal cancer. DESIGN: Retrospective case review. SETTING: The University of Connecticut Health Center, Farmington. PATIENTS: Ninety-eight patients admitted with a diagnosis of bowel obstruction and malignant neoplasm between November 1, 1987, and June 30, 1995. RESULTS: Data for 75 patients who developed a bowel obstruction within 5 years of a malignant diagnosis were analyzed. Forty-six patients (61%) were treated operatively and 29 (39%) were treated nonoperatively. The operative group included 32 patients (70%) whose obstruction was caused by carcinomatosis; 6 (19%) of these 32 patients had had at least 1 episode of previous obstruction requiring hospitalization. They had a 22% in-hospital mortality, stayed an average of 21 days in the hospital, and survived 7 +/- 6 months (mean +/- SD) after discharge; 5 (16%) had at least 1 episode of postoperative obstruction that required hospitalization. After discharge from the hospital, 53% had an excellent or good quality of life (assessed retrospectively). Of the 29 patients in the nonoperative group, 16 (55%) had carcinomatosis. These 16 patients had a 38% in-hospital mortality (6 of 16), stayed an average of 10 days in the hospital, and survived a mean of 13 +/- 9 months; 3 (19%) had at least 1 episode of recurrent obstruction requiring hospitalization. After discharge from the hospital, 6 (37%) had an excellent or good quality of life. CONCLUSION: The value of operative intervention for bowel obstruction in patients with cancer is derived from the possibility of a benign cause, not alleviation of the consequences of carcinomatosis.

Low dose dopamine infusion reduces renal tubular injury following cardiopulmonary bypass surgery.

BACKGROUND: The use of dopamine to protect the kidneys against hypoperfusion injury remains controversial with little clinical evidence of benefit and increasing concerns regarding safety. In this double-blind, prospective, randomised study, we investigated the effect of dopamine infusion (2.5 microg/kg/min) on glomerular filtration rate (GFR) and tubular injury in patients undergoing routine cardiopulmonary bypass (CPB). METHODS: Forty eight patients were randomly assigned to receive intravenous dopamine or saline from induction of anaesthesia until 48 hours post-operatively. There were no differences in mean age, bypass time or pre-op creatinine in the 36 patients (33 men) who completed the study. 51Cr-EDTA GFR (ml/min/1.73 m2) was measured pre-operatively and on day 5 only. Urinary markers of tubular injury (albumin, N-acetyl glucosaminidase, NAG; retinol binding protein, RBP) were measured pre-operatively, and on days 1, 2 and 5. RESULTS: GFR was preserved equally in both groups. All patients demonstrated significant tubular injury but urinary levels of NAG and RBP were lower in the dopamine group (41%, p=0.057 and 41%, p=0.007, respectively) on the first post-operative day. CONCLUSION: We conclude that low dose dopamine infusion may reduce renal tubular injury following CPB in patients with normal or near normal baseline renal function.

Renal disease and the heart.

Cardiovascular disease is responsible for significant morbidity and mortality in renal failure with increased prevalence of hypertension, left ventricular hypertrophy, ischaemic heart disease and valve disease. Optimum blood pressure control is fundamental to the management of these patients but the role of secondary prevention remains poorly defined.

Cyclosporin nephrotoxicity following cardiac transplantation.

The greatest change in GFR in response to treatment with cyclosporin occurs in the first 3-6 months and the magnitude of the decrement in the first year (or perhaps the first few months) appears to be a vital indicator of future problems. However, the apparent stabilization of renal function, particularly when monitored only by plasma creatinine, can conceal progressive tubulointerstitial injury, and increasing proteinuria is an ominous sign. Although lower doses of cyclosporin and careful monitoring of renal function may be helpful, there is at present no pharmacological intervention to protect or reverse the reduction in GFR that occurs. We believe that the vascular lesion induced by cyclosporin is fundamental, with early and initially reversible cyclosporin-induced vasospasm leading to progressive vascular damage with activation of endothelial cells and increased platelet interactions. Amongst other determinants, the renal response to this vasculopathy will depend on the balance between the presence of vasoactive factors with the vasoconstrictors promoting interstitial fibrosis and the vasodilators inhibiting proliferation. It is likely that the kidneys of heart-transplant recipients are chronically ischaemic and as a consequence their renin-angiotensin systems massively activated, which may further sensitize their kidneys to cyclosporin. Overproduction of angiotensin II, associated with the DD ACE genotype, has already been associated with poor prognosis in diabetic and IgA nephropathy. It is interesting to speculate that this ACE genotype, which is associated with a poor outcome in non-ischaemic heart disease can influence renal sensitivity to cyclosporin and predict the development of morphological injury. Extension of these experimental findings into the clinical arena with a placebo-controlled trial of early introduction of ACE inhibitor therapy in recipients of cardiac transplants would be timely.

Renal nuclear medicine: can it survive the millennium?

Much of the progress in renal nuclear medicine has been driven by technological development, but without rigorous assessment the value of some of these studies has been overestimated. The only tests to achieve gold standard status are the isotopic GFR, the DMSA renogram to detect cortical abnormalities and the captopril renogram when used to define those hypertensive patients who will not benefit from renovascular intervention. Consensus guidelines must be followed and routine protocols for combination tests must be developed, but even so isotopic renography is likely to be overtaken by competing technologies which can provide one test to give simultaneous information about both structure and function.

Effect of NG-monomethyl-L-arginine on endothelium-dependent relaxation of human subcutaneous resistance arteries.

1. Using a myograph to measure isometric tension, we have looked at the action of NG-monomethyl-L-arginine on the endothelium-dependent relaxation of human subcutaneous resistance arteries. 2. NG-Monomethyl-L-arginine, the novel inhibitor of endothelium-derived relaxing factor synthesis, caused concentration-dependent but only partial inhibition of maximal relaxation induced by acetylcholine in human subcutaneous resistance arteries. 3. The inhibitory action of NG-monomethyl-L-arginine on acetylcholine-induced maximal relaxation was partially reversed by incubation of the arteries in equimolar concentrations of L-arginine and NG-monomethyl-L-arginine. Subsequent incubation in L-arginine led to further reversal, but this was no greater than with incubation in physiological saline. 4. A component of acetylcholine-induced relaxation was sensitive to indomethacin, suggesting that this response is mediated by prostanoids as well as by endothelium-derived relaxing factor. 5. NG-Monomethyl-L-arginine did not increase the tension of resting human subcutaneous resistance arteries. NG-Monomethyl-L-arginine did enhance the contractile response to noradrenaline, possibly due to inhibition of release of endothelium-derived relaxing factor resulting from stimulation of alpha 2-adrenoreceptors on the endothelial cells.

The true clinical significance of renography in nephro-urology.

Isotopic renography is a non-invasive technique used routinely by the clinician to provide information about kidney structure and function. Whilst there is no doubt of its value in the accurate measurement of glomerular filtration rate and in the detection of parenchymal abnormalities, its role in the diagnosis of renovascular disease (especially in patients with renal insufficiency), the exclusion of obstruction and the evaluation of the patient with either acute renal failure or renal transplant dysfunction remains unproven. In part, this reflects a failure to standardise protocols and rigorously evaluate diagnostic techniques. Recent developments in ultrasound, computerised X-ray tomography and nuclear magnetic resonance now present the clinician with rival techniques and emphasise the need for the clinical development of isotopic renography.

Effects of sodium-transport inhibition in human resistance arteries.

It is hypothesized that endogenous inhibitors of active sodium transport may lead to an increase in peripheral vascular resistance. From studies in animal conduit arteries there is substantial evidence that cardiac glycosides may increase tension. A number of studies from our laboratory demonstrate that inhibition of active sodium transport may also increase tension in human resistance arteries, and that reduced Ca efflux via Na/Ca exchange could be a contributory mechanism. Further experiments also have suggested that endogenous inhibitors of sodium transport could lead to an increase in peripheral vascular resistance by reducing endothelium-dependent relaxation.

Low-concentration ouabain does not inhibit noradrenaline-induced contraction of human resistance arteries.

1. Using a Mulvany-Halpern myograph to measure changes in isometric tension, we have investigated the effect of ouabain on noradrenaline-induced contraction of human subcutaneous resistance arteries. 2. Low concentrations of ouabain (10 nmol/l or less) were shown not to alter vascular smooth muscle contractility or sensitivity to noradrenaline. 3. In contrast, higher concentrations of ouabain (100 nmol/l or more) were found to depress vascular smooth muscle contractility and to reduce the sensitivity of the noradrenaline concentration-response relationship. 4. These findings may have implications regarding the presence of an endogenous inhibitor of the sodium pump in essential hypertension and in pregnancy-associated hypertension.

Inhibition of nitric oxide synthesis reduces infarct size by an adenosine-dependent mechanism.

BACKGROUND: Nitric oxide (NO) is both a potent endogenous vasodilator with potential to attenuate ischemia-reperfusion injury and a mediator of tissue injury. The aim of the present study was to investigate the mechanism by which prior inhibition of NO synthesis can lessen ischemia-reperfusion injury in the isolated rabbit heart. METHODS AND RESULTS: We examined the effects of inhibition of NO synthesis on infarct size using a model of coronary artery ligation in isolated rabbit hearts perfused at a constant flow rate of 35 mL/min. Infarct size averaged 65% of the zone at risk after 45 minutes of ischemia and 180 minutes of reperfusion. The addition of 30 mumol/L NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, to the perfusate reduced the infarct-to-risk (I/R) ratio to an average of 41% (P < .05 versus control). This effect was abolished by pretreatment with 75.5 mumol/L 8-p-sulfophenyl theophylline (SPT), an adenosine receptor antagonist (I/R ratio, 63%). Ischemic preconditioning (5 minutes of ischemia and 10 minutes of reperfusion) before 45 minutes of ischemia and 3 hours of reperfusion reduced the I/R ratio to an average of 21%, and this was not augmented by pretreatment with L-NAME (I/R ratio, 20%). However, all protection due to preconditioning and L-NAME was lost in hearts pretreated with SPT (I/R ratio, 59%). In a separate set of experiments, adenosine concentration in the coronary perfusate and myocardial lactate concentrations were measured. Treatment with L-NAME increased the average adenosine concentration in the perfusate from 5.7 mumol/L per 100 g of heart (control) to a peak of 24.0 mumol/L per 100 g of heart; however, there was no effect on average myocardial lactate concentration (control, 4.6 mumol/g dry wt; L-NAME, 5.5 mumol/g dry wt). In contrast, after 5 minutes of global ischemia, the average adenosine concentration peaked at 139.0 mumol/L per 100 g of heart, and the average myocardial lactate concentration increased to 27.1 mumol/g dry wt. CONCLUSIONS: Infarct size limitation after inhibition of NO synthesis shares a common mechanism with that of ischemic preconditioning and is dependent on the release of adenosine. However, in this model, adenosine release after inhibition of NO synthesis is not secondary to myocardial ischemia. The protection of the heart against ischemic injury by adenosine appears to be concentration dependent.

Evaluation of therapy for cast nephropathy: failure of colchicine to alter urinary Tamm Horsfall glycoprotein excretion in normal subjects.

Tamm Horsfall glycoprotein (THG) is a major constituent of renal tubular casts including the light chain casts of myeloma. Animal studies suggest that the anti-inflammatory agent colchicine reduces urinary THG excretion and prevents light chain cast formation. Six normal male subjects were given therapeutic doses of colchicine (0.5 mg twice daily for 6 days) and excretion of THG, albumin, creatinine and N-acetyl glucosaminidase (NAG) was determined. Colchicine therapy had no effect on the urinary excretion of THG, albumin or NAG or on renal function as assessed by creatinine clearance. This suggests that colchicine will not be a useful therapeutic adjunct to the treatment of light-chain nephropathy.

Acute hypernatraemia during bicarbonate-buffered haemodialysis.

Five patients on maintenance haemodialysis were exposed to varying degrees of hypernatric dialysate, leading to acute hypernatraemia (plasma sodium concentrations 158 mmol/l to 179 mmol/l). With the exception of one patient, who developed pulmonary oedema, symptoms were minimal and in each case hypernatraemia was corrected without residual complications. The hypernatric dialysate resulted from a granular and less soluble batch of sodium bicarbonate powder. The extra effort required to dissolve the powder caused CO2 to be shaken out of solution, producing sodium carbonate and raising the pH. Mixing calcium from the 'acid' concentrate with excess carbonate in the 'bicarbonate' concentrate led to rapid precipitation of calcium carbonate on the conductivity monitoring cells. Dialysate conductivity was incorrectly sensed as low by the coated conductivity cells, so that an increasing amount of 'acid' concentrate, with its accompanying electrolytes, was delivered to the patient. When the granular powder was ground to a fine powder, passed through a 125 microns sieve and gently dissolved, the machine operated normally. We recommend that sodium bicarbonate powder is supplied with a sieve size no greater than 125 microns, kept dry to prevent the formation of large crystals, and dissolved gently.

Ouabain and responses to endothelium-dependent vasodilators in the human forearm.

Ouabain inhibits endothelium-dependent vascular relaxation in vitro, but has not been studied in this regard in vivo. We have therefore measured blood flow responses to carbachol, bradykinin and sodium nitroprusside (endothelium-dependent and endothelium-independent vasodilators) infused into the brachial artery with and without co-infusion of ouabain (2 micrograms min-1). Six healthy male volunteers were each studied on two occasions. Ouabain reduced basal forearm blood flow, by 18.0 +/- 4.1% (mean +/- s.e. mean, 2P less than 0.05), but had no significant effect on responses to any of the three vasodilators. These results indicate that effects of ouabain on endothelium-dependent relaxation in vitro must be interpreted with caution.