Thrombosis in systemic lupus erythematosus. Relation to the presence of circulating anticoagulants.

In an earlier report on the kidney in systemic lupus erythematosus (SLE), we described a subset of patients with circulating anticoagulants; many had glomerular and arteriolar thrombosis in the absence of necrosis and subendothelial deposits. The present study extends these observations to a larger group of patients with SLE and a circulating anticoagulant, and compares its findings with those in patients with SLE without evidence of an anticoagulant. It demonstrates (1) a higher prevalence of clinically recognizable thrombotic events in the venous and arterial circulations in patients with SLE and a detectable anticoagulant; (2) a probable shortening in life span; (3) a higher prevalence of glomerular thrombi; (4) elevated levels of factor VIII antigen and von Willebrand factor; and (5) significantly lower platelet counts and decreased in vitro platelet aggregation in response to adenosine diphosphate, epinephrine, and collagen. Since prednisone treatment often results in improvement or disappearance of a prolonged partial thromboplastin time, the test most commonly used for screening of a circulating anticoagulant, we suggest that the prevalence of this abnormality may be underestimated in patients with SLE.

Ancrod in systemic lupus erythematosus with thrombosis. Clinical and fibrinolysis effects.

A patient with systemic lupus erythematosus had severe hypertension, rapidly worsening renal failure, and multiple successive thrombotic cerebrovascular and retinal lesions develop. In a kidney biopsy specimen luminal thrombi were demonstrated in arteries and arterioles, without vasculitic or inflammatory changes. The patient's plasma was markedly deficient in both prostacyclin stimulating factor (PSF) and vascular plasminogen activator (VPA), and also contained a potent inhibitor of in vitro urokinase-induced fibrinolysis. Treatment with ancrod resulted in striking reversal of the progressive renal damage and clinical recovery from the thrombotic cerebrovascular and retinal lesions. This clinical improvement was associated with improved renal histologic appearance, correction of the PSF and VPA deficiencies, and disappearance of the urokinase inhibitor. Possible mechanisms of action of ancrod are discussed.

Pancreatitis in patients with end-stage renal disease.

In a population of 716 patients with end-stage renal disease (ESRD), 46 patients (6.4%) were identified as having pancreatitis. Pancreatitis was significantly more common in those with alcohol abuse, systemic lupus erythematosus (SLE), and polycystic kidney disease. It was not significantly associated with hyperlipidemia, biliary tract disease, or hypercalcemia. Acute pancreatitis occurring before the patient developed ESRD was mainly alcohol-related and did not appear to be a significant risk factor for future episodes of pancreatitis during dialysis. Chronic calcific pancreatitis diagnosed before ESRD was almost invariably due to alcohol abuse, and tended to be a marker for recurrent acute exacerbation after development of ESRD, whether alcohol consumption continued or not. Pancreatitis occurring for the first time after ESRD in patients on dialysis was generally benign, and was usually accompanied by an uneventful recovery and few recurrent episodes. However, a significant elevation of the calcium x phosphate product was observed in these patients, occurring in about half the patients without any known precipitating factor. After kidney transplantation, the development of pancreatitis was associated with higher morbidity and mortality. Chronic calcific pancreatitis diagnosed after ESRD occurred only in patients with SLE; reported here for the first time, it may be a manifestation of long-standing disease, chronic steroid therapy, or both.

A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients.

Current phosphate binders used in hemodialysis patients include calcium-based binders that result in frequent hypercalcemia and aluminum-based binders that result in total body aluminum accumulation over time. This investigation describes the use of a calcium- and aluminum-free phosphate-binding polymer in hemodialysis patients and compares it with a standard calcium-based phosphate binder. An open-label, randomized, crossover study was performed to evaluate the safety and effectiveness of sevelamer hydrochloride in controlling hyperphosphatemia in hemodialysis patients. After a 2-week phosphate binder washout period, stable hemodialysis patients were administered either sevelamer or calcium acetate, and the dosages were titrated upward to achieve improved phosphate control over an 8-week period. After a 2-week washout period, patients crossed over to the alternate agent for 8 weeks. Eighty-four patients from eight centers participated in the study. There was a similar decrease in serum phosphate values over the course of the study with both sevelamer (-2.0 +/- 2.3 mg/dL) and calcium acetate (-2.1 +/- 1.9 mg/dL). Twenty-two percent of patients developed a serum calcium greater than 11.0 mg/dL while receiving calcium acetate, versus 5% of patients receiving sevelamer (P < 0.01). The incidence of hypercalcemia for sevelamer was not different from the incidence of hypercalcemia during the washout period. Patients treated with sevelamer also sustained a 24% mean decrease in serum low-density lipoprotein cholesterol levels. Sevelamer was effective in controlling hyperphosphatemia without resulting in an increase in the incidence of hypercalcemia seen with calcium acetate. This agent appears quite effective in the treatment of hyperphosphatemia in hemodialysis patients, and its usage may be advantageous in the treatment of dialysis patients.

Deficiency of a plasma factor stimulating vascular prostacyclin generation in patients with lupus nephritis and glomerular thrombi and its correction by ancrod: in-vivo and in-vitro observations.

Glomerular thrombi occur frequently in active lupus nephritis. Their presence has been correlated with low platelet counts and with subsequent development of glomerular sclerosis. We have examined the plasma PGI2 generating capacity of 8 patients with active lupus nephritis with thrombi that were to undergo defibrination therapy with ancrod. PGI2 generation by these plasma samples was significantly decreased as compared both to normals and to 6 individuals with lupus nephritis and no glomerular thrombi. Significant improvement in the capacity to generate PGI2 was seen in the post-ancrod treatment plasma samples. the pathogenesis of this defect is discussed.

Diffuse proliferative lupus nephritis: long-term observations in patients treated with ancrod.

Twenty-two patients with histologically demonstrated diffuse proliferative lupus nephritis (DPLN) and glomerular thrombosis received a 14-day course of ancrod, followed in most by nitrogen mustard (mechlorethamine hydrochloride) 0.4 mg/kg. Many were referred when renal function was deteriorating despite large doses of prednisone. The patients had severe disease; there was a high degree of glomerular sclerosis; the median serum creatinine was 137 mumol/l, the diastolic blood pressure 101 mm Hg. Reported previously was a short-term improvement in renal function, blood pressure, and renal histology. Reported here is the long-term follow-up on all 22 patients for an average of 58 months. Three died of causes other than renal failure. Eleven developed end-stage renal disease an average of 27 months after ancrod treatment. The other 8 are alive with no deterioration of renal function after an average of 70 months. This outcome seems satisfactory when disease severity is taken into consideration. Factors present at treatment start that might be associated with subsequent renal function deterioration were: prior prolonged prednisone treatment, extensive glomerular sclerosis, high plasma alpha 2-antiplasmin and possibly triglycerides. During the follow-up period after completion of treatment, later relapses of SLE and DPLN appeared to be an important predictor of deterioration of renal function.

Nephrotic syndrome with renal vein thrombosis: pathogenetic importance of a plasmin inhibitor (alpha 2-antiplasmin).

Tests of fibrinolysis were measured by fibrin plate methods in 44 patients with nephrotic syndrome, in 14 of whom renal vein thrombosis was demonstrated. In both groups the level of total fibrinolytic activity was normal, that of vascular plasminogen activator was decreased, and that of an inhibitor of plasminogen activation was elevated. The level of a plasmin inhibitor, measured by the fibrin plate method, was elevated in 13 of 14 patients with, but only in 12 of 30 without, renal vein thrombosis (p less than 0.005). The plasmin inhibitor was identical with alpha 2-antiplasmin. The data suggest that an increased level of alpha 2-antiplasmin may be a factor in determining susceptibility to the development and persistence of renal vein thrombosis in patients with nephrotic syndrome.

Successful treatment by defibrination with ancrod in a patient with hyperacute renal allograft failure and a deficiency of plasma prostacyclin stimulating factor.

Hyperacute and renal allograft failure, whether due to rejection or other mechanisms, such as perfusion injury, is usually associated with extensive intraglomerular fibrin deposition and allograft loss. Defibrination with ancrod was used to treat a patient with hyperacute renal allograft failure and extensive glomerular fibrin deposition and necrosis. The patient's plasma had normal fibrinolytic activity but a complete absence of the ability to generate prostacyclin-like activity from rat aortic endothelium "in vitro". Treatment was associated with complete recovery of renal function, disappearance of glomerular fibrin, and restoration toward normal of glomerular structure.

Pain referred to teeth as the sole discomfort in undiagnosed mediastinal lymphoma: report of case.

The role of routine medical examination in dental diagnosis is described in a report of case involving a young, seemingly healthy patient whose only symptom, pain in the mandibular left molars, proved a manifestation of a malignant mediastinal lymphoma.

Catastrophic secondary antiphospholipid syndrome with concomitant antithrombin III deficiency.

The association between thrombotic events and primary or secondary antiphospholipid/anticardiolipin syndrome is now well recognized. A spectrum of renal involvement ranging from glomerular thrombosis to renal infarction has been described. A case of systemic lupus erythematosus with immunoglobulin G and M antiphospholipid/anticardiolipin antibodies is reported. The patient developed catastrophic thrombosis in multiple organs, and glomerular thrombosis was documented by renal biopsy. The patient had an acquired antithrombin III deficiency, and the combination of secondary antiphospholipid syndrome with accompanying antithrombin III deficiency predisposed to thrombosis. Several mechanisms by which antiphospholipid/anticardiolipin antibodies cause thrombosis have been proposed and are briefly reviewed.

Nephritis in systemic lupus erythematosus (natural history, treatment, and pathogenesis).

Nephritis in systemic lupus erythematosus is a prototype for immune complex mediated renal disease in man. The renal manifestations are pleomorphic in their expression. In the past 35 years, the natural history of the disease and its response to treatment have been related to the renal histology seen when the patient was initially studied. Patients with normal kidneys and those with membranous nephropathy have five-year survivals that are excellent and uninfluenced by treatment. Patients with mesangial disease may be a heterogeneous population--those with deposits doing comparatively worse; focal and diffuse proliferative nephritis carry a poorer prognosis. Extensive studies in the relatively homogeneous NZB/NZW F1 hybrid mouse have led to a better understanding of human lupus nephritis. Critical factors in getting a good response involve not only selection of the appropriate drug but also its mode of administration and timing in relation to the course of the disease. Intelligent must be based on an understanding of etiopathogenesis. Recent studies have cast some light on the role of the mediators of inflammation, e.g. platelets, fibrinolysis, and the modulating role of the reticuloendothelial system. Future studies must take these into account in the discovery and evaluation of a new forms of therapy.

Continuous quality improvement in chronic disease: a computerized medical record enables description of a severity index to evaluate outcomes in end-stage renal disease.

We have previously derived an index, based on retrospective data, for mortality in patients with end-stage renal disease (ESRD) treated by dialysis and transplantation. We used this index to calculate probability of death and rates of hospitalization, two measures of severity of illness, for 436 patients enrolled in our ESRD program after the original index was derived. Applied when ESRD treatment was initiated, it predicted future mortality and hospitalization rates. We then analyzed clinical characteristics, including variables in the predictive model, in all 718 patients enrolled in 3-year cohorts from 1976 to 1989. Over time, there was trend toward enrolling patients with a higher likelihood of dying, ie, more severely ill. The severity index facilitated description of the patients and their changing characteristics over time, and proved useful in comparing the degree of illness in different population groups.

Repeated use of dialyzers is safe: long-term observations on morbidity and mortality in patients with end-stage renal disease.

In treating patients with end-stage renal disease, the dialyzer may be used on multiple occasions rather than once. Long-term effects of this practice are unknown. We report 259 and 1,059 successive patients from facilities practicing reuse in Cincinnati and Detroit, followed, respectively, for 535 and 2,209 patient years. The morbidity was relatively low, expressed by the number of hospital admissions (1.63 and 2.19/year) and by days in hospital (14.24 and 22.71/year), respectively. In Cincinnati the unadjusted case fatality rate was 70% of that in the Ohio Valley Renal Disease Network, in Detroit it was 96% of that in the Michigan Renal Network. There were no adverse long-term effects of multiple use of dialyzers.

Effect of first and subsequent use of hemodialyzers on patient well-being: the rise and fall of a syndrome associated with new dialyzer use.

In a single large dialysis unit in which dialyzers are routinely subjected to multiple use, the incidence rates of intradialytic symptoms during first use and reuse were compared. Dialyses administered during two periods were analyzed: During the first (26,592 treatments), dialyzers were processed by a manual method before both first and subsequent use. During the second (12,395 treatments), dialyzers were processed by an automated machine method before first and subsequent use. During the first (manual processing) period, 12 symptoms were found to occur more frequently during first use than during reuse. The most striking findings related to chest pain (2.8 times more frequent with first use), back pain (6 times), and concurrent chest and back pain (42 times). Thus, a "first-use syndrome" characterized by chest and back pain was clearly evident. During the second (machine processing) period, the previously noted increased symptom incidence during first use was no longer present. In particular, the incidence of chest pain and back pain was no longer greater during first use than during reuse. Our results suggest that subjecting dialyzers to an automated reuse processing system before first use can markedly diminish the incidence of first-use syndrome.