Circulating immune complexes after renal transplantation. Correlation of increased 125I-Clq binding activity with acute rejection characterized by fibrin deposition in the kidney.

To assess the role of circulating immune complexes in the pathogenesis of acute rejection, sera were measured for such complexes by the (125)I-C1(q) binding assay in 45 normal subjects, 24 allografted patients undergoing acute rejection, and in 11 allografted patients in a quiescent phase. Increased C1(q)-binding activity (C1(q)-BA) was detected in 14 patients with acute rejection, 9 of whom had renal biopsies showing fibrin deposition in the vasculature together with cellular infiltrates in the tubulo-interstitial structures; renal histology was not available in the other 5 patients. The other 10 patients with acute rejection, whose biopsies showed only cellular infiltrates, and the 11 patients in a quiescent phase posttransplantation did not have increased levels of serum C1(q)-BA. Of the group with increased serum C1(q)-BA, serial studies in eight patients showed a correlation between increased serum C1(q)-BA and the occurrence of rejection; with reversal by therapy, serum C1(q)-BA returned to within normal levels. Complexes from six patients were analyzed by sucrose density gradient ultracentrifugation to have sedimentation coefficients ranging from 15S to 18.4S. After acid dissociation and analysis by double-diffusion techniques, C1(q)-reactive complexes were shown to contain IgG. Immunofluorescent studies done in five renal biopsies from this group revealed granular deposits of immunoglobulin, and (or) less frequently, of complement in the glomeruli or the tubular basement membranes. The findings suggest that circulating immune complexes may mediate the type of acute rejection characterized by fibrin deposition in the kidney. The role of circulating immune complexes arising from the recipient's original kidney disease could be excluded in 10 patients with humoral rejection, inasmuch as the underlying renal pathology was of a "nonimmunologic" nature; this was corroborated by sequential studies in six patients in whom circulating immune complexes could not be demonstrated before rejection. The participation of administered antilymphocyte globulin (ALG) as an antigen also appears to be excluded in four patients, two who were not given ALG, and in two of whom episodes of rejection occurred unrelated temporally to ALG administration.

On-line computerized data handling system for treating patients with renal disease.

Some patients with renal disease accrue 6,000 to 8,000 individual data items relating to symptoms, signs, laboratory information, and treatment in one year. To deal with the problem of handling so many data items, the following steps were taken: (1) a dictionary of terms peculiar to nephrology was created; (2) manual time-oriented records for nephrology were constructed; and (3) an on-line data processing system, using a PDP-11/70 computer and remote teleprocessing terminal, was developed. On the terminal screen, up to 11 consecutive patient visits can be displayed horizontally, with 18 data items displayed vertically. Up to 30 of the most recent patient visits are easily accessible. For patient treatment, a special feature allows a rearrangement and instantaneous display of any combination of data, thus permitting review of essential feedback relationships between clinical events and treatment.

Renal parenchymal malakoplakia. A case associated with renal vein thrombosis and partial recovery of kidney function.

A 65-year-old woman with bilateral renal parenchymal malakoplakia and renal vein thrombosis had severe azotemia, bilaterally enlarged kidneys, urinary tract infection, and sepsis. Angiographic studies demonstrated left renal vein thrombosis. A percutaneous kidney biopsy specimen showed the characteristic Michaelis-Gutmann bodies. After therapy with fluid replacement, antibiotics, and long-term anticoagulation, kidney function improved and both kidneys decreased in size. We suggest that, with adequate treatment of urinary tract infection and correction of potential insults to the kidney, progression of this peculiar disease can be prevented.

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.

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.

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.

Chronic membranoproliferative glomerulonephritis. A patient with recurrent episodes simulating rheumatic fever and acute nephritis.

A most unusual case of chronic membranoproliferative glomerulonephritis with nodule formation is reported in an elderly man in whom it was possible to document many episodes of acute oilguric and hemorrhagic glomerulonephritis and a syndrome resembling acute rheumatic fever. Severe renal failure necessitating peritoneal dialysis occurred on three occasions. Renal function returned to near preexacerbation levels in each episode. Although there was strong clinical evidence for streptococcal hypersensitivity, convincing laboratory documentation was lacking. The histologic and immunopathologic findings changed comparatively little during the several exacerbations. Impairment in fibrinolytic and coagulation activities by circulating macromolecular complexes is postulated for the induction and perpetuation of the glomerular injury.

Acute interstitial nephritis. A clinical and pathologic study based on renal biopsies.

To define interstitial nephritis without preselection bias, 25 consecutive renal biopsy specimens from patients with tubular damage, interstitial damage and interstitial inflammation were analyzed in detail. In four patients (all with acute renal failure), tubulitis, and interstitial eosinophil and lymphocyte infiltration were found, but no glomerular abnormalities. In four others, the findings were similar but some glomerular abnormalities were noted. Two patients had probable healed interstitial nephritis. The clinical presentation varied from transient renal insufficincy to oliguric renal failure. Three of the patients with glomerular abnormalities had significant proteinuria. When the 10 patients with interstitial nephritis were compared with the other 15 serving as controls, striking features in the former group were skin rash, eosinophilia, the absence of hypertension and the frequency of administration of penicillin and its analogs. Serum immunoglobulin E (IgE) levels were elevated in three of the patients. The striking eosinophilia, interstitial eosinophil infiltration and increased IgE levels suggest that allergen-reaginic complexes may be involved in the pathogenesis of the lesion.

Immunofluorescent localization of beta2-microglobulin in the human kidney.

Using antisera to human beta2-microglobulin and an immunofluorescent technique, beta2-microglobulin was found to be localized along tubular and glomerular basement membranes of renal bipsies studied. Since beta2-microglobulin is a subunit of HLA preparations, it may also serve as an indirect marker for the presence of HLA antigens in these structures.

Fish oil has beneficial effects on lipids and renal disease of nephrotic rats.

The effects of fish oil on serum lipids, eicosanoid production, fibrinolysis, and renal disease of nephrotic rats were studied. Three groups of rats were given adriamycin to induce nephrotic syndrome. They were pair-fed diets containing 14% beef fat, 3%, and 14% fish oil, and killed at 4 weeks. Marked beneficial effects of the fish oil on plasma triglycerides, total cholesterol, and LDL cholesterol were observed. Fish oil suppressed dienoic eicosanoid production. Protection of renal function and morphology was achieved in the fish oil fed groups, as evidenced by lower serum creatinine levels and lesser degrees of tubular dilatation and intraluminal protein in the kidney tubules. We conclude that fish oil, rich in n-3 fatty acids, is beneficial to the plasma lipids and may prevent progression of renal disease in this model of nephrotic syndrome. These two events may be interrelated.

Glomerular eicosanoid production in acute serum sickness nephritis.

To determine if the induction of immune-mediated glomerular injury influences the formation of glomerular cyclooxygenase products, we measured thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2) production by isolated glomeruli of rabbits induced with acute serum sickness nephritis by the administration of bovine serum ablumin (BSA). Animals were randomly assigned to one of three experimental groups: animals injected with BSA (BSA group; n = 11); animals injected with normal saline (control group; n = 11); and animals injected with BSA which were treated with the thromboxane synthetase inhibitor, OKY-046 (BSA + OKY-046; n = 6). Animals in the BSA and BSA + OKY groups developed severe proteinuria and glomerular histologic lesions of nephritis. No differences in proteinuria, serum creatinine and severity of histologic nephritis were observed between the two groups. Examination of glomerular eicosanoid production at the end of the experiment showed a marked reduction of glomerular PGE2 and 6-keto-PGF1 alpha production with a smaller reduction of glomerular TXB2 production in the BSA group. In the BSA + OKY-046 group, the production of TXB2 was significantly less than that in the BSA group; despite this, no effect on proteinuria could be discerned.

Enhancing effect of dietary supplementation with omega-3 fatty acids on plasma fibrinolysis in normal subjects.

A supplement of MaxEPA oil containing 5 g of omega-3 polyunsaturated fatty acids was given for two weeks to nine normal volunteers. The vascular plasminogen activator (VPA) level increased and there was a fall in the levels of inhibitors of vascular plasminogen activator (IPA) and of plasmin, alpha 2-antiplasmin (alpha 2-AP). No significant changes occur in serum cholesterol, triglycerides, HDL or LDL levels.

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.

Dietary fat in experimental nephrotic syndrome: beneficial effects of fish oil on serum lipids and, indirectly, on the kidney.

Three isocaloric diets with different fat composition were fed to rats for seven weeks after the production of nephrotic syndrome by adriamycin. The effects of feeding 3% and 14% fish oil were compared with those of feeding beef fat. At the fourth week of feeding the levels of triglycerides and cholesterol were lower in both fish oil fed groups. At the seventh week these levels, and the LDL cholesterol, were lower only in the 14% fish oil group. In rats fed beef fat, but not in those fed fish oil, there was a striking positive correlation of the four-week serum triglycerides and cholesterol with the seven-week serum creatinine level and with the degree of glomerular hyalinosis and endothelial swelling. The favorable effects of fish oil feeding on serum lipids may have a protective effect on the development of glomerular damage.

Unanticipated favorable effects of correcting iron deficiency in chronic hemodialysis patients.

BACKGROUND: Correction of anemia in hemodialysis patients is seldom completely attained, and the response of parameters other than hemoglobin concentration to anemia correction has not been evaluated in detail. METHODS: Laboratory parameters that suggest iron deficiency occurred in 10-15% of 206 recombinant human erythropoietin (rhEPO)-treated patients. Oral iron was given for 9 months and intravenous iron thereafter on a patient-specific basis when iron deficiency was evident. Eighty-seven hemodialysis patients with data for 12 months were followed for another 12 months. A computerized information system enabled data management and analysis. RESULTS: With oral iron, serum ferritin decreased (P < 0.001), indicating further iron depletion. With intravenous iron, hemoglobin increased, evidence of iron deficiency decreased, and less rhEPO was needed. Striking macrocytosis appeared. Serum albumin and serum creatinine/kg body weight (an index of muscle mass) increased, while blood pressure decreased. Data were reanalyzed in four mean corpuscular volume (MCV) quartiles and two ferritin subsets at study onset. Iron deficient erythropoiesis (low MCV, mean corpuscular hemoglobin [MCH], and transferrin saturation) was striking in quartile 1; low ferritin was prevalent in all quartiles. With intravenous iron, hemoglobin increased only in quartile 1, the quartile with the greatest decrease (52%) in rhEPO dose. MCV increased in all quartiles (P < 0.001). Serum albumin increased in all MCV quartiles and both ferritin subsets, but significant creatinine/kg increase and blood pressure decrease occurred only in the low-ferritin subset. CONCLUSIONS: Macrocytosis occurred with intravenous iron replacement. The universal MCV increase suggests unrecognized, inadequately treated, folic acid deficiency unmasked by an adequate iron supply. There was also improved well being. Effects were most clearly evident in patients with deficient iron stores.

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.

Ancrod causes rapid thrombolysis in patients with acute stroke.

Clot lysis is desirable in patients with thrombi in arteries and arterioles by a safe rapidly-acting thrombolytic agent. Ancrod cleaves fibrinogen; the resulting circulating ancrod-fibrin stimulates fibrinolysis. Ancrod action and effect were studied in 20 patients with acute developing stroke in a double-blind, placebo-controlled study. Patients were randomly assigned to one of two treatment groups, and received either normal saline or ancrod 0.5 mu/kg in normal saline administered as a constant-rate intravenous infusion over 6 hours. Subsequent doses of ancrod (or saline placebo) were determined daily thereafter for a total treatment period of 7 days. Neither bleeding nor re-thrombosis occurred within the 90 day follow-up period. That ancrod acted rapidly was shown by a significant decrease in functional plasminogen activator inhibitor (PA-I) within 60 minutes, and by significant elevations of fibrin(ogen) degradation products (FDP) and D-dimer within 3 and 4 hours. The biological effect of fibrinolysis in ancrod infused patients was demonstrated by a greater improvement in stroke score when compared to those infused with saline.

The influence of n-6 and n-3 fatty acids on kidney phospholipid composition and on eicosanoid production in aging rats.

Changes in eicosanoid production may contribute to some of the complications of the aging process such as atherosclerosis and glomerular sclerosis. Polyunsaturated fatty acids of the n-6 and n-3 series are precursors of eicosanoids. We fed diets containing safflower oil as a source of n-6 fatty acids, fish oil as a source of n-3 fatty acids or beef tallow as a source of saturated fats to three groups of normal rats from 2-18 months of age. We demonstrated incorporation of the n-3 fatty acids, 20:5n-3 and 22:6n-3 into kidney phospholipids. Feeding of the diet containing n-3 fatty acids was associated with a markedly decreased glomerular production of PGE, 6-keto-PGF1 alpha and TXB2. It also decreased the aortic production of 6-keto-PGF1 alpha and platelet production of TXB2. No significant effect of n-6 fatty acids on dienoic eicosanoid production was observed. There were no adverse effects on kidney function as measured by urinary protein excretion and serum creatinine levels or on renal morphology by any diet. A diet enriched in n-3 fatty acids for 18 months remains effective in decreasing dienoic eicosanoids in the aging rat.