Inhibition by anticoagulant drugs of the progressive hypertension and uremia associated with renal infarction in rats.

We confirmed our previously reported findings that subcutaneous administration of heparin (200 U q 12 hr) in rats with experimental partial renal infarction prevents the development of progressive renal failure and hypertension, as well as the glomerular abnormalities which occur in the remaining viable renal tissue. In the present study, heparin, in the dosage used to prevent progressive renal failure, caused a marked and sustained prolongation of the activated partial thromboplastin time and prothrombin time, as well as a transient prolongation of the bleeding time. Administration of coumadin at doses which caused a significant prolongation of the prothrombin time and bleeding time also inhibited the development of progressive hypertension and uremia in rats with experimental partial renal infarction. These findings indicate that inhibition of blood coagulation effectively protects rats with experimentally decreased renal mass from the development of progressive renal failure and hypertension and support the concept that the glomerular thrombosis plays an important role in the pathogenesis of these complications.

Inhibitory factors of lymphocyte transformation in sera from patients with minimal change nephrotic syndrome.

This study was undertaken to establish the specificity and relation to disease activity of serum inhibitors of lymphocyte function in minimal change nephrotic syndrome (MCNS). Sera from 21 children with MCNS were evaluated for their effect on blast transformation of normal human lymphocytes after stimulation with E-PHA, ConA, PWM or allogeneic cell surface antigens (mixed lymphocyte cultures;MLC). Sera from patients in relapse on no medication (n = 12), in relapse on steroids (n = 5), and in remission on steroids (n = 7) were significantly more inhibitory than sera from patients in late remission off steroids (n = 14 both in mitogen induced blast transformation and in MLC. Sera from eight children with other forms of nephrotic syndrome exhibited the same degree of inhibition of E-PHA, ConA, and PWM induced mitogenesis but significantly less inhibition of MLC when compared to 12 MCNS patients in untreated relapse. Thus serum inhibition of mitogen induced blast transformation is not specific for MCNS but occurs in other forms of nephrotic syndrome as well. Conversely, sera from MCNS patients does selectively inhibit MLC. Finally, the inhibitory activity of MCNS sera for both mitogen and cell surface antigen stimulation correlates with the course of the disease.

Reticuloendothelial and mesangial function in murine immune complex glomerulonephritis.

The function of the mesangial and reticuloendothelial system was evaluated in normal mice and in mice with nephritis induced by lymphocytic choriomeningitis (LCM) virus infection. Heat-aggregated human immunoglobulin (AlgG) and colloidal carbon served as traceable materials which could be detected in animals' blood and tissues. LCM virus-infected proteinuric (LCM-P) mice, as compared to normal mice or LCM-infected nonproteinuric (LCM) mice, had greater accumulation of AIgG in their glomeruli at all times of examination following i.p. injection of AIgG. The removal rate of AIgG from the kidney, however, was the same in normal and LCM-P mice, indicating an unimpaired mesangial clearing system. This suggested that other mechanisms were responsible for the increased glomerular accumulation of AIgG in LCM-P mice. Reticuloendothelial function was examined directly by i.v. injection of AIgG or colloidal carbon. The data demonstrate that in this model of immune complex glomerulonephritis, colloidal material tested was removed from the blood at a slower rate than it was in normal mice. Deficient clearance of endogenous blood-borne immune complex-like material may be one of the factors playing a role in the accumulation of immune complex-like material in the glomeruli of these nephritic animals.

Hyperkalemia after renal transplantation. Occurrence in a patient with insulin-dependent diabetes.

An insulin-dependent diabetic patient received a renal transplant from a living related donor without evidence of rejection. In the posttransplant period, his serum potassium concentration (3.7 to 6.7 mEq/liter) fluctuated widely with the serum glucose concentration (165 to 470 mg/dl) during the day. Serum glucose and potassium concentrations were directly correlated (r = .734, P less than .001). Other factors controlling the serum potassium concentration were examined. Plasma and urinary aldosterone levels were normal, plasma renin activity and aldosterone levels rose during upright activity, and urinary potassium excretion increased with the administration of exogenous mineralocorticoid. Thus, mineralocorticoid secretion and responsiveness were intact. These observations indicate that hyperkalemia in a diabetic patient can occur in the absence of a defect in potassium excretion and are consistent with the interpretation that insulinopenia, as evidenced by hyperglycemia, can result in hyperkalemia due to diminshed translocation of both potassium and glucose from the extracellular to the intracellular compartment.

T-cell deficiency in immune complex glomerulonephritis.

Mice chronically infected with the virus of lymphocytic choriomeningitis (LCM) develop immune complex glomerulonephritis. Others have shown that adoptive immunization of these mice by the i.p. injection of syngeneic immune spleen cells terminates the chronic viral carrier state. The present studies were designed to define the effector cell from the immune spleen responsible for adoptive immunization and to determine the effect of this procedure upon the immune complex nephritis which occurs in LCM carrier mice. The results indicate that the effector cell in adoptive immunization is a T-cell that functions directly as a killer cell when transferred to LCM carrier mice. Sixteen of nineteen adoptively immunized mice examined had less immune complex material deposited in their glomeruli than control unmanipulated litter mates. These data demonstrate that this animal model of immune complex glomerulonephritis is immunodeficient with respect to LCM virus-specific killer T-cells. Transfer of this cell population to the LCM carrier mouse diminishes the animal's viremia and improves its immune complex nephritis. In view of these observations, it is suggested that the rationale for the use of immunosuppressive therapy in spontaneously occurring glomerulonephritis should be carefully reconsidered.

Pathogenesis of the glomerulopathy associated with renal infarction in rats.

The present studies were designed to characterize the extent and pathogenesis of the glomerular lesions which occur in the viable portion of the kidney following partial renal infarction in rats. Control rats with two normal kidneys had a mean blood pressure of 112 mm Hg, minimal proteinuria and no glomerular pathology on light (LM), electron (EM) or immunofluorescence microscopy (IFM). Rats with two-thirds infarction of one kidney (stage II) became hypertensive, although less than 4% of the glomeruli from either kidney were abnormal. Rats with two-thirds infarction of one kidney and contralateral nephrectomy (stage III) developed proteinuria and hypertension whether fed a normal, low or high Na+ diet. By light microscopy 37% of glomeruli were abnormal 28 days after partial infarction and contralateral nephrectomy and thereafter the percent of abnormal glomeruli increased. Detectable amounts of immunoglobulin and complement (C3) were present in kidneys of stage II or III rats but were always accompanied by more extensive albumin and fibrin deposits. Basement membrane deposits characteristic of immune complexes were not seen on EM. Administration of antihypertensive medication to stage III rats significantly lowered blood pressure and reduced the number of abnormal glomeruli on LM; however, IFM abnormalities remained prominent. Platelet thrombi seen by EM and abundant glomerular fibrin deposits seen on IFM suggested that coagulation mechanisms may be prominent in the pathogenesis of the renal lesion. Heparin-treated stage III rats had significantly lower blood urea nitrogen concentrations, blood pressures and proportion of abnormal glomeruli although glomerular deposition of serum proteins was still present on IFM. These observations suggest that this glomerulopathy is initiated by an unknown agent(s) which increased capillary permeability. This lesion progresses via thrombotic mechanisms which are prevented by heparin administration.

Studies of abluminuria and proteinuria in normal mice and mice with immune complex glomerulonephritis.

Proteinuria is supposedly a frequent and early manifestation of glomerulonephritis. Since albuminuria rather than proteinuria is the hallmark of glomerular disease, the present studies were designed to study the occurrence of albuminuria in normal mice (SWR/J strain) and in mice with a reproducible and predictable immune complex glomerulonephritis induced by chronic infection with lymphocytic choriomeningitis (LCM) virus. A radial immunodiffusion technique, specific for mouse albumin, was employed to quantify the albuminuria. Column chromatography of concentrated urine obtained from normal and nephritic mice demonstrated that albumin excreted in the urine had the same molecular weight as serum albumin and that identifiable fragments of albumin did not appear in the urine. Some albuminuria did occur in normal mice, 0.12 +/- SD. 0.13 mg. per 18 hours for 80 males and 0.13 +/- 0.09 mg. per 18 hours for 55 females. Increased albuminuria, defined as values greater than a normal mean + 2 S.D. (0.40 mg. per 18 hours) occurred in only 25 per cent of nephritic mice, although in more than 600 animals studied, immunofluorescent microscopy invariably demonstrated abnormal accumulation of immune complexes in the glomeruli of SWR/J mice chronically infected with LCM virus. Values of total proteinuria measured by the sulfosalicylic acid method did not correlate with radial immunodiffusion measured albuminuria. The results indicate that measurement of total proteinuria in mice is not a useful parameter of glomerular disease. Albuminuria, while increased in 25 per cent of nephritic animals, was not abnormal even in the presence of marked histologic alterations in 75 per cent of mice, suggesting that abnormal immunopathology may very commonly not be reflected in increased or pathologic albuminuria. Recent observations also suggest that this is the case in humans.

Effect of immunosuppression on chronic LCM virus infection of mice.

C3H mice chronically infected with LCM virus were found to be lethally affected by small doses of immunosuppression which caused bone marrow aplasia but had no effect on the amount of virus carried by the mouse. Humoral immune response of SWR/J mice to acute LCM infection was found to be totally suppressed by repeated single doses of 300 R/wk with no alteration in the level of virus carried by the mouse. In contrast, the established anti-LCM humoral immune response encountered in mice chronically infected with LCM virus was not suppressed by the same irradiation procedure. Over half of the chronic LCM carrier SWR/J mice treated with cyclophosphamide for 6 mo had total anti-LCM humoral immunosuppression, but showed no change in the level of virus carried. The glomerulonephritis which occurs in chronic LCM carrier mice was prevented by cyclophosphamide treatment in 90% of the mice. The humoral immune response which occurs in chronic LCM carrier mice appears to play no role in controlling the amount of virus carried by the mouse. Suppression of the LCM immune response by cyclophosphamide does prevent the development of glomerulonephritis in these mice.