Morphologic correlates of glomerular oxidant injury induced by the myeloperoxidase-hydrogen peroxide-halide system of the neutrophil.

Neutrophilic polymorphonuclear leukocytes can mediate glomerulonephritis by releasing reactive oxygen species such as H2O2. We have previously demonstrated that H2O2-mediated glomerular injury can be potentiated by reaction with polymorphonuclear leukocyte myeloperoxidase (MPO). When MPO was perfused into renal arteries of rats, it bound to the glomerular capillary wall due to its cationic charge. Subsequent perfusion with nontoxic concentrations of H2O2 and halides resulted in acute glomerular injury, halogenation of the glomerular basement membrane, and proteinuria. The studies reported here document the morphologic changes that accompany MPO-mediated glomerular injury. Acutely, there is severe injury to the endothelium with cell swelling and lysis. Within 10 minutes, a marked platelet influx occurs. Platelets frequently occlude capillary lumens and bind to areas of denuded glomerular basement membrane where platelet degranulation results. By 4 days, the platelet infiltration has ceased, and a reparative phase develops characterized by marked proliferation of resident endothelial cells and possibly mesangial cells. By 21 days postperfusion, the glomerular lesion had largely resolved. In contrast, control rats perfused with MPO alone, H2O2 alone, or buffered saline alone demonstrate minimal glomerular injury at all times studied. MPO-mediated glomerular disease results in endothelial and mesangial cell injury, activation of platelets, and a subsequent proliferative response. These morphologic changes resemble those seen in several forms of inflammatory and proliferative glomerulonephritis in man.

Prevention of hypercalcemia-induced renal concentrating defect and tissue calcium accumulation.

The mechanism of the concentrating defect of hypercalcemia is explored by examining the effect of concomitant phosphate restriction. Rats were pair fed a normal phosphorus diet, without (group 1) or with dihydrotachysterol (group 2), or a low-phosphorus diet (group 3). Hypercalcemia was comparable in groups 2 (12.1 +/- 0.6 mg/dl) and 3 (11.8 +/- 0.4 mg/dl), but serum phosphate was lower in group 3 than group 2 (3.8 +/- 0.7 vs. 7.1 +/- 1.1 mg/dl, P less than 0.005). Group 2 rats had impaired maximum urinary concentration after 24 h of fluid deprivation (2,441 +/- 450 mosmol/kg H2O, P less than 0.001) compared with group 1 (3,263 +/- 466 mosmol/kg H2O) or group 3 (3,332 +/- 515 mosmol/kg H2O) animals. Polydipsia and polyuria were found in group 2 rats only. Tubular calcium reabsorption was higher in group 2 (83.1 +/- 33.5 mg/24 h, P less than 0.001) than group 1 (47.0 +/- 26.1 mg/24 h) or group 3 (52.8 +/- 19.3 mg/24 h) animals, and medullary calcium concentration was higher in group 2 (7.57 +/- 3.08 nmol/mg dry wt, P less than 0.05) as compared to group 1 (5.04 +/- 1.37 nmol/mg dry wt) or group 3 (5.32 +/- 0.98 nmol/mg dry wt) rats. Total medullary solute concentration was significantly higher in group 3 than group 2 animals. Thus phosphate restriction prevents the defect of urinary concentrating ability of chronic hypercalcemia, probably by decreasing tubular uptake and tissue accumulation of calcium.

Effect of pertussis toxin on water metabolism in the rat.

Pertussis toxin administered to rats resulted in a polyuric state that was due to enhanced renal water excretion. Pertussis toxin also induced a defect in renal water conservation. These abnormalities in renal water excretion could not be attributed to polydipsia, impaired synthesis and/or release of arginine vasopressin or renal tubular dysfunction with solute diuresis. No evidence of pertussis toxin-induced renal tubular damage was present. These results indicate that pertussis toxin induces nephrogenic diabetes insipidus and this defect occurs at the level of the renal collecting tubule.

Prednisone therapy of membranoproliferative glomerulonephritis in children.

Six children with biopsy-proved type 1 membranoproliferative glomerulonephritis (MPGN) improved clinically during a 2-year course of prednisone therapy. All children had nephrotic syndrome. Creatinine clearance was less than or equal to 80 ml/min/1.73 m2 in four patients. Initial prednisone dosage ranged from 20 mg every other day to 2 mg/kg/day (maximum 60 mg), with subsequent modifications based on improvement. After completion of a 2-year course of steroid therapy, a repeat kidney biopsy was performed in each child; a decrease in glomerular disease activity was noted in five of them. After a mean follow-up of almost 5 years, all children have creatinine clearance greater than 120 ml/min/1.73 m2, and only one remains nephrotic. Although the use of prednisone in children with MPGN remains controversial, we have observed a diminution in proteinuria and normalization of creatinine clearance with therapy initiated early in the disease course.

Tubulointerstitial renal disease in systemic lupus erythematosus.

Tubulointerstitial renal disease is found frequently in patients with systemic lupus erythematosus. Despite the frequency of this entity, little is known about the prognostic significance of this biopsy finding. We reviewed 46 consecutive renal biopsy specimens from patients with systemic lupus erythematosus who were followed up for a mean of 5.4 years. Tubulointerstitial abnormalities were present in 39% of the entire group of patients and in 51% of the patients who had clinical evidence of renal abnormalities. Tubulointerstitial inflammation was closely associated with diffuse proliferative glomerulonephritis, with elevation of serum creatinine (SCr) concentration at biopsy, and with increased frequency of proteinuria both at biopsy and at follow-up. Additionally, active interstitial inflammation was associated with an increased risk of doubling the entry SCr concentration. The presence or absence of tubulointerstitial disease, however, did not add additional prognostic information to the predictive power of the entry SCr concentration or the glomerular histologic features.

Systemic lupus erythematosus without clinical renal abnormalities: renal biopsy findings and clinical course.

The extent and significance of renal biopsy abnormalities in patients with systemic lupus erythematosus (SLE) without clinical renal abnormalities is controversial. We report 11 consecutive SLE patients who were biopsied without clinical renal abnormalities. All 11 patients had mesangial changes either by light microscopy or by immunofluorescent staining, and none had changes of focal or diffuse proliferative glomerulonephritis. Additionally none had deterioration of renal function during the mean follow-up period of 6.3 years.

The renal concentrating defect after gentamicin administration in the rat.

The present studies were carried out to delineate the mechanism of the polyuric state and renal concentration defect seen after gentamicin. Gentamicin was given at a dosage of 100 mg/kg/day subcutaneously for either 4 or 5 days to Sprague-Dawley rats and resulted in a reversible, polyuric form of acute renal failure. This nonoliguric acute renal failure was accompanied by significant polydipsia and a renal concentrating defect 11 days after gentamicin. To assess the role of polydipsia in the polyuria and renal concentrating abnormality, water intake was restricted in gentamicin-treated animals to match intake of control animals. Elimination of the polydipsia failed to eliminate the polyuria and to improve the renal concentrating abnormality. Postdehydration plasma vasopressin levels were higher in gentamicin-treated than control animals, suggesting that the renal concentrating defect was nephrogenic in origin. Daily urinary prostaglandin E2 excretion was comparable in gentamicin-treated and control animals. However, indomethacin failed to improve urinary concentrating ability, suggesting that the renal concentrating defect was prostaglandin E2 independent. Finally, depressed postdehydration inner medullary tonicity was found in gentamicin-treated animals In summary, gentamicin administration in the rat was associated with a reversible polyuric form of acute renal failure and a renal concentrating defect. This concentration defect was nephrogenic in origin, independent of polydipsia and prostaglandin E2, and was associated with a decrease in inner medullary tonicity.

Glomerular dynamics and morphologic changes in the generalized Shwartzman reaction in postpartum rats.

The roles of glomerular functional and morphologic changes were examined in the acute renal failure associated with generalized Shwartzman reaction in postpartum Munich Wistar rats. The susceptibility of postpartum rats to acute deterioration in renal function after a 2-h endotoxin infusion was found to be greater than in virgin litter mates: glomerular filtration rate fell by 93% in the former vs. 24% in the latter group (P less than 0.001). In postpartum rats there were marked changes in platelet count and fibrinogen level (P less than 0.025) compatible with consumption coagulopathy. Renal blood flow and glomerular filtration rate fell from 5.5 +/- 0.9 and 0.74 +/- 0.12 to 2.0 +/- 0.7 and 0.12 +/- 0.01 ml/min, respectively (both P less than 0.001). Blood pressure did not change. Results of glomerular dynamics studies showed decreases in single nephron filtration rate from 28 +/- 7 to 6 +/- 4 nl/min and in glomerular plasma flow rate from 77 +/- 26 to 23 +/- 12 nl/min (both P less than 0.001). Afferent net ultrafiltration pressure fell from 20 +/- 3 to 5 +/- 4 mm Hg due to a fall in glomerular capillary hydraulic pressure from 47 +/- 1 to 29 +/- 5 mm Hg (P less than 0.001). There were four- and twofold increases in afferent and efferent arteriolar resistances, respectively. Less than 20% of glomeruli had evidence of fibrin deposition after 2 h of endotoxin infusion, a time when glomerular filtration rate was reduced by greater than 90%. [1-Sar, 5-Ile, 8-Gly] angiotensin II infusion before endotoxin significantly protected glomerular filtration rate, 62 vs. 7% of control in rats with no preinfusion (P less than 0.01) despite consumption coagulopathy and glomerular fibrin deposition similar to rats without pretreatment. These data suggest that the early deterioration in renal function in the generalized Shwartzman reaction in the postpartum rat is due to major changes in glomerular dynamics induced by neurohumoral agents and that glomerular fibrin deposition plays a lesser pathogenetic role at this time in this disorder. The study does not address the pathogenesis of renal failure in pregnancy nor peripartum renal failure in another species.

Diffuse proliferative lupus glomerulonephritis. Recovery from prolonged renal failure.

A patient with systemic lupus of erythematosus, diffuse proliferative lupus glomerulonephritis, and deteriorating renal function was treated with immunosuppression. During the subsequent eight weeks of hemodialysis and immunosuppression, substantial recovery of renal function occurred, allowing for cessation of dialysis. In the following year, the endogenous creatinine clearance increased to 30 mL/min. A therapeutic trial of prednisone is indicated for patients with abrupt, severe deterioration in renal function in association with clinical, histological, or serological evidence of activity of lupus nephritis in the absence of other causes of renal failure.

Role of antidiuretic hormone in impaired urinary dilution associated with chronic bile-duct ligation.

1. The effect of chronic bile-duct ligation on systemic and renal haemodynamics and on the capacity to dilute the urine was studied in conscious rats. Sham-operated rats served as controls. 2. In the rats with bile-duct ligation, the maximal urinary diluting capacity was impaired, despite an expanded plasma volume, a normal mean arterial pressure and cardiac output, and normal intrarenal determinants of water excretion including distal delivery of fluid and function of the diluting segment. 3. In contrast, maximal urinary dilution capacity was intact in rats with congenital central diabetes insipidus and chronic bile-duct ligation. 4. It is concluded that the defect in urinary dilution in rats with chronic bile-duct ligation is dependent on antidiuretic hormone.

Renal toxicity of phosphate in rats.

To evaluate the mechanism by which phosphate induces renal injury, we placed uninephrectomized, partially nephrectomized, and intact rats on dietary phosphorus intakes varying between 0.5 and 2% for 18 weeks. None of the animals on a normal phosphorus intake (0.5%) had any abnormalities. Four out of six intact animals on a 1% phosphorus diet had kidney calcium concentrations within the normal range, and only one showed any histologic changes. In contrast, all but one partial and uninephrectomized animals on a 1% phosphorus diet had increased kidney calcium content concentration, and five of the six studied had histologic changes. The degree of calcification and histologic changes in the uninephrectomized animals on a 1% phosphorus diet was similar to that found in the intact animals on a 2% phosphorus diet. Animals on a 3% phosphorus diet plus disodium ethane-1-hydroxy-1-1-diphosphonate (EHDP) had significantly less calcification and histologic changes than did animals on a similar diet without EHDP. Conclusion. As renal functional mass is reduced, the nephrotoxicity of phosporus is greatly enhanced. Phosphorus-induced renal injury is mediated through calcium phosphate deposition in the kidney. This results from intrarenal caused, because the kidney calcification can be related to phosphate excreted per functional unit rather than plasma phosphate concentrations.

Simultaneous immunologic studies of skin and kidney in systemic lupus erythematosus clinicopathologic correlations.

Thirty-two biopsies of kidneys and of normal skin were performed simultaneously on patients with systemic lupus erythematosus (SLE) to determine whether the deposition of immune reactants in skin was correlated with the severity of renal injury or with several serologic measures of systemic disease activity. Immunofluorescent deposits at the dermal-epidermal junction (lupus band test) did not correlate with any clinical or histologic measures of glomerulonephritis or with serologic abnormalities. Immune deposits in dermal venules were found in 56% of the skin biopsies and were correlated with hypocomplementemia and higher levels of immune complexes in serum, and possibly with glomerular subendothelial electron dense deposits. Azathioprine therapy was correlated with absence of both sub-epidermal and vascular immune deposits. Immuno-fluorescent findings on serial skin biopsies on 13 patients were highly inconsistent. It is concluded that the lupus band test is clinically useful only as a diagnostic aid but not helpful in assessing renal or serologic activity of lupus, and that dermal vascular deposits of immunoglobulin or complement are more frequent than previoulsy recognized and correlate with measures of circulating immune complexes.

Etiologic variability of nephropathy in juvenile diabetes mellitus.

Clinicopathologic studies of four patients with juvenile diabetes mellitus and renal disease demonstrated the pathogenetic variability of nephropathy in diabetic patients. Only in one patient was the clinical nephropathy associated with the typical diabetic glomerulosclerosis. Another patient had steroid responsive nephrotic syndrome superimposed on minimal diabetic glomerulosclerosis. A third patient had steroid resistant nephrotic syndrome associated with mild diabetic glomerulosclerosis and with later appearance of Grave's disease. The fourth patient, in addition to moderate diabetic glomerulosclerosis had prominent tubulointerstitial nephritis, the latter probably being responsible for the rapidly declining renal function. The poor prognosis associated with diabetic nephropathy warrants a careful search for other potentially treatable causes of nephropathy in patients with juvenile diabetes mellitus.

Immune deposit nephritis and single-component cryoglobulinemia associated with chronic lymphocytic leukemia. Evidence for a role of circulating IgG-anti-IgG immune complexes in the pathogenesis of the renal lesion.

2 patients developed the nephrotic syndrome several years after diagnoses of chronic lymphocytic leukemia. In both cases light microscopy showed membranoproliferative glomerulonephritis. Electron microscopy and immunofluorescent staining revealed electron-dense deposits and deposition of immunoglobulins and C3. Both patients had single-component IgG cryoglobulinemia. The eluted glomerular-bound protein contained IgG only. IgG in patients' sera, cryoglobulins, and kidney eluate had kappa light chains only. Immune complexes were detected in the sera and in the cryoglobulins by the Clq binding test. Immunoadsorption studies revealed anti-IgG antibodies in the patients' sera, cryoglobulin, and kidney eluate. Direct immunofluorescent studies using the patients' sera, cryoglobulins, and kidney eluate on frozen sections of patients' kidneys were positive, providing additional evidence for the immune complex nature of the glomerulonephritis. The immunohistochemical studies of our patients are suggestive of the presence of circulating IgG-anti-IgG immune complexes and their possible involvement in the pathogenesis of the glomerulonephritis and the nephrotic syndrome in these 2 cases.

The kidney in progressive systemic sclerosis: a prospective study.

Nine normotensive progressive systemic sclerosis patients with normal renal function underwent renal biopsy. Four specimens had prominent vascular abnormalities, two mild vascular abnormalities, and three were normal. Vascular deposits of C3 were present in all specimens. Plasma renin activity was elevated in three of four patients with prominent vascular abnormalities, one of two patients with mild vascular lesions, and none of two patients with normal biopsies. Plasma renin activity elevation in response to cold pressor testing in the four patients with prominent vascular lesions was 5.6 ng/ml.h compared to 0.55 ng/ml.h in those with mild or no lesions and 0.26 ng/ml.h in six control subjects. These data indicate that renal vascular lesions may be present in normotensive patients. Elevation or a substantial rise in plasma renin activity (1.8 ng/ml.h or greater) in response to cold pressor testing suggests preclinical renal involvement.