Clinical correlates of eosinophiluria.

We assessed the clinical correlates of eosinophils in the urine in 65 patients. In 16% of 470 patients whose urine was specifically examined, eosinophils were noted in the urine sediment. Review of the 65 patients with eosinophiluria demonstrated that when eosinophils were expressed as a percentage of total urine white blood cells, 85% (55/65 patients) had less than 5% urine eosinophils and 45% (29/65 patients) had less than 1%. Infection of the upper and lower urinary tract accounted for 45% of the clinical conditions associated with eosinophiluria. In nine (14%) of the 65 patients a diagnosis of acute interstitial nephritis could be made by clinical criteria or from renal biopsy specimens. We conclude that the finding of urine eosinophils is associated with a variety of clinical conditions and may be most useful when expressed as a percentage of total white blood cells in the urine. At a low-percentage positive (less than 5%), it may not be a good predictor of acute interstitial nephritis, but at a higher level (greater than 5%) it may be a more valuable predictor.

Renal ablation acutely transforms 'benign' hypertension to 'malignant' nephrosclerosis in hypertensive rats.

The present studies examine the consequences of the hemodynamic changes associated with approximately 5/6 renal ablation in the spontaneously hypertensive rat (SHR), a strain that normally does not exhibit evidence of vascular and/or glomerular injury until late in life despite significant hypertension. Control SHR with intact renal mass demonstrated normal renal autoregulation and an absence of vascular or glomerular injury. Renal mass reduction resulted in an initial expected decrease in renal blood flow to the remnant kidney at 5 days (2.8 +/- 0.3 mL/min) compared with control SHR (8.1 +/- 0.7 mL/min) at a mean arterial pressure of approximately 160 mm Hg (P < .01). By 10 to 14 days after renal ablation, marked renal vasodilation was observed (renal blood flow 8.3 +/- 0.8 mL/min at mean arterial pressure of approximately 160 mm Hg) along with severe impairment of autoregulatory ability. Striking and florid vascular injury to interlobular arteries and afferent arterioles had also developed by 10 to 14 days after approximately 5/6 renal ablation in a pattern similar to that observed in "malignant" hypertension, despite systolic blood pressures that were not significantly different from those in control SHR (168.2 +/- 6.4 versus 165.6 +/- 4.7 mm Hg). An additional group of SHR that were made normotensive with a triple-therapy antihypertensive regimen before and after approximately 5/6 renal ablation also exhibited hemodynamic changes similar to those in the untreated rats at 10 to 14 days but did not develop significant vascular or glomerular injury.(ABSTRACT TRUNCATED AT 250 WORDS)

The prognosis of focal segmental glomerular sclerosis of adulthood.

We describe 46 adults with idiopathic focal segmental glomerular sclerosis (FSGS). The mean age was 36.9 years (range, 15 to 80 years). Males represented 61%, and 65.2% were white. Hypertension was a presenting feature in 63% and 32.6% had microscopic hematuria. Twenty-nine patients had nephrotic proteinuria (greater than or equal to 3.0 g/24 h) at presentation, and 13 had renal insufficiency (serum creatinine concentration greater than 1.5 mg/dl). A mean follow-up of 59.8 months (range, 3 to 255 months) was obtained. In addition to segmental sclerosis, glomerular hyalinosis was observed in 65.3% of biopsies, and this was similar irrespective of the severity of proteinuria. Sixteen of the 29 patients with nephrotic proteinuria received prednisone therapy (60 mg/day) for at least 1 month. Three received cytotoxic agents in addition. A response to therapy was observed in 50%, 5 achieving a complete remission and 3 a partial remission. No patient with non-nephrotic proteinuria received prednisone therapy. The clinical course of each patient was evaluated based on the slope calculated by the linear regression method using the inverse of serum creatinine from the time of presentation to follow-up. Patients with non-nephrotic proteinuria had a better prognosis than nephrotics (P less than .05). Nephrotic patients responding to therapy had a better course than non-responders or patients not treated (P less than 0.01). At the time of last follow-up, 8 patients had progressed to end-stage renal disease, 6 of whom had presented with nephrotic proteinuria. No patient responding to therapy had progressed to end-stage renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between renal pathology and the size of circulating immune complexes in patients with systemic lupus erythematosus.

Sera from 35 patients with biopsy-proven diffuse proliferative (WHO class IV) or membranous (WHO class V) lupus nephritis were analyzed for the presence and size of circulating immune complexes. Elevations of the C1q solid-phase assay (C1qSP) for immune complexes were found in sera from all patients with diffuse proliferative nephritis, with a mean +/- 1 SEM of 166.8 +/- 42.0 micrograms/AHG-equivalents/ml serum, and in 71.4% of the patients with membranous nephritis (83.1 +/- 26.7, p = 0.06). Using the WHO criteria for subclasses of membranous lupus nephritis, we also designated renal biopsies as nonproliferative (WHO classes Va and Vb) or proliferative (WHO classes IV and Vc). Employing the latter groupings, we observed significant differences between C1qSP results of patients with nonproliferative (30.3 +/- 8.8) and proliferative (172.8 +/- 36.8, p less than 0.001) lupus nephritis. These data suggest that the presence of C1q-binding material in serum is pathophysiologically related to proliferative glomerular lesions, and that levels of C1qSP binding reflect renal lesions in SLE patients. Sucrose density gradient ultracentrifugation was performed on each serum, and gradient fractions analyzed for C1qSP-binding and total IgG, using techniques to minimize losses of immune complexes. The predominant peak of C1qSP activity sedimented with the 6.6S monomeric IgG. The 6.6S C1q-binding IgG was increased only in 1 of 10 patients with membranous lupus nephritis without proliferative changes, and was elevated in 16 of 25 patients with proliferative lesions (WHO classes IV and Vc). A significant negative correlation was found between the presence of this C1q-binding material and subepithelial electron-dense deposits, suggesting that the presence of this material contributed to the absence of subepithelial immune deposits. Large-molecular-weight C1qSP-binding material was also present, mainly in sera from patients with proliferative lesions. Furthermore, highly positive correlations were found between immune deposits in interstitial blood vessels and peritubular areas, and the concentrations of C1qSP-binding IgG and rapidly sedimenting IgG in density gradient analysis. Overall, these findings are consistent with the hypotheses that circulating immune complexes contribute to the pathogenesis of glomerulonephritis and interstitial nephritis in patients with SLE, and that 6.6S C1q-binding IgG plays a role in the proliferative lesions of lupus glomerulonephritis.

Immunotactoid glomerulopathy.

We present 11 patients with immunotactoid glomerulopathy, a new syndrome characterized clinically by proteinuria (11/11), microscopic hematuria (9/11) and hypertension (9/11). The patients consisted of six females and five males, aged 25 to 59 years (mean, 44.6). Proteinuria was the presenting feature and the reason for renal biopsy in all patients. The diagnosis of immunotactoid glomerulopathy was established at renal biopsy by the presence of glomerular extracellular microtubules composed of immune reactants. All the biopsies studied by immunofluorescence (10 cases) had glomerular deposits of IgG and C3. In three biopsies studied with IgG subclass specific antisera, only one patient had monoclonal immunoglobulin deposits (IgG3 kappa). In six cases the glomerular deposits were analyzed for light chains. In three the deposits contained kappa only, and three consisted of both kappa and lambda. In two cases the immune aggregates were confined to the mesangium, and in the remaining eight cases, the deposits were present in the mesangium and the glomerular basement membranes. Electron-dense deposits composed of microtubules were present in the same distribution within the glomerulus as the immune reactants. The microtubules had a uniform diameter in each biopsy, but they varied in size from case to case. They were approximately the same size in eight cases (mean, 22.3 +/- 3 [SD] nm). Three cases had much larger microtubules: 34.2 nm, 35.4 nm, and 48.9 nm in diameter. Although the 22.3-nm microtubules resembled amyloid in their appearance, glomerular distribution and random orientation in the tissue, they were more than twice the diameter of amyloid (8.9 nm), and Congo red and thioflavin T stains for amyloid were negative. Similar microtubular structures have been described in patients with cryoglobulinemia, SLE and paraproteinemia, but these diseases were excluded in our patients on clinical, serologic and in some cases histologic grounds. More important, none of our patients had clinical or histochemical evidence of amyloidosis, an entity which may be confused with immunotactoid glomerulopathy on a morphologic basis. Follow-up, from 22 to 94 months (mean, 52.6) was obtained in all 11 patients, and 2 clinical courses were noted. Six patients had progressive deterioration of renal function, with five requiring dialysis. This group had severe hypertension (4/6) and nephrotic-range proteinuria (5/6) at some point in their course. The remaining five patients with stable renal function had proteinuria of less than 2.0 g/24 hr in most cases (4/5), and none had severe hypertension. This dichotomy correlated with the distribution of immunotactoids.(ABSTRACT TRUNCATED AT 400 WORDS)

Pulmonary hemorrhage in systemic lupus erythematosus.

The clinicopathological features of four patients with systemic lupus erythematosus and pulmonary hemorrhage are described. Our study confirms that pulmonary hemorrhage may be a dominant clinical expression of lung involvement in this disease. Its clinical manifestations are usually quite characteristic. However, hemoptysis may be absent. Radiographically, bilateral alveolar infiltrates resembling pulmonary edema or infection may be seen. Pulmonary hemorrhage was a major contributing factor to the death of three of our patients. The possible pathogenetic mechanisms responsible for pulmonary hemorrhage in our patients and other patients previously recorded in the literature are reviewed. Evidence supporting an immune complex pathogenesis is presented. Our immunopathological and ultrastructural studies demonstrate deposition of immune aggregates in the lungs in the alveolar septa, large blood vessels, and bronchioles in a manner similar to that which has been observed in the experimental serum sickness model of immune complex mediated pulmonary injury. The histological abnormalities, although nonspecific, are consistent with this interpretation, and collectively show diffuse alveolar lining cell and endothelial cell injury. However, an immune complex pathogenesis may not completely explain the occurrence of pulmonary hemorrhage in SLE. Other factors, including bleeding disorders, pulmonary infection, oxygen toxicity, and the "shock lung" syndrome, may also have contributed to lung hemorrhage in some of these patients.

Immune complex deposition and coronary vasculitis in systemic lupus erythematosus. Report of two cases.

Extramural coronary arteries were examined in two patients with systemic lupus erythematosus (SLE). Coronary vasculitis was found in both patients. One patient with clinically and serologically inactive SLE had died suddenly and was found to have a myocardial infarction secondary to the coronary vasculitis. Immunopathologic studies demonstrated immune reactants in the walls of inflamed and noninflamed arterial segments in a pattern consistent with immune complex aggregates. Immunologic injury secondary to immune complex deposition may be responsible for the development of coronary disease in patients with SLE. This has been demonstrated in experimental animals but not in humans. Although this is an uncommon complication of SLE, it represents a cause of sudden death and a potentially treatable lesion in this patient population. Its occurrence may be related to the deposition of immune aggregates in the walls of coronary vessels.

Immunopathology of cardiac lesions in fatal systemic lupus erythematosus.

Immunopathologic studies were performed on cardiac tissue obtained at autopsy in 10 patients with severe systemic lupus erythematosus (SLE). The immunopathologic findings were correlated with histopathologic and clinical evidence of cardiac injury, and with clinical and serologic features of SLE. Immune reactants were demonstrated by direct immunofluorescence in nine patients in a granular deposition pattern suggesting immune complex aggregates. Histologic and gross anatomic findings of inflammation were generally more focal than was the distribution of immune reactants. Most of the immune deposits were present in the walls of the blood vessels of myocardium (eight of 10) or pericardium (two of three). In one patient with Libman-Sacks endocarditis, immunoglobulin and complement components were present in the valve stroma and the vegetations. The immune deposits around epicardial nerve fibers in two patients with severe neurologic manifestations contained immunoglobulin E(IgE). In general, the most intense and widespread immune deposits were observed in patients with persistently increased serologic and clinical evidence of activity of their systemic disease. These results suggest a role for immune complex deposition in the pathogenesis of the cardiac lesions of SLE.

Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group.

In 1992, we published the results of a prospective, controlled trial of aggressive therapy (high-dose prednisone plus oral cyclophosphamide alone or with plasmapheresis) in 86 patients with severe lupus nephritis. During this study, remission (serum creatinine < or =1.4 mg/dL [< or =123 micromol/L] and proteinuria < or =330 mg/d of protein) in renal disease occurred in 37 patients (43%). To assess the long-term effect of remission on patient and renal survival, we now report the results of our extended follow-up of these patients. After an average of 10 years of follow-up in the 86 patients, patient survival rates at both 5 and 10 years were 95% in the group that had a remission and 69% at 5 years and 60% at 10 years in the no-remission group (P < 0.001). Renal survival rates were 94% at both 5 and 10 years in the remission group compared with 46% at 5 years and 31% at 10 years in the no-remission group (P < 0. 0001). Features predictive of remission included stable renal function after 4 weeks on therapy, category IV lesion, lower chronicity index, white race, lower urine protein excretion level at baseline, and lower baseline serum creatinine level. The features predictive of end-stage renal disease were higher baseline serum creatinine level, presence of anti-Ro antibodies, and failure to attain a remission. Thus, in patients with the most severe forms of lupus nephritis, a remission of clinical renal abnormalities is associated with dramatic improvement in long-term patient and renal survival.

Necrotizing glomerulitis of systemic lupus erythematosus.

The authors report four cases of systemic lupus erythematosus (SLE) with severe, active glomerulonephritis. Associated with histologic evidence of glomerular inflammation were focal, predominantly mesangial immune reactants. This finding contrasts with reports that massive subendothelial electron-dense deposits are the ultrastructural feature that correlates best with the severity of glomerular inflammation. The patients studied had significantly fewer subendothelial electron-dense deposits than did other patients with SLE with comparable glomerular lesions (8 +/- 3 per cent versus 42 +/- 14 per cent of glomerular capillaries involved, respectively; P less than 0.05). In addition, serologic evidence of disease activity, assessed by measurement of serum levels of C3, C4, circulating immune complexes (cryoglobulins), and serum antinative DNA activity, was either normal or only mildly abnormal. The lack of correlation between the severity of glomerular lesions on the one hand and the paucity of glomerular immune reactants and mild serologic abnormalities on the other may be interpreted as questionable evidence that these cases of glomerulonephritis were mediated by immune complexes. In the light of recent clinical and experimental studies that support a possible role for cell-mediated immunity in the pathogenesis of glomerulonephritis, the authors propose that a role for cell-mediated hypersensitivity be considered.

Pathologic changes in the renal tubule in systemic lupus erythematosus.

Interstitial nephritis may be prominent morphologic feature in systemic lupus erythematosus (SLE), but there are limited data relating the pathologic findings to renal function impairment. We studied 69 biopsy specimens from 55 patients by light, fluorescence, and electron microscopy and compared the results with the serum creatinine levels. The relative interstitial volume, a measure of tubular damage and interstitial expansion, was the only morphologic feature that correlated well with renal function (serum creatinine level). Fifty-nine per cent of the biopsy specimens studied by fluorescence microscopy and 31 per cent of the biopsy specimens studied by electron microscopy had extraglomerular deposits. Ultrastructural studies determined that the sites of the deposits were the tubular basal lamina in five cases, the peritubular capillaries in four, and both in 12. In addition, the deposits were irregularly deposited along the nephron, with examples of isolated proximal and distal tubular involvement. Ultrastructural changes in the tubular basal lamina were interpreted as reparative responses to injury. Tubular pathologic features included reduplicated basal lamina and the apparent incorporation of electron-dense deposits and cellular debris. These data support the concept of a role for immune deposits in the pathogenesis of the tubulointerstitial lesion in SLE.

Severe lupus nephritis: importance of re-evaluating the histologic classification and the approach to patient care.

The histopathology of severe lupus glomerulonephritis comprises distinct patterns of injury which were initially defined by the World Health Organization Classification of 1982 as focal and segmental glomerulonephritis (category III), diffuse proliferative glomerulonephritis (category IV) and complex membranous glomerulonephritis (categories Vc, Vd). It is assumed that the morphologic abnormalities demonstrated in this classification represent distinctive differences in the mediation of the immune response which leads to a specific type of glomerular inflammation. In 1995 the World Health Organizational committee recommended a change in categorization of focal and segmental glomerulonephritis (class III) and diffuse proliferative glomerulonephritis (class IV), which would overlook the morphological differences between these categories and treat them as a continuum, recommending that biopsies classified as focal and segmental glomerulonephritis (category III) with involvement of > or =50% of glomeruli be included into the diffuse proliferative glomerulonephritis category (category IV). Since the classification of severe lupus nephritis has significant impact on prognosis and the therapeutic approach to patients with this disease, it is the purpose of this review to critically re-examine the existing classification based on new insights into differences in morphologic features and long-term outcome.

Necrotizing glomerulonephritis in rheumatoid arthritis.

Rheumatoid arthritis may be associated with several glomerular lesions including amyloidosis, mesangial proliferation and membranous glomerulonephritis. Systemic vasculitis is a well-recognized extra-articular complication of rheumatoid arthritis, but necrotizing glomerulonephritis, the glomerular expression of vasculitis, has been described infrequently. This report comprises four patients with rheumatoid arthritis who underwent renal biopsy for declining renal function, proteinuria and active urine sediments. Pathology revealed that three patients had segmental necrotizing glomerulonephritis without significant glomerular immunoglobulin deposition. The fourth had segmental necrosis associated with diffuse membranous glomerulonephritis. We conclude that necrotizing glomerulonephritis is part of the spectrum of glomerular lesions seen in patients with rheumatoid arthritis. Because of therapeutic considerations involving the use of cyclophosphamide, necrotizing glomerulonephritis should be a diagnostic consideration in the rheumatoid arthritis patient with signs of glomerulonephritis and rapidly deteriorating renal function.

Acute renal failure following halothane anesthesia.

Acute renal failure was observed postoperatively in a patient after halothane anesthesia. The clinical and pathologic findings in this case were remarkably similar to those found in patients with renal failure after methoxyflurane anesthesia.