Benjamin H. Spargo

Changing etiologies of unexplained adult nephrotic syndrome: A comparison of renal biopsy findings from 1976–1979 and 1995–1997

Data compiled during the 1970s and early 1980s indicated that during these periods, membranous nephropathy was the most common cause of unexplained nephrotic syndrome in adults, followed in order of frequency by minimal-change nephropathy and focal segmental glomerulosclerosis (FSGS). However, we and others recently reported an increase in the incidence of FSGS over the past two decades, and the number of cases of FSGS diagnosed by renal biopsies in these centers now exceeds the number of cases of membranous nephropathy. Nonetheless, as a substantial fraction of patients with FSGS do not have the nephrotic syndrome, it remained unclear as to what extent the relative frequencies of FSGS and other glomerulopathies as causes of the nephrotic syndrome have changed over this time. To address this concern, we reviewed data from 1,000 adult native kidney biopsies performed between January 1976 and April 1979 and from 1,000 biopsies performed between January 1995 and January 1997, identified all cases with a full-blown nephrotic syndrome of unknown etiology at the time of biopsy, and compared the relative frequencies with which specific diseases were diagnosed in these latter cases between the two time intervals. The main findings of this study were that, first, during the 1976 to 1979 period, the relative frequencies of membranous (36%) and minimal-change (23%) nephropathies and of FSGS (15%) as causes of unexplained nephrotic syndrome were similar to those observed in previous studies during the 1970s and early 1980s. In contrast, from 1995 to 1997, FSGS was the most common cause of this syndrome, accounting for 35% of cases compared with 33% for membranous nephropathy. Second, during the 1995 to 1997 period, FSGS accounted for more than 50% of cases of unexplained nephrotic syndrome in black adults and for 67% of such cases in black adults younger than 45 years. Third, although the relative frequency of nephrotic syndrome due to FSGS was two to three times higher in black than in white patients during both study periods, the frequency of FSGS increased similarly among both racial groups from the earlier to the later period. Fourth, the frequency of minimal-change nephrotic syndrome decreased from the earlier to the later study period in both black and white adults. Fifth, the relative frequency of membranoproliferative glomerulonephritis as a cause of the nephrotic syndrome declined from the 1976 to 1979 period to the 1995 to 1997 period, whereas that of immunoglobulin A nephropathy appeared to increase; the latter accounted for 14% of cases of unexplained nephrotic syndrome in white adults during the latter study period. Finally, 10% of nephrotic adults older than 44 years had AL amyloid nephropathy; none of these patients had multiple myeloma or a known paraprotein at the time of renal biopsy.

IgA nephropathy: morphologic predictors of progressive renal disease.

IgA nephropathy has a variable course and leads to renal failure in a substantial number of cases. In an attempt to identify prognostic indicators in this disease, we evaluated the clinical and pathologic findings of 20 unselected patients with IgA nephropathy, 13 of whom were followed for 1.5 to 5 years (mean 2.8 years). Biopsy specimens were obtained from all patients and were examined by light and electron microscopy and by immunofluorescence. The activity and severity of the lesions were graded according to a modified classification used by Meadow et al. for the nephropathy associated with Henoch-Schönlein purpura. The results reveal a correlation between the histopathologic grading in the initial biopsy and the clinical outcome: Patients with mild (grade II) or moderate (grade III) lesions had a benign course or showed evidence of active disease without deterioration of renal function, whereas all patients with grade IV or V lesions who were followed for more than one year developed end-stage renal failure. These observations suggest that histologic grading at initial renal biopsy may be a useful prognostic indicator of the clinical outcome of IgA nephropathy.

Etiologies and outcome of acute renal insufficiency in older adults: A renal biopsy study of 259 cases

Acute renal insufficiency is a common problem, yet one that is frequently reversible with proper diagnosis and treatment. Although it has been argued that a renal biopsy is not needed for diagnosis in most cases of acute renal failure in the elderly, other studies have shown frequent disagreements between clinical and renal biopsy diagnoses in such cases. To investigate the causes of acute renal insufficiency in patients aged at least 60 years who underwent a renal biopsy and possible correlations between biopsy findings and renal survival, we first identified all native renal biopsy specimens from patients aged 60 years or older processed at The University of Chicago Medical Center (Chicago, IL) from 1991 through 1998 and reviewed the clinical records to determine the indication for the biopsy. We then reviewed again the records of those patients who underwent biopsy because of acute renal insufficiency, recorded the primary renal biopsy diagnosis in each of these cases, and obtained follow-up information for patients who underwent biopsy before July 1996. During the study period, 1,065 of 4,264 biopsy specimens (25.0%) received were obtained from patients aged 60 years or older, and acute renal insufficiency was the indication for biopsy in 259 of these patients (24.3%). The most frequent primary diagnoses on these latter biopsy specimens were pauci-immune crescentic glomerulonephritis (GN) with or without arteritis, 31.2% of biopsy specimens; acute interstitial nephritis, 18.6%; acute tubular necrosis (ATN) with nephrotic syndrome, 7.5%; atheroemboli, 7.1%; ATN alone, 6.7%; light chain cast nephropathy (LCCN), 5.9%; postinfectious GN, 5.5%; anti-glomerular basement membrane antibody nephritis, 4.0%; and immunoglobulin A (IgA) nephropathy and/or Henoch-Schönlein nephritis, 3.6%. Eight biopsy specimens (3.2%) showed only benign nephrosclerosis without an apparent cause of acute renal insufficiency, and another six specimens were inadequate. The renal biopsy diagnosis was in agreement with the prebiopsy clinical diagnosis (or differential diagnosis) in 107 of the 161 cases (67%) in which such information was provided. The distribution of diagnoses was similar in patients in the age groups of 60 to 69, 70 to 79, and 80 years or older, although younger age correlated significantly with improved renal and patient survival. The relative risk for progression to end-stage renal disease (ESRD) also increased according to diagnostic categories: LCCN (greatest risk) > GN other than pauci-immune > atheroemboli congruent with pauci-immune crescentic GN > tubulointerstitial diseases other than LCCN (the latter category including ATN with nephrotic syndrome). Development of ESRD correlated significantly with decreased patient survival. In summary, renal biopsy in patients aged 60 years or older with acute renal insufficiency uncovered the cause in greater than 90% of the cases and provided clinically useful information with respect to expectation for renal survival and potential treatment options.

Glomerular deposition of tumor antigen in membranous nephropathy associated with colonic carcinoma

Abstract Renal biopsy in a 60 year old man with idiopathic nephrotic syndrome revealed the characteristic light, immunofluorescent and electron microscopic features of membranous nephropathy. Elevated serum levels of carcinoembryonic antigen (CEA) were present, and a colonic carcinoma was found and resected. CEA could not be demonstrated in the glomerular immune deposits. An antibody was demonstrated in the patients serum 1 week after resection of the tumor which was reactive with an antigen deposited on the glomerular basement membrane. This reactivity was specifically abolished by absorption of the serum with homogenates of the patients tumor, but it was not altered by absorption with normal colon, colonic polyps, liver or spleen. The nephrotic syndrome persisted after resection of the tumor. A renal biopsy 4 months later showed evidence of complex resolution, and the tumor-associated antigen was no longer detectable in glomeruli. The nephrotic syndrome associated with colonic carcinoma in this patient appeared to be mediated by glomerular deposition of immune complexes containing a tumor antigen. Apparent complete removal of the source of antigen was followed by evidence of complex resolution but had no effect on the nephrotic syndrome.

Neuropsychiatric problems in mixed connective tissue disease

A group of 20 patients with mixed connective tissue disease, followed for up to five years, was found to have a 55 per cent incidence of neuropsychiatric problems. An aseptic meningitis-like syndrome was the most common presentation and was rapidly responsive to corticosteroid therapy. Other findings were psychosis, convulsions, peripheral neuropathy, trigeminal neuropathy and cerebellar ataxia. An abnormal cerebrospinal fluid was found in five patients; mild pleocytosis, an increased protein content and a first phase colloidal gold curve were the main abnormalities. These neuropsychiatric problems have not been a cause of mortality in this group of patients with mixed connective tissue disease.

C-type virus expression in systemic lupus erythematosus.

Kidneys from patients with lupus nephropathy, non-lupus immune-complex glomerulonephritis and other renal diseases were examined by indirect immunofluorescence for antigens related to a C-type virus from human cells (HEL-12 virus). All 11 specimens of lupus nephropathy contained HEL-12 virus antigens deposited in the same pattern as the immune complexes. The intensity of immunofluorescence with anti-HEL-12 virus serum correlated with the extent of immune-complex deposition. In contrast, nine renal lesions other than lupus nephropathy and seven normal tissues did not react with anti-HEL-12 virus serum. Antibody eluted from one kidney with lupus nephropathy reacted by indirect immunofluorescence with human and dog cells infected with HEL-12 virus but not with uninfected control cells. These findings demonstrate a specific association of lupus nephropathy with a C-type viral antigen that is deposited as antigen-antiviral antibody complex.

Endocytosis of Calcium Oxalate Crystals and Proliferation of Renal Tubular Epithelial Cells in a Patient with Type 1 Primary Hyperoxaluria

A patient with primary hyperoxaluria who received a liver-kidney transplant is presented. A postoperative renal biopsy showed apparent tubular cell endocytosis of calcium oxalate crystals and cell proliferation, indicating that renal epithelial cells do not perceive urinary crystals as inert. Such cellular responses to crystals may have a role in nephrolithiasis.

Immune Complex Nephropathy in Mixed Connective Tissue Disease

Initial reports on the clinical spectrum of mixed connective tissue disease (MCTD) indicated that renal involvement was uncommon. Four of 20 patients with MCTD underwent renal biopsy and all showed evidence of immune complex trapping with a membranous glomerulonephritis in three patients. Clinically evident renal disease was absent in two patients. These findings suggest that renal involvement in MCTD may be more prevalent than previously indicated.

Course of renal pathology in patients with systemic lupus erythematosus

Evaluation of the course of lupus nephropathy by serial kidney biopsy in 50 patients revealed a complex pattern of transitions from one histologic class to another. A high rate of transformations (56 percent) was observed, with fewer than half the patients remaining in the original category. Although the general trend was towards transformation to a less severe lesion (WHO classes III and IV transforming into classes II and V), this was certainly not the rule for all individual classes. These transformations were rarely predictable on the basis of available clinical, laboratory, or pathologic information, and were less common in younger patients. These results help clarify the pathologic behavior of lupus nephropathy in the modern therapeutic era and highlight the value of pathologic examination for the planning and evaluation of therapy in selected patients.

Clinicopathological Correlations in Idiopathic Nephrotic Syndrome with Membranous Nephropathy

The separation of patients with idiopathic nephrotic syndrome into those with lipoid nephrosis and membranous nephropathy on the basis of ultrastructural study of renal biopsy material is supported by contrasts in the natural history and response to therapy of the groups. Nineteen patients with the latter lesion have been followed for periods of up to eleven years. Nine are known to have expired with a mean duration of clinical illness of six years. Nine survivors are known with a mean duration of clinical illness of 5.3 years. Corticosteroid therapy rarely appears to provide sustained clinical improvement. However, remissions with loss of clinical features of the illness have been observed in five patients. Serial renal biopsies indicate the morphologic lesion is usually unchanged or progressive, despite subsidence of proteinuria and clinical remission. In one patient a renal biopsy in her third year of remission showed striking regression of a previously marked membranous change. Morphologic differentiation from renal involvement with systemic lupus erythematosus may be difficult and diagnosis depends on evidence of multisystem disease and additional laboratory studies. Review of reported immunofluorescent studies of biopsy material and comparison with experimental lesions suggest the glomerular membranous lesion is immunologically determined.