Bladder tumors in rats fed cyclohexylamine or high doses of a mixture of cyclamate and saccharin.

Papillary transitional cell tumors were found in the urinary bladders in 8 rats out of 80 that received 2600 milligrams per kilogram of body weight per day of a mixture of sodium cyclamate and sodium saccharin (10:1) for up to 105 weeks. From week 79 on, several of these rats received cyclohexylamine hydrochloride (125 milligrams per kilogram per day, the molecular equivalent of the conversion of about 10 percent of the cyclamate dosage to cyclohexylamine) in addition to the sodium cyclamate and sodium saccharin. In another study in which 50 rats were fed daily 15 milligrams of cyclohexylamine sulfate per kilogram of body weight for 2 years, eight males and nine females survived. One of the eight males had a tumor of the urinary bladder. In neither study were bladder tumors found in the control rats or in rats treated with lower doses of the compounds.

The effects of glucose and cyclic GMP on RNA synthesis and nuclear morphology in starved rats.

Feeding rats in diet high in glucose has been demonstrated to inhibit the induction of many enzymes, block the action of glucocorticoids, and, in general, appears to result in decreased cyclic AMP activity. We found that glucose feeding depresses both messenger RNA (mRNA) and non-mRNA synthesis. Electron microscopic examination of the nucleus revealed that glucose feeding decreases the granular component of liver cell nucleoli. It only slightly decreases liver cyclic AMP levels, but produces a sixfold elevation in levels of the cyclic AMP antagonist, cyclic GMP. Administration of bromocyclic GMP, like glucose feeding, depresses mRNA synthesis, but does not simulate the effect of the carbohydrate on nuclear morphology. In addition, glucose feeding halves liver inorganic phosphate and triples ATP levels. Phosphorylation of nuclear proteins, however, remains unaltered. Despite the antagonism between glucose feeding and glucocorticoid activity, the former compound did not change the binding of dexamethasone to liver nuclei.

Membranous lupus nephropathy initially seen as idiopathic membranous nephropathy. Possible diagnostic value of tubular reticular structures.

When a renal lesion is the sole manifestation of systemic lupus erythematosus (SLE), differentiation from other nephropathies is difficult. The membranous form of lupus nephritis is especially difficult to distinguish from idiopathic membranous nephropathy, particularly when multisystem and serologic features of SLE are absent. We report two cases in which the initial renal biopsy findings suggested idiopathic membranous nephropathy and in which the subsequent emergence of SLE might have been predicted by the presence of tubular reticular structures. We identified these structures in 177 of 183 (96.7%) renal biopsy specimens from patients with SLE, but in only three of 128 (2.3%) renal specimens from patients with membranous nephropathy. Tubular reticular structures are markers of the renal lesion of SLE and may be helpful in differentiation from membranous nephropathy.

Cure of membranous nephropathy after resection of carcinoma.

Clinical cure was effected in two patients with biopsy-proved membranous nephropathy associated with neoplasms. One had a complete histologic remission as well. The incidence of malignancy in an unselected group of patients with membranous nephropathy in our institution was 9%. Careful workup in all patients over age 40 years with membranous nephropathy should be done to exclude tumor.

Red blood cell casts in acute interstitial nephritis.

A 45-year-old woman receiving hydralazine and hydrochlorothiazide therapy was found to have a reduced glomerular filtration rate, a positive antinuclear antibody reaction, and RBC casts in the urinary sediment. Glomeruli with normal morphology (light, immunofluorescence, electron microscopy) were found on renal biopsy; however, a mild interstitial nephritis was observed that predominantly involved the distal tubules. The etiology of this inflammatory process is unknown. Changes in distal tubular function correlated with the morphology: acidification was impaired whereas concentrating ability was normal. Although RBC casts have been thought to be diagnostic of glomerular diseases, the present case demonstrates that tubulointerstitial disease can be responsible for RBC cast formation.

Light-chain glomerulopathy with amyloid-like deposits.

A 40-year-old man with rapidly progressive renal failure was found to have a lobular glomerulonephritis by renal biopsy. Immunofluorescent microscopy showed prominent glomerular deposition of both kappa and lambda light chains but no significant heavy-chain component. Ultrastructurally, electron-dense deposits in the mesangium and capillary basement membranes had a fibrillar appearance indistinguishable from amyloid. This case illustrates a "light-chain glomerulopathy" distinct from previously reported glomerulopathies associated with the deposition of light chains of a single subclass.

Single light chain subclass (kappa chain) immunoglobulin deposition in glomerulonephritis.

Renal glomerular disease characterized by the deposition of immunoglobulin light chains or monoclonal immunoglobulins was demonstrated by immunofluorescence microscopy in 11 patients. The most common histopathologic findings were those of mesangiocapillary glomerulonephritis, but considerable variability was observed. Lesions resembling diabetic glomerulosclerosis and amyloidosis were seen in some patients. Immunofluorescence findings in seven patients showed concomitant, equally intense staining for kappa light chain and immunoglobulin heavy chain (IgG or IgA), indicative of monoclonal immunoglobulin deposition. Specimens in the remaining cases stained predominantly for kappa light chain alone. In six cases the histologic and ultrastructural pattern was similar to that of type I mesangiocapillary glomerulonephritis. In three cases linear deposits were present, predominantly in subendothelial and inner glomerular basement membranes and, to a lesser degree, in mesangial locations, as in type II mesangiocapillary glomerulonephritis. In one of the latter cases dense deposits were intermixed with aggregates of amorphous fibrillar material indistinguishable from amyloid. In two cases involving IgA kappa chain deposition the histologic and ultrastructural appearance was that of mesangial glomerulonephritis. Considerable heterogeneity was found in the clinical features of the patient population. Specific clinical or serologic parameters for this disease could not be identified. Only one patient had an associated lymphoplasmacytic disorder. After follow-up periods ranging from six months to 17 years, all of the patients were alive, including four who had progressed to end-stage renal disease and required dialysis. Two of the latter patients underwent successful renal transplantation; one had been alive for five years and the other for three months without evidence of recurrence of the renal disease at the last follow-up examination.

Chondroid chordoma. A hyalinized chordoma without cartilaginous differentiation.

"Chondroid chordoma" is a controversial and confusing entity that was originally described by Heffelfinger and colleagues as a biphasic malignant neoplasm possessing elements of both chordoma and cartilaginous tissue. Because the premise for this distinction was based strictly on histomorphologic criteria, the light microscopic, immunohistochemical, and electron microscopic features of the chondroid and chordoid areas of five chondroid chordomas of the skull base were evaluated separately, and compared to five typical chordomas and six low grade chondrosarcomas. Using light microscopy, chondroid chordoma revealed areas that resembled typical chordoma (chordoid areas) and areas that resembled low grade chondrosarcoma (chondroid areas). However, both the chordoid and chondroid areas had an epithelial phenotype and stained strongly for cytokeratin and EMA as well as S-100. 5'-nucleotidase, an enzyme that has been described in chordoma but not in chondrosarcoma, was found in both the chordoid and chondroid areas of one chondroid chordoma. Electron microscopic studies of both the chordoid and chondroid areas in four of the tumors demonstrated both tonofibrils and desmosomes. Chordoma demonstrated immunohistochemical and electron microscopic features that were nearly identical to chondroid chordoma. Chordoma was cytokeratin, EMA, S-100, and 5'-nucleotidase positive. Ultrastructurally, chordoma exhibited variably-sized vacuoles, abundant rough endoplasmic reticulum (RER), and desmosomes with tonofilaments. In contrast to chondroid chordoma, chondrosarcoma consistently stained for only S-100 protein and was cytokeratin, EMA and 5'-nucleotidase negative. Ultrastructurally, chondrosarcoma demonstrated a flocculogranular matrix, glycogen, abundant RER, and scalloped cellular outlines, but lacked desmosomes with tonofilaments. These findings indicate that "chondroid chordoma" is a variant of chordoma with histologic features that may mimic chondrosarcoma. Despite the resemblance of these hyalinized areas to cartilaginous tissue, these tumors retain their epithelial phenotype. Biphasic differentiation is not present. These findings undermine the original premise for distinguishing "chondroid chordoma" from typical chordoma. The authors propose that these tumors be classified as "hyalinized chordomas," rather than "chondroid chordoma," to clarify their histogenesis and avoid confusion with chondrosarcomas of the base of the skull.

Idiopathic lobular glomerulonephritis (nodular mesangial sclerosis): a distinct diagnostic entity.

Lobular glomerulonephritis is an entity first thought to have represented a primary disease of uncertain histogenesis, but more recently has generally been considered to represent a morphologic variant of membranoproliferative glomerulonephritis. We have encountered five patients who were found to have a lobular glomerulonephritis by renal biopsy, but in whom features of membranoproliferative glomerulonephritis types I, II, or III, could not be demonstrated and in whom alternate known diagnostic categories could be excluded. We suggest that lobular glomerulonephritis, or alternately, idiopathic nodular mesangial sclerosis, is an uncommon but persistent disease entity with a distinctive pathologic appearance and unknown pathogenesis.

Membranous nephropathy: its relative benignity in women.

By means of renal biopsy and light, immunofluorescence, and electron microscopy, a diagnosis of membranous nephropathy (MN) was made in 100 patients. The nephrotic syndrome was present in 83 of these patients. 65 of the patients were men and 35 were women. The average period of follow-up was 99.8 months. As judged by the incidence of death and of improvement or complete healing, the women fared better than the men, whether given high-dose alternate-day prednisone therapy or not. The incidence of improvement or complete healing in the patients given prednisone was higher than the reported for patients who were not given corticosteroids. We have shown that occurrence of MN is more frequent in women than men and the course of MN is more benign in women than in men; alternate-day prednisone therapy appears to be beneficial in patients with MN.

Membranous nephropathy: high-dose alternate-day therapy with prednisone.

Fifteen cases were selected for study from 100 consecutive cases of membranous nephropathy diagnosed by renal biopsy and light, immunofluorescence, and electron microscopy. The cases were chosen because during a pretreatment observation period ranging from 8 to 66 months (median, 18 months), the patients' disease state had progressed. Data gathered during this period served as a baseline against which to evaluate the effects of treatment with prednisone; thus, the patients served sequentially as their own controls. All but one of the patients had nephrotic syndrome, and 11 had renal insufficiency. Treatment with prednisone administered on alternate days was accompanied by decreasing proteinuria and increasing serum levels of albumin in all the patients. Healing, defined as proteinuria of no greater than 0.2 grams per 24 hours for at least a year with maintenance of normal creatinine clearance, occurred in eight patients. Renal function, judged by rate of creatinine clearance or level of creatinine in serum, improved in all 11 patients with renal insufficiency; in eight of these, normal function was attained. Poor renal function could not be attributed to diminished blood volume measured by chromium 51 red-blood-cell tag.

Glomerular basement membrane attenuation in familial nephritis and "benign" hematuria.

Lamination of the basement membrane has been considered to be the lesion characteristic of familial nephritis and attenuation to be the lesion of "Benign" familial hematuria. Electron micrographs were reviewed of 57 children who had renal biopsies for persistent hematuria. Attenuation or lamination of the glomerular capillary basement membrane was found in each. Twenty of the 57 children had familial nephritis; 20 had familial hematuria; and 17 had no involved relatives. Follow-up data were available for 14 of 20 children with familial nephritis, 12 of 20 with familial hematuria, and 12 of 17 with sporadic hematuria for 13.6 +/- 6.3, 6.7 +/- 4.6, and 7.0 +/- 4.8 years, respectively, after discovery of hematuria. Five children developed end-stage renal disease: three with familial nephritis, one with familial hematuria, and one with sporadic hematuria. Only two no longer had hematuria. Attenuation of the glomerular capillary basement membrane was seen in every biopsy, whereas lamination was not. Because hematuria and ultrastructural abnormalities were findings shared by all the children, we suggest the possibility that familial nephritis, and familial or sporadic hematuria as defined in this study, may be variations in a spectrum of inherited abnormality or abnormalities in the formation of the glomerular capillary basement membrane.

Crescentic glomerulonephritis associated with nonrenal malignancies.

A review of 80 patients with the renal biopsy diagnosis of idiopathic glomerulonephritis with extracapillary proliferation (crescentic GN) disclosed 7 cases with a coexistent nonrenal malignancy; 6 carcinomas and 1 lymphoma. In a control group of 80 patients with the renal biopsy diagnosis of minimal change or focal segmental glomerulosclerosis, only 1 case of coexistent malignancy was found (chi-square = 4.74, p less than 0.05). All of the malignancies occurred in patients older than 40 years of age and the prevalence of malignancy in patients with crescentic GN over the age of 40 was 20%. Light microscopy, immunofluorescence, and electron microscopy revealed fibrin deposition in all cases and no evidence of anti-GBM or immune complex disease. 3 patients experienced a rapidly progressive course while renal function improved in 4 patients following treatment of the underlying malignancy. The pathogenic mechanisms leading to crescentic GN in patients with malignancy are unknown; however, the high prevalence of malignancy in crescentic GN patients older than 40 along with the improvement during the treatment of the underlying malignancy suggests an etiological relationship.

Membranous nephropathy: predictors of terminal renal failure.

By univariate analysis of patients with membraneous nephropathy, terminal renal failure was associated with male sex, a large amount of proteinuria, low serum albumin concentration, low creatinine clearance rate, high serum creatinine concentration, and high systolic blood pressure, but was not associated with age or prednisone treatment. In a multivariate life table analysis that controlled for all these factors simultaneously, the risk of developing terminal renal failure was significantly independently associated only with sex, serum albumin concentration, and prednisone treatment, being higher in men, lower in those treated with prednisone, and inversely related to serum albumin. Except for the minimal electron-dense deposition, the electron microscopic findings had no predictive value.

Late development of systemic lupus erythematosus in patients with glomerular "fingerprint" deposits.

Two patients presenting with nephrotic syndrome but without evidence of collagen vascular disease had organized glomerular immune deposits with a "fingerprint" pattern. This finding has been previously associated with lupus nephritis and, in our institution, has been seen in 6% of the biopsy specimens from patients with lupus nephritis. Clinical signs and symptoms of systemic lupus erythematosus in these two patients did not develop until 2 and 5 years later, respectively. The cases of these patients suggest that glomerular deposits with a fingerprint pattern may be a specific marker for lupus erythematosus even when overt clinical features of this disease are lacking. Patients with this finding on renal biopsy should have an extended follow-up for possible development of lupus erythematosus.