Changing incidence of glomerular diseases in adults.

Studies performed at large metropolitan medical centers have reported an increasing incidence of idiopathic focal segmental glomerulosclerosis (FSGS) in adults. To determine whether a similar trend occurs in small urban and rural communities and to determine the role of race in these observations, we reviewed the patient records of all adults who underwent renal biopsies at our institution over the 20-year period from 1974 to 1994. The patients were grouped for analysis in 5-year intervals, 1975 to 1979, 1980 to 1984, 1985 to 1989, and 1990 to 1994, for the following diagnoses: FSGS, membranous nephropathy (MN), minimal change nephropathy (MCN), membranoproliferative glomerulonephritis (MPGN), immunoglobulin A (IgA) nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, and chronic interstitial nephritis. Patients with secondary causes for these lesions were excluded. The relative frequency of FSGS increased from 13.7% during 1975 to 1979 to 25% during 1990 to 1994 (P < 0.05). The relative frequency of MN decreased from 38.3% during 1975 to 1979 to 14.5% during 1990 to 1994 (P < 0.01). There were no changes in the frequencies of MCN, MPGN, IgA nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, or chronic interstitial nephritis over the 20-year period. However, there was a significant increase in the percentage of blacks with FSGS, from 0% in 1975 to 1979 to 22.6% in 1990 to 1994, and an increased percentage of Hispanics with FSGS, from 0% in 1975 to 1979 to 21.3% in 1990 to 1994 (P < 0.05). The modest increase in whites with FSGS did not reach statistical significance. The incidence of MN in blacks and whites decreased over the 20-year period. In the last 5 years, 15 patients per year had FSGS compared with 7 patients per year with MN (P < 0.05). No changes in age or sex between groups or over time accounted for these results. We conclude that FSGS is now diagnosed twice as often as MN and is the most common idiopathic glomerular disease at our hospital. Reasons for this increase include the emergence of FSGS in both Hispanics and blacks, with a modest increase of FSGS in whites. The increase in FSGS in the three most common races in our community suggests that factors other than genetic, perhaps environmental, have a role in the pathogenesis of FSGS.

Acquired renal cystic disease and adenocarcinoma following renal transplantation--a current urologic perspective.

Two patients treated with chronic dialysis and renal transplantation developed acute hemorrhage from a native kidney. Bilateral native nephrectomy demonstrated acquired cystic disease and adenocarcinoma in each of the four kidneys. The etiology of acquired cystic kidney disease (ACKD) is unclear and its incidence increases with the duration of dialysis. ACKD patients have a propensity to develop adenomas and adenocarcinomas. The increased incidence of renal neoplasms in ACKD patients warrants careful radiologic monitoring of native end-stage kidneys in selected patients.

Necrosis and apoptosis of polymorphonuclear cells exposed to peritoneal dialysis fluids in vitro.

Conventional peritoneal dialysis (PD) fluids are known to inhibit polymorphonuclear cells (PMN) phagocytosis, oxidative burst and enzyme release. However, the relative contributions of apoptosis and/or necrosis to this dysfunction have not been examined. We investigated the effects of osmolality, glucose concentration and heat-sterilization of PD fluids on necrosis and apoptosis of PMN. Polymorphonuclear cells were isolated from 8 healthy volunteers and exposed to different PD fluids for four hours. PMN were then double-stained with Hoechst 33342 and propidium iodide to study the proportion of viable, apoptotic and necrotic cells. Transmission electron microscopy (TEM) was performed to confirm the results obtained with flow cytometry. The fluids studied were conventionally heat-sterilized 1.5% Dianeal (1.5% D), conventionally heat-sterilized 4.25% Dianeal (4.25% D), 1.5% D in which the osmolality was increased to that of 4.25% D by adding mannitol (1.5% D + M), a filter-sterilized version of 4.25% D (4.25% D-F) and a 1.1% amino acid PD fluid (AA) (Nutrineal PD4). All PD fluids had their pH equilibrated (pH = 7.4) by the addition of sodium bicarbonate. Compared to PMN exposed to culture medium, a significantly higher proportion of necrosis was observed in PMN exposed to 1.5% D (P = 0.04). The 4.25% D induced greater necrosis than 1.5% D (P = 0.001), and the 4.25% D also induced significantly more necrosis (P = 0.002) compared to 4.25% D-F. These data suggest that the consequences of heat-sterilization, rather than high glucose concentration are responsible for the necrosis observed. Indeed, the proportion of necrotic PMN with 4.25% D-F was not significantly different from 1.5% D. The 1.5% D + M and AA induced significantly more apoptosis compared to 1.5% D (P = 0.006 and P < 0.05, respectively), suggesting that apoptosis can be induced by the high osmolality of PD fluids. However, 1.5% D +/- M also induced significantly more apoptosis (P = 0.007) compared to 4.25% D-F. This suggests that the apoptosis effect is specific for the osmolyte present in PD fluids, and that mannitol and amino acids induce more apoptosis than glucose. In summary, the different non-physiological components of conventional PD fluids evaluated in this study had a differential effect on PMN survival. Heat sterilization of high glucose-containing PD fluids was associated predominantly with necrosis of PMN, and high osmolality with apoptosis.

Chondroid syringoma of the scrotum.

A 65-year-old man presented with a 3.5 cm scrotal mass. Ultrasound showed a solid mass of indeterminate aetiology within the skin. Excisional biopsy revealed a benign chondroid syringoma. This is the first report of chondroid syringoma involving the scrotum.

Rapidly progressive glomerulonephritis after immunotherapy for cancer.

Cytokines have been used in experimental and standard protocols for immune enhancement for cancer. The combination of interleukin-2 and interferon-alpha 2 beta has been used in experimental protocols for metastatic renal cell carcinoma. A man who developed rapidly progressive renal failure after receiving this combination therapy is reported. A renal biopsy revealed a pauci-immune crescentic glomerulonephritis. Antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies were absent. The spectrum of renal disease and potentially related extrarenal manifestations associated with interleukin-2 and inteferon-alpha are reviewed. A pathogenesis of altered cell-mediated immunity, consistent with abnormalities in extrarenal organs after immune enhancement, is proposed.

Activation of bladder mast cells in interstitial cystitis: a light and electron microscopic study.

Interstitial cystitis, a sterile bladder condition, is characterized by urinary frequency, urgency, burning and suprapubic pain. Increasing evidence indicates that interstitial cystitis is a heterogeneous syndrome that reflects an immune response to a variety of triggers. More than 50% of the patients have allergies, 30% have the irritable bowel syndrome and almost 20% suffer from migraine headaches. Increased numbers of mast cells have been reported in interstitial cystitis. Mast cell activation, which is critical if these cells were to be implicated in this syndrome, has been investigated by electron microscopy, which definitively shows mast cell secretion. Recently, methylhistamine, the major metabolite of histamine, and the specific mast cell marker, tryptase, were shown to be significantly elevated in urine of interstitial cystitis patients. Bladder biopsies from 53 patients were analyzed blindly for the number and degree of activation of mast cells using 4 different stains for light microscopy, as well as electron microscopy. Controls included 16 patients with incontinence and chronic bacterial cystitis. Mast cells in controls were less than 10/mm.2 and were all nearly intact. Surprisingly, mast cells from 11 cancer patients averaged 50/mm.2 but almost all were intact. In contrast, mast cells from 26 interstitial cystitis patients averaged 40/mm.2 and more than 90% were activated to various degrees. Therefore, bladder mast cell activation is a characteristic pathological finding in at least a subset of patients with interstitial cystitis.

New matrix material for potential use in "reversible" vasectomy. Preliminary animal biocompatibility studies.

The biocompatibility of a new elastomeric-hydrogel matrix biomaterial for use as an intravasal occlusive device was assessed by inserting it into the vas deferens of dogs. The vas was removed and examined histologically after varying periods of time. The biomaterial resulted in total occlusion of the vas. Epithelial changes were limited to squamous metaplasia in areas adjacent to the implant. Changes in the subepithelium were minimal. This new material is biocompatible with the dog vas, and it has potential as an occlusive device for "reversible" vasectomy in men. Semen analysis studies are needed to assess the completeness and reversibility of the vasal occlusion achieved with this implant.

Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites.

To investigate the capacity of lupus autoAb to produce glomerular immune deposits (ID) and nephritis, 24 murine monoclonal (m) anti-DNA antibodies (Ab), derived from either MRL-lpr/lpr, SNF1 or NZB lupus-prone mice and selected based on properties shared with nephritogenic Ig, were administered i.p. (as hybridomas) and i.v. (as purified Ig) to normal mice; at least four mice/mAb were evaluated. Three general patterns of immune deposit formation (IDF) were observed: extracellular ID within glomeruli (+/- blood vessels, N = 8); intranuclear ID (N = 5); or minimal or no ID (N = 11). The four MRL m anti-DNA Ab that produced significant extracellular ID demonstrated different disease profiles including: (a) mesangial and subendothelial ID with anti-basement membrane staining, associated with proliferative glomerulonephritis, PMN infiltration, and proteinuria; (b) diffuse fine granular mesangial and extraglomerular vascular ID, associated with proliferative glomerulonephritis and proteinuria; (c) dense intramembranous ID and intraluminal ID, associated with capillary wall thickening, mesangial interposition and expansion, aneurysmal dilatation and intraluminal occlusion of glomerular capillary loops, and heavy proteinuria; and (d) mesangial and extraglomerular vascular ID, associated with mild segmental mesangial expansion, without proteinuria. These MRL mAb were derived from four different mice, and they had variable pIs and isotypes. They all cross reacted with multiple autoantigens (autoAg), however, their autoAg binding profiles were distinguishable. Among the SNF1 derived mAb, four produced histologically and clinically indistinguishable disease characterized by diffuse mesangial and capillary wall ID, associated with cellular proliferation/infiltration and proteinuria. Three of the four mAb were derived from the same mouse and were clonally related; they were: IgG2b with SWR allotype, relatively cationic, highly cross reactive with similar Ag binding patterns, idiotypically related and encoded by identical VH and nearly identical VL sequences. We conclude that both the capacity of lupus autoAb to form ID and the location of IDF are dependent on properties unique to individual Ig. The results also indicate that the Ag binding region of the autoAb is influential in this process, and they suggest that multiple Ab-Ag interactions contribute to IDF in individuals with lupus nephritis. Furthermore, these observations raise the possibility that the pathologic and clinical abnormalities resulting from these interactions are influenced by the location of IDF, and that the dominant interaction, in a given individual, may be highly influential in the phenotypic expression of nephritis.

Murine monoclonal anti-DNA antibodies penetrate cells, bind to nuclei, and induce glomerular proliferation and proteinuria in vivo.

The production of relatively high quantities of autoantibodies (autoAb) that react with DNA and other intranuclear antigens is characteristic of individuals with systemic lupus erythematosus and other autoimmune diseases. However, the capacity of these Ab to penetrate cells and induce functional perturbations in vivo is not well appreciated. To address this issue, monoclonal (m) anti-DNA Ab (mAb), derived from MRL-lpr/lpr and (NZB x SWR)F1 mice, were administered to normal mice, and the animals were examined for morphologic and functional abnormalities. A subset of five mAb produced intranuclear immunoglobulin deposits in multiple organs. Intranuclear immunoglobulin deposits were also observed after cross-linking the tissue before direct immunofluorescence and after i.v. injection of F(ab')2 fragments of one anti-DNA Ab. This phenomenon was reproducible and was only associated with this subset of autoAb. Furthermore, intranuclear deposits of anti-DNA Ab within glomeruli were associated with morphologic and functional abnormalities including: hypercellularity, epithelial foot process fusion, new fiber bundle formation within the mesangium suggestive of new collagen synthesis, and proteinuria. These results indicate that a subset of autoAb may penetrate cells in vivo to influence normal cellular and nuclear function and to contribute to functional and pathologic abnormalities in individuals with systemic lupus.

Aldosterone induces apical vesicles in rat distal colon.

Mineralocorticoid steroids markedly alter ion transport in responsive epithelia. Increases in absorption of Na+ and secretion of K+ and H+ are accompanied by increases in surface area of the basolateral membrane. The basolateral membrane changes are associated with increased Na(+)-K(+)-ATPase activity and increased numbers of Na(+)-K(+)-ATPase pump sites. It is thought that H+ secretion is mediated by H+ pumps contained in apical vesicles that are added to the luminal membrane in response to acidifying stimuli. Whether there are changes in the number or volume of apical vesicles in response to aldosterone has not been evaluated. To this purpose, we evaluated apical membrane morphology in rat distal colon, a mineralocorticoid-responsive epithelium. We found that aldosterone infused for 4-7 days by osmotic minipump significantly increased the number, surface density, and total volume of apical vesicles. Exposure of tissues to 5% CO2 for 15 min before fixation resulted in significant decreases in vesicle number, surface density, and volume in aldosterone-stimulated tissues. After CO2, apical vesicles in aldosterone-stimulated tissues tended to be closer to the luminal membrane; apical membrane surface density was increased but not to a significant degree. Fluorescence microscopy demonstrated acridine orange accumulation in discrete points under the lumen, suggesting the presence of acidic vesicles in this location. We propose that aldosterone increases the activity of a membrane shuttle system that is regulated by CO2 as found in other H(+)-secreting epithelia. This system may mediate aldosterone-induced changes in colonic H+ transport.

Fine needle aspiration biopsy in the diagnosis of renal angiomyolipoma.

Exclusive reliance on radiographic techniques for the diagnosis of renal angiomyolipoma can lead to misdiagnosis when the histological status is atypical, computerized tomographic findings are equivocal or renal cell carcinoma coexists. We report our experience and those of others in combining fine needle aspiration biopsy and radiological imaging to identify renal angiomyolipoma. Fine needle aspiration biopsy is safe and provides accurate histological diagnosis of renal angiomyolipoma.

Bladder detrusor endometriosis mimicking interstitial cystitis.

Endometriosis involving the muscular wall of the bladder may cause symptoms similar to those of interstitial cystitis. Vesical endometriosis should be considered in the differential diagnosis of interstitial cystitis, especially in patients with a history of prior gynecologic or pelvic surgery.

Glomerular localization of circulating single-stranded DNA in mice. Dependence on the molecular weight of DNA.

Although it has been observed that DNA has a high binding affinity for the glomerular basement membrane (GBM) in vitro, glomerular localization of DNA has not been demonstrated in vivo. To evaluate this possibility, after injection of 125I ssDNA of varying molecular weight (mol. wt.) to normal mice, we measured glomerular levels of DNA in vivo. Following administration of 2 mg of 125I high mol. wt. purified single stranded(ss) DNA (2-6 kilobases; 0.7-2.0 x 10(6)D) to normal mice, DNA was not detected in glomeruli, despite measurable blood levels of DNA for 72 h. In contrast, after injection of 280 micrograms of low mol. wt. 125ssDNA (160-200 bases; mol. wt. = 5.3-6.6 x 10(4)D) to normal mice, glomerular localization was observed throughout the 24-h study period despite relatively low 125IssDNA blood levels. The results of these studies indicate that free circulating DNA can bind to sites within glomeruli in vivo, and that the size of DNA is crucial for this interaction. Since low mol. wt. DNA is present in the plasma of patients with active lupus, these findings raise the possibility that DNA may bind to glomeruli and serve as a planted antigen for in situ immune complex formation with circulating anti-DNA antibodies.

Lectin histochemistry and ultrastructure of kidneys from patients with I-cell disease.

The undegraded stored material in I-cell disease (ICD) includes mucopolysaccharides, lipids, and oligosaccharides. We used ten different lectins as histochemical probes to identify specific carbohydrate residues in stored materials, and electron microscopy to examine the morphology of abnormally stored material in kidneys from two patients with ICD. In both cases, all the glomerular epithelial cells (ie, podocytes), endothelial cells, and renal tubular cells were enlarged and vacuolated. Ultrastructural studies revealed both fibrillogranular material and lamellated membrane structures in the vacuoles. The cytoplasm of affected cells stained with Concanavalia ensiformis agglutinin, wheat-germ agglutinin, and succinylated-wheat-germ agglutinin, but no corresponding control cells stained with lectins. The latter findings indicate an accumulation of N-linked oligosaccharides containing alpha-mannosyl, beta-N-acetylglucosaminyl, and sialyl residues in renal cells affected by ICD.

Lectin histochemistry and ultrastructure of feline kidneys from six different storage diseases.

We have compared the pattern of lectin staining with the ultrastructural features of kidneys from normal cats and 19 cats with 6 different lysosomal storage diseases. The diseases studied include GM1 and GM2 gangliosidosis, mucopolysaccharidosis (MPS)-I and MPS-VI, sphingomyelin-lipidosis (i.e., Niemann-Pick disease) and mannosidosis. Ten different biotinylated lectins were used as histochemical probes for carbohydrate residues and avidin-biotin-peroxidase complex as visualant. Concanavalia ensiformis agglutinin (Con A) stained mesangial cells in all storage diseases but GM1, epithelial cells in sphingomyelin-lipidosis and mannosidosis, endothelial cells in GM1 and mannosidosis and Bowman's capsule cells in all but GM2. Griffonia simplicifolia agglutinin I (GS-I) stained the glomerular endothelium in all six diseases, but not in control kidneys. Ricinus communis agglutinin-I (RCA-I) stained the glomerular epithelium only in GM1 and MPS-I. Succinylated wheat germ agglutinin (SWGA) stained the glomerular endothelium and epithelium in mannosidosis, and the glomerular epithelium and Bowman's capsule in MPS-I. Ultrastructure studies demonstrated an accumulation of oligosaccharides in cases of mannosidosis and GM1 gangliosidosis, a mixture of oligosaccharides and lipids in MPS-I, MPS-VI and GM2 gangliosidosis and only lipid storage in sphingomyelin lipidosis. These studies show that morphologic and histochemical changes are manifested in some kidney cell types in lysosomal storage diseases, even though the enzyme deficiency occurs in all cell types. Furthermore, we show that the nature of the undegraded stored material is complex and that other factors, such as rate of membrane turn over, membrane composition, and cell function may influence the amount and nature of the "stored" material.

Modulation of carbohydrate residues in regenerative nodules and neoplasms of canine and feline pancreas.

The glycoconjugates of regenerative acinar cells, acinic cell carcinomas, islet cell tumors, and normal canine and feline pancreas were studied. The authors used biotinylated lectins as probes and avidin-biotin-peroxidase complex as visualant to identify and to compare the distribution of carbohydrate residues on paraffin sections from 74 cases. The findings demonstrate a difference in the staining pattern between normal acinar, islet, and ductal cells in each species and small differences in the staining pattern between the species. It is shown that in nodules of regenerative acinar cells and acinic cell carcinomas there is an increased staining intensity with Concanavalia ensiformis agglutinin, Ricinus communis agglutinin-I, and wheat germ agglutinin. The pattern of lectin staining in regenerative cells and malignant acinar cells reflects the degree of cellular differentiation. Intensive apical staining characterizes a higher degree of differentiation, while dispersed staining is a major feature of poor differentiation. These findings suggest that malignant transformation of pancreatic acinar cells is associated with enhanced expression of glycoconjugates, which resembles that seen in a normal immature acinar cells.

Multicentric angiomyolipoma: renal and lymph node involvement.

A retrospective review of 6 patients with renal angiomyolipoma treated surgically revealed regional lymph node involvement in 2--an incidence of 33 per cent. The clinical behavior in these patients suggests that nodal involvement is an expression of multicentricity rather than metastatic disease.

Multifocal pigmentation of prostatic and bladder urothelium.

Multifocal pigmentation of the bladder and prostatic urothelium is described in 2 white men. The light microscopic, electron microscopic and histochemical characterization of these foci identified the contained pigment as melanin.

Lectin histochemistry of glycolipid storage diseases on frozen and paraffin-embedded tissue sections.

Lectin histochemical studies were performed on frozen and paraffin-embedded brain tissue sections from six cases of galactosylceramide lipidosis (i.e., globoid cell leukodystrophy, or Krabbe's disease) in Twitcher mice and one case of canine infantile GM1-gangliosidosis. The globoid cells in Krabbe's disease stained with Ricinus communis agglutinin-I (RCA-I), peanut agglutinin (PNA), and Bandeirea simplicifolia agglutinin-I (BS-I) in frozen sections. However, paraffin sections and frozen sections pretreated with chloroform-methanol or xylene, from the same animals, stained with Concanavlia ensiformis agglutinin (ConA), wheat germ agglutinin (WGA), and succinylated-WGA (S-WGA), in addition to staining with RCA-I, PNA, and BS-I. The affected neurons of canine infantile GM1-gangliosidosis stained only with RCA-I in frozen sections. In paraffin sections, however, these cells were negative with RCA-I but positive with BS-I, ConA, Dolichos biflorus agglutinin (DBA), soybean agglutinin (SBA) and Ulex europaeus agglutinin (UEA-I) in paraffin sections. These results indicate that in paraffin processing of glycolipid storage disease tissue, some lectin receptors are lost and others are unmasked. The retained receptors can be stained with specific lectins and could serve as markers to characterize and differentiate among the various glycolipid storage diseases.