Robert G. Horn

Morphologic and Clinical Features of Fibrillary Glomerulonephritis Versus Immunotactoid Glomerulopathy

Renal diseases characterized by Congo red-negative extracellular fibrillary deposits, either organized arrays of larger, microtubular fibrils (immunotactoid glomerulopathy [IT]) or smaller, randomly organized fibrils (fibrillary glomerulonephritis), have been recognized recently. The clinical significance, if any, of the distinction of these patterns has not been determined. On review of all renal biopsy specimens evaluated in a private referral renal pathology laboratory over the last 11 years, 26 cases with fibrillary glomerulonephritis pattern were identified and compared with our six most recent cases with the IT pattern. The fibrillary glomerulonephritis patients, 17 women and nine men, had an average age of 50 +/- 2 years and contributed 1% of the renal biopsy specimens examined. All patients had marked proteinuria and 16 had microscopic hematuria. Follow-up at 23 +/- 5 months in 25 of these patients revealed end-stage renal disease in 11 patients (44%) and one death due to renal failure. End-stage renal disease developed an average of 10 +/- 5 months after biopsy. One patient developed multiple myeloma. Twenty-four renal biopsy specimens showed proliferation, with crescents in seven. Immunofluorescence showed moderate to intense staining for immunoglobulin G and weaker staining for C3, in a predominantly mesangial pattern, with weaker glomerular basement membrane (GBM) staining, corresponding to electron microscopic deposit localization. In four cases, linear GBM staining by immunofluorescence corresponded to extensive subendothelial or transmembranous deposits. The average fibril diameter was 14.0 +/- 0.5 nm (range, 10.4 to 18.4 nm). Immunotactoid glomerulopathy patients (three women and three men) were significantly older, 62 +/- 2 years (P < 0.025). All had marked proteinuria, with microscopic hematuria in two patients. Associated hematopoietic diseases were present in four patients, with monoclonal proteins and/or abnormal plasma cell proliferation in three. One patient died of nonrenal causes. The remaining five patients have stable renal function at 20 +/- 5 months. Biopsy specimens showed proliferative (n = 3) or membranous-like (n = 3) patterns. Immunofluorescence showed immunoglobulin G and weaker C3 staining in a granular GBM pattern, with lesser mesangial staining. The microtubular fibril diameter was on average 43.2 +/- 10.3 nm (range, 16.8 to 90.0 nm). Thus, fibrillary glomerulonephritis and IT can be separated based on ultrastructurally distinct features. Patients with fibrillary glomerulonephritis are less likely than those with IT to have associated hematopoietic disease and also have poorer renal survival. We propose that classification based on these morphologic differences appears to have clinical significance.

Monoclonal gammopathy: significance and possible causality in renal disease

BACKGROUND Patients with monoclonal gammopathy can develop a variety of related renal lesions or possibly have kidney disease unrelated to their monoclonal gammopathy. We characterized the spectrum of renal diseases associated with monoclonal gammopathy and renal diseases. METHODS Patients who underwent renal biopsy and had monoclonal gammopathy on serum and/or urine electrophoresis and/or had a renal biopsy diagnosis related to paraprotein (cryoglobulinemic glomerulonephritis [CG], monoclonal immunoglobulin deposition disease [MIDD], light chain cast nephropathy [CN], or light chain amyloidosis [AL]) were identified. RESULTS One hundred twenty-one patients met the inclusion criteria and were classified as having renal disease related or unrelated to monoclonal gammopathy. Among 66 cases of renal disease related to monoclonal gammopathy, diagnoses were CG (30.3%), MIDD (28.8%), CN (19.7%), AL (19.7%), and CN plus MIDD (1.5%). Among patients with monoclonal gammopathy in serum and/or urine (n = 87), 32 patients (36.8%, included in listing above) had related renal disease. Among 55 patients with monoclonal gammopathy and unrelated renal disease (63.2% of all patients with monoclonal gammopathy), various lesions were found, including diabetic nephropathy (18.1%), focal segmental glomerulosclerosis (18.1%), arterionephrosclerosis (12.7%), membranous glomerulonephritis (9.0%), minimal change disease (7.3%), various immune complex diseases, interstitial nephritis, or nonspecific changes. CONCLUSION The majority of patients with serum and/or urine monoclonal gammopathy who undergo renal biopsy have disease unrelated to monoclonal gammopathy deposition. This likely reflects the high frequency of monoclonal gammopathy of undetermined significance in older patients and the frequent use of serum and/or urine protein electrophoresis as screening tools in adult patients with renal disease.

Incorporation of C14-acetate into intestinal fatty acids of rats with cannulated bile ducts.

Summary 1. Deprivation of bile flow to the rat intestine by means of cannulation of the bile duct did not affect the ability of the intestine to accumulate normal amounts of highly labeled fatty acids after administration of C14-acetate as shown by comparison with sham-operated, pair-fed controls. 2. Total radioactivity in the biliary fatty acids amounted to only 5-16% of the amount found in the intestinal fatty acids in the time periods studied. 3. Fatty acids of combined intestinal and cecal contents of cannulated animals contained more fatty acid but of a lower specific activity than those of control rats.

Identification of Promonocytes and Monocytoid Precursors in Acute Leukaemia of Adults: Ultrastructural and Cytochemical Observations

Summary. Examination of 25 cases of adult non‐lymphoid acute leukaemia by electron microscopy and esterase cytochemistry revealed that most cases contained a majority of classifiable cells, however undifferentiated they may have appeared by routine light microscopy. The major proliferating cell in most cases (72%) was found to be a promonocyte or monocytoid precursor cell, characterized by extreme nuclear convolution, large cytoplasmic bundles of microfilaments, and numerous small electron‐dense lysosomal granules, which strongly stained for alpha‐naphthyl acetate esterase. Pure granulocytic cases, representing a minority (24%), were composed of blasts and typical promyelocytes and myelocytes, staining for Naphthol‐AS‐D chloroacetate esterase. Only one case was totally composed of undifferentiated, unclassifiable blasts. These results show that electron microscopy and cytochemistry increase the accuracy of classification of leukaemia and that the true incidence of monocytic leukaemia may be much higher than generally recognized.

Fine structural features of eosinophile granulocyte development in human bone marrow: Evidence for granule secretion

Stages in the maturation of human eosinophiles were characterized by electron microscopy. An early stage of development was distinguished by prominent nucleoli, dilated segments of RER, and vacuoles that were partially filled with an electron dense matrix. It appeared that such vacuoles might be formed as saccular dilatations of the RER rather than by fusion of Golgi-associated vesicles. Progressive accumulation of dense material within these precursor vacuoles resulted in the formation of spherical homogeneously dense immature granules which constituted the predominant granule found in eosinophiles of intermediate maturity. Many intermediate eosinophiles contained tubular sinusoids filled with dense material resembling granule matrix. Such sinusoids often communicated with the extracellular space, and dense material resembling sinusoidal contents was present on adjacent cell surfaces. These configurations suggested that some material of granule origin was secreted by developing eosinophiles. Other immature granules apparently persisted, were condensed and transformed into crystalloid-containing granules that are typical of mature eosinophiles.

Precipitation of Soluble Fibrin Monomer Complexes by Lysosomal Protein Fraction of Polymorphonuclear Leukocytes

Summary A lysosomal protein fraction (LPF) isolated from rabbit PMN leukocytes is able to interact with soluble fibrin monomer complexes to form a precipitate. The reaction seems to be nonenzymatic and similar to that induced by polycationic protamine sulfate and polyanionic polyanethol sulfonate (Liquoid). The fibrin precipitating activity of LPF is thermostable and destroyed by proteolysis. The reaction between LPF and soluble fibrin monomer complexes is inhibited by 1 M urea. Heparin in a concentration of 100 U/ml has no effect on precipitate formation. The fibrin precipitating activity of LPF suggests that this material may be important in producing intravascular fibrin deposition in those situations in which there is destruction of PMN leukocytes and a concurrent rise of soluble fibrin monomer complexes in the circulation.

Electron Microscopy of Fibrin‐like Precipitate Formed during the Paracoagulation Reaction between Soluble Fibrin Monomer Complexes and Protamine Sulphate

Summary. The fine structure of the insoluble material formed during the paracoagulation reaction between soluble fibrin monomer complexes (SFMC) and protamine sulphate was studied by electron microscopy. This precipitate was found to be a fibrillar material with prominent cross striations. The cross striations produced well‐defined axial periodicity which averaged 181 Å. The ultrastructural pattern of the protamine‐induced SFMC precipitate suggested that it was a highly ordered polymer similar to fibrin. These findings indicate that material resembling fibrin may be produced not only by the interaction between fibrinogen and thrombin, but also by the non‐enzymatic mechanisms responsible for the paracoagulation reaction.

An electron microscopic study of human polymorphonuclear leukocyte injury induced by rabbit antiserum

Abstract Electron microscopic examination of human leukocytes treated with antiserum revealed marked degenerative changes. These changes appeared limited to PMNs. Initial alterations included loss of cytoplasmic density and focal aggregation of granules against the plasma membrane. Nuclear chromatin became homogeneous and less dense. There were no morphologic changes suggesting intracytoplasmic granule lysis. Degenerating PMNs apparently fragmented and released cytoplasmic structures into the medium. Portions of cell debris were ingested by undamaged PMNs and monocytes. The changes described above did not occur in divalent cation-depleted plasma, suggesting that the damage is complement-dependent. However, in preparations devoid of divalent cations, PMNs developed increased pseudopod activity and formed peculiar, lamellar vesicles thought to represent cell surface response to antiserum. It is postulated that antibodies directed against PMNs may damage these cells and cause release of lysosomal material.

A 51-year-old woman with nephrotic syndrome, hematuria, and renal insufficiency

This case illustrates the utility of all modalities of the renal biopsy in arriving at a correct diagnosis in an adult patient with nephrotic syndrome. Unlike the clinical situation in children, where minimal change disease is presumed to underlie the nephrotic syndrome unless the patient shows steroid resistance, the list of differential diagnosis of nephrotic syndrome in the adult is lengthy. The renal biopsy is essential in establishing the specific diagnosis. We discuss the diagnostic approach in an adult patient with a relatively uncommon disease causing the common manifestations of nephrotic syndrome, hematuria and renal insufficiency.

A 37-year-old woman with systemic lupus erythematosus and acute allograft failure

THE RENAL BIOPSY is considered the gold standard method for the diagnosis of the processes that cause graft dysfunction. Complete morphological studies must be systematically applied to these samples to specifically assess the etiology of those processes. The likelihood of a particular etiology largely depends on the interval since transplantation. In the early posttransplantation period, most cases of renal dysfunction are etiology by acute tubular necrosis, reperfusion injury, acute rejection, drug toxicity, obstruction, surgical complications, or infection. Later in the time course, other causes of graft dysfunction include chronic transplant nephropathy, cyclosporine toxicity, and recurrent or de novo glomerular diseases. However, recurrent disease also should be considered in some cases in the immediate posttransplantation period. We present a renal transplant recipient with systemic lupus erythematosus (SLE) and early allograft dysfunction and rapid graft failure. The serial biopsies and complete morphological studies permitted a specific diagnosis in this case.