Gloria Gallo

Variant-Sequence Transthyretin (Isoleucine 122) in Late-Onset Cardiac Amyloidosis in Black Americans

BACKGROUND After the age of 60, isolated cardiac amyloidosis is four times more common among blacks than whites in the United States; 3.9 percent of blacks are heterozygous for an amyloidogenic allele of the normal serum carrier protein transthyretin in which isoleucine is substituted for valine at position 122 (Ile 122). We hypothesized that the high prevalence of transthyretin Ile 122 is at least partially responsible for the increased frequency of senile cardiac amyloidosis among blacks. METHODS Paraffin blocks of cardiac tissue were obtained from an earlier study of 52,370 autopsies in Los Angeles and were examined by immunohistochemical and DNA analyses. Samples were available from 32 of 55 blacks and 20 of 78 whites over 60 years of age with isolated cardiac amyloidosis and from two control groups (228 cases). RESULTS Transthyretin amyloidosis was identified in 31 of the 32 cardiac-tissue samples from the black patients and in 19 of the 20 samples from the white patients. Six of the 26 analyzable DNA samples (23 percent) from the black patients and none of the 19 samples from the white patients were heterozygous for the Ile 122 variant. Four of 125 DNA samples obtained at autopsy (3.2 percent) from a second, more recent, age-matched cohort of blacks without amyloidosis at the same institution were heterozygous for the transthyretin Ile 122 allele. On reexamination the cardiac tissue from these four patients contained small amounts of amyloid not detected at the initial autopsies. All subjects with the Ile 122 variant had ventricular amyloid. CONCLUSIONS The assessment of elderly black patients with unexplained heart disease should include a consideration of transthyretin amyloidosis, particularly that related to the Ile 122 allele.

Renal Failure and Interstitial Nephritis Due to Penicillin and Methicillin

Abstract Nephropathy due to penicillin or methicillin was observed in seven patients. Maximum dosage ranged from 20 to 24 gm per day for methicillin and from 20,000,000 to 60,000,000 units for peni...

Lupus nephritis: Clinical course as related to morphologic forms and their transitions

An intensive study of the course of lupus nephritis has been undertaken in 88 patients in whom strict morphologic criteria were utilized in classification. All were treated with steroid, and 17 received cytotoxic drugs in addition. Focal proliferative lupus nephritis generally follows a benign course except in the occasional instances when transition to the diffuse proliferative or membranous forms occurs. Membranous lupus nephritis, when characterized by persistent nephrotic syndrome, leads slowly to renal failure, but this progression is aborted in the one-third in whom remission of the nephrotic syndrome can be achieved. A fatal outcome occurs within five years in the majority of those with diffuse proliferative lupus nephritis and the nephrotic syndrome, often in association with necrotizing renal vasculitis, severe hypertension and accelerated renal failure. A small number with the diffuse proliferative form have a remission and then show only mesangial abnormalities, usually, however, with the appearance of glomerular sclerosis. Progressive glomerular sclerosis is observed in some patients and may be a sequel of the remission of the diffuse or focal proliferative lesions, or it may represent still another form of lupus nephritis. Mesangial immune deposits with or without proliferation, at times in the absence of clinical renal disease, are observed early in the course of systemic lupus erythematosus (SLE) and may proceed to the diffuse proliferative or membranous forms. The present observations serve to emphasize the importance of strict morphologic classification in the comparison of different treatment regimens for lupus nephritis. In view of the grave prognosis of established diffuse proliferative lupus nephritis, which probably evolves from a mesangial involvement common to all patients with SLE from its onset, early therapy may be the key to the management of lupus nephritis.

The clinical course of the proliferative and membranous forms of lupus nephritis.

Abstract By using histologic, immunofluorescent, and electron microscopic observations of 52 patients with systemic lupus erythematosus and renal involvement, three different forms of lupus nephrit...

Monoclonal Immunoglobulin Deposition Disease: Light Chain and Light and Heavy Chain Deposition Diseases and Their Relation to Light Chain Amyloidosis: Clinical Features, Immunopathology, and Molecular Analysis

Monoclonal immunoglobulin deposition occurs in tissues as Congo Red binding fibrils in light chain amyloidosis, as less structured deposits in light chain deposition disease, and as similar but distinct deposits in light and heavy chain deposition disease. The nonamyloid forms were found in 13 patients who had evidence of plasmacytic dyscrasia by the immunohistochemical detection of immunoglobulin light chains of kappa or lambda class (with or without staining for a single heavy chain isotype) and by the absence of amyloid P component in tissue sections that did not show the birefringence characteristic of amyloid after Congo Red staining. All but two of the patients presented with proteinuria with or without azotemia. Clinical syndromes involving other organ systems were less common but occasionally severe. Four patients had overt multiple myeloma. Three others had hypercalcemia and mild bone marrow plasmacytosis but no lytic lesions. Analyses of immunoglobulin synthesis in bone marrow cells from seven patients showed excess light chains in all and incomplete light chains or heavy chain fragments in six, regardless of whether an intact monoclonal protein or related subunit was in the serum or urine. The fibrillar (amyloidotic) and nonfibrillar forms of monoclonal immunoglobulin deposition occur either in overt multiple myeloma or in the course of less neoplastically aggressive plasmacytic dyscrasias. Bone marrow cells from patients with either type produce immunoglobulin fragments that are related to those deposited in the affected tissues.

The Long-Term Course of Poststreptococcal Glomerulonephritis

Abstract Clinical, pathologic, and functional observations have been made in 126 patients (89 adults and 37 children) with poststreptococcal glomerulonephritis, 60 of whom were followed for 2 to 15...

Charge of circulating immune complexes as a factor in glomerular basement membrane localization in mice.

The effect of the charge of circulating immune complexes on glomerular localization was studied in a model of passive serum sickness. Preformed immune complexes of heterogeneous or restricted charge, prepared in vitro from isoelectrically focused or chemically modified proteins, were injected intravenously into mice. The distribution of immune complexes in the kidney was compared by immunofluorescence and electron microscopy. Cationic but not anionic or electrophoretically heterogeneous immune complexes gave rise to diffuse localization in the glomerular basement membrane. The binding in subepithelial and subendothelial sites correlated with the known distribution of structural anionic sites. The observations suggest that electrostatic interactions between fixed anionic sites and immune complexes may be an important factor in glomerular trapping. Alternative mechanisms based on initial localization of excess free cationic antigen cannot be completely excluded and are also considered.

Glomerulonephritis in Bacterial Endocarditis

For a modern assessment of the clinical and morphologic features of glomerulonephritis accompanying bacterial endocarditis, postmortem and renal biopsy files were reviewed for the years 1965 to 1979, a period of changing epidemiology, etiology, and therapeutic regimens in infective endocarditis. The incidence of glomerulonephritis in 107 patients examined at postmortem was 22.4%; focal glomerulonephritis was present in 8.4%, diffuse glomerulonephritis in 14%. Glomerulonephritis occurred as frequently in acute as in subacute bacterial endocarditis. Staphylococcus aureus, which has replaced Streptococcus viridans as the predominant etiology of fatal bacterial endocarditis, was frequently associated with glomerulonephritis, especially in parenteral drug abusers. Renal functional impairment due to focal glomerulonephritis did not necessitate dialysis or contribute to the death of any patient. Presentation with advanced renal insufficiency due to diffuse glomerulonephritis was associated with both failure of antibiotic therapy to eradicate infection and failure to recover renal function. In patients with diffuse glomerulonephritis and less severe impairment of renal function, antibiotic therapy was successful in achieving bacteriologic cure, and complete recovery of renal function occurred in the majority. Features of persistent glomerular disease were frequent in patients with diffuse glomerulonephritis long after bacteriologic cure of endocarditis.

Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin: a possible model for senile systemic amyloidosis.

The human serum protein transthyretin (TTR) is highly fibrillogenic in vitro and is the fibril precursor in both autosomal dominant (familial amyloidotic polyneuropathy [FAP] and familial amyloidotic cardiomyopathy [FAC]) and sporadic (senile systemic amyloidosis [SSA]) forms of human cardiac amyloidosis. We have produced mouse strains transgenic for either wild-type or mutant (TTRLeu55Pro) human TTR genes. Eighty-four percent of C57Bl/6xDBA/2 mice older than 18 months, transgenic for the wild-type human TTR gene, develop TTR deposits that occur primarily in heart and kidney. In most of the animals, the deposits are nonfibrillar and non-Congophilic, but 20% of animals older than 18 months that bear the transgene have human TTR cardiac amyloid deposits identical to the lesions seen in SSA. Amino terminal amino acid sequence analysis and mass spectrometry of the major component extracted from amyloid and nonamyloid deposits revealed that both were intact human TTR monomers with no evidence of proteolysis or codeposition of murine TTR. This is the first instance in which the proteins from amyloid and nonfibrillar deposits in the same or syngeneic animals have been shown to be identical by sequence analysis. It is also the first time in any form of amyloidosis that nonfibrillar deposits have been shown to systematically occur temporally before the appearance of fibrils derived from the same precursor in the same tissues. These findings suggest, but do not prove, that the nonamyloid deposits represent a precursor of the fibril. The differences in the ultrastructure and binding properties of the deposits, despite the identical sizes and amino terminal amino acid sequences of the TTR and the dissociation of deposition and fibril formation, provide evidence that in vivo factors, perhaps associated with aging, impact on both systemic precursor deposition and amyloid fibril formation.

Acquired cystic disease of kidney in chronic dialysis patients

Eight cases of acquired cystic disease of the kidney (ACDK) associated with chronic renal failure and hemodialysis are described. No patient had a family history or clinical evidence of congenital adult polycystic kidney disease (CAPKD). Glomerulonephritis was the cause of renal failure in 6, and pyelonephritis in 2. Massive renal and perirenal hemorrhage necessitated 3 nephrectomies in 2 patients. Single kidney weights did not exceed 280 Gm., a major feature in the distinction of ACDK from CAPKD. Morphologically, in addition to the usual stigmata of end-stage kidneys, 40 to 80 per cent of the renal parenchyma was replaced by small cysts. Continuity of cysts with tubules was established by nephron dissection.