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F B Waldo

Publications and source records attributed to F B Waldo.

At least 37 records · Page 2Linked to original sources
PubMed1991

Macroscopic hematuria and proteinuria preceding renal IgA deposition in patients with IgA nephropathy.

Although the clinical onset of IgA nephropathy is frequently impossible to define, macroscopic hematuria apparently heralds the onset of the disease in some patients. We describe the clinical course and renal histologic findings of four adults with IgA nephropathy who were diagnosed by the characteristic immunohistologic features in a second renal biopsy specimen. IgA was not detected in the initial renal biopsy specimens obtained 9 months to 4 years earlier. The first renal biopsy had been performed to evaluate macroscopic hematuria (recurrent in three patients), accompanied by pathologic proteinuria in two patients. Our observations suggest that the pathognomonic immunohistologic findings of IgA nephropathy may follow the clinical onset and raise questions about the presumed pathogenetic role of IgA in the early stages of this disease.

Adult↗
PubMed1991

Nasal immunization with tetanus toxoid increases the subsequent systemic dimeric IgA1 antibody response to intramuscular immunization.

We have investigated the effects of nasal immunization with tetanus toxoid (TT) on the subsequent systemic IgA response. Healthy adult volunteers who had not had a TT boost for at least five years received either an intra-muscular (IM) TT immunization alone (n = 19) or first an intra-nasal and then two weeks later an IM immunization (n = 27). The serum and circulating B cell IgG and IgA1 antibody response to TT were measured. When compared to subjects who received only an IM immunization, those who were nasally primed had increased serum levels of dimeric IgA1 antibodies to TT and an increased number of B cells secreting IgA1 antibodies to TT. These data indicate that mucosal antigen exposure is one of the mechanisms involved in the induction of systemic serum IgA1 response.

Administration, Intranasal↗
PubMed1990

Role of IgA in IgA nephropathy.

IgA nephropathy (Berger disease) is defined by the dominant or codominant deposition of IgA in the renal mesangium. There is much evidence in vitro to suggest up-regulation of the IgA immune response in patients. Data from tonsillar and bone marrow-derived lymphocytes and from in vivo immunization studies indicate that the primary defect is an up-regulated systemic one, rather than mucosal IgA production. Several lines of evidence suggest that increased IgA production alone is inadequate to explain the pathogenesis of Berger disease. Murine models of IgA nephropathy indicate that local complement activation mediated by deposited IgG is essential for mesangial cell proliferation and subsequent renal injury. Circulating immune complexes from patients with Berger disease contain IgA and IgG within the same lattice. In vitro studies of model immune aggregates containing various mixtures of IgA and IgG indicate that the IgG is the site of complement activation and fixation. The IgA in the aggregate actually inhibits both complement activation and binding to erythrocyte complement receptor CR1. This effect of IgA may prevent effective immune complex clearance. In future studies, more emphasis should be placed on the roles of IgG and complement in the pathogenesis of IgA nephropathy.

Animals↗
PubMed1990

Descriptions of the participating centers and patient population in the Growth Failure in Children with Renal Diseases Study.

The Growth Failure in Children With Renal Diseases Study, a double-blind, multicenter clinical trial with 108 children entered into the control period over 4.3 years of patient enrollment (December 1984 to April 1989), is being extended for 3 years (December 1988 to December 1991) to provide the time needed to accrue additional patients, aged between 1 1/2 and 10 years, with glomerular filtration rates of 20 to 75 ml/min/1.73 m2. The study design of randomization to two treatment arms (1,25-dihydroxyvitamin D vs dihydrotachysterol) requires a total of 108 patients with a minimum of 6 months of treatment to test the long-term effectiveness and safety of 1,25-dihydroxyvitamin D, an essential part of the therapeutic regimen for children with chronic renal insufficiency. The frequent longitudinal assessments of nutrition and growth in children with chronic renal insufficiency can better define the natural history of renal disease and its influence on growth. Similar data in the treatment period will define the impact of treatment with 1,25-dihydroxyvitamin D3 versus dihydrotachysterol on this natural history. Linear growth must be observed long enough (6 to 12 months minimum) to permit valid quantitation and comparison of the two vitamin D treatment arms, the multiple confounding variables that affect growth (e.g., steroid therapy, diabetes mellitus, prior vitamin D treatment) must be rigorously excluded or controlled, and the assignment of patients to the two groups must be random. These controls--sufficient study duration, sufficient patient numbers, and randomization--should eliminate extraneous sources of variation, including seasonal periodicity. This carefully developed, double-blind clinical trial with multiple participating centers and an effective organizational structure is coming close to achieving the goals of the study. An explosion of data regarding the natural history of chronic renal insufficiency and its treatment with vitamin D metabolites will be forthcoming at the conclusion of the study.

Child↗
PubMed1989

Mixed IgA-IgG aggregates as a model of immune complexes in IgA nephropathy.

Patients with IgA nephropathy have circulating immune complexes containing IgA, IgG, and C3. We have mixed human IgG and IgA1 and heated them to form mixed aggregate. On sucrose density gradients IgG aggregates were 11 to 19S whereas IgA aggregates were either 11S or greater than 19S. Mixed aggregates had both an 19 and 11 S peak. The isoelectric point of aggregates with only IgG was 7 to 9 and of only IgA 4.5 to 5.5. The isoelectric point of mixed aggregates decreased as the percent IgA increased. IgG aggregates mixed with normal human serum caused 30% C3 activation (20 min, 37 degrees C) whereas IgA aggregates causes no activation. There was a linear decrease in C3 activation as the percent IgA increased. Mixed aggregates that contained either radiolabeled IgG or IgA were mixed with normal human serum (1 h, 37 degrees C) and then solubilized, reduced, and separated by 10% SDS-PAGE. Heavy m.w. bands, consistent with covalent bonding of C3b and C3bi to Ig H chain were only seen in lanes with labeled IgG. This was confirmed by Western blot analysis. A human dimeric IgA1 myeloma protein with rheumatoid factor activity was also studied. It caused 15% alternative pathway C3 activation but did not fix C3 to its H chain. Binding of aggregates (+/- C3) to E was tested. Aggregates with IgG C3 bound but IgA (+/- C3) did not. Addition of greater than 10% IgA to an IgG-C3 aggregate inhibited E binding. We conclude that IgG in mixed aggregates is the site of C3 fixation. In contrast, IgA does not fix C3 but instead lowers the isoelectric point, increases the size and inhibits binding to E. These properties would inhibit clearance and promote mesangial deposition and local C activation.

Antigen-Antibody Complex↗
PubMed1989

Non-specific mesangial staining with antibodies against cytomegalovirus in immunoglobulin-A nephropathy.

The glomerular staining of a commercial polyclonal antiserum against cytomegalovirus (CMV) and of a mixture of 13 monoclonal anti-CMV antibodies in twelve patients with immunoglobulin-A (IgA) nephropathy was examined. The polyclonal antiserum stained the mesangium in all patients. The CMV staining coincided only partially with that of IgA in five patients and the staining distributions were discordant in six. The monoclonal antibodies stained mesangium in only one patient. Serum levels of IgA and IgG anti-CMV antibodies did not differ between patients and controls. In western blot analysis, the polyclonal antiserum reacted with three proteins in uninfected human fibroblasts. Absorption of the antiserum with uninfected fibroblasts reduced the reactivity on western blot analysis and eliminated glomerular staining in five of six renal biopsy samples. It is concluded that the previously reported binding of anti-CMV antibodies to glomeruli from patients with IgA nephropathy may be the result of contaminating antibodies to human antigens.

Antibodies, Monoclonal↗
PubMed1989

Zinc and copper balance in children on continuous ambulatory peritoneal dialysis.

We monitored serum zinc and copper levels for 4 months in six patients treated with continuous ambulatory peritoneal dialysis (CAPD). Zinc and copper fluxes were studied during a single dialysis exchange and over a 3-day period. Routine oral trace element supplements were then discontinued for 2 months. Serum zinc levels declined but serum copper levels remained unchanged. One month after oral supplements had been restarted, serum zinc levels returned to normal and serum copper levels rose above initial values. Zinc and copper concentrations in dialysis exchange indicated that the patients absorbed zinc and lost copper in significant amounts. The patients had poor dietary intakes of both minerals. These data suggest that patients treated with CAPD benefit from oral zinc supplementation.

Adolescent↗
PubMed1989

Alternate-day prednisone therapy in children with IgA-associated nephritis.

IgA nephropathy (IgAN) leads to renal failure in up to 30% of affected children and adults. There is currently no consensus on therapy in IgAN. Six patients with risk factors for disease progression were identified based on clinical or histologic findings. These patients were treated with alternate-day prednisone for 12 to 60 (mean, 36) months and followed for 28 to 60 (mean, 54) months. Follow-up biopsies were available in four patients. At last examination all treated patients had normal urinalysis and serum creatinine level. Follow-up biopsies showed stable or improved glomerular histology in three of four patients. One patient had a slight worsening of the interstitial disease. No steroid toxicity was observed. The outcome of these treated patients was compared with that of 15 comparable patients from another center who received no treatment and with patients from two published clinical pathology series. A normal urinalysis was found at follow-up in all treated patients, compared with one of 15 untreated patients (P = 0.003). None of the patients in the published series with comparable disease had normal urinalysis at follow-up. End-stage renal disease or renal insufficiency occurred in seven of 15 untreated and no treated patients (P = 0.19). The data strongly support the need for a prospective control trial of prednisone therapy in IgAN.

Adolescent↗
PubMed1989

Systemic immune response to oral polio immunization in patients with IgA nephropathy.

The systemic immune response to a booster dose of attenuated polio vaccine has been studied in a group of patients with IgA nephropathy, their parents and healthy unrelated controls. The serum IgA and IgG antibody response and the antibody response in cultured lymphocyte supernatants was quantitated by a sensitive radio-immunoassay. Three of eight patients and two of their parents had elevated serum IgA antibody to polio pre-immunization. There was no significant rise in serum IgA or IgG antibody to polio post-immunization in any group. However, the five subjects with elevated pre-immunization levels fell into the normal range post-immunization, suggesting IgA specific suppression. Total and antigen specific IgA rose post-immunization in culture supernatants in all groups. The rise did not differ among the groups. The patients and parents with high serum antibody also had high culture supernatant levels and these fell post-immunization. There was an increased antigen non-specific IgG response in four patients and three of their parents. The data provide additional in vivo evidence of an upregulated IgA immune response in patients with IgA nephropathy. In addition, the data provide the first in vivo evidence of aberrant immune responses in the first degree relatives of patients with IgA nephropathy. This appears to be one of perhaps several inherited traits which may predispose an individual to develop this common and progressive nephropathy.

Administration, Oral↗
PubMed1988

IgA nephropathy, the most common glomerulonephritis worldwide. A neglected disease in the United States?

Although its prevalence and clinical importance in the United States are stated to be low, we believe IgA nephropathy occurs as commonly in this country as in Western Europe. Initial reports suggested the disease was perhaps restricted to France and synonymous with "benign recurrent hematuria," but longer follow-up has proven both conclusions incorrect. Obviously, major gaps persist in our understanding of the immunopathogenesis and the natural history. The latency of the American investigative response calls for more intensive clinical and laboratory studies of the most common primary glomerulonephritis worldwide.

Antigen-Antibody Complex↗
PubMed1988

Binding of IgA to erythrocytes from patients with IgA nephropathy.

Primate erythrocytes (RBCs) may be involved in the transport and processing of C3b-containing immune complexes (IC). Compared to RBCs from healthy controls, increased amounts of IgA were detectable on RBCs from 7 of 17 patients with IgA nephropathy (IgA NP). There was no difference in the amount of IgG or IgM. The highest amount of RBC-bound IgA corresponded to 6 ng IgA/10(8) cells. The mechanisms involved in the binding of IgA to RBCs were investigated in vitro. Isolated IgA1 or IgA2 did not bind to RCBs from a patient with IgA deficiency. In contrast, incubation of RBCs with a polyethyleneglycol (PEG) precipitate of serum from a patient with IgA NP which contained IgA-IC resulted in IgA1 binding. However, this binding was not inhibited by monoclonal anti-CR1 or by an excess of IgG or IgM. Factor I did not cause release of IgA from RBCs from patients with IgA NP. Heat-aggregated IgA1 also bound to RBCs and this binding was not affected by the presence of complement. We conclude that minute amounts of IgA-IC are bound to RBCs by a complement- and Fc receptor-independent mechanism. The quantity of IgA-IC associated with RBC is so small that it is unlikely to represent an important in vivo route of IgA-IC transport or processing.

Antigen-Antibody Complex↗
PubMed1988

Is Henoch-Schönlein purpura the systemic form of IgA nephropathy?

Despite different clinical features, IgA nephropathy (IgAN) and Henoch-Schönlein purpura (HSP) are indistinguishable by histopathology, leading to the suggestion that HSP is a systemic form of IgAN. This review compares and contrasts the clinical, pathologic, and experimental similarities and differences of these two disorders. Many patients with HSP have minimal extrarenal disease, while up to 30% of patients with IgAN will subsequently have systemic symptoms. Although patients with HSP are usually much younger than those with IgAN, the age distributions often overlap. Both may have recurrent macroscopic hematuria associated with pharyngitis, a similar risk of developing renal insufficiency, and recurrent disease after kidney transplantation. Although the pattern of IgA subclass and complement deposition are similar, monocytic and T lymphocytic infiltrates have been observed only in HSP. Dermal blood vessels of many patients with IgAN have IgA immunofluorescence similar to that in HSP, supporting a systemic process in IgAN. Although the pathogenesis is not clearly understood for either disease, investigations of potential disease mechanisms have revealed striking similarities. These include an up-regulated in vitro IgA immune response, circulating IgA-containing immune complexes and autoantibodies, and decreased Fc receptor-mediated immune clearance. Finally, immunogenetic studies suggest that patients with both conditions inherit a predisposition for disease.

Antigen-Antibody Complex↗
PubMed1987

Aggressive therapy of infants with renal failure.

Nine infants, who presented with renal failure within the first 3 months of life, were treated with continuous ambulatory peritoneal dialysis (CAPD). Seven infants survived to an age of 12-15 months, when they received transplants. Two patients died while on CAPD. Six infants are alive with a functioning renal allograft, at an average age of 35.5 months and an average of 22 months post-transplant. Neurological development is normal in four of the six infants tested. The mean current height of the six transplant recipients is just below 2 SD from the mean.

Humans↗
PubMed1987

Therapy of focal segmental glomerulosclerosis with cyclosporine A.

Six patients with biopsy-documented focal segmental glomerulosclerosis were treated with cyclosporine A (CyA) a new and potent T-cell suppressant. Dosage was adjusted to maintain trough levels between 100 and 300 ng/ml (whole blood radioimmunoassay). Patients were treated for 6 weeks or until unacceptable drug toxicity occurred. In one patient proteinuria was significantly reduced. This same individual was the only patient treated within 6 months of diagnosis. Therapy was discontinued in two patients at week 4, one because of worsening renal failure and one because of hypertension. These complications occurred despite trough CyA blood levels of less than 300 ng/ml. The results suggest that further and controlled studies of CyA are warranted in the therapy of nephrotic syndrome associated with focal segmental glomerulosclerosis, especially when used early in the course of disease. The data also suggest enhanced toxicity of CyA in patients with active nephrotic syndrome.

Adolescent↗
PubMed1987

Quantitation of (C1INH)2 C1r-C1s complexes in glomerulonephritis as an indicator of C1 activation.

C1 activation was assessed in several forms of glomerulonephritis by radioimmunoassay quantitation of circulating (C1INH)2 C1r-C1s complexes (INC). Eight patients with active systemic lupus erythematosus (SLE) and nephritis had elevated serum INC (mean = 15.3 vs control = 5.8, P less than 0.01). Their INC levels were normal during remission. Serum INC had a weak inverse correlation with serum C1q greater than 3 mg/dl (r = 0.42, P = 0.02). In longitudinal studies, serum INC also had a weak inverse correlation with serum C3 and C4. Only 1 of 10 patients with type I and 1 of 15 with type III membrano-proliferative glomerulonephritis (MPGN) had elevated serum INC. No patient with type II MPGN had elevated levels. Two of 10 patients with poststreptococcal glomerulonephritis (P-SGN) had elevated serum INC, but all normalized with convalescence. Patients with IgA nephropathy had normal serum INC. The data demonstrate the importance of C1 activation in SLE and P-SGN. The mechanism of complement activation in types I and III MPGN remains unclear; the data suggest, but do not prove, that C1-independent complement activation may occur in these patients.

Antigen-Antibody Complex↗