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Biomedical subjects

B A Julian

Publications and source records attributed to B A Julian.

At least 19 recordsLinked to original sources
PubMed1992

Musculoskeletal complications after renal transplantation: pathogenesis and treatment.

Renal transplantation is associated with several abnormalities of function and structure of the musculoskeletal system. Some of these skeletal problems result from incomplete resolution of abnormalities of bone and mineral metabolism present at the time of transplantation. In this regard, persistent hyperparathyroidism, diabetes mellitus type 1, and accumulation of beta 2-microglobulin may lead to residual skeletal effects despite excellent function of the allograft. Persistent hyperparathyroidism may accelerate bone loss and increase the risk for osteonecrosis, as well as cause hypercalcemia and hypophosphatemia; some patients with severe hyperparathyroidism require parathyroid surgery. Osteonecrosis is the most debilitating skeletal complication after transplantation and frequently requires surgical therapy. Although osteomalacia associated with aluminum overload generally resolves after transplantation, bone complications due to dialysis amyloidosis and diabetes mellitus type 1 often fail to improve. Alternatively, skeletal abnormalities can be acquired after transplantation. Most of the new derangements of bone and mineral metabolism are due to the immunosuppressive medications. Toxic effects of glucocorticoids on bone contribute to the pathogenesis of osteonecrosis, increase the risk for fractures by decreasing cancellous bone mass and synthesis of bone matrix, and dampen the linear growth response in pediatric recipients. Whether cyclosporine independently causes appreciable toxic effects on bone metabolism is not yet clear, but use of this drug increases the prevalence of gout and dental problems. Osteonecrosis, osteopenia, and short stature remain important skeletal complications in recipients of renal allografts. Therapeutic efforts should be directed toward alleviating pretransplant bone disease and attenuating bone loss after transplantation.

Bone Diseases, Metabolic↗
PubMed1992

Cytokine-induced immunoglobulin production in primary IgA nephropathy.

Increased IgA synthesis probably plays a role in the pathogenesis of IgA nephropathy (IgAN). We investigated whether an increased sensitivity to the effect of various growth factor combinations leads to increased immunoglobulin synthesis by peripheral blood mononuclear cells (PBMC) from IgAN patients, in comparison to healthy controls. Although none of the growth factors studied (pokeweed mitogen [PWM], interleukin [IL]-2, IL-6, transforming growth factor-beta [TGF-beta], and combinations) led to greater IgA synthesis in IgAN patients than in controls, the IgA subclass ratio was shifted in favor of IgA1. In controls, but not in IgAN patients, IL-2 enhanced the production of IgA and IgA1 compared with media alone. This possibly reflects previous in vivo activation by IL-2 in IgAN patients. The suppressive effect of TGF-beta on immunoglobulin synthesis was modestly greater in IgAN patients than in controls. Increased production of IL-2 and perhaps other cytokines by T cells in vivo may be responsible for the elevated IgA immune response in these patients.

Adolescent↗
PubMed1992

Familial IgA nephropathy associated with bilateral sensorineural deafness.

Alport's syndrome is the most frequent disorder with familial nephritis and deafness, but other types of nephropathy have been occasionally associated with hereditary hearing loss. The familial occurrence of IgA nephropathy has been well documented. We report a family with hereditary, bilateral, sensorineural deafness spanning four generations. Three of five members with deafness had microscopic hematuria. Renal histology of the two deaf members undergoing biopsy showed mesangial glomerulonephritis with mesangial IgA deposits, without ultrastructural abnormalities of the glomerular basement membranes. Familial nephritis with deafness should not be equated with the diagnosis of Alport's syndrome.

Deafness↗
PubMed1992

Binding of serum immunoglobulins to collagens in IgA nephropathy and HIV infection.

The mechanism of the binding of IgA to the mesangium in IgA nephropathy (IgAN) is unknown. Interactions between IgA and components of the mesangial matrix may contribute. We measured by enzyme-linked immunosorbent assay the binding of serum IgA, IgG, and IgM from patients with IgAN, human immunodeficiency virus type I (HIV) infection, and healthy controls to purified native collagen types I to VI, and to an extract of normal kidney tissue. HIV infection is an appropriate disease control because of the lack of mesangial IgA deposits, despite high serum levels of IgA and IgA1-containing immune complexes. Increased levels of IgA-binding to collagen types I and V and the kidney extract were found only in IgAN. Both IgAN and HIV-infected patients had increased IgA-binding to collagen types II, III, and VI. Preabsorption of the sera with gelatin substantially reduced the IgA-binding to collagen types I to IV, but not to types V and VI. This finding suggests that the binding to collagen type V is not fibronectin-mediated, but may reflect autoantibody formation. Thus, fibronectin-mediated IgA-collagen interactions are not specific for IgAN, and their pathogenetic role is questionable. The role of IgA anti-collagen type V antibodies requires further study.

Adolescent↗
PubMed1992

Benefits of quadruple immunosuppressive therapy in recipients of living related donor kidneys. A review of 855 operations.

Eight hundred fifty-five living related donor transplant recipients were analyzed according to 15 potential risk factors with regard to patient and graft survival according to immunosuppression. Group I, 1968 to 1983, (n = 440 patients) received azathioprine and prednisone; group II, 1984 to 1987, (n = 229 patients) received triple therapy--azathioprine, prednisone, and cyclosporine; and group III, 1988-1991, (n = 186 patients), quadruple therapy--azathioprine, prednisone, cyclosporine, and Minnesota antilymphocyte globulin. Three important risk factors included immunosuppression, tissue typing, and race. Groups II and III had improved allograft survival over group I (p = 0.03). Patients with two haplotype matches had similar survival in all three groups. Kidney survival in one-haplotype-matched recipients improved in group II and was equal to that of the two-haplotype-matched patients in group III. Cyclosporine improved allograft survival in both races when combined with azathioprine and prednisone. Quadruple therapy improved early survival in one-haplotype black patients, even though long-term results remained better in whites. Cyclosporine did not improve graft survival in two-haplotype recipients. The addition of cyclosporine and quadruple therapy did not increase morbidity and mortality rates.

Adolescent↗
PubMed1992

Improved survival of primary cadaveric renal allografts in blacks with quadruple immunosuppression.

Black recipients of cadaveric kidneys have been shown to have a lower rate of allograft survival than whites. Data were reviewed from 642 primary cadaveric transplants: results in 276 patients (163 white and 113 black) (group 1) who had received triple therapy (azathioprine-CsA-prednisone, 1985-87) were compared with those in 366 patients (180 white and 186 black) (group 2) receiving quadruple immunosuppression (MALG-azathioprine-CsA-prednisone, 1987-90). Blacks in group 2 had better patient (97% vs. 91%, P = 0.03) and graft (77% vs. 55%, P = 0.0002) survival at 1 year than in group 1. There was no difference in these parameters among whites in either group. Racial differences in graft survival noted in group 1 disappeared in group 2. While HLA BDR matching improved in group 2 patients (P = 0.0001), whites received better matched kidneys than blacks in both groups (P = 0.001). HLA matching was associated with improved graft survival only in white recipients of 4 BDR-matched kidneys. In group 1, more blacks than whites had at least one episode of acute rejection (76% vs. 57%, P = 0.001); blacks also lost more grafts to acute and chronic rejection. In group 2, there were no racial differences in the number of rejection episodes or immunologic graft losses. Of 14 potential variables examined by parametric analysis, only quadruple therapy significantly reduced risk of graft loss in blacks. Quadruple immunosuppression improved primary cadaveric renal allograft survival in black recipients, abrogating previously noted racial differences.

Adult↗
PubMed1992

The impact of the UNOS mandatory sharing policy on recipients of the black and white races--experience at a single renal transplant center.

The impact of the United Network for Organ Sharing mandatory sharing policy on a large transplant center procuring kidneys primarily from caucasians while serving a pool of prospective recipients composed mainly of blacks is described. This policy requires that all 6-antigen-matched and phenotypically identical donor kidneys be shipped to the appropriately matched recipients. The study consisted of 49 kidneys from 25 cadaveric donors; one kidney was unusable. In general, the 33 recipients of the mandatorily shared kidneys were caucasian (94%), unsensitized (70%), and first-time transplants (73%). Allograft survival for the 24 first-time recipients was 100% (mean graft survival = 11.3 months). Of the 9 regraft kidneys, 2 have failed (mean graft survival = 11.9 months) due to chronic rejection. In comparison, the 16 paired kidneys transplanted into non-6-antigen-matched recipients exhibited a 1-year graft survival of 80% versus 92% for the 33 recipients of mandatorily shared kidneys (P = 0.01). These 16 recipients were composed of more blacks (38%), fewer regrafts (6%), and most were unsensitized (75%). All 25 cadaveric donors were caucasians with very common HLA types. Thus, kidneys provided by the UNOS mandatory sharing policy had excellent allograft survival, and the recipients were largely unsensitized caucasians receiving their first kidney. The low number of blacks receiving allografts under this policy may be due to two factors. First, the histocompatibility differences between black recipients and the primarily caucasian cadaveric donor pool limit the number of kidneys available to blacks. Secondly, blacks do not have access to the best-matched kidneys, in part due to few black donors, their best source for well-matched kidneys. Thus, the mandatory sharing program is of clear benefit to the recipients of these well-matched kidneys; however, for a local program servicing a waiting list composed of 64% blacks the policy has been of limited value. In contrast, over 50% of local cadaveric transplants are into black recipients in a waiting time of 197 days, one third the national average for blacks. In conclusion, this study supports efforts to improve graft survival through matching but emphasizes the need to broaden our efforts in all areas of research and organ procurement to serve the entire recipient population, regardless of race.

Black People↗
PubMed1992

IgA-containing immune complexes after challenge with food antigens in patients with IgA nephropathy.

The possibility that patients with IgA nephropathy (IgAN) might have abnormal IgA immune responses to immunogens commonly encountered at mucosal surfaces, resulting in the formation of circulating immune complexes (CIC), was examined. Since it is generally held that such increased IgA responses are characterized by detectable aberrancies in handling of IgA-containing CIC, IgAN patients and controls were given a large volume of bovine milk (after dietary deprivation of bovine antigens) and immune complex levels were measured over a period of 12 h. An assay based on binding of CIC containing C3 to solid-phase anti-C3 and subsequent development with isotype-specific antibody revealed no differences in responses of patients and controls with respect to IgG- and IgM-containing CIC. Although IgAN patients tended to have higher levels of IgA-containing CIC, there were no differences in response patterns when IgA CIC levels after ingestion of the milk stimulus were related to baseline levels. Polymorphonuclear leucocytes (PMNC), which bear surface receptors for IgA, were isolated from some subjects at the same times as the samples for CIC levels and examined by two-colour immunofluorescence for the coincident presence of IgA and milk antigens. In contrast to the data obtained in the CIC assays, these experiments revealed the simultaneous presence of IgA and two of three milk proteins in PMNC of IgAN patients but not controls. Follow-up experiments designed to assess more quantitatively the coincidental presence of IgA and milk antigens indicated no significant differences between patients and controls. However, milk proteins seemed to be more commonly associated with IgA in PMNC of IgAN patients, suggesting the presence of non-complement-fixing IgA/antigen CIC after mucosal challenge of some IgAN patients.

Adolescent↗
PubMed1991

Rapid loss of vertebral mineral density after renal transplantation.

BACKGROUND: Osteopenia is a major complication of renal transplantation. Immunosuppressive regimens including cyclosporine, which permit the use of lower doses of glucocorticoids, may reduce glucocorticoid-induced osteopenia. METHODS: We prospectively studied the magnitude, distribution, and mechanism of bone loss in 20 adults who received renal allografts from living related donors, who had good renal function, and who were treated with azathioprine, cyclosporine, and low doses of prednisone. We measured serum biochemical markers of bone metabolism, determined the bone mineral density of the second, third, and fourth lumbar vertebrae and the shaft of the radius, and analyzed the histomorphometric features of iliac bone at the time of transplantation and six months later. Measurements of vertebral mineral density were repeated 18 months after transplantation in 17 of the patients. RESULTS: After transplantation, the mean serum concentrations of parathyroid hormone, phosphorus, and alkaline phosphatase decreased and the serum calcitriol concentration increased. The mean (+/- SD) bone mineral density of the vertebrae had decreased 6.8 +/- 5.6 percent 6 months after transplantation (P less than 0.05) and 8.8 +/- 7.0 percent 18 months after transplantation. In contrast, the bone mineral density of the radius had increased six months after transplantation (P less than 0.05). The histomorphometric studies showed that the rate of bone formation decreased from 50.5 +/- 44.8 to 23.1 +/- 13.8 microns3 per square micrometer per year (P less than 0.05), and the formation period lengthened from 70 +/- 42 to 146 +/- 144 days (P less than 0.05). Consequently, the amount of bone replaced during a remodeling cycle diminished. CONCLUSIONS: Osteopenia associated with renal transplantation remains a problem in the cyclosporine era. The loss of vertebral bone in our subjects was due to an imbalance in bone remodeling consistent with a toxic effect of glucocorticoids.

Adult↗
PubMed1991

Selective elevation of monomeric IgA1 in IgA nephropathy patients with normal renal function.

The molecular form of the pathognomonic IgA in IgA nephropathy (IgAN) remains controversial. Because characterization of the molecular form of IgA molecules can lend insight into their origin (systemic v mucosal), we developed immunoassays to measure both total and J chain-containing (polymeric) IgA1 and IgA2. These assays were used to measure IgA in sera from two groups of IgAN patients (with normal or decreased renal function), as well as from a group of normal individuals. IgA1 levels were higher in both groups of patients with IgAN when compared with the controls. The elevation appeared to be restricted to non-J chain-containing (monomeric) IgA1 in patients with normal renal function, whereas polymeric IgA1 was also slightly elevated in patients whose renal function was diminished. While there were no significant differences between the groups in terms of the levels of total IgA2, the patient group with normal kidney function appeared to have lower levels of polymeric IgA2. The observation that the elevation in serum IgA appears to be restricted to the monomeric form of IgA1, at least when renal function is normal, implies a systemic origin of the pathognomonic IgA in IgAN and further suggests an abnormality in the regulation of IgA secretion by immunoglobulin-producing cells in bone marrow, the site of systemic IgA synthesis.

Adolescent↗
PubMed1991

Epstein-Barr virus transformation of B lymphocytes from IgA nephropathy patients and first-degree relatives results in increased immunoglobulin synthesis not restricted to IgA.

In order to study B-cell activation patterns independent of T-cell regulation in patients with IgA nephropathy (IgAN), peripheral blood mononuclear cells from 67 patients with IgAN, 15 first-degree relatives of patients with familial disease, and 13 normal controls were transformed with Epstein-Barr virus (EBV). Culture supernatants of these transformed cells were assayed for levels of IgG, IgA, and IgM, and results obtained on the three populations were compared. EBV-transformed cells of IgAN patients, as well as the population of first-degree relatives, secreted significantly elevated levels of all three isotypes as compared with the normal controls. However, in comparing ratios of secreted isotypes, it was determined that more IgA relative to IgG and IgM was synthesized by cells of these two populations as compared with the normal controls. Our results imply that (1) the population of B cells susceptible to EBV activation is increased in IgAN patients; (2) this population of "activatable" B lymphocytes is polyclonal and not restricted to the IgA class; and (3) even though there may be a primary B-cell abnormality in IgAN, an additional defect(s) is probably operative in the pathogenesis, since cells of clinically unaffected relatives behaved in a pattern similar to that of patients.

B-Lymphocytes↗
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

IgA nephropathy in blacks: studies of IgA2 allotypes and clinical course.

The prevalence of IgA nephropathy (IgAN) varies among racial groups, being most common among Caucasians and Orientals and rare in Blacks. Other investigators have hypothesized that the risk for IgAN may be influenced by the IgA2 allotype. It has been suggested that the rare Black patients with IgAN may be homozygous for the A2m(1) allele which predominates in Whites, but is less common in Blacks. In a multicenter study, 27 Black IgAN patients were enrolled to investigate this hypothesis and analyze the clinical course of disease in Blacks. The IgA2 allotypes of 18 Black patients and 14 controls were determined using restriction fragment length polymorphism analysis. Three patients were homozygous for the A2m(1) allele, four were homozygous for A2m(2) and 11 were heterozygous. The respective allelic frequencies of A2m(1) and A2m(2) were 0.47 and 0.53 and did not differ significantly from Black controls. Most clinical manifestations of disease did not significantly differ with respect to distribution of the two alleles, although the gender ratio differed between the homozygous A2m(1) and heterozygous patients. The presence of the A2m(1) allele did not increase the risk for IgAN, and the presence of the A2m(2) allele or homozygosity for this allele did not protect Blacks from the development of IgAN.

Adult↗
PubMed1991

OKT3 first-dose reaction: association with T cell subsets and cytokine release.

Use of the monoclonal antibody OKT3 to prevent or treat allograft rejection has become commonplace. Its administration is often complicated by serious side effects, usually occurring within one to two hours after OKT3 is given, and is termed first-dose reaction. The mechanism underlying these signs and symptoms is poorly defined, but may be related to cytokine release. Twenty-three kidney or kidney/pancreas transplant recipients received OKT3 as treatment of acute rejection. Signs and symptoms occurring after the first dose were observed and quantitated prospectively, and a reaction score was calculated. Blood was drawn immediately before, and at 2 and 24 hours after the first dose of OKT3 for determination of interleukin-2 (IL2), interferon-gamma (IFN gamma), and tumor necrosis factor-alpha (TNF alpha) levels, and flow cytometric analysis of T cell subsets. Two groups were defined based on severity of first-dose reaction. Group 1 patients (N = 11) had very mild reactions (reaction score less than or equal to 3); Group 2 patients (N = 12) had more severe reactions (score greater than or equal to 5). All patients demonstrated a significant rise in serum TNF alpha from baseline to two hours after OKT3 (9 +/- 3 pg/ml to 378 +/- 54 pg/ml, P less than 0.0001), and there was significant correlation between reaction scores and two-hour TNF alpha levels (P = 0.005). Group 2 patients had higher TNF alpha levels at two hours than did Group 1 patients (484 +/- 75 pg/ml vs. 263 +/- 62 pg/ml, P = 0.04). Levels of IL2 and IFN gamma were not elevated at any sampling time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Role for specific complement phenotypes and deficiencies in the clinical expression of IgA nephropathy.

IgA nephropathy, the most commonly occurring type of chronic glomerulonephritis in individuals of European and Asian descent, exhibits marked heterogeneity of clinical signs and ultimate prognosis. Based upon their studies of regional clustering of the ancestors of related patients in eastern Kentucky, the authors have postulated the existence of an inherited disease susceptibility for IgA nephropathy. They examined serum concentrations of individual complement proteins and phenotypes for C3, C4A, C4B, and factor B (Bf) for related and unrelated patients with IgA nephropathy from Kentucky and for patients from the Mid-South region of Tennessee, Mississippi, and Alabama. In these populations, they have described partial complement deficiencies or specific phenotypes which may be associated with the disease. Their findings include the following: (1) partial deficiencies for C2, beta 1H (H), properdin (P), or C4 binding protein (C4BP) in four patients with end-stage renal disease, (2) an association between the C3*F allele with IgA nephropathy in the combined group of unrelated patients from Kentucky and the Mid-South, (3) the occurrence of C4B deficiency in two siblings with IgA nephropathy, and (4) an association between C4A deficiency and poor outcome in patients with IgA nephropathy diagnosed as adults. In addition, the related patients differ from the unrelated patients from Kentucky with respect to frequencies of Bf*F and the BfF (FF + FS + F1F + F1S) phenotype, suggestive of immunogenetic difference between these groups. Important functional differences exist between C4A and C4B isotypes and functional differences are also possible based upon C3 or Bf phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Carrier Proteins↗
PubMed1991

Long-term results of a controlled prospective study with transfusion of donor-specific bone marrow in 57 cadaveric renal allograft recipients.

Experimental studies have shown that antilymphocyte globulin combined with transfusion of donor-specific bone marrow cells can induce partial tolerance to allograft tissue. We have adapted these protocols to clinical use and present the results of 57 cadaveric renal allograft recipients who received Minnesota ALG followed by the transfusion of cryopreserved donor-specific bone marrow. A group of 54 patients received the contralateral kidney and similar immunosuppression without the marrow transfusion and serve as controls. Both groups received quadruple immunosuppression with MALG, cyclosporin, azathioprine, and prednisone. In the bone marrow group, after a 10-14 day induction course of ALG, cryopreserved marrow was transfused on the seventh day after the last dose of ALG. The median follow-up in both groups is 16 months, (range 2.5-33 months). Six grafts have been lost in the bone marrow group, (three rejections, 2 deaths [Cr 2.0, 2.3], 1 recurrent disease). In the control group 16 grafts have been lost (13 rejections, 3 deaths [Cr 1.7, 2.5, 3.0]). Five patients in the control group have biopsy-proved chronic rejection compared to one in the bone marrow group. 17 patients in the bone marrow group have been tapered off the prednisone, and three of these patients have had mild late rejection episodes without graft loss. The two groups were compared for differences in the number of rejection episodes, estimated renal plasma flow, glomerular filtration rate, and urine protein. No differences were found. The allograft survival of the bone marrow group was significantly greater (P less than .01) than the control group. The graft survival rates for the bone marrow group at 12 and 18 months were 90% (confidence limits [CL] 85-94) and 85% (CL 78-90), respectively. In the the control group the 12 and 18 month allograft survival rates were 71% (CL 63-78) and 67% (CL 58-74), respectively. The survival in the control group was similar to our overall transplant experience with quadruple therapy. Mixed lymphocyte culture analysis shows a trend to diminished donor-specific responsiveness in the bone marrow group. The use of cryopreserved donor-specific bone marrow is associated with improved allograft survival in cadaveric kidney allograft recipients. However, a more effective induction protocol is needed to reduce the overall number of rejection episodes.

Antilymphocyte Serum↗
PubMed1991

Analysis of 22 years experience in living-related transplantation at the University of Alabama in Birmingham.

Over the 22 years comprising this review of living-related renal allografts, 3 distinct eras of immunosuppression protocols were used; Era I-aziathioprine and prednisone, Era II-cyclosporine, azathioprine, and prednisone; and Era III-Minnesota antilymphocyte globulin, cyclosporine, azathioprine, and prednisone. We analyzed both recipient and donor populations for graft and patient survival related to race, haplotype matching, diabetes, and immunosuppressive agents. Graft and patient survival have remained unchanged in 2-haplotype-matched recipients throughout the differing immunosuppression eras. The addition of cyclosporine, however, improved graft survival in the 1-haplotype living-related recipient. During the cyclosporine era, 1-haplotype White living-related recipient graft survival was significantly greater than 1-haplotype Black living-related recipient survivals. The reason for this disparity in graft survival does not appear to be related to noncompliance. The parametric hazard function analysis of the constant phase did not identify cyclosporine as a risk factor for late graft loss, suggesting that long-term cyclosporine usage may decrease the risk of graft loss. However, diabetes was demonstrated to be a risk factor for late graft loss. In diabetics, late graft loss is most likely secondary to death (usually cardiovascular) with a functioning graft. The organ donor pool is being expanded through the utilization of both older donors and living-unrelated donors. Graft survival in the living-unrelated group has been comparable to that of 1- and 2-haplotype-matched recipients. Results with older donors reveal donor age as a risk factor for late graft loss. The issue of living-unrelated transplantation remains controversial. In over 20 years of follow-up on our living-related donor population, we were unable to demonstrate any adverse long-term effects on renal function. Results of our analysis indicate that living-related renal donation continues to be a safe and valuable avenue for kidney transplantation.

Adolescent↗