Harry J. Ward

Predictive Validity of A Medication Adherence Measure in an Outpatient Setting

This study examines the psychometric properties and tests the concurrent and predictive validity of a structured, self‐reported medication adherence measure in patients with hypertension. The authors also assessed various psychosocial determinants of adherence, such as knowledge, social support, satisfaction with care, and complexity of the medical regimen. A total of 1367 patients participated in the study; mean age was 52.5 years, 40.8% were male, 76.5% were black, 50.8% graduated from high school, 26% were married, and 54.1% had income <

Induction of Membranous Nephropathy in Rabbits by Administration of an Exogenous Cationic Antigen: DEMONSTRATION OF A PATHOGENIC ROLE FOR ELECTRICAL CHARGE

5,000. The 8‐item medication adherence scale was reliable (α=.83) and significantly associated with blood pressure control (P<.05). Using a cutpoint of <6, the sensitivity of the measure to identify patients with poor blood pressure control was estimated to be 93%, and the specificity was 53%. The medication adherence measure proved to be reliable, with good concurrent and predictive validity in primarily low‐income, minority patients with hypertension and might function as a screening tool in outpatient settings with other patient groups.

Serum Erythropoietin Levels after Renal Transplantation

We examined the role of antigenic electrical charge as a determinant of glomerular immune complex localization in the rabbit. Serum sickness nephritis was induced in groups of New Zealand white rabbits by daily 25-mg intravenous injections of bovine serum albumin (BSA) chemically modified to be cationic (pI > 9.5) or more anionic (pI, 3.5-4.6); an additional group received unmodified native BSA (pI, 4.5-5.1). Factors known to influence immune complex localization, e.g., molecular size of the administered antigen and resulting circulating immune complexes, immunogenicity, and disappearance time from the circulation were examined and found to be similar for both anionic and cationic BSA. Charge modification did increase the nonimmune clearance of cationic and anionic BSA compared with native BSA. Injected cationic BSA was shown in paired label experiments to bind directly to glomeruli compared with native BSA. The renal lesion produced by cationic BSA was markedly different from that found in rabbits given anionic or native BSA. Animals receiving cationic BSA uniformly developed generalized diffuse granular capillary wall deposits of IgG, C3, and BSA detected after 2 wk of injections and increasing until death at 6 wk. Qualitatively similar deposits were produced by the administration of low doses of cationic BSA of only 1 or 10 mg/d. In contrast, the injection of both anionic and native BSA resulted in mesangial deposits at 2 and 4 wk with capillary wall deposits appearing by 6 wk. Ultrastructural examination of animals receiving cationic BSA revealed pure, extensive formation of dense deposits along the lamina rara externa of the glomerular basement membrane whereas such deposits were absent or rare in animals injected with the anionic or native BSA. Albuminuria was significantly greater at 6 wk in the groups receiving cationic BSA with a mean of 280 mg/24 h compared with 53 mg/24 h in the combined groups injected with anionic or native BSA. Blood urea nitrogen values were similar in all groups at 2 and 4 wk but higher in the animals receiving cationic BSA at 6 wk. These experiments describe the reproducible induction of epimembranous immune deposits by administration of an exogenous cationic antigen. They suggest that antigenic charge can play an important role in the pathogenesis of membranous nephropathy by permitting direct glomerular binding of an antigen and predisposing to in situ immune complex formation.

Electrical Charge. ITS ROLE IN THE PATHOGENESIS AND PREVENTION OF EXPERIMENTAL MEMBRANOUS NEPHROPATHY IN THE RABBIT

We measured serum erythropoietin levels serially in 31 renal-transplant recipients treated with cyclosporine, using the recently developed recombinant human erythropoietin-based radioimmunoassay. The mean (+/- SEM) serum erythropoietin concentration in these patients before transplantation (14 +/- 2 U per liter) was similar to that in normal subjects who did not have anemia. A transient postoperative 9-fold increase (range, 0- to 74-fold) in the serum erythropoietin levels was followed by a smaller (3-fold) and sustained (28 +/- 3 days) second elevation. The initial increase occurred in the absence of graft function and was not accompanied by an erythropoietic response, whereas the second increase was associated with graft recovery and the complete resolution of the anemia. Serum erythropoietin levels returned to normal as the hematocrit rose above 0.32. Thereafter, the hematocrit continued to rise toward normal, while the serum erythropoietin levels remained normal. The patients in whom erythrocytosis or iron-deficiency anemia developed had persistently elevated serum erythropoietin levels. We conclude that in patients who have undergone renal transplantation, slight increases in endogenous erythropoietin levels induce erythropoiesis to the same extent as do large doses of exogenous erythropoietin in patients with uremia. Moreover, once initiated, erythropoiesis in renal-transplant recipients may be sustained by normal serum erythropoietin levels. These results suggest that the restoration of renal function improves the erythropoietic response to erythropoietin.

Reducing Disparities in Hypertension Control: A Community-Based Hypertension Control Project (CHIP) for an Ethnically Diverse Population:

Intravenous cationic bovine serum albumin (BSA, pI > 9.5) induces membranous nephropathy in immunized rabbits. In this study, unimmunized rabbits received intravenous injections of cationic (n = 3) or native (n = 3) or native (n = 3) BSA, followed by ex vivo isolated left renal perfusions with sheep anti-BSA antibody. Capillary wall deposits of IgG and C3 were seen exclusively in the group receiving cationic BSA, confirming an in situ pathogenesis for cationic, BSA-induced membranous nephropathy, and demonstrating the importance of a cationic antigen for its production. We then explored whether membranous nephropathy in this model is prevented by the concomitant injection of protamine sulfate, a filterable, relatively non-immunogenic polycation. An in vitro study demonstrated that protamine sulfate incubated with glomerular basement membrane (GBM) decreased the subsequent binding of radiolabeled cationic BSA (P < 0.05). In vivo, protamine sulfate was shown to bind to anionic sites in the glomerular capillary wall after intravenous injection.Groups of rabbits received 3 wk of daily intravenous injections of cationic BSA alone (n = 15) or cationic BSA and protamine (n = 18). After 2 wk of injection of cationic BSA alone, typical membranous nephropathy developed. Granular deposits of IgG and C3 were present along the GBM associated with subepithelial dense deposits, foot process effacement, and marked albuminuria. Protamine significantly reduced or prevented the formation of deposits (P < 0.001) and in6 of 18 protamine-treated animals, existing deposits decreased or disappeared between 2 and 3 wk of injection. Albuminuria was significantly reduced in protamine-treated animals with a mean of 124+/-55 mg/24 h compared to 632+/-150 mg/24 h in the control group receiving cationic BSA alone. No significant differences between the groups were noted in serum lev9lsof IgG, C3, anti-BSA antibody, or circulating immune complex size. Studies in additional animals (n = 5) given radiolabeled cationic BSA showed that protamine did not alter the clearance of cationic BSA from serum. Control experiments showed that protamines beneficial effects were not related to its weak anticoagulant property or toits theoretical ability to deplete tissue histamine. The administration of heparin (n = 6) or diphenhydramine (n = 6) had no effect on the development of the epimembranous lesion compared to the group receiving cationic BSA alone. In addition, homogenized whole kidney histamine content was not significantly different in the group receiving cationic BSA alone compared to the group receiving cationic BSA and protamine. This work shows that a cationic BSA-induced glomerular lesion can be produced by a renal perfusion technique involving in situ complex formation and that this process requires a cationic antigen for its development. We believe that the demonstrated beneficial effects of protamine are due to its ability to bind to glomerular anionic sites, and that this electrostatic interaction results in inhibition for the further binding of the cationic antigen, thereby limiting the severity of glomerulonephritis in this model.

Erythropoietin upregulates angiotensin receptors in cultured rat vascular smooth muscle cells

The Community Hypertension Intervention Project (CHIP) is investigating medical, environmental, and psychosocial factors related to adherence to treatment for hypertension and examining the efficacy of three interventions designed to improve treatment adherence in a high-risk, underserved, ethnically diverse population. There were 1,367 Black (76%) and Hispanic (21%) adults who participated in a 4-year longitudinal study. Participants were randomized to either usual care or one of three interventions: (a) individualized counseling sessions with community health workers (CHWs), (b) a computerized appointment tracking system, or (c) home visits/focus group discussions with CHWs. At baseline, a total of 33% of the participants had one or more comorbidities in addition to hypertension; only 35% had their blood pressure under control. Participants assigned to the patient tracking intervention exhibited the most significant improvement in appointment keeping and blood pressure control status at 6 months; however, the 12-month follow-up assessments indicated that individualized counseling and home visits resulted in significant, sustained improvements in appointment keeping and blood pressure control status. These findings are now being integrated into the patient care delivery system of the participating outpatient clinics.

Recurrent Henoch-Schönlein purpura following renal transplantation.

Objective Plasma renin is not elevated in recombinant human erythropoietin (rhEPO)-induced hypertension but angiotensin converting enzyme inhibitors reduce blood pressure in both human and animal studies. Since rhEPO elevates renin and angiotensinogen messenger RNAs in angiotensin II target tissues such as the aorta, we explored the actions of rhEPO on renin–angiotensin system-related gene transcription of cultured rat vascular smooth muscle cells. Design and methods To separate direct actions of rhEPO from those mediated secondarily by potential activation of the renin–angiotensin system, vascular smooth muscle cells were cultured with rhEPO and enalapril to inhibit the angiotensin converting enzyme and losartan to inhibit angiotensin II type 1 receptors. Results Vascular smooth muscle cells cultured with rhEPO (6–8 units/ml) demonstrated elevations (40–120%) in messenger RNAs of the renin-angiotensin system (renin, angiotensinogen, angiotensin receptor types 1 and 2) and increased levels of several messenger RNAs known to respond to angiotensin II (transforming growth factor-β, insulin-like growth factor-II, epidermal growth factor, c-fos and platelet-derived growth factor). In contrast, cells cultured in the presence of rhEPO and enalapril or losartan showed elevations of messenger RNA for only the two types of angiotensin II receptor. This increase was higher than that obtained when cells were cultured with rhEPO or either antagonist alone. The increase in specific binding of angiotensin II to cells cultured in the presence of rhEPO and enalapril or rhEPO and losartan paralleled the changes in receptor messenger RNA. Conclusions rhEPO exerts its primary action on vascular smooth muscle cells via an increase in angiotensin receptor messenger RNA, resulting in a parallel increase in angiotensin II receptor expression. We suggest that increased receptor expression secondarily mediates the expression of other renin-angiotensin system messenger RNAs, which leads to angiotensin II-responsive gene transcription. The elevation in angiotensin II receptors, as observed in response to rhEPO, may provide a mechanism by which other forms of renin-dependent hypertension are initiated.

A clinic and community-based approach to hypertension control for an underserved minority population: design and methods

A 20-year-old patient with Henoch-Schönlein purpura leading to end-stage renal failure received a living-related renal transplant. She was treated with conventional immunosuppressive therapy. Following a quiescent period of 18 months pretransplant, at 3 months after engraftment there was recurrence of purpuric lesions with subsequent abdominal pain and glomerulonephritis. Renal and skin biopsies confirmed the immunopathologic changes of Henoch-Schönlein purpura. This case represents the second report of an adult with multiorgan recurrence of Henoch-Schönlein purpura following transplantation.

Improved survival of en bloc renal allografts from pediatric donors

This paper describes the design and methodology of the Community Hypertension Intervention Project (CHIP). CHIP is investigating the environmental and psychosocial factors related to treatment adherence and examining the effects of combining usual hypertension care with the effects of three interventions designed to improve patient compliance with treatment for high blood pressure in a high-risk, underserved minority population. Thirteen hundred and sixty-seven inner-city hypertension patients (75% black and 25% Hispanic) have agreed to participate in the 4-year longitudinal study. These participants were randomized to usual care or one of three intervention groups: individualized counseling sessions; home visits/discussion groups; or computerized appointment-tracking system. Participants are representative of the surrounding, predominantly low-income minority community and are treated in a hospital-based clinic and in a private clinic in the community. About 65% have blood pressure levels considered to be out of control. It was concluded that structural changes at the clinic site, along with the targeted interventions, would improve patient satisfaction, increase treatment adherence, and improve blood pressure control.

A lipid-protein hybrid model for tight junction

PURPOSE We developed a technical and immunological protocol to increase survival of renal transplants from pediatric donors. MATERIALS AND METHODS En bloc kidneys (22) were procured from donors weighing 2 to 14 kg. (1 to 60 months old) and transplanted into adult recipients. In group 1 (12 patients) sequential therapy was used for kidneys with more than 35 hours of cold storage and immediate triple therapy (cyclosporine, azathioprine and prednisone) was used for those with less than 35 hours of cold storage. In group 2 (10 patients) OKT3 induction therapy was used. Mean followup was 4.7 years. RESULTS Mean blood pressure at 1 and 4 years was not significantly different between the groups. Mean serum creatinine was not significantly different between the groups at 1 year but it was significantly less in group 2 at 4 years (1.9 +/- 1.0 versus 1.2 +/- 0.24 mg./dl., p <0.05). At 1 year of followup the complication rate was 75% in 9 of 12 patients in group 1, including 4 infections or leaks (2 lost), 6 rejections (3 lost) and 3 cases of thrombosis or hemorrhage, and 20% (p <0.01) in group 2 (1 patient had the hemolytic uremic syndrome leading to graft loss). Graft survival was significantly greater in group 2 at all 4 years of followup (p = 0.05). CONCLUSIONS The success of pediatric en bloc renal transplantation can be enhanced by induction therapy in healthy recipients.