Antiproteinuric versus antihypertensive effects of high-dose ACE inhibitor therapy.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors effectively reduce proteinuria; however, the optimal antiproteinuric dose is still unknown. We conducted this study to determine whether an increase in ACE-inhibitor dose above the maximal antihypertensive effect has additional antiproteinuric potential. METHODS: Twenty-three proteinuric patients were administered the ACE inhibitor spirapril at a starting dose of 3 to 6 mg/d. The dose was increased every 6 weeks until the maximal antihypertensive effect, assessed by 24-hour ambulatory blood pressure (ABP) monitoring, was achieved (spir(max)), then increased to a supramaximal dose (spir(supramax)). Renal parameters, urinary protein excretion, and systemic activity of the renin-angiotensin system were compared between baseline, spir(max), and spir(supramax). Glomerular filtration rate and renal plasma flow were determined before the administration of spirapril and after administration of the supramaximal dose. RESULTS: Median ABP and proteinuria decreased significantly between baseline and spir(max) (median, 102 mm Hg; range, 82 to 122 mm Hg versus 97 mm Hg; range, 82 to 113 mm Hg; median protein, 2.56 g/d; range, 1.05 to 22.1 g/d versus 1.73 g/d; range, 0.42 to 4.7 g/d). Both creatinine level and creatinine clearance remained unchanged. Suppression of angiotensin II formation led to a significant increase in renin and angiotensin I concentrations and a nonsignificant decrease in aldosterone levels. The increase in spirapril to a supramaximal dose had no further effect on serum renin or angiotensin I levels or proteinuria. There was an additional slight decrease in aldosterone levels and, subsequently, a significantly lower level than at baseline. CONCLUSION: Our results show that the antiproteinuric effect of spirapril is associated with its antihypertensive effect. Although high-dose ACE-inhibitor therapy has no additional influence on proteinuria, a possible beneficial long-term effect cannot be ruled out.

Osteoprotegerin and parathyroid hormone as markers of high-turnover osteodystrophy and decreased bone mineralization in hemodialysis patients.

Osteoprotegerin (OPG) has a profound inhibitory effect on osteoclast differentiation and bone resorption. Because high-turnover renal osteodystrophy (ROD) is characterized by increased osteoclast activity, serum OPG concentrations might be used to distinguish between forms of ROD. Twenty-six patients on maintenance hemodialysis therapy underwent a transiliac crest biopsy for evaluation of histopathologic characteristics and histomorphometric studies. ROD was diagnosed as type II (normal or low turnover) or type III (high turnover plus osteoidosis) disease. Bone mineralization density distribution (BMDD) was characterized by measuring the mean trabecular calcium concentration in the biopsy specimen with quantitative backscattered electron imaging. Patients underwent additional dual-energy x-ray absorptiometry (DEXA) of the spine and hip and measurement of such biochemical markers of bone turnover as OPG, intact parathyroid hormone (iPTH), osteocalcin, calcitonin, bone alkaline phosphatase, and cross-laps. OPG levels were significantly reduced in patients with ROD III compared with ROD II (118 +/- 38 versus 204 +/- 130 pg/mL; P < 0.05) and correlated with BMDD (r = 0.43; P < 0.05). Patients with ROD III showed significantly lower BMDD compared with healthy controls (21.42% +/- 0.12% versus 22.17% +/- 0.81% weight; P < 0.01). Besides iPTH, which showed significantly greater levels in patients with ROD III than ROD II (382 +/- 322 versus 136 +/- 156 pg/mL; P < 0.05), none of the serological markers or DEXA was useful in separation of the groups. Discriminant function analysis showed that a combination of OPG and iPTH correctly classifies ROD II in 72% and ROD III in 88% of patients. We conclude that OPG in combination with iPTH can be used as a marker for noninvasive diagnosis of ROD in hemodialysis patients. Furthermore, OPG serum levels might be used to estimate trabecular bone mineralization in these subjects.

Peri-operative immunoadsorption in sensitized renal transplant recipients.

BACKGROUND: Re-transplanted kidney allograft recipients with high levels of panel reactive antibodies (PRA) are at increased risk of early immunologic graft loss. In these patients, prophylactic peri-operative antibody depletion by immunoadsorption (IA) could prevent humoral graft injury and thus, in combination with anti-cellular rejection therapy, improve graft survival. METHODS: Twenty re-transplanted and broadly immunized cadaver kidney recipients (median PRA reactivity 87%, range 55-100%) were treated with IA (protein A) immediately before transplantation and during the early post-transplantation period (median number of IA sessions 11, range 1-24). Patients received additional prophylactic anti-lymphocyte antibody therapy. Nineteen patients had a negative pre-transplant cross-match. In one patient, a positive cross-match was rendered negative by the pre-transplant IA session. RESULTS: One-year graft survival was 80% and patient survival 95%. Median (range) serum creatinine in functioning grafts was 1.6 (0.8-2.7) mg/dl at discharge and 1.5 (1.0-5.8) mg/dl at 1 year. Two grafts were lost due to acute vascular rejection, whereby one rejection occurred after withdrawal of immunosuppression due to septicaemia. One patient had acute cellular rejection, which was reversed by a second course of anti-lymphocyte antibody therapy. Thrombotic microangiopathy and surgical complications were the causes for one graft loss each. Retrospective immunohistochemistry revealed peritubular C4d staining, a presumed marker for humoral alloreactivity, in 12 out of 15 biopsies. CONCLUSIONS: These results suggest that prophylactic peri-operative IA and anti-lymphocyte antibody therapy might be an effective therapeutic strategy for the prevention of early graft failure in sensitized re-transplant recipients.

Zoledronic acid to prevent bone loss in the first 6 months after renal transplantation.

BACKGROUND: Bisphosphonates can prevent bone mineral density loss after renal transplantation, but their effect on trabecular mineralization and bone morphology, two key factors of bone stability, remains unknown. METHODS: In a 6-month, randomized, placebo-controlled study, 20 kidney transplant recipients received either 4 mg zoledronic acid or placebo twice within 3 months after engraftment. At transplantation and after 6 months, mean trabecular calcium concentration and trabecular morphometry were measured in bone biopsies. Bone mineral density (BMD) of the femoral neck and the lumbar spine were evaluated by dual-energy x-ray absorptiometry, and serum biochemical markers of bone metabolism were determined monthly. RESULTS: Trabecular calcium content increased significantly in the zoledronic acid group, but remained unchanged in the placebo group. BMD at femoral neck showed no change in the zoledronic acid group, but decreased in the placebo group. BMD of the lumbar spine was increased in the zoledronic acid group without change in the placebo group. High-turnover bone disease resolved similarly in both groups, as evidenced by a significant decrease of eroded bone surface, osteoclast and osteoblast surface. Serologic markers of bone formation and resorption were significantly lower in zoledronic acid-treated patients throughout the study. Kidney transplant function was stable after zoledronic acid therapy. CONCLUSIONS: Our results show that administration of zoledronic acid improves the calcium content of cancellous bone after kidney transplantation. The beneficial effect of bisphosphonate therapy is further evidenced by an increase of lumbar spine BMD, and stabilization of femur BMD.