Ferric citrate controls phosphorus and delivers iron in patients on dialysis.

Patients on dialysis require phosphorus binders to prevent hyperphosphatemia and are iron deficient. We studied ferric citrate as a phosphorus binder and iron source. In this sequential, randomized trial, 441 subjects on dialysis were randomized to ferric citrate or active control in a 52-week active control period followed by a 4-week placebo control period, in which subjects on ferric citrate who completed the active control period were rerandomized to ferric citrate or placebo. The primary analysis compared the mean change in phosphorus between ferric citrate and placebo during the placebo control period. A sequential gatekeeping strategy controlled study-wise type 1 error for serum ferritin, transferrin saturation, and intravenous iron and erythropoietin-stimulating agent usage as prespecified secondary outcomes in the active control period. Ferric citrate controlled phosphorus compared with placebo, with a mean treatment difference of -2.2±0.2 mg/dl (mean±SEM) (P<0.001). Active control period phosphorus was similar between ferric citrate and active control, with comparable safety profiles. Subjects on ferric citrate achieved higher mean iron parameters (ferritin=899±488 ng/ml [mean±SD]; transferrin saturation=39%±17%) versus subjects on active control (ferritin=628±367 ng/ml [mean±SD]; transferrin saturation=30%±12%; P<0.001 for both). Subjects on ferric citrate received less intravenous elemental iron (median=12.95 mg/wk ferric citrate; 26.88 mg/wk active control; P<0.001) and less erythropoietin-stimulating agent (median epoetin-equivalent units per week: 5306 units/wk ferric citrate; 6951 units/wk active control; P=0.04). Hemoglobin levels were statistically higher on ferric citrate. Thus, ferric citrate is an efficacious and safe phosphate binder that increases iron stores and reduces intravenous iron and erythropoietin-stimulating agent use while maintaining hemoglobin.

Modification of collagen IV by glucose or methylglyoxal alters distinct mesangial cell functions.

Diabetic nephropathy (DN) affects both glomerular cells and the extracellular matrix (ECM), yet the pathogenic mechanisms involving cell-matrix interactions are poorly understood. Glycation alters integrin-dependent cell-ECM interactions, and perturbation of these interactions results in severe renal pathology in diabetic animals. Here, we investigated how chemical modifications of the ECM by hyperglycemia and carbonyl stress, two major features of the diabetic milieu, affect mesangial cell functions. Incubation of collagen IV with pathophysiological levels of either the carbonyl compound methylglyoxal (MGO) or glucose resulted in modification of arginine or lysine residues, respectively. Mouse mesangial cells plated on MGO-modified collagen IV showed decreased adhesion and migration. Cells plated on glucose-modified collagen IV showed reduced proliferation and migration and increased collagen IV production. Inhibiting glucose-mediated oxidative modification of collagen IV lysine residues rescued the alterations in cell growth, migration, and collagen synthesis. We propose that diabetic ECM affects mesangial cell functions via two distinct mechanisms: modification of arginine residues by MGO inhibits cell adhesion, whereas oxidative modification of lysine residues by glucose inhibits cell proliferation and increases collagen IV production. These mechanisms may contribute to mesangial cell hypertrophy and matrix expansion in DN.

Mechanism of perturbation of integrin-mediated cell-matrix interactions by reactive carbonyl compounds and its implication for pathogenesis of diabetic nephropathy.

Perturbation of interactions between cells and the extracellular matrix (ECM) of renal glomeruli may contribute to characteristic histopathological lesions found in the kidneys of patients with diabetic nephropathy. However, the mechanism by which the diabetic conditions may affect cell-ECM interactions is unknown. Existing hypotheses suggest a role of glucose in direct modification of ECM. Here, we have demonstrated that carbonyl compound methylglyoxal (MGO) completely inhibited endothelial cell adhesion to recombinant alpha3 noncollagenous 1 domain of type IV collagen mediated via a short collagenous region containing RGD (Arg-Gly-Asp) sequence as well as binding of purified alpha(v)beta(3) integrin to this protein. Specific MGO adducts of the arginine residue were detected within RGD sequence using mass spectrometry. Modification by carbonyl compounds glyoxal or glycolaldehyde had similar but smaller effects. MGO strongly inhibited adhesion of renal glomerular cells, podocytes, and mesangial cells to native collagen IV and laminin-1 as well as binding of collagen IV to its major receptor in glomerular cells, alpha(1)beta(1) integrin. In contrast, modification of these proteins by glucose had no effect on cell adhesion. Pyridoxamine, a promising drug for treatment of diabetic nephropathy, protected cell adhesion and integrin binding from inhibition by MGO. We suggest that in diabetes, perturbation of integrin-mediated cell-matrix interactions occurs via the modification of critical arginine residues in renal ECM by reactive carbonyl compounds. This mechanism may contribute to the development of diabetic nephropathy.

Ezetimibe in renal transplant patients with hyperlipidemia resistant to HMG-CoA reductase inhibitors.

Hyperlipidemia affects the majority of renal transplant patients. Multiple risk factors contribute to elevated serum cholesterol including the use of certain immunosuppressant agents. HMG-Co A reductase inhibitors have become the preferred class of cholesterol-lowering medication with an increasing body of evidence to support their safety, efficacy, and outcomes in both the normal and renal transplant populations. New guidelines recommend lowering previous LDL-c goals as outcomes appears to continually improve. As a result, ezetimibe has been added to patients with persistently elevated triglycerides and/or LDL-c in individuals who possessed a renal transplant and were deemed to be on a maximum safe dose of statin agent. After the addition of ezetimibe, total cholesterol, LDL-c, and triglycerides fell by 21%, 31%, and 13%, respectively. Creatinine phosphokinase, liver enzyme serum levels, and renal function were not affected to any level of clinical significance with the addition of ezetimibe. Large interpatient variability of measurable immunosuppressant levels was seen but no serious adverse events were attributed to a change in levels.

Polyclonal antibody-induced serum sickness in renal transplant recipients: treatment with therapeutic plasma exchange.

Serum sickness is an immune-complex mediated illness that frequently occurs in patients after polyclonal antibody therapy (ATGAM or thymoglobulin). Serum sickness presents with significant morbidity but is self-limited and resolves with prolonged steroid therapy. We present five renal transplant patients who developed serum sickness after polyclonal antibody treatment with severe symptoms that persisted after being started on systemic steroids. These patients underwent one or two courses of therapeutic plasma exchange (TPE) with subsequent complete resolution of their symptoms. Renal transplant recipients with serum sickness after polyclonal antibody therapy may benefit from TPE by accelerating their time to recovery and thereby reducing overall morbidity.

Ezetimibe reduces low-density lipoprotein cholesterol (LDL-C) in renal transplant patients resistant to HMG-CoA reductase inhibitors.

Hyperlipidemia is common after renal transplantation. On the basis of current lipid guidelines, the majority of renal transplant recipients should have plasma low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL. Even with statin (HMG-CoA [3-hydroxy-3-methylglutaryl CoA] reductase inhibitor) therapy, a significant number of renal transplant recipients have LDL-C levels >100 mg/dL. We report that ezetimibe, a novel inhibitor of intestinal cholesterol absorption, was well tolerated and effectively reduced the LDL-C level to <100 mg/dL in our cohort of renal transplant recipients with persistently elevated LDL-C levels during treatment with maximally tolerated statin medications.

The management of the failed renal allograft: an enigma with potential consequences.

The number of patients returning to dialysis after their renal allograft fails is increasing in absolute numbers year after year. The management of the failed allograft that is not immediately symptomatic remains controversial. Surgical mortality and morbidity, a rising number of circulating antibodies, reduced erythropoietin, and diuresis are among the arguments to support simply observing the failed allograft. Chronic inflammation, potential for malignancy, infection, and the need for low-dose immunosuppression are concerns that might goad one into performing a preemptive nephrectomy. Based on the current literature and our own clinical experience, we believe allograft nephrectomies should not be routinely performed. They should be reserved for those patients who develop particular symptoms attributable to the allograft or those who require space for retransplantation. Future studies that address this issue in addition to testing various immunosuppression attrition rates may be able to discern a protocol that minimizes drug exposure while leading to reduced nephrectomy rates after returning to dialysis.

Urinary tract infections after renal transplantation: a retrospective review at two US transplant centers.

Urinary tract infections (UTIs) are the most common infectious complication following renal transplantation. Previous studies uniformly report that renal transplant recipients develop UTIs more often than the general population, but widely differ on how frequently UTIs occur after transplantation. These studies also disagree on the risk factors associated with developing post-transplant UTIs, as well as the effect that UTIs may have on graft outcomes and patient mortality. We performed a retrospective cohort study including all the adult patients who received a renal transplant at two US transplant centers from January 1996 to December 2002 (500 patients). Two hundred and thirteen (43%) patients developed one or more post-transplant UTIs over a mean follow-up period of 42 months. Significant risk factors for post-transplant UTIs were advanced age, female gender, reflux kidney disease, use of azathioprine and cadaveric donor. UTIs did not increase risk for renal graft loss, but were associated with increased mortality (3.5 odds ratio, 95% confidence interval 1.68-7.23). We conclude UTIs may be associated with an increased mortality risk in renal transplant recipients. Prevention of UTIs in high-risk renal transplant patients or those with recurrent UTIs may possibly decrease post-transplant mortality.