Long-term efficacy and safety of iron-based phosphate binders, ferric citrate hydrate and sucroferric oxyhydroxide, in hemodialysis patients.

PURPOSE: Iron-based phosphate binders, including ferric citrate hydrate (FCH) and sucroferric oxyhydroxide (SFOH), have been used for the treatment of hyperphosphatemia in end-stage renal disease patients on dialysis. However, the long-term efficacy and safety of these agents have not yet been clearly elucidated. METHODS: Laboratory data of 56 hemodialysis patients who had been prescribed either FCH (n = 33) or SFOH (n = 23) were retrospectively examined. RESULTS: We showed that both FCH and SFOH significantly and consistently decreased serum phosphate concentrations in the patients undergoing maintenance hemodialysis during the 36-month observation period. Serum levels of calcium, intact parathyroid hormone, as well as hemoglobin levels were unaltered. No overshoot of parameters of iron metabolism, such as transferrin saturation and serum ferritin levels, was observed, and serum ferritin level remained under 300 ng/mL in most patients. A trend towards decrease in the doses of erythropoiesis-stimulating agents used and frequency of intravenous iron use was observed in both treatment groups. No severe adverse drug reactions were observed in either the patients receiving FCH or SFOH. CONCLUSION: The results of the present study suggest that the iron-based phosphate binders, FCH and SFOH, decrease serum phosphate concentrations consistently and are safe to use over the long-term in maintenance hemodialysis patients.

Proton pump inhibitors may hinder hypophosphatemic effect of lanthanum carbonate, but not of ferric citrate hydrate or sucroferric oxyhydroxide, in hemodialysis patients.

Because end-stage renal disease patients undergoing hemodialysis frequently take acid suppressants for the treatment or prevention of gastrointestinal diseases, it is important to clarify the drug-interactions between acid suppressants and phosphate binders on the control of serum phosphate levels. In the present study, we examined whether the phosphate-lowering effects of three phosphate binders, lanthanum carbonate (LC), ferric citrate hydrate (FCH), and sucroferric oxyhydroxide (SFOH), were affected by proton pump inhibitors (PPIs) in maintenance hemodialysis patients. Laboratory data for 71 patients who had been newly prescribed one of the three phosphate binders were examined. LC at a dosage of 500 ± 217 mg/day significantly decreased serum phosphate levels by -18% in the absence of a PPI (n = 9), while a dosage of 700 ± 230 mg/day only decreased it by -3% in the presence of a PPI (n = 10). Thus, the efficacy of LC in reducing serum phosphate levels was significantly hindered by the presence of PPIs. FCH significantly decreased serum phosphate levels by -18% in the absence of a PPI (n = 7, FCH: 571 ± 189 mg/day) and by -17% in the presence of a PPI (n = 20, FCH: 638 ± 151 mg/day). The decrease in serum phosphate levels by SFOH (393 ± 197 mg/day) was -7% in the absence of a PPI (n = 7), and SFOH at a dosage of 556 ± 316 mg/day significantly decreased serum phosphate levels by -13% in the presence of a PPI (n = 18). These results suggest that the phosphate-lowering effect of LC, but not of FCH or SFOH, is diminished in the presence of PPIs in hemodialysis patients.

Role of matrix metalloproteinase-2 in recovery after tubular damage in acute kidney injury in mice.

BACKGROUND/AIMS: Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix and are involved in the pathogenesis of ischemic damage in acute kidney injury (AKI). In the present study, we analyzed the role of MMP-2 in the repair process in ischemic AKI. METHODS: AKI was induced in MMP-2 wild-type (MMP-2(+/+)) and MMP-2-deficient (MMP-2(-/-)) mice by 90-min renal artery clamping followed by reperfusion. Renal histology and the activity and distribution of MMP-2 were examined from day 1 to day 14. During the recovery from AKI, MMP-2(+/+) mice were also treated with MMP-2/MMP-9 inhibitor. RESULTS: In both MMP-2(+/+) and MMP-2(-/-) mice, AKI developed on day 1 after ischemia/reperfusion with widespread acute tubular injury, but subsequent epithelial cell proliferation was evident on days 3-7. During the repair process, active MMP-2 and MMP-9 increased in regenerating tubular epithelial cells in MMP-2(+/+) mice on days 7-14, and the tubular repair process was almost complete by day 14. On the other hand, in MMP-2(-/-) mice, less prominent proliferation of tubular epithelial cells was evident on days 3 and 7, and damaged tubules that were covered with elongated and immature regenerated epithelial cells were identified on days 7 and 14. Incomplete recovery of injured microvasculature was also noted with persistent macrophage infiltration. Similarly, treatment with MMP-2/MMP-9 inhibitor resulted in impaired recovery in MMP-2(+/+) mice. CONCLUSION: MMP-2 is involved in tubular repair after AKI. The use of the MMP-2/MMP-9 inhibitor was a disadvantage when it was administered during the repair stage of ischemic AKI. Treatment with MMP inhibitor for AKI needs to be modified to enhance recovery from AKI.

Renal thrombotic microangiopathy associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Thrombotic microangiopathy (TMA) is a major complication after hematopoietic stem cell transplantation (HSCT). In this study, we examined the clinical and pathologic features of 2 patients and 5 autopsy cases with HSCT-associated renal TMA to clarify the association between graft-versus-host disease (GVHD) and renal TMA. The median interval between HSCT and renal biopsy or autopsy was 7 months (range 3-42 months). Clinically, acute and chronic GVHD occurred in 7 and 4 patients, respectively. Clinical evidence for TMA was detected in 2 patients, while chronic kidney disease developed in all patients. The main histopathological findings were diffuse endothelial injury in glomeruli, peritubular capillaries (PTCs), and small arteries. In addition, all cases showed glomerulitis, renal tubulitis, and peritubular capillaritis with infiltration of CD3+ T cells and TIA-1+ cytotoxic cells, suggesting that GVHD occurred during the development of TMA. Diffuse and patchy C4d deposition was noted in glomerular capillaries and PTCs, respectively, in 2 biopsy and 2 autopsy cases, suggesting the involvement of antibody-mediated renal endothelial injury in more than 50% of renal TMA cases. In conclusion, the kidney is a potential target of chronic GVHD that may induce the development of HSCT-associated TMA. Importantly, some cases are associated with chronic humoral GVHD.

Renal thrombotic microangiopathy associated with chronic humoral graft versus host disease after hematopoietic stem cell transplantation.

Thrombotic microangiopathy (TMA) is a known complication of hematopoietic stem cell transplantation (HSCT). The pathogenesis of TMA is controversial but considered to involve various factors such as total body irradiation, use of calcineurin inhibitors for prophylaxis against graft versus host disease (GVHD), viral infection, and GVHD. Herein we describe a case with renal TMA after HSCT, which was probably associated with antibody-mediated endothelial cell injury from chronic GVHD (termed here 'chronic humoral GVHD'). A 49-year-old man presented two years after HSCT with renal dysfunction and proteinuria but without the clinical features of TMA. Histopathological examination of renal biopsy showed chronic glomerular endothelial cell injury with double contour of the glomerular basement membrane, microthrombi and the deposition of complement split product C4d along the glomerular capillaries. Renal tubulitis and peritubular capillaritis were also noted with a multilayered basement membrane and patchy C4d deposition on peritubular capillaries. These findings resemble those of chronic antibody-mediated rejection after kidney transplantation. Furthermore, C4d deposition suggests complement activation. Although circulating anti-blood type and anti-human leukocyte antigen antibodies were not detected, the renal TMA in this case was probably associated with chronic humoral GVHD.

Methylprednisolone pulse therapy combined with mizoribine following tonsillectomy for immunoglobulin A nephropathy: clinical remission rate, steroid sparing effect, and maintenance of renal function.

BACKGROUND: The long-term prognosis of immunoglobulin A nephropathy (IgAN) is reportedly poor. In Japan, tonsillectomy-steroid pulse therapy has frequently been used for treatment of early IgAN, with favorable outcomes. However, steroid usage is sometimes limited due to adverse reactions. To reduce the total dose of steroids, we have been using mizoribine (MZR) in combination with tonsillectomy-steroid pulse therapy since 2004. Here we report a retrospective evaluation of our protocol outcome. METHODS: Forty-two patients aged <70 years with histopathologically confirmed IgAN and an estimated glomerular filtration rate (eGFR) of 30 ml/min/1.73 m(2) or higher were enrolled. After giving informed consent, all the patients underwent bilateral tonsillectomy. One week later, intravenous methylprednisolone pulse therapy (500 mg/day) was administered for 3 days, followed by oral prednisolone (30 mg/day and tapered to 0 over 7 months) and MZR (150 mg/day for 11 months). The complete remission (CR) rate and renoprotective effect were assessed. RESULTS: The CR rate at 6, 12, and 24 months was 33.3, 69.1, and 76.2%, respectively. Despite a relatively low total steroid dose, renal function was satisfactorily maintained for 24 months or longer with no relapse. The eGFR in patients with stage 3 chronic kidney disease was significantly improved at 6 months after start of treatment. Three patients (7.1%) had mild and transient adverse events. CONCLUSION: This protocol appears to be highly effective and safe for IgAN patients with renal dysfunction.