Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits.

Recently, several cases of novel apolipoprotein E (apoE)-related glomerular disease known as membranous nephropathy (MN)-like apoE deposition disease with apoE Toyonaka (Ser197Cys) and homozygous apoE2/2 have been reported. However, the clinical and pathological characteristics are uncertain due to the small number of reports. Here, we report an additional case with various clinical and pathological characteristics. A 28-year-old Japanese man with mild proteinuria and hematuria underwent a kidney biopsy. Examination under a light microscope revealed mesangial proliferation, mesangial matrix expansion, and segmental spike lesion. An immunofluorescence study showed no immunoglobulin or complement depositions. In the electron microscopic (EM) examination, massive deposits with various electron densities in the subepithelial, subendothelial, and paramesangial areas were more prominent than those reported in previous cases, which resembled microbubbles or microcysts on higher magnification. The glomerular basement membrane (GBM) structure was partly degenerated by these deposits. Serum triglyceride and cholesterol levels were within the normal range. However, the serum apoE concentration was significantly high, and glomerular apoE accumulation was detected in immunohistochemistry. The DNA sequence revealed apoE Toyonaka and homozygous apoE2/2 similar to that of the previous cases with MN-like apoE deposition disease. MN-like apoE deposition disease can manifest as only mild hematuria and proteinuria without dyslipidemia. Various characteristic deposits associated with GBM degeneration can be observed in the EM study.

Optimal Serum Ferritin Levels for Iron Deficiency Anemia during Oral Iron Therapy (OIT) in Japanese Hemodialysis Patients with Minor Inflammation and Benefit of Intravenous Iron Therapy for OIT-Nonresponders.

Background: We determined optimal serum ferritin for oral iron therapy (OIT) in hemodialysis (HD) patients with iron deficiency anemia (IDA)/minor inflammation, and benefit of intravenous iron therapy (IIT) for OIT-nonresponders. Methods: Inclusion criteria were IDA (Hb <120 g/L, serum ferritin <227.4 pmol/L). Exclusion criteria were inflammation (C-reactive protein (CRP) ≥ 5 mg/L), bleeding, or cancer. IIT was withheld >3 months before the study. ΔHb ≥ 20 g/L above baseline or maintaining target Hb (tHB; 120-130 g/L) was considered responsive. Fifty-one patients received OIT (ferrous fumarate, 50 mg/day) for 3 months; this continued in OIT-responders but was switched to IIT (saccharated ferric oxide, 40 mg/week) in OIT-nonresponders for 4 months. All received continuous erythropoietin receptor activator (CERA). Hb, ferritin, hepcidin-25, and CERA dose were measured. Results: Demographics before OIT were similar between OIT-responders and OIT-nonresponders except low Hb and high triglycerides in OIT-nonresponders. Thirty-nine were OIT-responders with reduced CERA dose. Hb rose with a peak at 5 months. Ferritin and hepcidin-25 continuously increased. Hb positively correlated with ferritin in OIT-responders (r = 0.913, p = 0.03) till 5 months after OIT. The correlation equation estimated optimal ferritin of 30-40 ng/mL using tHb (120-130 g/L). Seven OIT-nonresponders were IIT-responders. Conclusions: Optimal serum ferritin for OIT is 67.4-89.9 pmol/L in HD patients with IDA/minor inflammation. IIT may be a second line of treatment for OIT-nonreponders.

Regulation of Hepcidin-25 by Short- and Long-Acting rhEPO May Be Dependent on Ferritin and Predict the Response to rhEPO in Hemodialysis Patients.

BACKGROUND/AIMS: We examined whether regulation of hepcidin-25 by short- or long-acting recombinant human erythropoietin (rhEPO) is dependent on ferritin and predicts the response to rhEPO in hemodialysis (HD) patients. METHODS: Two studies with rhEPO were performed in 9 HD patients with a 2-year interval. Serum hepcidin-25 was measured at 0-18 h after intravenous epoetin-ß (EPO) or methoxy polyethylene glycol-epoetin-ß (PEG-EPO) administration and on days 3-7 after PEG-EPO. Hemoglobin (Hb), serum ferritin, transferrin, C-reactive protein (CRP), and interleukin (IL)-6 were analyzed before hepcidin measurement and 6 months after rhEPO. Based on the serum ferritin levels before hepcidin measurement, the patients in the two studies with EPO or PEG-EPO were combined into low (11; serum ferritin of <15.0 ng/ml) and high ferritin groups (7; serum ferritin of ≥15.0 ng/ml). The response of hepcidin-25 to rhEPO and the effect of rhEPO on anemia were compared between the groups. RESULTS: The serum hepcidin-25 levels rose at 6-9 h and returned to the baseline at 18 h after EPO. They rose at 6-9 h, returned to the baseline at 18 h, and decreased on day 5-7 after PEG-EPO. Serum hepcidin-25 levels were low (<5.0 ng/ml) in the low ferritin group, but rose at 6-9 h after rhEPO in the high ferritin group. Serum transferrin levels were similar, and CRP and IL-6 were normal in both groups. Hb tended to increase in the low ferritin group, but it significantly decreased in the high ferritin group after rhEPO. CONCLUSION: Regulation of hepcidin-25 by rhEPO may be dependent on ferritin, affecting the response to rhEPO in HD patients.

Hepcidin-25, mean corpuscular volume, and ferritin as predictors of response to oral iron supplementation in hemodialysis patients.

The benefit of oral iron therapy (OIT) and factors predictive of OIT response are not established in hemodialysis (HD) patients with iron deficiency anemia (IDA). We examined the values of hepcidin-25, mean corpuscular volume (MCV), and ferritin as predictors of OIT response. Oral ferrous fumarate (50 mg/day, 8 weeks) was given to 51 HD patients with IDA (hemoglobin (Hb) < 12 g/dL, ferritin < 100 ng/mL) treated with an erythropoietin activator. Sixteen patients were responders (improvement of Hb (ΔHb) ≥ 2 g/dL) and 35 were non-responders (ΔHb < 2g/dL). Baseline Hb, MCV, serum hepcidin-25, ferritin, iron parameters, and C-reactive protein (CRP) before and ΔHb after OIT were compared between groups. Hepcidin-25, MCV, ferritin, and transferrin saturation were lower in the responders than in the non-responders. Hepcidin-25 positively correlated with ferritin. Hepcidin-25, MCV, and ferritin positively correlated with baseline Hb and negatively correlated with ΔHb. Despite normal CRP levels in all patients, CRP correlated positively with hepcidin-25 and ferritin. Stepwise multiple linear regression analysis and receiver operating characteristics curve analysis revealed that hepcidin-25, MCV, and ferritin could predict OIT response. We conclude that hepcidin-25, MCV, and ferritin could be useful markers of iron storage status and may help predict OIT response in HD patients.

Effect of sevelamer hydrochloride on markers of bone turnover in Japanese dialysis patients with low biointact PTH levels.

BACKGROUND: In hemodialysis patients, adynamic bone disease has been reported to be closely associated with low levels of parathyroid hormone (PTH) due to exposure to high levels of serum calcium following the administration of calcium carbonate (CaCO3) or vitamin D agents. This study was conducted to clarify the therapeutic effect of a non-calcemic phosphate binder, sevelamer hydrochloride (sevelamer), for hypoparathyroidism in hemodialysis patients with or without diabetes mellitus. METHODS: Based on entry criteria, 40 Japanese chronic hemodialysis patients (22 males and 18 females with a mean age of 60.6, 14 diabetic patients and 26 non-diabetic patients) were switched from CaCO3 to sevelamer for 48 weeks. Serum calcium, phosphate, intact (i) PTH and PTH-(1-84) were analyzed. Bone remodeling activity was evaluated by determining intact osteocalcine (iOC), bone-specific alkaline phosphatase (BAP). RESULTS: The switch from CaCO3 to sevelamer significantly decreased the serum levels of calcium, resulting in the elevation of iPTH levels from 31+/-18 pg/mL to 95+/-96 pg/mL by 48 weeks. In contrast, serum phosphate levels remained similar to those in patients with CaCO3 treatment. Concomitantly, the levels of BAP and iOC were elevated. Further, these beneficial effects on bone turnover were observed in both diabetic and non-diabetic patients. CONCLUSION: Sevelamer reduced the calcium concentration and thereby increased PTH levels, resulting in the improvement of markers of bone turnover. The administration of sevelamer is of therapeutic benefit for the improvement of bone remodeling activity even in hemodialysis patients with diabetes.

High endothelial venule-like vessels in the interstitial lesions of human glomerulonephritis.

To clarify the characteristics of high endothelial venule (HEV) -like vessels in the interstitium of human glomerulonephritis, we investigated the expression of HEVs related molecules such as P-selectin and L-selectin ligands; MECA-79 epitope and variant sulfated forms of sialyl Lewis X (variant sLe(X), clones 2H5, 2F3, GS-13 and GS-36) in kidney specimens by means of immunohistochemical studies, and P-selectin and hevin mRNA signals by using in situ hybridization analyses. In lymphoid organs, HEVs strongly expressed P-selectin, MECA-79, variant sLe(X) and hevin mRNA signals. In normal kidneys (n = 4), only P-selectin was faintly positive in the vessels of interstitium, but other molecules could not be detected. Interstitial P-selectin expression was upregulated in patients with tubulointerstitial diseases (n = 4) and proliferative glomerulonephritis (n = 51) such as IgA-related nephropathy (n = 39), membranoproliferative glomerulonephritis (n = 4) and crescentic glomerulonephritis (n = 2), but not in nonproliferative glomerular diseases (n = 39) such as minimal change nephrotic syndrome (n = 18) (1.00 +/- 0.41, 0.64 +/- 0.11, 0.21 +/- 0.05, respectively). Interstitial P-selectin expression also correlated with interstitial local cellular infiltration (r = 0.60, p < 0.0001). In addition, P-selectin mRNA signals were detected on the peritubular capillaries and HEV-like vascular endothelial cells. MECA-79 and variant sLe(X) (2H5 and 2F3) were weakly expressed on the HEV-like vessels located at the corticomedullary regions in three cases (7%) and in nine cases (27%) with interstitial cellular infiltration, respectively. However, we could not detect GS-13, GS-36 or hevin mRNA signals in the diseased kidney specimens. In conclusion, HEV-like vessels in renal interstitium expressed molecules somewhat different from HEVs in lymphoid organs and were associated with interstitial leukocyte accumulation in human proliferative glomerulonephritis possibly through the de novo expression of P-selectin and partly L-selectin ligands (MECA-79 epitope and variant sLe(X)) in the interstitial lesions.