Yugo Shibagaki

Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder

Masafumi Fukagawa, Keitaro Yokoyama, Fumihiko Koiwa, Masatomo Taniguchi, Tetsuo Shoji, Junichiro James Kazama, Hirotaka Komaba, Ryoichi Ando, Takatoshi Kakuta, Hideki Fujii, Msasaaki Nakayama, Yugo Shibagaki, Seiji Fukumoto, Naohiko Fujii, Motoshi Hattori, Akira Ashida, Kunitoshi Iseki, Takashi Shigematsu, Yusuke Tsukamoto, Yoshiharu Tsubakihara, Tadashi Tomo, Hideki Hirakata, and Tadao Akizawa for CKD-MBD Guideline Working Group, Japanese Society for Dialysis Therapy

How Do Living Kidney Donors Develop End-Stage Renal Disease?

The clinical course and risk factors for developing end‐stage renal disease (ESRD) after heminephrectomy in living kidney donors have scarcely been investigated. We reviewed medical records and identified eight case donors who developed chronic kidney disease (CKD) stage 5 or ESRD, and subsequently investigated the association between postoperative clinical courses and changes in renal function. To conduct a case‐control study, we also selected a control group comprising 24 donors who had maintained stable renal function and were matched for age, sex and follow‐up time since donation. Except for one donor who developed ESRD caused by a traffic accident, none of the donors developed progressive renal dysfunction immediately after donation. Their renal functions remained stable for a long period of time, but started to decline after developing new comorbidities, especially risk factors known as progression factors (proteinuria or hypertension) or accelerating factors (cardiovascular [CV] event or infection) of CKD. As compared with the control donors, incidence of postoperative persistent proteinuria, acute CV event, severe infection and hospitalization due to accelerating factors of CKD were significantly higher in the case donors. These results suggest the importance of long‐term (more than 10 years) follow‐up of donors with special attention on the risk factors of CKD.

Safety, efficacy and renal effect of febuxostat in patients with moderate-to-severe kidney dysfunction.

Hyperuricemia (HU) is common in patients with chronic kidney disease (CKD), and accumulating evidence suggests it has a pathogenic role in the progression of the disease. However, a major challenge in treating patients with HU is the adverse effects caused by urate-lowering drugs used to treat CKD. Because of these untoward effects, doses need to be reduced, which leads to suboptimal efficacy. Febuxostat has been shown to be highly efficacious in reducing serum uric acid (sUA) and is well tolerated in patients with mild kidney dysfunction. However, its safety and efficacy have not been well studied in more advanced cases of CKD. We studied the safety and efficacy of escalating doses of febuxostat over a 24-week period in 70 patients with CKD stages 3b, 4 and 5, and we also observed the changes in blood pressure, estimated glomerular filtration rate (eGFR) and proteinuria following the reduction of sUA. Drug-related adverse events (AEs) occurred in only 5 out of 70 patients. All but one of the events were mild, and all five patients fully recovered. By 24 weeks, the reduction of sUA levels was >40% in CKD stage 3b and >50% in CKD stages 4 and 5. More than 70% of patients achieved target sUA levels of 6 mg dl−1 or less. Multivariate analysis showed that a greater reduction in sUA with febuxostat was associated with an increase in eGFR and a tendency toward decreased proteinuria. Febuxostat was safe and efficacious in the treatment of CKD stages 3b–5.

Persistent Glomerular Hematuria in Living Kidney Donors Confers a Risk of Progressive Kidney Disease in Donors After Heminephrectomy

Although glomerular hematuria is likely a sign of chronic kidney disease that will develop into overt nephropathy after donation, it remains unclear whether prospective donors with hematuria should be excluded. We reviewed the medical records of 242 donors who donated at our institution from 2001 to 2007 and surveyed the prevalence of hematuria pre‐ and postdonation. We then investigated the association of hematuria with proteinuria postdonation and trends in glomerular filtration rate. Before donation, 8.3% of 242 donors presented with persistent hematuria, a finding that was significantly associated with dysmorphic hematuria before donation. Most cases of predonation persistent hematuria persisted after donation, and the overall prevalence increased to 15.3%. During a median follow‐up period of 2.3 years after donation, 8.3% developed persistent proteinuria, with incidence being significantly higher in donors having persistent hematuria with dysmorphic red blood cells (d‐RBC) both before and after donation. Postdonation persistent hematuria with d‐RBC was also associated with a progressive decline in renal function. These results indicate that persistent glomerular hematuria is strongly associated with a higher incidence of postdonation progressive kidney disease. Potential donors with persistent glomerular hematuria should be excluded, while those with isolated hematuria need to be evaluated with heightened caution.

Mogamulizumab, an Anti-CCR4 Antibody, Targets Human T-Lymphotropic Virus Type 1–infected CD8+ and CD4+ T Cells to Treat Associated Myelopathy

BACKGROUND Human T-lymphotropic virus type 1 (HTLV-1) can cause chronic spinal cord inflammation, known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Since CD4(+)CCR4(+) T cells are the main HTLV-1 reservoir, we evaluated the defucosylated humanized anti-CCR4 antibody mogamulizumab as a treatment for HAM/TSP. METHODS We assessed the effects of mogamulizumab on peripheral blood mononuclear cells from 11 patients with HAM/TSP. We also studied how CD8(+) T cells, namely CD8(+) CCR4(+) T cells and cytotoxic T lymphocytes, are involved in HTLV-1 infection and HAM/TSP pathogenesis and how they would be affected by mogamulizumab. RESULTS Mogamulizumab effectively reduced the HTLV-1 proviral load (56.4% mean reduction at a minimum effective concentration of 0.01 µg/mL), spontaneous proliferation, and production of proinflammatory cytokines, including interferon γ (IFN-γ). Like CD4(+)CCR4(+) T cells, CD8(+)CCR4(+) T cells from patients with HAM/TSP exhibited high proviral loads and spontaneous IFN-γ production, unlike their CCR4(-) counterparts. CD8(+)CCR4(+) T cells from patients with HAM/TSP contained more IFN-γ-expressing cells and fewer interleukin 4-expressing cells than those from healthy donors. Notably, Tax-specific cytotoxic T lymphocytes that may help control the HTLV-1 infection were overwhelmingly CCR4(-). CONCLUSIONS We determined that CD8(+)CCR4(+) T cells and CD4(+)CCR4(+) T cells are prime therapeutic targets for treating HAM/TSP and propose mogamulizumab as a new treatment.

The relative role of fibroblast growth factor 23 and parathyroid hormone in predicting future hypophosphatemia and hypercalcemia after living donor kidney transplantation: a 1-year prospective observational study

BACKGROUND Kidney transplantation (KTx) restores many of the disorders accompanying end-stage renal failure. However, hypercalcemia and hypophosphatemia are both common complications after renal transplantation. Prospective observation of these complications has not been well described and pre-transplant predictors also remain unknown. This prospective observational cohort study was carried out to clarify pre-transplant risk factors of persistent hypophosphatemia and/or hypercalcemia at 12 months after transplantation. METHODS Consecutive living donor KTx recipients (n = 39) at Tokyo Womens Medical University were prospectively recruited. Parameters of bone and mineral metabolism including intact parathyroid hormone (iPTH) and full-length fibroblast growth factor (FGF) 23 were followed. RESULTS FGF23 decreased to comparable levels for renal function while hyperparathyroidism persisted at 12 months after transplantation. Multivariate linear regression analysis revealed that pre-transplant iPTH correlated with hypercalcemia at 12 months and pre-transplant FGF23 was the best pre-transplant predictor of persistent hypophosphatemia at 12 months. CONCLUSIONS It is intriguing that although FGF23 is not a causal factor for hypophosphatemia at 12 months post-transplantation, it is a significant predictor of this common complication.

Postmortem examination of the kidney in allogeneic hematopoietic stem cell transplantation recipients: possible involvement of graft-versus-host disease

To investigate the association between graft-versus-host disease (GVHD) and renal injury after allogeneic stem cell transplantation (allo-SCT), we compared autopsy findings of 26 consecutive allo-SCT recipients with two control groups: patients with hematologic malignancies who received cytotoxic chemotherapy alone (Control 1, n = 21) and those with non-hematologic diseases (Control 2, n = 12). We evaluated the following renal pathology; renal tubulitis, allograft glomerulitis, intimal arteritis, allograft nephropathy, and peritubular capillaritis. These changes were found in 11 allo-SCT recipients and 10 patients in Control 1, but none in Control 2. While overall frequency of renal impairments was similar between allo-SCT recipients and Control 1 (3/26 vs. 1/21), allo-SCT recipients were more likely to have renal tubulitis and peritubular capillaritis compared to Control 1 (5/26 vs. 1/21), but less likely to present with glomerulitis (1/26 vs. 6/21). Grade III–IV acute or extensive-type chronic GVHD were seen in all of the three patients with renal tubulitis and four of the five patients with peritubular capillaritis. Allo-SCT recipients with severe GVHD tended to have tubulitis and peritubular capillaritis. These findings have implications of some renal impairment attributable to GVHD.

The effect of different apheresis modalities on coagulation factor XIII level during antibody removal in ABO-blood type incompatible living related renal transplantation

Apheresis therapy is used to remove pathogenic antibodies within the recipient blood during ABO-incompatible living related renal transplantation (LRRT). Factor XIII (FXIII) is a coagulating factor. Its deficiency reportedly engenders perioperative bleeding. This study compared apheresis modalities from the perspective of the FXIII level. Cases 1-3 were treated only with double-filtration plasmapheresis (DFPP) without (case 1) or with (cases 2 and 3) fresh frozen plasma (FFP) supplementation. Cases 4 and 5 were treated with simple plasma exchange (PEx) with FFP supplementation for the last session. Cases 1-3 showed a marked (case 1, 8.6%) or moderate (case 2, 26.2%; case 3, 28.4%) decrease in FXIII on the day before the procedure after the last apheresis session, although cases 4 (81.9%) and 5 (66.2%) did not. Case 1 experienced perioperative bleeding. The last session is usually performed the day before the surgical procedure. Therefore, FXIII elimination by DFPP might cause bleeding complications because of its slow recovery. The fact warrants that the last apheresis modality during the course might be PEx from the viewpoint of FXIII depletion.

Low-dose continuous renal replacement therapy for acute kidney injury.

Background: Continuous renal replacement therapy (CRRT) is used increasingly to treat acute kidney injury (AKI), which is a common condition in the intensive care unit (ICU). However, the optimal CRRT dose for the treatment of AKI is still a matter of controversy This study was conducted to ascertain the minimal dose of CRRT that can be effective on AKI patient outcomes. Methods: This was a retrospective observational study in two ICUs of academic medical centers in Japan. Patients aged 15 years or older admitted to the ICUs from January 2007 to July 2010 and treated with CRRT for AKI during their ICU stay were included. Data were retrospectively collected from patient records. Patients were categorized by doses that were above (higher-dose group) or below (lower-dose group) the median. Major outcome measures were hospital mortality, ICU mortality, and renal recovery at hospital discharge. Results: 131 AKI patients were treated with continuous veno-venous hemodiafiltration (CVVHDF) during the study period. The median dose of CVVHDF was 16 ml/kg per hr (IQR = 14 to 20). Hospital mortality was 44%, which was significantly lower than the predicted mortality (56%, p<0.01). Patients who received lower-dose CRRT tend to have lower mortality rates (36% vs. higher-dose 53%; p = 0.055). Conclusions: We found that low-dose CRRT did not increase mortality in critically ill patients with AKI. We also found that AKI patients treated with lower-dose CRRT non-significantly but numerically lower hospital mortality compared to higher-dose CRRT.

Natural history of mineral and bone disorders after living-donor kidney transplantation: a one-year prospective observational study.

Mineral and bone disorders (MBD), including hypercalcemia and hypophosphatemia, are common complications after renal transplantation; however, the natural course of these disorders has not been well documented, and the pathogenesis of persistent post‐transplant MBD still remains elusive. This study was carried out to show the natural history of mineral metabolism in recipients after living‐donor kidney transplantation and also to clarify post‐transplant risk factors of persistent hypercalcemia and/or hypophosphatemia at 12 months after transplantation. Living‐donor kidney transplant recipients (N = 34) at Tokyo Womens Medical University were prospectively and consecutively recruited. Parameters of MBD, including intact parathyroid hormone and full‐length fibroblast growth factor 23, were followed. Serum calcium levels increased until the fourth week post‐transplantation, after which it reached a plateau; and serum phosphate decreased substantially at one week post‐kidney transplantation, but recovered to the reference level at two months. Fibroblast growth factor 23 gradually decreased to comparable levels for renal function, while hyperparathyroidism persisted for 12 months after transplantation. Multivariate linear regression analysis revealed that intact parathyroid hormone was the best correlating factor with both hypercalcemia and persistent hypophosphatemia at 12 months. This study suggests the need for testing of other interventions used for treatment of hyperparathyroidism which may help to offer better management of MBD after kidney transplantation.