Cyst infection is a frequent and serious complication of autosomal dominant polycystic kidney disease (ADPKD). Lipid-soluble antibiotics like fluoroquinolones show good penetration into cysts and are recommended for cyst infection, but causative microorganisms are often resistant to these agents. This study investigated the profile of the microorganisms causing cyst infection in ADPKD, their susceptibility to lipid-soluble antibiotics, and clinical outcomes. This retrospective study reviewed all ADPKD patients admitted to Toranomon Hospital with a diagnosis of cyst infection from January 2004 to March 2014. All patients who underwent cyst drainage and had positive cyst fluid cultures were enrolled. Patients with positive blood cultures who satisfied our criteria for cyst infection or probable infection were also enrolled. There were 99 episodes with positive cyst fluid cultures and 93 episodes with positive blood cultures. The majority of patients were on dialysis. The death rate was high when infection was caused by multiple microorganisms or when there were multiple infected cysts. Gram-negative bacteria accounted for 74-79 % of the isolates in all groups, except for patients with positive hepatic cyst fluid cultures. The susceptibility of Escherichia coli to fluoroquinolones was very low in patients with hepatic cyst infection, especially those with frequent episodes and those with hepatomegaly. Fungi were detected in two episodes. Fluoroquinolone-resistant microorganisms showed a high prevalence in cyst infection. It is important to identify causative microorganisms to avoid the overuse of fluoroquinolones and to improve the outcome of cyst infection in ADPKD.

BackgroundThe quality of life (QOL) of patients with autosomal dominant polycystic kidney disease (ADPKD) has not been investigated well. This study was performed to clarify the QOL of patients with ADPKD and to identify factors that affected their QOL.MethodsThe present cross-sectional study is part of a prospective observational study on the QOL of ADPKD patients. Patients with ADPKD who were referred to Toranomon Hospital between March 2010 and November 2012 were enrolled. The short form-36 (SF-36) questionnaire and our original 12-item questionnaire were used to evaluate QOL. We analyzed the results of the questionnaire survey and then investigated correlations between QOL and clinical features.ResultsA total of 219 patients (93 men and 126 women) were enrolled and their mean age was 55.1±10.8 years. There were 108 patients on dialysis. The SF-36 scores (PCS, MCS, and RCS) of all patients were significantly lower than the mean scores for the Japanese population. Stepwise multiple regression analysis demonstrated that Hb, serum Alb, ascites, and cerebrovascular disease all had a significant influence on the PCS, while mental disease had a significant influence on the MCS and serum Alb significantly influenced the RCS. The total liver and kidney volume (TLKV) and the dialysis status were not significantly associated with any of the SF-36 scores by multiple regression analysis, but TLKV was closely correlated with abdominal distention and distention had an important influence on QOL. Pain, sleep disturbance, heartburn, fever, gross hematuria, and anorexia also affected QOL, but these variables were not correlated with TLKV.ConclusionsSeveral factors influence QOL, so improving symptoms unrelated to TLKV as well as reducing abdominal distention can improve the QOL of ADPKD patients.

Fanconi anemia (FA) is a rare autosomal recessive disorder of hematopoiesis, with at least 11 complementation groups. FANCA, a gene for group A, accounts for the majority of FA patients. Previous studies of FANCA mutations revealed high allelic heterogeneity, frequent occurrence of large deletions, and interpopulation differences. However, systematic mutational analysis, including gene dosage assay to detect large deletions, has not been documented for Asian populations. A newly developed TaqMan quantitative PCR-based gene dosage assay, combined with sequencing of exons and cDNA fragments, allowed for detection of 48 mutant alleles of FANCA in 27 (77%) of 35 unrelated Japanese FA families with no detectable mutations in FANCC or FANCG. We identified 29 different mutations (21 nucleotide substitutions or small deletions/insertions and eight large deletions), at least 20 of which were novel. The FANCA mutational spectrum of the Japanese was different from that of other ethnic groups so far studied. This is the largest scale of mutation analysis of FANCA in the Japanese population. Characterization of these mutations provided new information regarding the mutagenesis mechanisms and structure-function relationship of FANCA. Specifically, our data suggest that diverse mechanisms including nonhomologous recombination as well as Alu-mediated homologous recombination are involved in the generation of large deletions in FANCA.

SummaryA pilot study was undertaken using a fludarabine-based conditioning regimen to improve haematopoietic cell transplantation (HCT) from alternative donors in 27 Fanconi anaemia (FA) patients. Patients were conditioned with 150-180 mg/m 2 of fludarabine, 40 mg/kg of cyclophosphamide, 5-10 mg/kg of antithymocyte globulin, and 300-450 cGy of thoracoabdominal/total body irradiation. One patient who received unrelated cord blood transplantation failed to engraft, another patient died of sepsis. The 1-year overall survival was 96AE3% (95% CI, 89-100). This conditioning regimen exerted an immunosuppressive effect that enabled durable engraftment in alternative donor HCT without severe toxicity.

Familial Mediterranean fever (FMF) is a well-known cause of secondary AA amyloidosis. Colchicine is generally considered to be the most effective treatment for FMF and FMF-associated amyloidosis, but the management of patients who are refractory to colchicine remains controversial. We encountered a 51-year-old Japanese man with suspected FMF, who had periodic fever with abdominal pain, polyarthritis, and nephropathy (serum creatinine of 1.9 mg/dL and 24-h protein excretion of 3.8 g). FMF was diagnosed by mutation analysis of the Mediterranean fever (MEFV) gene, which revealed that the patient was compound heterozygous for the marenostrin/pyrin variant E148Q/M694I. AA amyloidosis was diagnosed by renal and gastric biopsy. Colchicine was administered, but his arthritis persisted, and serum creatinine increased to 2.4 mg/dL. Therefore, a humanized anti-interleukin-6 receptor antibody (tocilizumab) was administered at a dose of 8 mg/kg on a monthly basis. Both arthritis and abdominal pain subsided rapidly, and C-reactive protein (CRP) decreased from 2.5 to 0.0 mg/dL. After 2 years, his serum creatinine was decreased to 1.5 mg/dL and proteinuria was improved to 0.3 g daily. In addition, repeat gastric biopsy showed a marked decrease of AA amyloidosis. This case suggests that tocilizumab could be a new therapeutic option for patients with FMF-associated AA amyloidosis if colchicine is not effective.

Summary Fanconi anaemia (FA) is a genetically heterogeneous chromosome instability syndrome characterised by bone marrow failure and congenital anomalies. Although an increasing number of reports suggest that reversion mosaicism noted in peripheral blood lymphocytes (PBLs) is associated with mild haematopoietic failure in FA, myeloid cells are rarely directly examined. We here report a patient with prolonged mild pancytopenia in whom proliferation of revertant cells was detected in mature myeloid cells but not in PBLs. While this patient had inherited heterozygous mutations, 2546delC and 3720–3724del, in the major FA gene FANCA, Epstein–Barr virus‐immortalised lymphoblastoid cells from the patient had 2546C > T instead of 2546delC, resulting in expression of a functional missense protein. As the identical reversion was detected in polymorphonuclear granulocytes and mononuclear phagocytes, sustained haematopoiesis in the patient can be attributed to a selective growth advantage of revertant myeloid cells. It is noteworthy that such a myeloid lineage‐selective mosaicism is overlooked in routine examination of PBLs. Recognition of this status will expand the role of reversion mosaicism in the pathophysiology of FA.

Designing stem cell transplantation (SCT) conditioning regimens for Fanconi anemia (FA) has proved difficult because of hypersensitivity to the DNA cross-linking agents. We performed chromosome fragility tests with 56 FA patients and with 50 non-FA patients with severe aplastic anemia or myelodysplastic syndrome. We evaluated peripheral blood lymphocyte specimens cultured for 72 hours and treated with mitomycin C, diepoxybutane (DEB), cyclophosphamide (CY) metabolites, cytosine arabinoside (Ara-C), and fludarabine (Flu) metabolite (9-beta-D-arabinofuranosyl-2-fluoroadenine [2-F-Ara-A]). The DEB and CY metabolite tests were highly sensitive and specific for FA (P<10(-4)) for both tests), and the number of aberrations per cell for DEB correlated with that for the CY metabolite test (P < 10(-4)) but did not correlate with the number of aberrations per cell for the Ara-C and 2-F-Ara-A tests. The difference in breakage frequencies between FA and non-FA patients for cultures treated with 2-F-Ara-A was not statistically significant. Most of the breakages observed in cells treated with 2-F-Ara-A-and Ara-C were chromatid breaks. It may be possible to determine the appropriate CY dose in the preconditioning regimen for SCT in FA patients on the basis of the in vitro effects on fragility, and Flu or Ara-C may be a safer drug than high-dose CY for conditioning in FA patients.

We evaluated the influence of kidney volume (KV) and liver volume (LV) on continuation of peritoneal dialysis (PD) in patients with autosomal dominant polycystic kidney disease (PKD). Twenty-two PKD patients on PD were retrospectively investigated after being divided into two groups. Group 1 comprised 15 patients who started PD at our hospital and group 2 was composed of seven patients referred from other hospitals for treatment of renomegaly by transcatheter arterial embolization (TAE) at 47.1 ± 21.8 months after commencing PD. In group 1, KV for both kidneys (mean ± SD) was 2787 ± 1945 mL (range: 1043 to 6816 mL), LV was 2198 ± 1139 mL (1005 to 4116 mL), and the total organ volume (TV=KV+LV) was 4985 ± 1815 mL (2320 to 8912 mL). In the patient with the largest TV from group 1 (KV of 6816 mL, TV of 8912 mL, and TV/BMI ratio of 426, PD was stopped due to dialysate leakage. However, dialysate leakage did not occur in the other 14 patients (TV ≦ 7963 mL and TV/BMI ratio of 353 at the start of PD). In group 2, KV was 5822 ± 1597 mL (3832 to 8862 mL), LV was 1776 ± 519 mL (1271 to 2671 mL), and TV was 7597 ± 1431 mL (5505 to 10358) before TAE. Leakage of dialysate did not occur with a mean infusion volume of 1530 ± 370 mL (1000 mL to 2000 mL), even after renomegaly and hepatomegaly progressed to the maximum TV/BMI ratio of 359. Six patients from the two groups developed new abdominal hernias at 36 ± 5 months (6-55 months) after starting PD. These findings suggest that performance of PD may be limited by renomegaly and hepatomegaly in patients with PKD.