A nonhuman primate model of liver fibrosis towards cell therapy for liver cirrhosis.

Orthotopic liver transplantation (OLT) is the only curative treatment for refractory chronic liver failure in liver cirrhosis. However, the supply of donated livers does not meet the demand for OLT due to donor organ shortage. Cell therapy using hepatocyte-like cells derived from human induced pluripotent stem cells (hiPSC-HLCs) is expected to mitigate the severity of liver failure, postpone OLT and ameliorate the insufficient liver supply. For the successful clinical translation of hiPSC-based cell therapy against liver cirrhosis, realistic animal models are required. In this study, we created a nonhuman primate (NHP) liver fibrosis model by repeated administrations of thioacetamide (TAA) and evaluated the short-term engraftment of hiPSC-HLCs in the fibrotic liver. The NHP liver fibrosis model reproduced well the pathophysiology of human liver cirrhosis including portal hypertension. Under immunosuppressive treatment, we transplanted ALBUMIN-GFP reporter hiPSC-HLC aggregates into the fibrotic livers of the NHP model via the portal vein. Fourteen days after the transplantation, GFP-expressing hiPSC-HLC clusters were detected in the portal areas of the fibrotic livers. These results will facilitate preclinical studies using the NHP liver fibrosis model and help establish iPSC-based cell therapies against liver cirrhosis.

Ability of vitamin D receptor activator to prevent pulmonary congestion in advanced chronic kidney disease.

BACKGROUND: Vitamin D deficiency is common among patients with chronic kidney disease (CKD). However, the benefits of vitamin D supplementation versus vitamin D receptor activator (VDRA) administration have yet to be established. Recently, an association between activated vitamin D and cardiovascular factors was reported. To evaluate the benefits of VDRA in advanced CKD, we analyzed the association between VDRA administration and the prevalence of pulmonary congestion. METHODS: This retrospective, cross-sectional analysis included patients initiated on dialysis between October 2011 and September 2013 at 17 Japanese institutions. Data from 952 participants were analyzed using a multivariate logistic regression model and a linear regression model. We also analyzed subgroup data for groups classified by selection of peritoneal dialysis or hemodialysis. RESULTS: Of the 952 participants, 303 patients received VDRA. VDRA administration was associated with a low prevalence of pulmonary congestion in the multivariate logistic regression model (odds ratio [OR], 0.64; 95 % confidence interval [CI], 0.44-0.94; P = 0.02). There was no significant association between VDRA administration and systolic blood pressure, diastolic blood pressure, or pulse pressure. Subgroup analysis revealed a tendency that VDRA administration was associated with low prevalence of pulmonary congestion in both groups. CONCLUSIONS: In this study, VDRA administration was associated with a low prevalence of pulmonary congestion in patients initiated on dialysis. Appropriate VDRA administration may prevent pulmonary congestion.

[A case report of hepatitis B virus reactivation in a hepatitis B core antibody-positive, hepatitis B surface antigen-negative hemodialysis patient].

Reactivation of the hepatitis B virus (HBV) has been reported in patients receiving immunosuppressive therapy or chemotherapy. We report a case of HBV reactivation in a patient negative for hepatitis B surface antigen (HBsAg), positive for hepatitis B core antibody (anti-HBc), and positive for hepatitis B surface antibody (anti-HBs), who was undergoing chronic maintenance hemodialysis without immunosuppressive therapy or chemotherapy. The patient was an 85-year-old woman with end-stage renal disease due to nephrosclerosis who had undergone maintenance hemodialysis for a year. She had been HBsAg-negative, anti-HBc- and anti-HBs-positive previously, but biannual routine surveillance for HBV showed positivity for HBsAg, negativity for anti-HBs, and positivity for HBV DNA (5.9 log copies/mL). She was asymptomatic, and transaminases were within normal limits. She was dialyzed in an isolated room with a dedicated staff member for the control of infection. HBV is a blood-borne pathogen, which is highly infectious. Hemodialysis is a procedure associated with high risk for blood-borne infection. We should recognize the risk of reactivation of HBV in HBsAg-negative, anti-HBc-positive patients, and consider how to incorporate anti-HBc screening and infection control in isolated anti-HBc-positive hemodialysis patients in clinical practice.

[Case of lead nephropathy due to chronic occupational lead exposure].

We report a case of a patient with chronic kidney disease likely due to lead nephropathy. He was a manufacturer of Buddhist altar fittings and had chronic lead exposure. The blood lead level was 41 microg/dL and urinary lead excretion at 24 hours after the administration of ethylenediaminetetraacetic acid (EDTA)was 600 microg (first time)and 687 microg (second time), respectively. Urinary lead excretion at 72 hours was 834 microg (first time) and 1,071 microg (second time), respectively. Renal biopsy showed interstitial fibrosis and focal monocyte infiltration. Lead content in the renal biopsy specimen was 130 ng/g of wet weight. We preformed weekly EDTA chelation therapy twelve times. During the therapy, serum creatinine was 1.1 mg/dL. The chelation therapy was interrupted by an episode of acute renal failure due to hypotension and heart failure. Urinary lead excretion exceeding 600 microg at 72 hours after chelation therapy indicated a lead body burden capable of causing lead nephropathy. In this case, urinary lead excretion exceeded 600 microg at 72 hours. Based on the report that repeated lead chelation therapy can slow the progression of non-diabetic chronic kidney disease with 72-hour-urinary lead excretion of 60-600 microg, we performed chelation therapy. This case suggests that lead nephropathy currently can occur in Japan. It is possible that renal dysfunction from lead nephropathy is reversed by minimizing lead exposure and chelation therapy. Lead nephropathy should be included in the differenitial diagnosis of causes of chronic kidney disease and occupational and environmental lead exposure should be investigated carefully during the medical history.

A Modular Differentiation System Maps Multiple Human Kidney Lineages from Pluripotent Stem Cells.

Recent studies using human pluripotent stem cells (hPSCs) have developed protocols to induce kidney-lineage cells and reconstruct kidney organoids. However, the separate generation of metanephric nephron progenitors (NPs), mesonephric NPs, and ureteric bud (UB) cells, which constitute embryonic kidneys, in in vitro differentiation culture systems has not been fully investigated. Here, we create a culture system in which these mesoderm-like cell types and paraxial and lateral plate mesoderm-like cells are separately generated from hPSCs. We recapitulate nephrogenic niches from separately induced metanephric NP-like and UB-like cells, which are subsequently differentiated into glomeruli, renal tubules, and collecting ducts in vitro and further vascularized in vivo. Our selective differentiation protocols should contribute to understanding the mechanisms underlying human kidney development and disease and also supply cell sources for regenerative therapies.

Author Correction: Development of new method to enrich human iPSC-derived renal progenitors using cell surface markers.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Higher dialysate calcium concentration is associated with incident myocardial infarction among diabetic patients with low bone turnover: a longitudinal study.

This is a longitudinal study on 53,560 hemodialysis patients from the Japan Renal Data Registry. Predictor was D[Ca] ≥3.0 vs 2.5 mEq/L. Outcomes were the first CV events during 1-year observation period. Association of D[Ca] with CV events and effect modifications were tested using multivariate logistic regression analyses. Diabetes mellitus (DM) was a significant effect modifier for association of higher D[Ca] and myocardial infarction (MI) (OR: 1.26 (1.03-1.55) among DM and 0.86 (0.72-1.03) among non-DM, p for interaction <0.01). The effect size was not affected by further adjustment for serum albumin-corrected Ca or intact parathyroid hormone (iPTH) levels, but was attenuated by adjustment for intradialytic change in serum Ca concentration (ΔCa) (1.16 [0.89-1.51]). Among DM, D[Ca] ≥3.0 mEq/L was significantly associated with MI in the first tertile of corrected Ca or iPTH ≤60 pg/ml (p for interaction 0.03 and 0.03, respectively). In conclusion, higher D[Ca] was associated with incident MI in DM, especially with low serum Ca or iPTH levels. Attenuation of the effect size by adjustment for ΔCa and stratified analyses suggest that larger Ca influx during dialysis with higher D[Ca] in patients suggestive of low bone turnover leads to vascular calcification and subsequent MI in DM.

Author Correction: Higher dialysate calcium concentration is associated with incident myocardial infarction among diabetic patients with low bone turnover: a longitudinal study.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Development of new method to enrich human iPSC-derived renal progenitors using cell surface markers.

Cell therapy using renal progenitors differentiated from human embryonic stem cells (hESCs) or induced pluripotent stem cells (hiPSCs) has the potential to significantly reduce the number of patients receiving dialysis therapy. However, the differentiation cultures may contain undifferentiated or undesired cell types that cause unwanted side effects, such as neoplastic formation, when transplanted into a body. Moreover, the hESCs/iPSCs are often genetically modified in order to isolate the derived renal progenitors, hampering clinical applications. To establish an isolation method for renal progenitors induced from hESCs/iPSCs without genetic modifications, we screened antibodies against cell surface markers. We identified the combination of four markers, CD9-CD140a+CD140b+CD271+, which could enrich OSR1+SIX2+ renal progenitors. Furthermore, these isolated cells ameliorated renal injury in an acute kidney injury (AKI) mouse model when used for cell therapy. These cells could contribute to the development of hiPSC-based cell therapy and disease modeling against kidney diseases.

Cell Therapy Using Human Induced Pluripotent Stem Cell-Derived Renal Progenitors Ameliorates Acute Kidney Injury in Mice.

UNLABELLED: Acute kidney injury (AKI) is defined as a rapid loss of renal function resulting from various etiologies, with a mortality rate exceeding 60% among intensive care patients. Because conventional treatments have failed to alleviate this condition, the development of regenerative therapies using human induced pluripotent stem cells (hiPSCs) presents a promising new therapeutic option for AKI. We describe our methodology for generating renal progenitors from hiPSCs that show potential in ameliorating AKI. We established a multistep differentiation protocol for inducing hiPSCs into OSR1+SIX2+ renal progenitors capable of reconstituting three-dimensional proximal renal tubule-like structures in vitro and in vivo. Moreover, we found that renal subcapsular transplantation of hiPSC-derived renal progenitors ameliorated the AKI in mice induced by ischemia/reperfusion injury, significantly suppressing the elevation of blood urea nitrogen and serum creatinine levels and attenuating histopathological changes, such as tubular necrosis, tubule dilatation with casts, and interstitial fibrosis. To our knowledge, few reports demonstrating the therapeutic efficacy of cell therapy with renal lineage cells generated from hiPSCs have been published. Our results suggest that regenerative medicine strategies for kidney diseases could be developed using hiPSC-derived renal cells. SIGNIFICANCE: This report is the first to demonstrate that the transplantation of renal progenitor cells differentiated from human induced pluripotent stem (iPS) cells has therapeutic effectiveness in mouse models of acute kidney injury induced by ischemia/reperfusion injury. In addition, this report clearly demonstrates that the therapeutic benefits come from trophic effects by the renal progenitor cells, and it identifies the renoprotective factors secreted by the progenitors. The results of this study indicate the feasibility of developing regenerative medicine strategy using iPS cells against renal diseases.

Membranous nephropathy associated with type 1 autoimmune pancreatitis and dominant glomerular IgG4 deposit.

We report a case of membranous nephropathy associated with type 1 autoimmune pancreatitis. A 58-year-old man presented with anorexia. Work-up revealed a mass in the pancreatic head, which was subsequently resected. Pathological examination showed diffuse infiltration of immunoglobulin (Ig) G4-positive plasma cells, which was compatible with the diagnosis of type 1 autoimmune pancreatitis. Serum IgG4 was elevated. He developed nephrotic syndrome around the time of the surgery. Kidney biopsy confirmed the diagnosis of membranous nephropathy. Immunofluorescent staining showed predominant glomerular IgG4 deposit among IgG subclasses. Tubulointerstitial nephritis, which is usually a dominant feature of renal involvement in IgG4-related disease, was not observed. The patient was treated with prednisolone and several immunosuppressants. During the course, the degree of proteinuria was associated with the serum IgG4 level. Serum antibody against phospholipase A2 receptor was negative. These findings together with IgG4-dominant glomerular deposit suggest that IgG4 may play a unique role in the pathogenesis of secondary membranous nephropathy caused by IgG4-related diseases.