Regeneration and Diagnosis of Kidney Disease Using Exosomes

: A growing global prevalence of acute kidney injury (AKI) and chronic kidney disease (CKD), high costs of kidney transplantation, a shortage of kidney donors, and low survival rate after dialysis have popularized mesenchymal stem cell (MSC) therapy via transplantation. However, the risks of tumorigenesis, immune rejection, pathogen transmission, loss of differentiation, and morphological changes after long-term culture have prompted researchers to develop a safer and more effective therapy method. Therefore, cell-free approaches have been developed to reduce the risks associated with stem cell-based therapies. In cell-free therapy of AKI and CKD, MSC-derived extracellular vesicles, with nanometer sizes, are used, called exosomes. Exosomes have a lipid bilayer membrane with various genes, microRNAs, and proteins for kidney repair. As known, MSC-derived exosomes have improved the kidney regeneration process for various reasons, such as increased safety and reduced inflammation, immune rejection, and tumorigenesis. With the advancement of exosome isolation techniques, the possibility of using biologically active molecules for renal injury prediction and diagnosis has emerged. The use of urinary exosomes in AKI and CKD diagnosis is based on changes in the expression of specific molecule cargos of exosomes. This review article summarizes the diagnosis and therapeutic applications of exosomes in AKI and CKD.

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Stem cell-based treatment of kidney diseases

Experimental Biology and Medicine ◽

10.1177/1535370220915901 ◽

2020 ◽

Vol 245 (10) ◽

pp. 902-910

Author(s):

Binbin Pan ◽

Guoping Fan

Keyword(s):

Chronic Kidney Disease ◽

Stem Cells ◽

Acute Kidney Injury ◽

Stem Cell ◽

Kidney Disease ◽

Cell Therapy ◽

Kidney Diseases ◽

Kidney Injury ◽

Great Promise ◽

Kidney Organoids

Kidney dysfunction, including chronic kidney disease and acute kidney injury, is a globally prevalent health problem. However, treatment regimens are still lacking, especially for conditions involving kidney fibrosis. Stem cells hold great promise in the treatment of chronic kidney disease and acute kidney injury, but success has been hampered by insufficient incorporation of the stem cells in the injured kidney. Thus, new approaches for the restoration of kidney function after acute or chronic injury have been explored. Recently, kidney organoids have emerged as a useful tool in the treatment of kidney diseases. In this review, we discuss the mechanisms and approaches of cell therapy in acute kidney injury and chronic kidney disease, including diabetic kidney disease and lupus nephritis. We also summarize the potential applications of kidney organoids in the treatment of kidney diseases. Impact statement Stem cells hold great promise in regenerative medicine. Pluripotent stem cells have been differentiated into kidney organoids to understand human kidney development and to dissect renal disease mechanisms. Meanwhile, recent studies have explored the treatment of kidney diseases using a variety of cells, including mesenchymal stem cells and renal derivatives. This mini-review discusses the diverse mechanisms underlying current renal disease treatment via stem cell therapy. We postulate that clinical applications of stem cell therapy for kidney diseases can be readily achieved in the near future.

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Therapeutic potential of regulatory macrophages generated from peritoneal dialysate in adriamycin nephropathy

AJP Renal Physiology ◽

10.1152/ajprenal.00538.2017 ◽

2018 ◽

Vol 314 (4) ◽

pp. F561-F571 ◽

Cited By ~ 4

Author(s):

Qi Cao ◽

Yiping Wang ◽

Changqi Wang ◽

Xin M. Wang ◽

Vincent W. S. Lee ◽

...

Keyword(s):

Kidney Disease ◽

Therapeutic Potential ◽

Morphological Changes ◽

Kidney Injury ◽

Peritoneal Macrophages ◽

Great Promise ◽

M2 Macrophages ◽

Peritoneal Dialysate ◽

Adriamycin Nephropathy ◽

M2 Phenotype

Cell therapy using macrophages requires large amounts of cells, which are difficult to collect from patients. Patients undergoing peritoneal dialysis (PD) discard huge numbers of peritoneal macrophages in dialysate daily. Macrophages can be modulated to become regulatory macrophages, which have shown great promise as a therapeutic strategy in experimental kidney disease and human kidney transplantation. This study aimed to examine the potential of using peritoneal macrophages (PMs) from peritoneal dialysate to treat kidney disease. Monocytes/macrophages accounted for >40% of total peritoneal leukocytes in both patients and mice undergoing PD. PMs from patients and mice undergoing PD were more mature than peripheral monocytes/macrophages, as shown by low expression of C-C motif chemokine receptor 2 (CCR2) and morphological changes during in vitro culture. PMs from patients and mice undergoing PD displayed normal macrophage function and could be modulated into a regulatory (M2) phenotype. In vivo, adoptive transfer of peritoneal M2 macrophages derived from PD mice effectively protected against kidney injury in mice with adriamycin nephropathy (AN). Importantly, the transfused peritoneal M2 macrophages maintained their M2 phenotype in kidney of AN mice. In conclusion, PMs derived from patients and mice undergoing PD exhibited conventional macrophage features. Peritoneal M2 macrophages derived from PD mice are able to reduce kidney injury in AN, suggesting that peritoneal macrophages from patients undergoing PD may have the potential for clinical therapeutic application.

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P0624INCREASED URINARY BIOMARKERS OF KIDNEY INJURY IN PATIENTS AFTER ALLOGENETICHEMATOPOETIC STEM CELL TRANSPLANTATION REFLECT KIDNEY DAMAGE EVEN IN NORMALN KIDNEY FUNCTION

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0624 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Malgorzata Kepska ◽

Inga Chomicka ◽

Ewa Karakulska-Prystypiuk ◽

Agnieszka Tomaszewska ◽

Grzegorz Basak ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Stem Cell ◽

Kidney Disease ◽

Healthy Volunteers ◽

Kidney Function ◽

Kidney Injury ◽

Allogeneic Hsct ◽

Ckd Stage ◽

Nephrotoxic Drugs

Abstract Background and Aims Chronic kidney disease (CKD) and acute kidney injury (AKI) are common complications of hematopoietic stem cell transplantation (HSCT) associated with increased morbidity and mortality. On the other hand, presence of CKD is often used as an exclusion criterion when selecting patients who undergo HSCT, especially when fludarabine in conditioning or GVHD prophylaxis with a calcineurin inhibitor is contemplated. There is also no threshold (CKD stage, level of serum creatinine etc) below which patients should not undergo allogeneic HSCT. Kidney function in patients undergoing HSCT is frequently worsened by previous chemotherapy and exposure to a variety of nephrotoxic drugs. Several biomarkers were widely investigated for early diagnosis of acute kidney injury, including neutrophil gelatinase associated lipocalin (NGAL), urinary liver-type fatty acid-binding protein (uL-FABP) and others, however, in patients undergoing HSCT, the published literature is exceptionally scarce. A few studies with inconclusive results stress the knowledge gap and need for further research. The aim of the study was to assess biomarkers of kidney injury in patients at least 3 months after HSCT (to avoid the effect of calcineurin inhibitors) under ambulatory care of Hematology, Oncology and Internal Medicine Department, University Teaching Hospital. Method We studied 80 prevalent patients after allogeneic HSCT and 32 healthy volunteers to obtained normal ranges for biomarkers. In this cross-sectional study following biomarkers of kidney injury in urine were evaluated: IGFBP-7/TIMP2 (insulin growth factor binding protein-7/, tissue inhibitor of metalloproteinases-2), netrin-1, semaphorin A2 using commercially available assays. Results All the biomarkers studied were significantly higher in patients after HSCT when compared to healthy volunteers (all p<0.001). When we divided patients according to kidney function (below and over 60 ml./min/1.72m2), we found that only concentration of IGFBP-7 was significantly higher in 23 patients with CKD stage 3 (i.e. eGFR below 60ml.min/1.72m2) relative to patients with eGFR over 60 ml.min.1.72m2. All biomarkers in both subgroups of patients with eGFR below and over 60 ml./min/1.72m2 were significantly higher relative to healthy volunteers. In univariate correlations sempahorinA2 was related to netrin 1 (r=0.47, p<0.001), IGFBP7 (r=0.35, p<0.01), TIMP2 (r=0.32, p<0.01), whereas IGFBP7 was positively related to serum creatinine (r=0.38, p<0.001) and inversely to eGFR (r=-0.36, p<0.001). Conclusion Concluding, patients after allogeneic HSCT despite normal or near normal kidney function show evidence of kidney injury, which might be due to comorbidities, previous chemotherapy, conditioning regimen,complement activation, calcineurin therapy after HSCT, other possible nephrotoxic drugs etc. Nephroprotective strategies are to be considered as chronic kidney disease is a risk factor for increased morbidity and mortality in this vulnerable population.

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Chronic Kidney Disease and That Risk Factor In Patients Alive More Than 10 Years After Allogenic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v116.21.3463.3463 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3463-3463

Author(s):

Tatsunori Shimoi ◽

Minoru Ando ◽

Takeshi Kobayashi ◽

Kazuhiko Kakihana ◽

Takuya Yamashita ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Stem Cell ◽

Kidney Disease ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cox Regression ◽

Kidney Injury ◽

Hematopoietic Stem

Abstract Abstract 3463 Introduction: Chronic kidney disease (CKD) is common in survivors of hematopoietic stem cell transplantation (SCT). However, evolution over time of kidney dysfunction and its association with post-SCT acute kidney injury (AKI) are unclear. Methods: A retrospective cohort study was performed in 86 myeloablative allogenic SCT patients who received SCT between 1990 and 1999 and lived without relapse for 10 years or more. CKD was defined as a sustained decrease in estimated GFR less than 60 ml/min/1.73 m2 at least for a period more than 3 months. Post-SCT AKI was classified into three stages according to the acute kidney injury network (AKIN) criteria within 100 days after SCT. Incidence of new-onset CKD was studied by 1-year interval along the course of follow-up. Cumulative CKD incidence was evaluated by the Kaplan-Meier analysis. The factors associated with CKD at the time of 10 years after SCT were examined using Cox regression analysis. Results: The incident of new CKD was the highest (10.5%) at the first year after SCT and then remained almost constant (2.3 to 3.5%) (Figure 1). The prevalence of CKD increased along the follow-up time (Table 1). The cumulative incidence of CKD increased according to increasing AKI stages with significant difference between stages ≥1 and no AKI (Figure 2). Cox regression showed that each AKIN stage was a significant predictor of CKD: stage 3: hazard ratio (HR) 12.7, 95% confidence interval (CI) 2.42–97.6; stage 2: HR 7.75, 95% CI 1.83–53.6; and stage 1: HR 4.36, 95% CI 1.06–29.5. Other predictors included total body irradiation (TBI) (HR, 4.00; 95% CI, 1.63–10.5) and age on SCT (HR, 1.08; 95% CI, 1.03–1.13). Conclusions: CKD accumulated among long-term survivors receiving myeloablative allogenic SCT. Post-SCT AKI, regardless of the AKIN stages, is the most significant risk of CKD in such SCT population. Disclosures: No relevant conflicts of interest to declare.

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Angiotensin-(1–7) in kidney disease: a review of the controversies

Clinical Science ◽

10.1042/cs20120111 ◽

2012 ◽

Vol 123 (6) ◽

pp. 333-346 ◽

Cited By ~ 63

Author(s):

Danielle Zimmerman ◽

Kevin D. Burns

Keyword(s):

Angiotensin Ii ◽

Kidney Disease ◽

Kidney Diseases ◽

Biological Effects ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Biologically Active ◽

Renal Vasculature ◽

Experimental Conditions ◽

Enzymatic Pathways

Ang-(1–7) [angiotensin-(1–7)] is a biologically active heptapeptide component of the RAS (renin–angiotensin system), and is generated in the kidney at relatively high levels, via enzymatic pathways that include ACE2 (angiotensin-converting enzyme 2). The biological effects of Ang-(1–7) in the kidney are primarily mediated by interaction with the G-protein-coupled receptor Mas. However, other complex effects have been described that may involve receptor–receptor interactions with AT1 (angiotensin II type 1) or AT2 (angiotensin II type 2) receptors, as well as nuclear receptor binding. In the renal vasculature, Ang-(1–7) has vasodilatory properties and it opposes growth-stimulatory signalling in tubular epithelial cells. In several kidney diseases, including hypertensive and diabetic nephropathy, glomerulonephritis, tubulointerstitial fibrosis, pre-eclampsia and acute kidney injury, a growing body of evidence supports a role for endogenous or exogenous Ang-(1–7) as an antagonist of signalling mediated by AT1 receptors and thereby as a protector against nephron injury. In certain experimental conditions, Ang-(1–7) appears to paradoxically exacerbate renal injury, suggesting that dose or route of administration, state of activation of the local RAS, cell-specific signalling or non-Mas receptor-mediated pathways may contribute to the deleterious responses. Although Ang-(1–7) has promise as a potential therapeutic agent in humans with kidney disease, further studies are required to delineate its signalling mechanisms in the kidney under physiological and pathophysiological conditions.

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Kidney Disease Associated with Hematopoietic Stem Cell Transplant

Journal of Onco-Nephrology ◽

10.5301/jo-n.5000011 ◽

2017 ◽

Vol 1 (1) ◽

pp. 24-29

Author(s):

Deirdre Sawinski

Keyword(s):

Stem Cell ◽

Kidney Disease ◽

Hematopoietic Stem Cell ◽

Hematopoietic Stem Cell Transplant ◽

Stem Cell Transplant ◽

Kidney Injury ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Increased Risk ◽

The Usa

Hematopoietic stem cell transplantation in the USA is growing, and stem cell transplant recipients are at risk for both acute and chronic renal injury. Some etiologies of acute kidney injury are shared with the general population, such as prerenal azotemia and acute tubular necrosis, while others are unique to aspects of the stem cell procedure and include hepatic veno-occlusive disease and BK cystitis. Long-term hematopoietic stem cell transplant survivors are also at increased risk for chronic kidney disease, and important etiologies include calcineurin inhibitor toxicity, nephrotic syndrome, and thrombotic microangiopathy. Stem cell transplant patient survival on chronic dialysis is poor, but well-selected patients can have excellent outcomes with renal transplantation.

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Risk Factors for Acute Kidney Injury and Chronic Kidney Disease following Allogeneic Hematopoietic Stem Cell Transplantation for Hematopoietic Malignancies

Acta Haematologica ◽

10.1159/000504354 ◽

2019 ◽

Vol 143 (5) ◽

pp. 452-464 ◽

Cited By ~ 1

Author(s):

Masahiro Sakaguchi ◽

Kazutaka Nakayama ◽

Hiroki Yamaguchi ◽

Akiko Mii ◽

Akira Shimizu ◽

...

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Stem Cell ◽

Kidney Disease ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Kidney Injury ◽

Hematopoietic Stem ◽

Nephrotoxic Drugs

Background: Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Objectives and Method: In this study, 114 patients who had undergone allo-HSCT were retrospectively analyzed to investigate the risk factors for onset of posttransplant AKI and CKD as defined by the new Kidney Disease Improving Global Outcomes criteria. Results: Seventy-four patients (64.9%) developed AKI and 25 (21.9%) developed CKD. The multivariate analysis showed that the risk factors for developing stage 1 or higher AKI were age ≥46 years at the time of transplant (p = 0.001) and use of ≥3 nephrotoxic drugs (p = 0.036). For CKD, the associated risk factors were disease status other than complete remission at the time of transplantation (p = 0.018) and onset of AKI after transplant (p = 0.035). The 5-year overall survival (OS) was significantly reduced by development of AKI (p < 0.001), but not CKD. Posttransplant AKI significantly increased the 5-year nonrelapse mortality (p < 0.001), whereas posttransplant CKD showed an increasing tendency, but the difference was not significant. Conclusions: Posttransplant AKI impacts OS, significantly increases the risk of CKD, and is significantly associated with disseminated intravascular coagulation and use of ˃3 nephrotoxic drugs.

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Liraglutide protects against high-fat diet-induced kidney injury by ameliorating apoptosis

Endocrine Connections ◽

10.1530/ec-20-0294 ◽

2020 ◽

Vol 9 (9) ◽

pp. 946-954

Author(s):

Riying Liang ◽

Meijun Wang ◽

Chang Fu ◽

Hua Liang ◽

Hongrong Deng ◽

...

Keyword(s):

Kidney Disease ◽

High Fat Diet ◽

Mesangial Cells ◽

Morphological Changes ◽

Kidney Injury ◽

Sirtuin 1 ◽

High Fat ◽

Interacting Protein ◽

Urine Albumin ◽

Glucagon Like Peptide 1

Background: Obesity is associated with the development and progression of chronic kidney disease. Emerging evidence suggests that glucagon-like peptide-1 receptor agonist could reduce renal damage and albuminuria. Sirtuin 1 (SIRT1) was considered as a crucial regulator in metabolism-related kidney disease. Herein, the role of SIRT1 in liraglutide-ameliorated high-fat diet (HFD)-induced kidney injury was illustrated. Methods: Male C57BL/6 mice were fed HFD for 20 weeks to induce kidney injury that was then treated with liraglutide for 8 weeks to estimate its protective effect on the kidney. Also, the mechanism of the drug in SV40 MES 13 (SV40) mouse mesangial cells was elucidated. Results: Liraglutide treatment ameliorated HFD-induced metabolic disorders, including hyperglycemia, increasing body weight, and insulin resistance. In addition, kidney weight, urine albumin-to-creatinine, and kidney morphological changes such as vacuolated tubules, glomerulomegaly, thickened glomerular basement membrane, and tubulointerstitial fibrosis were also significantly ameliorated. Furthermore, apoptotic cells and apoptosis markers were downregulated in the kidney of liraglutide-treated mice. In addition, the expression of SIRT1 protein was upregulated, whereas thioredoxin-interacting protein (TXNIP), which serves as a mediator of oxidative stress and apoptosis in metabolism disease, was downregulated by liraglutide. In SV40 cells, the effect of liraglutide on reversing the upregulation of cleaved caspase-3 induced by high glucose (30 mM) was hampered when SIRT1 was knocked down; also, the downregulation of TXNIP by liraglutide was blocked. Conclusions: Liraglutide might have a beneficial effect on metabolism-related kidney damage by inhibiting apoptosis via activation of SIRT1 and suppression of TXNIP pathway.

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Incidence of acute kidney disease after receiving hematopoietic stem cell transplantation: a single-center retrospective study

PeerJ ◽

10.7717/peerj.6467 ◽

2019 ◽

Vol 7 ◽

pp. e6467 ◽

Cited By ~ 2

Author(s):

Akira Mima ◽

Kousuke Tansho ◽

Dai Nagahara ◽

Kazuo Tsubaki

Keyword(s):

Stem Cell ◽

Kidney Disease ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Kidney Injury ◽

Hematopoietic Stem ◽

Hematological Disorders ◽

Acute Kidney Disease

BackgroundPrevious reports have shown that acute kidney injury (AKI) is common after hematopoietic stem cell transplantation (HSCT), which is a crucial treatment for patients with hematological disorders. AKI could increase mortality and induce adverse effects including the development of chronic kidney disease. The incidence of AKI in association with HSCT reportedly varies significantly because several definitions of AKI have been adopted. Acute kidney disease (AKD) is a new concept that can clinically define both AKI and persistent decreases in glomerular filtration rate (GFR) state. We conducted a retrospective cohort study to determine the incidence of AKD after HSCT.MethodsThis study included 108 patients aged between 16 and 70 years undergoing HSCT. In this study, AKD included clinical condition of AKI or subacute decreases in GFR. AKI was defined according to the Kidney Disease: Improving Global Outcomes guidelines based on serum creatinine. However, urine output data were not included to define AKI because the database lacked some of these data. Comparisons were made between groups using the Mann–Whitney U test.ResultsAcute kidney disease occurred in 17 patients (15.7%). There were significant differences between the AKD and non-AKD with respect to ABO-incompatible HSCT (p= 0.001) and incidence of acute graft versus host disease (GVHD) after HSCT (p< 0.001). The 100-day overall survival of patients with AKD and without AKD after HSCT was 70.6% and 79.8%, respectively (p= 0.409).DiscussionABO-incompatible HSCT and acute GVHD after HSCT were risk factors for the incidence of AKD. However, we could not find a significant association between AKD after HSCT and mortality.

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