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Biomedicines
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Pathogenesis and Treatment Progress of Chronic Kidney Diseases
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Pathogenesis and Treatment Progress of Chronic Kidney Diseases

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 33056

Special Issue Editor

Dr. Jer-Ming Chang

E-Mail Website
Guest Editor
Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Interests: glomerulonephritis; podocyte biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD) care has been recognized by the WHO as one of global burdens, and the related health threat is becoming more serious in most countries. Understanding the detailed pathogenesis is of prime importance to ameliorate disease care and improve outcome. Aging and metabolic derangement are undoubtedly universal causes, even though the pathogenic factors may vary between areas and countries. Against the backdrop of hyperendemic obesity and epidemic diabetes, diabetic kidney disease has taken over a large part of clinical care in nephrology practice. Nevertheless, glomerulonephritis is still prevalent, and the principal role of basic researches on cellular pathogenic mechanism still holds. In the past, it is fair to state that there is no specific pharmacological treatment for CKD, with only a renin-angiotensin system blockade and others which are rare and barely qualified. Optimistically, several lines of recently developed agents have cast new light on the effective treatment of CKD. Of them, inhibitors of sodium-dependent glucose cotransporters receive the most worldwide attention. Clinical studies with other lines of medications are ongoing and may hopefully reshape the specific treatment in the future. Eventually, we can advance the care of chronic kidney disease patients through the continuous efforts of both basic and clinical researches.

Dr. Jer-Ming Chang
Guest Editor

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Keywords

  • kidney disease
  • kidney health
  • chronic kidney disease
  • glomerulonephritis
  • diabetic kidney disease
  • SGLT2i

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Related Special Issue

Published Papers (11 papers)

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Editorial

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3 pages, 181 KiB  
Editorial
Chronic Kidney Disease—How Does It Go, and What Can We Do and Expect?
by Li-Yun Chang and Jer-Ming Chang
Biomedicines 2023, 11(3), 977; https://doi.org/10.3390/biomedicines11030977 - 22 Mar 2023
Viewed by 1504
Abstract
Chronic kidney disease (CKD), as a worldwide threat to public health, is a key determinant of poor health outcomes, but the severity of the problem is probably not fully appreciated [...] Full article
(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)

Research

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21 pages, 7321 KiB  
Article
Multi-Mechanistic and Therapeutic Exploration of Nephroprotective Effect of Traditional Ayurvedic Polyherbal Formulation Using In Silico, In Vitro and In Vivo Approaches
by Gaurav, Ikshit Sharma, Mohammad Umar Khan, Sultan Zahiruddin, Parakh Basist and Sayeed Ahmad
Biomedicines 2023, 11(1), 168; https://doi.org/10.3390/biomedicines11010168 - 9 Jan 2023
Cited by 8 | Viewed by 3123
Abstract
Based on traditional therapeutic claims, NEERI KFT (a traditional Ayurvedic polyherbal preparation) has been innovatively developed in recent time on the decades of experience for treating kidney dysfunction. Due to the lack of scientific evidence, the present investigations are needed to support the [...] Read more.
Based on traditional therapeutic claims, NEERI KFT (a traditional Ayurvedic polyherbal preparation) has been innovatively developed in recent time on the decades of experience for treating kidney dysfunction. Due to the lack of scientific evidence, the present investigations are needed to support the rationale use of NEERI KFT. Considering the facts, the study investigated the nephroprotective effect of NEERI KFT against kidney dysfunction using in silico, in vitro and in vivo approaches. In this study, phytochemical and network pharmacology studies were performed for the developed formulation to evaluate the molecular mechanism of NEERI KFT in the amelioration of kidney disease. In vitro nephroprotective and antioxidant effect of NEERI KFT was determined on HEK 293 cells against cisplatin-induced cytotoxicity and oxidative stress. In vivo nephroprotective effect of NEERI KFT was determined against cisplatin-induced nephrotoxicity in Wistar rats, via assessing biochemical markers, antioxidant enzymes and inflammatory cytokines such as TNF-α, IL-1β, CASP-3, etc. The results showed that the compounds such as gallic acid, caffeic acid and ferulic acid are the major constituents of NEERI KFT, while network pharmacology analysis indicated a strong interaction between polyphenols and several genes (CASPs, ILs, AGTR1, AKT, ACE2, SOD1, etc.) involved in the pathophysiology of kidney disease. In vivo studies showed a significant (p < 0.05) ameliorative effect on biochemical markers and antioxidant enzymes (SOD, CAT, GSH, etc.), and regulates inflammatory cytokine (TNF-α, IL-1β, CASP-3) expression in kidney tissue. Hence, it can be concluded that NEERI KFT subsequently alleviates renal dysfunction mediated by cisplatin via attenuating oxidative and inflammatory stress, thus preserving the normalcy of kidney function. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)
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Graphical abstract

12 pages, 1941 KiB  
Article
UMOD Mutations in Chronic Kidney Disease in Taiwan
by Huan-Da Chen, Chih-Chuan Yu, I-Hsiao Yang, Chi-Chih Hung, Mei-Chuan Kuo, Der-Cherng Tarng, Jer-Ming Chang and Daw-Yang Hwang
Biomedicines 2022, 10(9), 2265; https://doi.org/10.3390/biomedicines10092265 - 13 Sep 2022
Cited by 1 | Viewed by 2068
Abstract
UMOD is the first identified and the most commonly mutated gene that causes autosomal dominant tubulointerstitial kidney disease (ADTKD). Recent studies have shown that ADTKD-UMOD is a relatively common cause of chronic kidney disease (CKD). However, the status of ADTKD-UMOD in [...] Read more.
UMOD is the first identified and the most commonly mutated gene that causes autosomal dominant tubulointerstitial kidney disease (ADTKD). Recent studies have shown that ADTKD-UMOD is a relatively common cause of chronic kidney disease (CKD). However, the status of ADTKD-UMOD in Taiwan remains unknown. In this study, we identified three heterozygous UMOD missense variants, c.121T > C (p.Cys41Arg), c.179G > A (p.Gly60Asp), and c.817G > T (p.Val273Phe), in a total of 221 selected CKD families (1.36%). Two of these missense variants, p.Cys41Arg and p.Gly60Asp, have not been reported previously. In vitro studies showed that both uromodulin variants have defects in cell membrane trafficking and excretion to the culture medium. The structure model predicted altered disulfide bond formation in both variants, but only p.Gly60Asp was predicted to cause protein destabilization. Our findings extend the mutation spectrum and indicate that the ADTKD-UMOD contributed to a small but significant cause of CKD in the Taiwanese population. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)
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13 pages, 1341 KiB  
Article
Oral Absorbent AST-120 Is Associated with Compositional and Functional Adaptations of Gut Microbiota and Modification of Serum Short and Medium-Chain Fatty Acids in Advanced CKD Patients
by Cheng-Kai Hsu, Shih-Chi Su, Lun-Ching Chang, Kai-Jie Yang, Chin-Chan Lee, Heng-Jung Hsu, Yih-Ting Chen, Chiao-Yin Sun and I-Wen Wu
Biomedicines 2022, 10(9), 2234; https://doi.org/10.3390/biomedicines10092234 - 8 Sep 2022
Cited by 9 | Viewed by 2360
Abstract
Background: Animal studies have demonstrated that an oral absorbent AST-120 modulates gut environment. However, this phenomenon remains unclear in humans. This study aimed to assess the effects of AST-120 on the gut microbiota, related functional capability and metabolomic profiling in advanced chronic kidney [...] Read more.
Background: Animal studies have demonstrated that an oral absorbent AST-120 modulates gut environment. However, this phenomenon remains unclear in humans. This study aimed to assess the effects of AST-120 on the gut microbiota, related functional capability and metabolomic profiling in advanced chronic kidney diseases (CKD) patients. Methods: Eight advanced CKD patients with AST-120 (CKD+AST), 24 CKD patients (CKD), and 24 non-CKD controls were enrolled. We analyzed 16S rRNA pyrosequencing of feces and serum metabolomics profiling. Results: The CKD+AST group exhibited dispersed microbial community structure (β-diversity, p < 0.001) compared to other groups. The relative abundances of at least 16 genera were significantly different amongst the three groups. Increases of fatty acids-producing bacteria (Clostridium_sensu_stricto_1, Ruminococcus_2, Eubacterium_nodatum and Phascolarctobacterium) associated with elevated serum acetic acid and octanoic acid levels were found in CKD+AST group. Analysis of microbial gene function indicated that pathway modules relevant to metabolisms of lipids, amino acids and carbohydrates were differentially enriched between CKD+AST and CKD groups. Specifically, enrichments of gene markers of the biosynthesis of fatty acids were noted in the CKD+AST group. Conclusion: Advanced CKD patients exhibited significant gut dysbiosis. AST-120 can partially restore the gut microbiota and intervenes in a possible signature of short- and medium-chain fatty acids metabolism. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)
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11 pages, 835 KiB  
Article
Association between Anti-Erythropoietin Receptor Antibodies and Cardiac Function in Patients on Hemodialysis: A Multicenter Cross-Sectional Study
by Yasuhiro Mochida, Akinori Hara, Machiko Oka, Kyoko Maesato, Kunihiro Ishioka, Hidekazu Moriya, Megumi Oshima, Tadashi Toyama, Shinji Kitajima, Yasunori Iwata, Norihiko Sakai, Miho Shimizu, Yoshitaka Koshino, Takayasu Ohtake, Sumi Hidaka, Shuzo Kobayashi and Takashi Wada
Biomedicines 2022, 10(9), 2092; https://doi.org/10.3390/biomedicines10092092 - 26 Aug 2022
Cited by 2 | Viewed by 1905
Abstract
Cardiac dysfunction is an important prognostic predictor of cardiovascular mortality in patients on hemodialysis (HD). Erythropoietin (EPO) has been reported to improve cardiac function by binding to the EPO receptor (EPOR) on cardiomyocytes. This study investigated whether anti-EPOR antibodies were associated with left [...] Read more.
Cardiac dysfunction is an important prognostic predictor of cardiovascular mortality in patients on hemodialysis (HD). Erythropoietin (EPO) has been reported to improve cardiac function by binding to the EPO receptor (EPOR) on cardiomyocytes. This study investigated whether anti-EPOR antibodies were associated with left ventricular cardiac function in patients undergoing HD. This multicenter, cross-sectional observational study included 377 patients (median age, 70 years; 267 (70.8%) males) with chronic kidney disease (CKD) undergoing stable maintenance HD. Serum levels of anti-EPOR antibodies were measured, and echocardiography was used to assess the left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF). Anti-EPOR antibodies were found in 17 patients (4.5%). LVMI was greater (median of 135 g/m2 vs. 115 g/m2, p = 0.042), and the prevalence of LVEF < 50% was higher (35.3% vs. 15.6%, p = 0.032) in patients with anti-EPOR antibodies than in those without. Multivariable linear regression and logistic regression analysis (after adjusting for known risk factors of heart failure) revealed that anti-EPOR antibodies were independently associated with LVMI (coefficient 16.2%; 95% confidence interval (CI) 1.0–35.0%, p = 0.043) and LVEF <50% (odds ratio 3.20; 95% CI 1.05–9.73, p = 0.041). Thus, anti-EPOR antibody positivity was associated with left ventricular dysfunction in patients undergoing HD. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)
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10 pages, 276 KiB  
Article
Predictive Value of HbA1c and Metabolic Syndrome for Renal Outcome in Non-Diabetic CKD Stage 1–4 Patients
by Chi-Chih Hung, Yen-Yi Zhen, Sheng-Wen Niu, Kun-Der Lin, Hugo You-Hsien Lin, Jia-Jung Lee, Jer-Ming Chang and I-Ching Kuo
Biomedicines 2022, 10(8), 1858; https://doi.org/10.3390/biomedicines10081858 - 2 Aug 2022
Cited by 2 | Viewed by 2907
Abstract
Glycated hemoglobin (HbA1c) levels are commonly used to indicate long-term glycemic control. An HbA1c level of 6.5–5.7% is defined as pre-diabetes and is proposed as a criterion for diagnosing metabolic syndrome (MetS). However, HbA1c levels can be affected by chronic kidney disease (CKD). [...] Read more.
Glycated hemoglobin (HbA1c) levels are commonly used to indicate long-term glycemic control. An HbA1c level of 6.5–5.7% is defined as pre-diabetes and is proposed as a criterion for diagnosing metabolic syndrome (MetS). However, HbA1c levels can be affected by chronic kidney disease (CKD). Whether HbA1c is associated with clinical outcomes in nondiabetic CKD patients with or without MetS is still unknown. This study included 1270 nondiabetic CKD stage 1–4 Asian patients, divided by HbA1c and MetS. Through linear regression, HbA1c was positively associated with age, waist circumference, hemoglobin levels, and C-reactive protein and was negatively associated with malnutrition–inflammation. HbA1c levels were 5.5% (0.6%) and 5.7% (0.6%) in non-MetS and MetS, respectively (p < 0.001). In Cox regression, higher-level HbA1c was associated with worse composite renal outcome in MetS patients, but with better renal outcome in non-MetS patients: Hazard ratio (HR) (95% confidence interval [CI]) of HbA1c ≥5.7%, compared with HbA1c <5%, was 2.00 (1.06–3.78) in MetS and 0.25 (0.14–0.45) in non-MetS. An association between HbA1c and all-cause mortality was not found. In conclusion, higher HbA1c levels are associated with worse renal outcomes in nondiabetic CKD stage 1–4 patients modified by the presence of MetS. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)
13 pages, 602 KiB  
Article
Metabolic Syndrome and Obesity-Related Indices Are Associated with Rapid Renal Function Decline in a Large Taiwanese Population Follow-Up Study
by Wei-Yu Su, I-Hua Chen, Yuh-Ching Gau, Pei-Yu Wu, Jiun-Chi Huang, Yi-Chun Tsai, Szu-Chia Chen, Jer-Ming Chang, Shang-Jyh Hwang and Hung-Chun Chen
Biomedicines 2022, 10(7), 1744; https://doi.org/10.3390/biomedicines10071744 - 19 Jul 2022
Cited by 11 | Viewed by 2255
Abstract
A rapid decline in renal function can cause many complications, and therefore it is important to detect associated risk factors. Few studies have evaluated the associations among obesity-related indices and metabolic syndrome (MetS) with renal function decline. This longitudinal study aimed to explore [...] Read more.
A rapid decline in renal function can cause many complications, and therefore it is important to detect associated risk factors. Few studies have evaluated the associations among obesity-related indices and metabolic syndrome (MetS) with renal function decline. This longitudinal study aimed to explore these relationships in a large cohort of Taiwanese participants. The studied obesity-related indices were waist-to-height ratio (WHtR), A body shape index (ABSI), visceral adiposity index (VAI), lipid accumulation product (LAP), waist-to-hip ratio (WHR), body roundness index (BRI), conicity index (CI), body mass index (BMI), body adiposity index (BAI) and abdominal volume index (AVI). We included 122,068 participants in the baseline study, of whom 27,033 were followed for a median of four years. The baseline prevalence of MetS was 17.7%. Multivariable analysis showed that the participants with MetS and high VAI, WHtR, WHR, LAP, CI, BRI, BMI, BAI, AVI, and ABSI values were significantly associated with a high baseline estimated glomerular filtration rate (eGFR) (all p < 0.001). In addition, the participants with MetS (p < 0.001), high WHtR (p = 0.007), low LAP (p < 0.001), high BRI (p = 0.002), high CI (p = 0.002), high AVI (p = 0.001), high VAI (p = 0.017), and high ABSI (p = 0.013) were significantly associated with a low △eGFR, indicating a rapid decline in renal function. These results showed associations between MetS and high values of obesity-related indices except LAP with high baseline eGFR and rapid decline in kidney function. These findings suggest that screening for MetS and obesity may help to slow the decline in renal function in high-risk populations. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)
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11 pages, 762 KiB  
Article
Hyperuricemia, a Non-Independent Component of Metabolic Syndrome, Only Predicts Renal Outcome in Chronic Kidney Disease Patients without Metabolic Syndrome or Diabetes
by Sheng-Wen Niu, Hugo You-Hsien Lin, I-Ching Kuo, Yen-Yi Zhen, Eddy-Essen Chang, Feng-Ching Shen, Yi-Wen Chiu, Jer-Ming Chang, Chi-Chih Hung and Shang-Jyh Hwang
Biomedicines 2022, 10(7), 1719; https://doi.org/10.3390/biomedicines10071719 - 16 Jul 2022
Cited by 1 | Viewed by 2309
Abstract
Uric acid (UA) is elevated in metabolic syndrome (MS) and diabetes (DM). UA is associated with central obesity and blood glucose and is proposed as a criterion of MS. Previous reports showed that UA could predict renal outcome in CKD. However, recent clinical [...] Read more.
Uric acid (UA) is elevated in metabolic syndrome (MS) and diabetes (DM). UA is associated with central obesity and blood glucose and is proposed as a criterion of MS. Previous reports showed that UA could predict renal outcome in CKD. However, recent clinical trials did not demonstrate the benefits of urate-lowering agents (ULA) for renal outcome. Whether the prognostic value of UA for renal outcome is independent of MS or secondary to MS in CKD patients is unknown. Our study included 2500 CKD stage 1–4 Asian patients divided by UA tertiles and MS/DM. In linear regression, UA was associated with obesity, C-reactive protein, and renal function. In Cox regression, high UA was associated with worse renal outcome in non-MS/DM, but not in MS/DM: hazard ratio (95% confidence interval) of UA tertile 3 was 3.86 (1.87–7.97) in non-MS/DM and 1.00 (0.77–1.30) in MS/DM (p for interaction < 0.05). MS was associated with worse renal outcome, but redefined MS (including hyperuricemia as the 6th criteria) was not. In conclusion, hyperuricemia is associated with worse renal outcome in non-MS/DM and is not an independent component of MS in CKD stage 1–4 patients. Hyperuricemia secondary to MS could not predict renal outcome. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)
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Review

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15 pages, 424 KiB  
Review
Diabetic Kidney Disease in Post-Transplant Diabetes Mellitus: Causes, Treatment and Outcomes
by Lee-Moay Lim, Jer-Ming Chang and Hung-Tien Kuo
Biomedicines 2023, 11(2), 470; https://doi.org/10.3390/biomedicines11020470 - 6 Feb 2023
Cited by 4 | Viewed by 2854
Abstract
Kidney transplant recipients are a unique subgroup of chronic kidney disease patients due to their single functioning kidney, immunosuppressive agent usage, and long-term complications related to transplantation. Post-transplant diabetes mellitus (PTDM) has a significant adverse effect on renal outcomes in particular. As transplantations [...] Read more.
Kidney transplant recipients are a unique subgroup of chronic kidney disease patients due to their single functioning kidney, immunosuppressive agent usage, and long-term complications related to transplantation. Post-transplant diabetes mellitus (PTDM) has a significant adverse effect on renal outcomes in particular. As transplantations enable people to live longer, cardiovascular morbidity and mortality become more prevalent, and PTDM is a key risk factor for these complications. Although PTDM results from similar risk factors to those of type 2 diabetes, the conditions differ in their pathophysiology and clinical features. Transplantation itself is a risk factor for diabetes due to chronic exposure to immunosuppressive agents. Considering current evidence, this article describes the risk factors, pathogenesis, diagnostic criteria, prevention strategies, and management of PTDM. The therapeutic options are discussed regarding their safety and potential drug–drug interactions with immunosuppressive agents. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)
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11 pages, 598 KiB  
Review
SGLT2 Inhibitors in Diabetic and Non-Diabetic Chronic Kidney Disease
by Manuel Alfredo Podestà, Gianmarco Sabiu, Andrea Galassi, Paola Ciceri and Mario Cozzolino
Biomedicines 2023, 11(2), 279; https://doi.org/10.3390/biomedicines11020279 - 19 Jan 2023
Cited by 17 | Viewed by 7650
Abstract
Results from recent randomized controlled trials on inhibitors of the sodium-glucose cotransporter 2 (SGLT2) have determined a paradigm shift in the treatment of patients with type 2 diabetes mellitus. These agents have been shown not only to ameliorate metabolic control, but also to [...] Read more.
Results from recent randomized controlled trials on inhibitors of the sodium-glucose cotransporter 2 (SGLT2) have determined a paradigm shift in the treatment of patients with type 2 diabetes mellitus. These agents have been shown not only to ameliorate metabolic control, but also to independently protect from cardiovascular events and to reduce the progression of chronic kidney disease (CKD) in these patients. The magnitude of the nephroprotective effect observed in these studies is likely to make SGLT2 inhibitors the most impactful drug class for the treatment of diabetic patients with CKD since the discovery of renin–angiotensin system inhibitors. Even more surprisingly, SGLT2 inhibitors have also been shown to slow CKD progression in non-diabetic individuals with varying degrees of proteinuria, suggesting that activation of SGLT2 is involved in the pathogenesis of CKD independent of its etiology. As indications continue to expand, it is still unclear whether the observed benefits of SGLT2 inhibitors may extend to CKD patients at lower risk of progression and if their association with other agents may confer additional protection. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)
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13 pages, 985 KiB  
Review
Mucosal Immune System Dysregulation in the Pathogenesis of IgA Nephropathy
by Toshiki Kano, Hitoshi Suzuki, Yuko Makita, Yoshihito Nihei, Yusuke Fukao, Maiko Nakayama, Mingfeng Lee, Rina Kato, Ryosuke Aoki, Koshi Yamada, Masahiro Muto and Yusuke Suzuki
Biomedicines 2022, 10(12), 3027; https://doi.org/10.3390/biomedicines10123027 - 24 Nov 2022
Cited by 17 | Viewed by 3063
Abstract
The mucosal immune system, via a dynamic immune network, serves as the first line of defense against exogenous antigens. Mucosal immune system dysregulation is closely associated with the pathogenesis of immunoglobulin A nephropathy (IgAN), as illustrated by IgAN having the clinical feature of [...] Read more.
The mucosal immune system, via a dynamic immune network, serves as the first line of defense against exogenous antigens. Mucosal immune system dysregulation is closely associated with the pathogenesis of immunoglobulin A nephropathy (IgAN), as illustrated by IgAN having the clinical feature of gross hematuria, often concurrent with mucosal infections. Notably, previous studies have demonstrated the efficacy of tonsillectomy and found that a targeted-release formulation of budesonide reduced proteinuria in patients with IgAN. However, it remains unclear how exogenous antigens interact with the mucosal immune system to induce or exacerbate IgAN. Thus, in this review, we focus on the dysregulation of mucosal immune response in the pathogenesis of IgAN. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)
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