Pub Date : 2024-01-01Epub Date: 2023-05-31DOI: 10.1159/000531297
Omar Mamlouk, Farhad R Danesh
Context: The clinical indications for immune checkpoint inhibitors (ICIs) are rapidly expanding. However, adverse events affecting multiple organs, including kidneys leading to ICI-associated acute kidney injury (AKI), remain a significant challenge with ICI therapy. Although AKI is considered a rare complication, it can be severe and result in treatment interruption or discontinuation of ICIs. Despite a generally favorable kidney prognosis, the possibility of re-challenging ICI therapy remains a subject of debate, particularly for patients who have exhausted other treatment options or experienced severe AKI. Subject of Review: In a recent review article, Sprangers et al. provide a comprehensive overview of the possible mechanisms and clinical manifestations of ICI-associated AKI [Nat Rev Nephrol. 2022;18(12):794-805]. The authors propose a practical strategy for diagnosing and managing suspected cases of ICI-associated AKI, which includes identifying a subset of eligible patients who may be re-exposed to ICIs following an episode of AKI. Second Opinion: The authors of the review article offer several recommendations on the diagnosis and treatment of ICI-associated nephrotoxicity. While we generally agree with the recommendations proposed by the authors, it is important to acknowledge that the available data primarily rely on small retrospective studies, as the authors have recognized. In addition, there are two key questions that need be carefully addressed in future studies: (1) the optimal dose and duration of corticosteroids and the use of alternative immunosuppressive agents in patients with ICI-associated nephrotoxicity and (2) a clear guideline for restarting ICI treatment in patients with AKI who have not fully recovered their kidney function.
背景:免疫检查点抑制剂(ICIs)的临床适应症正在迅速扩大。然而,影响包括肾脏在内的多个器官的不良事件导致 ICI 相关急性肾损伤(AKI),这仍然是 ICI 治疗面临的重大挑战。虽然 AKI 被认为是一种罕见的并发症,但其严重程度可能导致 ICI 治疗中断或停药。尽管肾脏预后普遍良好,但是否有可能重新接受 ICI 治疗仍是一个争论不休的话题,尤其是对于已用尽其他治疗方案或出现严重 AKI 的患者。评论主题:在最近的一篇综述文章中,Sprangers 等人全面概述了 ICI 相关性 AKI 的可能机制和临床表现[Nat Rev Nephrol. 2022;18(12):794-805]。作者提出了诊断和管理 ICI 相关性 AKI 疑似病例的实用策略,其中包括识别符合条件的患者子集,这些患者可能在 AKI 发作后再次接触 ICIs。第二种观点:综述文章的作者就 ICI 相关肾毒性的诊断和治疗提出了若干建议。虽然我们基本同意作者提出的建议,但必须承认,正如作者所承认的,现有数据主要依赖于小型回顾性研究。此外,还有两个关键问题需要在今后的研究中仔细探讨:(1) 在 ICI 相关性肾毒性患者中皮质类固醇的最佳剂量和持续时间以及替代免疫抑制剂的使用;(2) 肾功能尚未完全恢复的 AKI 患者重新开始 ICI 治疗的明确指南。
{"title":"Immune Checkpoint Inhibitor-Associated Nephrotoxicity.","authors":"Omar Mamlouk, Farhad R Danesh","doi":"10.1159/000531297","DOIUrl":"10.1159/000531297","url":null,"abstract":"<p><strong>Context: </strong>The clinical indications for immune checkpoint inhibitors (ICIs) are rapidly expanding. However, adverse events affecting multiple organs, including kidneys leading to ICI-associated acute kidney injury (AKI), remain a significant challenge with ICI therapy. Although AKI is considered a rare complication, it can be severe and result in treatment interruption or discontinuation of ICIs. Despite a generally favorable kidney prognosis, the possibility of re-challenging ICI therapy remains a subject of debate, particularly for patients who have exhausted other treatment options or experienced severe AKI. Subject of Review: In a recent review article, Sprangers et al. provide a comprehensive overview of the possible mechanisms and clinical manifestations of ICI-associated AKI [Nat Rev Nephrol. 2022;18(12):794-805]. The authors propose a practical strategy for diagnosing and managing suspected cases of ICI-associated AKI, which includes identifying a subset of eligible patients who may be re-exposed to ICIs following an episode of AKI. Second Opinion: The authors of the review article offer several recommendations on the diagnosis and treatment of ICI-associated nephrotoxicity. While we generally agree with the recommendations proposed by the authors, it is important to acknowledge that the available data primarily rely on small retrospective studies, as the authors have recognized. In addition, there are two key questions that need be carefully addressed in future studies: (1) the optimal dose and duration of corticosteroids and the use of alternative immunosuppressive agents in patients with ICI-associated nephrotoxicity and (2) a clear guideline for restarting ICI treatment in patients with AKI who have not fully recovered their kidney function.</p>","PeriodicalId":18998,"journal":{"name":"Nephron","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9606853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-03-25DOI: 10.1159/000536248
Pedro Lisboa Gonçalves, Hugo Diniz, Isabel Tavares, Sofia Dória, Juan Dong, McKenna Kyriss, Lynette Fairbanks, João Paulo Oliveira
Hereditary xanthinuria (HXAN) is a rare metabolic disorder that results from mutations in either the xanthine dehydrogenase (XDH) or the molybdenum cofactor sulfurase genes (MOCOS), respectively defining HXAN type I and type II. Hypouricemia, hypouricosuria, and abnormally high plasma and urine levels of xanthine, causing susceptibility to xanthine nephrolithiasis and deposition of xanthine crystals in tissues, are the metabolic hallmarks of HXAN. Several pathogenic variants in the XDH gene have so far been identified in patients with HXAN type I, but the clinical phenotype associated with the whole deletion of the human XDH gene is unknown. Herein, we report the case of a woman diagnosed with HXAN, whose molecular genetic testing revealed a homozygous microdeletion involving the XDH gene. Distinctive features of her medical history were the diagnosis of arterial hypertension and microalbuminuria at 22 years of age; a single pregnancy at the age of 25, complicated by proteinuria and transient kidney function deterioration in the third trimester; unexplained severe hypouricemia incidentally discovered during pregnancy; inability to breastfeed her newborn daughter due to primary agalactia; chronic kidney disease (CKD) stage 3 diagnosed at age 35; and progression to end-stage kidney disease over the next 12 years. Protocol noninvasive laboratory and imaging investigation was not informative as to the cause of CKD. This is the first description of the clinical phenotype associated with a natural knockout of the human XDH gene. Despite the lack of kidney histopathology data, the striking similarities with the phenotypes exhibited by comparable murine models validate the latter as useful sources of mechanistic insights for the pathogenesis of the human disease, supporting the hypothesis that the absence of xanthine dehydrogenase activity might represent a susceptibility factor for chronic tubulointerstitial nephritis, even in patients without kidney stones.
{"title":"Kidney Failure Secondary to Hereditary Xanthinuria due to a Homozygous Deletion of the XDH Gene in the Absence of Overt Kidney Stone Disease.","authors":"Pedro Lisboa Gonçalves, Hugo Diniz, Isabel Tavares, Sofia Dória, Juan Dong, McKenna Kyriss, Lynette Fairbanks, João Paulo Oliveira","doi":"10.1159/000536248","DOIUrl":"10.1159/000536248","url":null,"abstract":"<p><p>Hereditary xanthinuria (HXAN) is a rare metabolic disorder that results from mutations in either the xanthine dehydrogenase (XDH) or the molybdenum cofactor sulfurase genes (MOCOS), respectively defining HXAN type I and type II. Hypouricemia, hypouricosuria, and abnormally high plasma and urine levels of xanthine, causing susceptibility to xanthine nephrolithiasis and deposition of xanthine crystals in tissues, are the metabolic hallmarks of HXAN. Several pathogenic variants in the XDH gene have so far been identified in patients with HXAN type I, but the clinical phenotype associated with the whole deletion of the human XDH gene is unknown. Herein, we report the case of a woman diagnosed with HXAN, whose molecular genetic testing revealed a homozygous microdeletion involving the XDH gene. Distinctive features of her medical history were the diagnosis of arterial hypertension and microalbuminuria at 22 years of age; a single pregnancy at the age of 25, complicated by proteinuria and transient kidney function deterioration in the third trimester; unexplained severe hypouricemia incidentally discovered during pregnancy; inability to breastfeed her newborn daughter due to primary agalactia; chronic kidney disease (CKD) stage 3 diagnosed at age 35; and progression to end-stage kidney disease over the next 12 years. Protocol noninvasive laboratory and imaging investigation was not informative as to the cause of CKD. This is the first description of the clinical phenotype associated with a natural knockout of the human XDH gene. Despite the lack of kidney histopathology data, the striking similarities with the phenotypes exhibited by comparable murine models validate the latter as useful sources of mechanistic insights for the pathogenesis of the human disease, supporting the hypothesis that the absence of xanthine dehydrogenase activity might represent a susceptibility factor for chronic tubulointerstitial nephritis, even in patients without kidney stones.</p>","PeriodicalId":18998,"journal":{"name":"Nephron","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2023-12-19DOI: 10.1159/000535876
Paolo Lopedote, Juliano Alhaddad, Guoliang Zheng, Mu'taz Abualshar, Shree Ghanta, Olga Kozyreva, Bertrand L Jaber
Introduction: Multiple myeloma (MM) frequently involves the kidneys, resulting in acute, subacute, or chronic kidney disease (CKD). Patient- and treatment-related factors are associated with the long-term development of CKD. The aim of our study was to examine the association of serum free light chain (FLC) levels, measured at the time of diagnosis of MM, and CKD at subsequent follow-up.
Methods: Patients with newly diagnosed MM were identified using cancer registries at five hospitals. The primary outcome was low eGFR (<60 mL/min/1.73 m2) or dialysis dependence and a secondary composite outcome of low eGFR, dialysis dependence, or death at the last follow-up, up to 12 months from diagnosis. Logistic regression analyses were performed.
Results: A total of 149 patients met the inclusion criteria. Patients with an FLC level above the median had a higher frequency of hypertension (54% vs. 81%; p < 0.001), hyperlipidemia (37% vs. 56%; p = 0.018), low eGFR at the time of diagnosis (43% vs. 66%; p = 0.006), and a higher MM stage (p = 0.018). On multivariable analyses, after adjustment for several covariates, serum FLC level (per each 100 mg/L) was independently associated with low eGFR or dialysis dependence at follow-up (adjusted odds ratio [aOR] 1.021; 95% CI: 1.002, 1.041; p = 0.033). This association persisted for the composite outcome of low eGFR, dialysis dependence, or death (aOR 1.034; 95% CI: 1.006, 1.063; p = 0.018).
Discussion/conclusion: Higher serum FLC level measured at the time of MM diagnosis is independently associated with CKD at up to 12 months of follow-up.
{"title":"Association of Serum Free Light Chain Level with Long-Term Kidney Function in Patients with Newly Diagnosed Multiple Myeloma.","authors":"Paolo Lopedote, Juliano Alhaddad, Guoliang Zheng, Mu'taz Abualshar, Shree Ghanta, Olga Kozyreva, Bertrand L Jaber","doi":"10.1159/000535876","DOIUrl":"10.1159/000535876","url":null,"abstract":"<p><strong>Introduction: </strong>Multiple myeloma (MM) frequently involves the kidneys, resulting in acute, subacute, or chronic kidney disease (CKD). Patient- and treatment-related factors are associated with the long-term development of CKD. The aim of our study was to examine the association of serum free light chain (FLC) levels, measured at the time of diagnosis of MM, and CKD at subsequent follow-up.</p><p><strong>Methods: </strong>Patients with newly diagnosed MM were identified using cancer registries at five hospitals. The primary outcome was low eGFR (<60 mL/min/1.73 m2) or dialysis dependence and a secondary composite outcome of low eGFR, dialysis dependence, or death at the last follow-up, up to 12 months from diagnosis. Logistic regression analyses were performed.</p><p><strong>Results: </strong>A total of 149 patients met the inclusion criteria. Patients with an FLC level above the median had a higher frequency of hypertension (54% vs. 81%; p < 0.001), hyperlipidemia (37% vs. 56%; p = 0.018), low eGFR at the time of diagnosis (43% vs. 66%; p = 0.006), and a higher MM stage (p = 0.018). On multivariable analyses, after adjustment for several covariates, serum FLC level (per each 100 mg/L) was independently associated with low eGFR or dialysis dependence at follow-up (adjusted odds ratio [aOR] 1.021; 95% CI: 1.002, 1.041; p = 0.033). This association persisted for the composite outcome of low eGFR, dialysis dependence, or death (aOR 1.034; 95% CI: 1.006, 1.063; p = 0.018).</p><p><strong>Discussion/conclusion: </strong>Higher serum FLC level measured at the time of MM diagnosis is independently associated with CKD at up to 12 months of follow-up.</p>","PeriodicalId":18998,"journal":{"name":"Nephron","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138797626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-06-21DOI: 10.1159/000539834
Fabry Update.
法布里更新。
{"title":"8th Update on Fabry Disease: Biomarkers, Progression and Treatment Opportunities in 2024.","authors":"","doi":"10.1159/000539834","DOIUrl":"10.1159/000539834","url":null,"abstract":"<p><p>Fabry Update.</p>","PeriodicalId":18998,"journal":{"name":"Nephron","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Thrombotic microangiopathy (TMA) is an important risk factor for the prognosis of lupus nephritis (LN). Patients with LN complicated with TMA tend to be critically ill with high mortality and poor prognosis. In the present study, we retrospectively analyzed the clinical manifestations, laboratory results, renal pathological manifestations, and prognosis of children with LN-TMA and analyzed the risk factors for end-stage renal disease (ESRD) in children with LN-TMA.
Methods: Seventy-four patients with LN and renal TMA (rTMA) were selected and compared to 128 LN controls without TMA (1:2 ratio) matched according to demographics, pathological type and treatments.
Results: The mean values of systolic blood pressure, diastolic blood pressure (DBP), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), urinary protein quantitation (PRO), urine red blood cells, N-acetyl-β-D-glucosidase (NAG), retinol-binding protein, systemic lupus erythematosus disease activity score (SLEDAI), and activity index (AI) scores in the TMA group were all higher than those in the non-TMA group (p < 0.05 and p < 0.01). The mean values of complement C3, hemoglobin, platelets, estimated glomerular filtration rate, and chronic index (CI) score in the TMA group were all lower than those in the non-TMA group (p < 0.05 and p < 0.01). The number of cases of glomerular crescent, fibrous crescent, endocapillary proliferation, tubular atrophy, interstitial fibrosis, C3 and C1q deposition in the TMA group was higher than that in the non-TMA group (p < 0.05 and p < 0.01). The 3-year and 5-year renal survival rates in the TMA group (88.93% vs. 97.00%, p < 0.05) and TMA group (61.41% vs. 82.31%, p < 0.05) were significantly lower than those in the non-TMA group. Multivariate Cox regression analysis showed that serum creatinine before treatment (≥110 μmol/L), TMA and interstitial fibrosis were independent risk factors for the development of ESRD in LN children.
Conclusion: The general condition of children with TMA is critical, and the prognosis is poor. Early detection, early treatment and the development of new treatments are key to improving LN-TMA outcomes in children.
背景:血栓性微血管病(TMA血栓性微血管病(TMA)是狼疮性肾炎(LN)预后的一个重要危险因素。并发 TMA 的狼疮肾炎患者往往病情危重,死亡率高,预后差。在本研究中,我们回顾性分析了LN-TMA患儿的临床表现、实验室结果、肾脏病理表现和预后,并分析了LN-TMA患儿终末期肾病(ESRD)的危险因素:方法:选取74例LN和肾TMA(rTMA)患者,与128例无TMA的LN对照组(1:2)进行比较,根据人口统计学、病理类型和治疗方法进行配对:结果:收缩压、舒张压(DBP)、乳酸脱氢酶(LDH)、血尿素氮(BUN)、尿蛋白定量(PRO)、尿红细胞、N-乙酰基-β-D-葡萄糖苷酶(NAG)、视黄醇结合蛋白、全身血红蛋白、尿蛋白定量(PRO)、N-乙酰基-β-D-葡萄糖苷酶(NAGTMA组的视黄醇结合蛋白、系统性红斑狼疮疾病活动评分(SLEDAI)和活动指数(AI)均高于非TMA组(P <;0.05 和 p < 0.01)。TMA 组的补体 C3、血红蛋白、血小板、估计肾小球滤过率和慢性指数(CI)评分的平均值均低于非 TMA 组(p < 0.05 和 p < 0.01)。TMA组出现肾小球新月体、纤维新月体、毛细血管内增生、肾小管萎缩、肾间质纤维化、C3和C1q沉积的病例数高于非TMA组(p < 0.05和p < 0.01)。TMA组(88.93% vs. 97.00%,p < 0.05)和TMA组(61.41% vs. 82.31%,p < 0.05)的3年和5年肾脏存活率明显低于非TMA组。多变量Cox回归分析显示,治疗前血清肌酐(≥110 μmol/L)、TMA和间质纤维化是LN患儿发生ESRD的独立危险因素:结论:TMA患儿病情危重,预后不良。早期发现、早期治疗和开发新的治疗方法是改善 LN-TMA 儿童预后的关键。
{"title":"Risk Factors and Clinical Outcomes of Renal Thrombotic Microangiopathy in Children with Lupus Nephritis in Terms of Pathological and Clinical Features.","authors":"Pei Zhang, Xiao Yang, Meng-Zhen Fu, Chun-Lin Gao, Xiang Fang, Zheng-Kun Xia","doi":"10.1159/000538240","DOIUrl":"10.1159/000538240","url":null,"abstract":"<p><strong>Background: </strong>Thrombotic microangiopathy (TMA) is an important risk factor for the prognosis of lupus nephritis (LN). Patients with LN complicated with TMA tend to be critically ill with high mortality and poor prognosis. In the present study, we retrospectively analyzed the clinical manifestations, laboratory results, renal pathological manifestations, and prognosis of children with LN-TMA and analyzed the risk factors for end-stage renal disease (ESRD) in children with LN-TMA.</p><p><strong>Methods: </strong>Seventy-four patients with LN and renal TMA (rTMA) were selected and compared to 128 LN controls without TMA (1:2 ratio) matched according to demographics, pathological type and treatments.</p><p><strong>Results: </strong>The mean values of systolic blood pressure, diastolic blood pressure (DBP), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), urinary protein quantitation (PRO), urine red blood cells, N-acetyl-β-D-glucosidase (NAG), retinol-binding protein, systemic lupus erythematosus disease activity score (SLEDAI), and activity index (AI) scores in the TMA group were all higher than those in the non-TMA group (p < 0.05 and p < 0.01). The mean values of complement C3, hemoglobin, platelets, estimated glomerular filtration rate, and chronic index (CI) score in the TMA group were all lower than those in the non-TMA group (p < 0.05 and p < 0.01). The number of cases of glomerular crescent, fibrous crescent, endocapillary proliferation, tubular atrophy, interstitial fibrosis, C3 and C1q deposition in the TMA group was higher than that in the non-TMA group (p < 0.05 and p < 0.01). The 3-year and 5-year renal survival rates in the TMA group (88.93% vs. 97.00%, p < 0.05) and TMA group (61.41% vs. 82.31%, p < 0.05) were significantly lower than those in the non-TMA group. Multivariate Cox regression analysis showed that serum creatinine before treatment (≥110 μmol/L), TMA and interstitial fibrosis were independent risk factors for the development of ESRD in LN children.</p><p><strong>Conclusion: </strong>The general condition of children with TMA is critical, and the prognosis is poor. Early detection, early treatment and the development of new treatments are key to improving LN-TMA outcomes in children.</p>","PeriodicalId":18998,"journal":{"name":"Nephron","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-03-08DOI: 10.1159/000538241
Simona Buelli, Barbara Imberti, Marina Morigi
The complement system, a cornerstone of the innate immune defense, typically confers protection against pathogens. However, in various clinical scenarios the complement's defensive actions can harm host cells, exacerbating immune and inflammatory responses. The central components C3 and C5 undergo proteolytic cleavage during complement activation, yielding small active fragments C3a and C5a anaphylatoxins. Traditionally, these fragments were associated with inflammation via the specific receptors C3a receptor (R), C5aR1 and C5aR2. Recent insights, however, spotlight the excessive C3a/C3aR and C5a/C5aR1 signaling as culprits in diverse disorders of inflammatory and autoimmune etiology. This is particularly true for several kidney diseases, where the potential involvement of anaphylatoxins in renal damage is supported by the enhanced renal expression of their receptors and the high levels of C3a and C5a in both plasma and urine. Furthermore, the production of complement proteins in the kidney, with different renal cells synthesizing C3 and C5, significantly contributes to local tissue injury. In the present review, we discuss the different aspects of C3a/C3aR and C5a/C5aR signaling in acute and chronic kidney diseases and explore the therapeutic potential of emerging targeted drugs for future clinical applications.
{"title":"The Complement C3a and C5a Signaling in Renal Diseases: A Bridge between Acute and Chronic Inflammation.","authors":"Simona Buelli, Barbara Imberti, Marina Morigi","doi":"10.1159/000538241","DOIUrl":"10.1159/000538241","url":null,"abstract":"<p><p>The complement system, a cornerstone of the innate immune defense, typically confers protection against pathogens. However, in various clinical scenarios the complement's defensive actions can harm host cells, exacerbating immune and inflammatory responses. The central components C3 and C5 undergo proteolytic cleavage during complement activation, yielding small active fragments C3a and C5a anaphylatoxins. Traditionally, these fragments were associated with inflammation via the specific receptors C3a receptor (R), C5aR1 and C5aR2. Recent insights, however, spotlight the excessive C3a/C3aR and C5a/C5aR1 signaling as culprits in diverse disorders of inflammatory and autoimmune etiology. This is particularly true for several kidney diseases, where the potential involvement of anaphylatoxins in renal damage is supported by the enhanced renal expression of their receptors and the high levels of C3a and C5a in both plasma and urine. Furthermore, the production of complement proteins in the kidney, with different renal cells synthesizing C3 and C5, significantly contributes to local tissue injury. In the present review, we discuss the different aspects of C3a/C3aR and C5a/C5aR signaling in acute and chronic kidney diseases and explore the therapeutic potential of emerging targeted drugs for future clinical applications.</p>","PeriodicalId":18998,"journal":{"name":"Nephron","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Arteriolar hyalinosis (AH) has been shown to be associated with albuminuria and GFR. In this study, we investigated whether or not index of AH (IAH) is a predictor of the onset of macroalbuminuria and impaired renal function (eGFR <60 mL/min/1.73 m2 [eGFR <60]) in type 2 diabetic patients with early diabetic nephropathy.
Methods: The study population consisted of 35 patients with type 2 diabetes (25 men; age: 47 ± 9 years; eGFR: 92.7 ± 18.0 mL/min/1.73 m2) with normo- or microalbuminuria who underwent percutaneous renal biopsy. These patients were followed for at least 5 (18 ± 6, range: 6-28) years. The study endpoint was the onset of macroalbuminuria or eGFR <60. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate glomerular and interstitial structural changes.
Results: During the observation period, 9 out of the 35 patients progressed to macroalbuminuria, and 15 out of the 35 patients developed eGFR <60. The annual rate of eGFR decline was significantly correlated with IAH (r = -0.40, p = 0.016). Kaplan-Meier analysis demonstrated that AH was associated with a significantly higher risk of onset of macroalbuminuria and eGFR <60, and microalbuminuria is associated with the onset of macroalbuminuria but not the onset of eGFR <60.
Conclusions: Aggravated AH is a histological risk factor which predicts the onset of macroalbuminuria and eGFR <60 in patients with type 2 diabetes. These findings provide novel insights into the mechanism of progression of diabetic nephropathy.
{"title":"Arteriolar Hyalinosis Predicts the Onset of Both Macroalbuminuria and Impaired Renal Function in Patients with Type 2 Diabetes.","authors":"Akihiko Suzuki, Tatsumi Moriya, Akinori Hayashi, Madoka Matsubara, Takeshi Miyatsuka","doi":"10.1159/000535875","DOIUrl":"10.1159/000535875","url":null,"abstract":"<p><strong>Introduction: </strong>Arteriolar hyalinosis (AH) has been shown to be associated with albuminuria and GFR. In this study, we investigated whether or not index of AH (IAH) is a predictor of the onset of macroalbuminuria and impaired renal function (eGFR <60 mL/min/1.73 m2 [eGFR <60]) in type 2 diabetic patients with early diabetic nephropathy.</p><p><strong>Methods: </strong>The study population consisted of 35 patients with type 2 diabetes (25 men; age: 47 ± 9 years; eGFR: 92.7 ± 18.0 mL/min/1.73 m2) with normo- or microalbuminuria who underwent percutaneous renal biopsy. These patients were followed for at least 5 (18 ± 6, range: 6-28) years. The study endpoint was the onset of macroalbuminuria or eGFR <60. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate glomerular and interstitial structural changes.</p><p><strong>Results: </strong>During the observation period, 9 out of the 35 patients progressed to macroalbuminuria, and 15 out of the 35 patients developed eGFR <60. The annual rate of eGFR decline was significantly correlated with IAH (r = -0.40, p = 0.016). Kaplan-Meier analysis demonstrated that AH was associated with a significantly higher risk of onset of macroalbuminuria and eGFR <60, and microalbuminuria is associated with the onset of macroalbuminuria but not the onset of eGFR <60.</p><p><strong>Conclusions: </strong>Aggravated AH is a histological risk factor which predicts the onset of macroalbuminuria and eGFR <60 in patients with type 2 diabetes. These findings provide novel insights into the mechanism of progression of diabetic nephropathy.</p>","PeriodicalId":18998,"journal":{"name":"Nephron","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11151987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138830667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2023-12-02DOI: 10.1159/000533472
Gabriel Brayan Gutiérrez-Peredo, Márcia Tereza Silva Martins, Fernanda Albuquerque da Silva, Marcelo Barreto Lopes, Gildete Barreto Lopes, Keith C Norris, Antonio Alberto Lopes
Background: The existing data support the Chalder Fatigue Questionnaire (CFQ-11) as a valid instrument to assess fatigue in maintenance hemodialysis (MHD) patients. The objective of this work was to investigate whether self-reported fatigue can serve as an independent prognostic indicator for mortality in MHD patients.
Methods: The data are from 233 adult patients enrolled in the cohort "The Prospective Study of the Prognosis of Chronic Hemodialysis Patients" (PROHEMO) developed in Salvador, BA, Brazil. The Brazilian version of the validated CFQ-11 was used to calculate self-reported fatigue. The CFQ-11 scores may range from 0 to 33; higher scores represent more fatigue. Fatigue categories were created based on proposed cut point: absence or mild degree if CFQ-11 scores <4 and moderate to severe if scores ≥4. Cox models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of associations between fatigue and mortality with adjustments for sociodemographic factors, time on dialysis, education, economic class, hemoglobin concentration, diabetes, heart failure, depression, and other psychiatric disorders.
Results: The mean age was 51.5 ± 2.5 years, 58% were male, and 30% were diabetic. Self-reported moderate to severe fatigue was reported by 71% of patients. The mortality rate was 8.6 cases/100 person-years. Patients with moderate to severe fatigue had a more than threefold mortality rate (HR = 3.07, 95% CI: 1.19, 7.93) compared to patients with absent or mild fatigue, after extensive adjustments for covariates.
Conclusion: The study provides evidence that self-reported fatigue can help identify MHD patients at higher risk of earlier death.
{"title":"Self-Reported Fatigue by the Chalder Fatigue Questionnaire and Mortality in Brazilian Hemodialysis Patients: The PROHEMO.","authors":"Gabriel Brayan Gutiérrez-Peredo, Márcia Tereza Silva Martins, Fernanda Albuquerque da Silva, Marcelo Barreto Lopes, Gildete Barreto Lopes, Keith C Norris, Antonio Alberto Lopes","doi":"10.1159/000533472","DOIUrl":"10.1159/000533472","url":null,"abstract":"<p><strong>Background: </strong>The existing data support the Chalder Fatigue Questionnaire (CFQ-11) as a valid instrument to assess fatigue in maintenance hemodialysis (MHD) patients. The objective of this work was to investigate whether self-reported fatigue can serve as an independent prognostic indicator for mortality in MHD patients.</p><p><strong>Methods: </strong>The data are from 233 adult patients enrolled in the cohort \"The Prospective Study of the Prognosis of Chronic Hemodialysis Patients\" (PROHEMO) developed in Salvador, BA, Brazil. The Brazilian version of the validated CFQ-11 was used to calculate self-reported fatigue. The CFQ-11 scores may range from 0 to 33; higher scores represent more fatigue. Fatigue categories were created based on proposed cut point: absence or mild degree if CFQ-11 scores <4 and moderate to severe if scores ≥4. Cox models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of associations between fatigue and mortality with adjustments for sociodemographic factors, time on dialysis, education, economic class, hemoglobin concentration, diabetes, heart failure, depression, and other psychiatric disorders.</p><p><strong>Results: </strong>The mean age was 51.5 ± 2.5 years, 58% were male, and 30% were diabetic. Self-reported moderate to severe fatigue was reported by 71% of patients. The mortality rate was 8.6 cases/100 person-years. Patients with moderate to severe fatigue had a more than threefold mortality rate (HR = 3.07, 95% CI: 1.19, 7.93) compared to patients with absent or mild fatigue, after extensive adjustments for covariates.</p><p><strong>Conclusion: </strong>The study provides evidence that self-reported fatigue can help identify MHD patients at higher risk of earlier death.</p>","PeriodicalId":18998,"journal":{"name":"Nephron","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2023-11-24DOI: 10.1159/000535192
Ji Yeon Song, Seung Hwan Oh, Younga Kim
Introduction: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) disease entity primarily attributed to genetic or acquired abnormalities in the alternative complement pathway. TMA can manifest in kidney transplant (KT) recipients owing to various factors, resulting in diverse clinical presentations. Given its adverse effects on allograft function and patient prognosis, genetic diagnostic approaches for aHUS are essential. Although rarely associated with diffuse alveolar hemorrhage, only a few mild cases have been reported to date. In this report, we present a case of the patient who experienced recurrent and life-threatening diffuse alveolar hemorrhage shortly after KT accompanied by graft failure.
Case presentation: An 18-year-old girl who underwent deceased donor KT developed recurrent diffuse alveolar hemorrhage with acute kidney injury, leading to graft failure. Microangiopathic hemolytic anemia, thrombocytopenia, and schistocytes in blood smears suggested the presence of TMA. The patient underwent therapeutic plasma exchange, and clinical condition improved during the procedure. Genetic testing confirmed a heterozygous c.1273C>T mutation in C3 gene, leading to the diagnosis of aHUS. However, after discontinuing the plasma exchange, the patient experienced seizures, recurrent pulmonary hemorrhage, and oliguria with recurring TMA features. The patient subsequently underwent eculizumab treatment, which resulted in complete remission, although hemodialysis was continued after graft nephrectomy.
Conclusion: In patients presenting with unexplained pulmonary hemorrhage and kidney injury following KT, genetic aHUS should be considered as a potential differential diagnosis for TMA.
{"title":"Life-Threatening Diffuse Alveolar Hemorrhage and Graft Failure in Atypical Hemolytic Uremic Syndrome with C3 Gene Mutation following Kidney Transplant.","authors":"Ji Yeon Song, Seung Hwan Oh, Younga Kim","doi":"10.1159/000535192","DOIUrl":"10.1159/000535192","url":null,"abstract":"<p><strong>Introduction: </strong>Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) disease entity primarily attributed to genetic or acquired abnormalities in the alternative complement pathway. TMA can manifest in kidney transplant (KT) recipients owing to various factors, resulting in diverse clinical presentations. Given its adverse effects on allograft function and patient prognosis, genetic diagnostic approaches for aHUS are essential. Although rarely associated with diffuse alveolar hemorrhage, only a few mild cases have been reported to date. In this report, we present a case of the patient who experienced recurrent and life-threatening diffuse alveolar hemorrhage shortly after KT accompanied by graft failure.</p><p><strong>Case presentation: </strong>An 18-year-old girl who underwent deceased donor KT developed recurrent diffuse alveolar hemorrhage with acute kidney injury, leading to graft failure. Microangiopathic hemolytic anemia, thrombocytopenia, and schistocytes in blood smears suggested the presence of TMA. The patient underwent therapeutic plasma exchange, and clinical condition improved during the procedure. Genetic testing confirmed a heterozygous c.1273C>T mutation in C3 gene, leading to the diagnosis of aHUS. However, after discontinuing the plasma exchange, the patient experienced seizures, recurrent pulmonary hemorrhage, and oliguria with recurring TMA features. The patient subsequently underwent eculizumab treatment, which resulted in complete remission, although hemodialysis was continued after graft nephrectomy.</p><p><strong>Conclusion: </strong>In patients presenting with unexplained pulmonary hemorrhage and kidney injury following KT, genetic aHUS should be considered as a potential differential diagnosis for TMA.</p>","PeriodicalId":18998,"journal":{"name":"Nephron","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11216361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138440965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Living kidney donors (LKD) may experience some untoward consequences following donation such as development of chronic kidney disease (CKD). In this study, we aimed to investigate the rate of development of CKD and factors affecting the development of CKD in LKDs during long-term follow-up from a center in Turkey.
Methods: This study was a retrospective analysis of LKDs followed between January 2000 and December 2017. Pre-transplant and post-transplant clinical data of the 338 LKDs were recorded and compared. Factors affecting the development of stage 3 and later stages of CKD were analyzed.
Results: Majority of the donors were females (64.2%), and the median age of all donors was 47 (39-54) years. Stage 3 CKD developed in 50 donors during the median follow-up of 71 months. Older age at the time of transplantation and a low pre-transplant estimated glomerular filtration rate (eGFR) were determined as the factors affecting the development of stage 3 CKD (p < 0.001, p < 0.001). The receiver operating characteristic analysis showed that the cut-off age for the development of stage 3 CKD was 50.5 years. Newly diagnosed hypertension was detected in 57 patients (16.8%) after the transplantation. While hypertension was seen at a rate of 42% in those with an eGFR <60 mL/min/1.73 m2, it was detected at 19.4% in the group with an eGFR >60 mL/min/1.73 m2 (p < 0.001).
Conclusion: These results reveal that being a LKD is associated with the development of CKD and hypertension. Age and eGFR values at the time of transplantation were the determinants for the development of CKD.
{"title":"Chronic Kidney Disease Risk in Living Kidney Transplant Donors: A Long-Term Follow-Up Study.","authors":"Guldehan Haberal, Tolga Yildirim, Seref Rahmi Yilmaz, Bulent Altun, Fazil Tuncay Aki, Yunus Erdem, Mustafa Arici","doi":"10.1159/000534397","DOIUrl":"10.1159/000534397","url":null,"abstract":"<p><strong>Background: </strong>Living kidney donors (LKD) may experience some untoward consequences following donation such as development of chronic kidney disease (CKD). In this study, we aimed to investigate the rate of development of CKD and factors affecting the development of CKD in LKDs during long-term follow-up from a center in Turkey.</p><p><strong>Methods: </strong>This study was a retrospective analysis of LKDs followed between January 2000 and December 2017. Pre-transplant and post-transplant clinical data of the 338 LKDs were recorded and compared. Factors affecting the development of stage 3 and later stages of CKD were analyzed.</p><p><strong>Results: </strong>Majority of the donors were females (64.2%), and the median age of all donors was 47 (39-54) years. Stage 3 CKD developed in 50 donors during the median follow-up of 71 months. Older age at the time of transplantation and a low pre-transplant estimated glomerular filtration rate (eGFR) were determined as the factors affecting the development of stage 3 CKD (p < 0.001, p < 0.001). The receiver operating characteristic analysis showed that the cut-off age for the development of stage 3 CKD was 50.5 years. Newly diagnosed hypertension was detected in 57 patients (16.8%) after the transplantation. While hypertension was seen at a rate of 42% in those with an eGFR <60 mL/min/1.73 m2, it was detected at 19.4% in the group with an eGFR >60 mL/min/1.73 m2 (p < 0.001).</p><p><strong>Conclusion: </strong>These results reveal that being a LKD is associated with the development of CKD and hypertension. Age and eGFR values at the time of transplantation were the determinants for the development of CKD.</p>","PeriodicalId":18998,"journal":{"name":"Nephron","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41157039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}