Pub Date : 2024-09-01Epub Date: 2024-06-24DOI: 10.1097/MNH.0000000000001007
Yi-Jing G Cheng, Chien-Chou Chen, Chih-Jen Cheng
Purpose of review: Postnatal renal tubule development is critical to adult kidney function. Several postnatal changes regulate the differentiation and proliferation of renal tubular cells. Here, we review the literature and our efforts on thick ascending limb (TAL) development in Bartter syndrome (BS).
Recent findings: Glomerular filtrate quickly increases after birth, imposing fluid shear stress and circumferential stretch on immature renal tubules. Recent studies showed that kidney organoids under flow (superfusion) have better development of tubular structures and the expression of cilia and solute transporters. These effects are likely mediated by mechanosensors, such as cilia and the piezo1 channel. Improved renal oxygenation and sodium pump-dependent active transport can stimulate mitochondrial respiration and biogenesis. The functional coupling between transport and mitochondria ensures ATP supply for energy-demanding reactions in tubular cells, including cell cycle progression and proliferation. We recently discovered that postnatal renal medulla maturation and TAL elongation are impaired in Clc-k2-deficient BS mice. Primary cultured Clc-k2-deficient TAL cells have G1-S transition and proliferation delay. These developmental defects could be part of the early pathogenesis of BS and worsen the phenotype.
Summary: Understanding how tubular flow and transepithelial ion fluxes regulate renal tubule development may improve the treatment of congenital renal tubulopathies.
综述的目的:出生后肾小管的发育对成年后的肾功能至关重要。出生后的一些变化调节着肾小管细胞的分化和增殖。在此,我们回顾了有关巴特综合征(BS)粗升肢(TAL)发育的文献和我们的工作:最近的发现:出生后肾小球滤过液迅速增加,对未成熟的肾小管造成液体剪切应力和周向拉伸。最近的研究表明,在流动(超灌注)条件下,肾脏器官组织的肾小管结构发育更好,纤毛和溶质转运体的表达也更好。这些影响可能是由纤毛和 piezo1 通道等机械传感器介导的。肾脏氧合和钠泵依赖性活性运输的改善可刺激线粒体呼吸和生物生成。运输和线粒体之间的功能耦合确保了肾小管细胞内能量需求反应的 ATP 供应,包括细胞周期的进展和增殖。我们最近发现,Clc-k2 缺失的 BS 小鼠出生后肾髓质成熟和 TAL 延长功能受损。原代培养的 Clc-k2 缺陷 TAL 细胞出现 G1-S 过渡和增殖延迟。小结:了解肾小管流动和跨上皮离子通量如何调控肾小管发育可能会改善先天性肾小管疾病的治疗。
{"title":"Postnatal renal tubule development: roles of tubular flow and flux.","authors":"Yi-Jing G Cheng, Chien-Chou Chen, Chih-Jen Cheng","doi":"10.1097/MNH.0000000000001007","DOIUrl":"10.1097/MNH.0000000000001007","url":null,"abstract":"<p><strong>Purpose of review: </strong>Postnatal renal tubule development is critical to adult kidney function. Several postnatal changes regulate the differentiation and proliferation of renal tubular cells. Here, we review the literature and our efforts on thick ascending limb (TAL) development in Bartter syndrome (BS).</p><p><strong>Recent findings: </strong>Glomerular filtrate quickly increases after birth, imposing fluid shear stress and circumferential stretch on immature renal tubules. Recent studies showed that kidney organoids under flow (superfusion) have better development of tubular structures and the expression of cilia and solute transporters. These effects are likely mediated by mechanosensors, such as cilia and the piezo1 channel. Improved renal oxygenation and sodium pump-dependent active transport can stimulate mitochondrial respiration and biogenesis. The functional coupling between transport and mitochondria ensures ATP supply for energy-demanding reactions in tubular cells, including cell cycle progression and proliferation. We recently discovered that postnatal renal medulla maturation and TAL elongation are impaired in Clc-k2-deficient BS mice. Primary cultured Clc-k2-deficient TAL cells have G1-S transition and proliferation delay. These developmental defects could be part of the early pathogenesis of BS and worsen the phenotype.</p><p><strong>Summary: </strong>Understanding how tubular flow and transepithelial ion fluxes regulate renal tubule development may improve the treatment of congenital renal tubulopathies.</p>","PeriodicalId":10960,"journal":{"name":"Current Opinion in Nephrology and Hypertension","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11290981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-06-19DOI: 10.1097/MNH.0000000000001008
Marcelle Tuttle, Mark J Sarnak, Sankar D Navaneethan
Purpose of review: Pulmonary hypertension is a common comorbidity in patients with chronic kidney disease (CKD), but therapeutic options are limited. We discuss the epidemiology of pulmonary hypertension in patients with CKD and review therapies for pulmonary hypertension with a focus on emerging treatments for pulmonary arterial hypertension (PAH).
Recent findings: The definition of pulmonary hypertension has been updated to a lower threshold of mean pulmonary artery pressures of more than 20 mmHg, potentially leading to more patients with CKD to qualify for the diagnosis of pulmonary hypertension. Endothelin receptor antagonists, a class of medications, which demonstrated efficacy in patients with PAH, have been shown to slow progression of CKD, but their efficacy in lowering pulmonary artery pressures and their effects on reducing cardiovascular mortality in this population remains unproven. Sotatercept, a novel activin signaling inhibitor, which was previously studied in dialysis patients has been shown to increase exercise capacity in patients with PAH. These studies may lead to new specific therapies for pulmonary hypertension in patients with CKD.
Summary: Pulmonary hypertension is common in patients with CKD. Although our understanding of factors leading to pulmonary hypertension in this population have evolved, evidence supporting disease-specific therapy in CKD is limited arguing for larger, long-term studies.
{"title":"Therapeutic approaches for pulmonary hypertension in patients with chronic kidney disease.","authors":"Marcelle Tuttle, Mark J Sarnak, Sankar D Navaneethan","doi":"10.1097/MNH.0000000000001008","DOIUrl":"10.1097/MNH.0000000000001008","url":null,"abstract":"<p><strong>Purpose of review: </strong>Pulmonary hypertension is a common comorbidity in patients with chronic kidney disease (CKD), but therapeutic options are limited. We discuss the epidemiology of pulmonary hypertension in patients with CKD and review therapies for pulmonary hypertension with a focus on emerging treatments for pulmonary arterial hypertension (PAH).</p><p><strong>Recent findings: </strong>The definition of pulmonary hypertension has been updated to a lower threshold of mean pulmonary artery pressures of more than 20 mmHg, potentially leading to more patients with CKD to qualify for the diagnosis of pulmonary hypertension. Endothelin receptor antagonists, a class of medications, which demonstrated efficacy in patients with PAH, have been shown to slow progression of CKD, but their efficacy in lowering pulmonary artery pressures and their effects on reducing cardiovascular mortality in this population remains unproven. Sotatercept, a novel activin signaling inhibitor, which was previously studied in dialysis patients has been shown to increase exercise capacity in patients with PAH. These studies may lead to new specific therapies for pulmonary hypertension in patients with CKD.</p><p><strong>Summary: </strong>Pulmonary hypertension is common in patients with CKD. Although our understanding of factors leading to pulmonary hypertension in this population have evolved, evidence supporting disease-specific therapy in CKD is limited arguing for larger, long-term studies.</p>","PeriodicalId":10960,"journal":{"name":"Current Opinion in Nephrology and Hypertension","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11290985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-05-10DOI: 10.1097/MNH.0000000000001002
Shweta Bansal
Purpose of review: As compared to controlled or uncontrolled hypertension, resistant hypertension in patients with chronic kidney disease (CKD) poses a significantly increased healthcare burden due to greater target end-organ damage including cardiovascular disease and CKD progression. Patients with CKD have two to three times higher risk of developing resistant hypertension. True resistant hypertension needs to be distinguished from apparent treatment resistant hypertension (aTRH); however, it is usually not possible in epidemiological studies. Moreover, impact of contemporary guidelines changes in the target blood pressure (BP) goal to less than 130/80 mmHg remains to be determined.
Recent findings: Up to half of patients with CKD meet aTRH criteria using 2017 ACC/AHA target BP less than 130/80 mmHg. Excess sodium retention in extracellular and tissue compartment remains the cornerstone cause of resistance to the treatment in CKD. Maximizing and optimizing the diuretic regimen in addition to dietary sodium restriction plays a critical role in these patients. Management requires a trustworthy provider-patient relationship facilitating identification and intervention for the barriers restricting the uptake of lifestyle modifications and medications. Recently, renal denervation has been approved and many other novel agents are on the horizon for treatment of true resistant hypertension associated with CKD.
Summary: This review discusses the latest in the pathophysiology, definition, identification and treatment strategies of resistant hypertension in individuals with CKD. Further investigations are required to identify the prevalence, future implication and treatment outcome data for true resistant hypertension associated with CKD.
{"title":"Revisiting resistant hypertension in kidney disease.","authors":"Shweta Bansal","doi":"10.1097/MNH.0000000000001002","DOIUrl":"10.1097/MNH.0000000000001002","url":null,"abstract":"<p><strong>Purpose of review: </strong>As compared to controlled or uncontrolled hypertension, resistant hypertension in patients with chronic kidney disease (CKD) poses a significantly increased healthcare burden due to greater target end-organ damage including cardiovascular disease and CKD progression. Patients with CKD have two to three times higher risk of developing resistant hypertension. True resistant hypertension needs to be distinguished from apparent treatment resistant hypertension (aTRH); however, it is usually not possible in epidemiological studies. Moreover, impact of contemporary guidelines changes in the target blood pressure (BP) goal to less than 130/80 mmHg remains to be determined.</p><p><strong>Recent findings: </strong>Up to half of patients with CKD meet aTRH criteria using 2017 ACC/AHA target BP less than 130/80 mmHg. Excess sodium retention in extracellular and tissue compartment remains the cornerstone cause of resistance to the treatment in CKD. Maximizing and optimizing the diuretic regimen in addition to dietary sodium restriction plays a critical role in these patients. Management requires a trustworthy provider-patient relationship facilitating identification and intervention for the barriers restricting the uptake of lifestyle modifications and medications. Recently, renal denervation has been approved and many other novel agents are on the horizon for treatment of true resistant hypertension associated with CKD.</p><p><strong>Summary: </strong>This review discusses the latest in the pathophysiology, definition, identification and treatment strategies of resistant hypertension in individuals with CKD. Further investigations are required to identify the prevalence, future implication and treatment outcome data for true resistant hypertension associated with CKD.</p>","PeriodicalId":10960,"journal":{"name":"Current Opinion in Nephrology and Hypertension","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11296285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140897501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-17DOI: 10.1097/MNH.0000000000000991
John Danziger
Purpose of review: While high levels of lead exposure, as occurs accidentally or occupationally, can cause toxicity across multiple organ systems, the hazard of commonly encountered levels of lead in the environment remains unresolved. Challenges to researching the health effects of lead include its complex interplay with renal function, rendering analyses at risk of unaccounted confounding, and the likely small effect size of environmental levels of exposure. While children are known to be disproportionately susceptible to lead toxicity, resulting in appropriately more stringent regulatory surveillance for those under 5 years old, emerging evidence suggests that those with chronic kidney disease (CKD) similarly are at a greater risk. This review summarizes the role of environmental lead toxicity as a potential cause and consequence of CKD.
Recent findings: Whether environmental lead exposure causes CKD remains debatable, with little recent research advancing the conflicting, mostly cross-sectional, analyses from years ago. However, an emerging body of evidence suggests that CKD increases the susceptibility to lead toxicity. Higher circulating lead levels and lower urinary excretion result in greater lead accumulation in CKD, with simultaneous greater risk of clinically meaningful disease. Recent studies suggest that levels of lead found commonly in the United States drinking water supply, and currently permissible by the Environmental Protection Agency, associate with hematologic toxicity in those with advanced CKD. Whether environmental lead contamination may have additional negative health impact among this at-risk population, including cardiovascular and neurocognitive disease, warrants further study.
Summary: The underlying pathophysiology of kidney disease synergizes the susceptibility to environmental lead toxicity for those with CKD. Low levels of exposure, as found commonly in the United States water supply, may have adverse health impact in CKD. Further research will be needed to determine if more stringent environmental regulations are warranted to protect the health of all.
{"title":"Synergistic susceptibility to environmental lead toxicity in chronic kidney disease.","authors":"John Danziger","doi":"10.1097/MNH.0000000000000991","DOIUrl":"10.1097/MNH.0000000000000991","url":null,"abstract":"<p><strong>Purpose of review: </strong>While high levels of lead exposure, as occurs accidentally or occupationally, can cause toxicity across multiple organ systems, the hazard of commonly encountered levels of lead in the environment remains unresolved. Challenges to researching the health effects of lead include its complex interplay with renal function, rendering analyses at risk of unaccounted confounding, and the likely small effect size of environmental levels of exposure. While children are known to be disproportionately susceptible to lead toxicity, resulting in appropriately more stringent regulatory surveillance for those under 5 years old, emerging evidence suggests that those with chronic kidney disease (CKD) similarly are at a greater risk. This review summarizes the role of environmental lead toxicity as a potential cause and consequence of CKD.</p><p><strong>Recent findings: </strong>Whether environmental lead exposure causes CKD remains debatable, with little recent research advancing the conflicting, mostly cross-sectional, analyses from years ago. However, an emerging body of evidence suggests that CKD increases the susceptibility to lead toxicity. Higher circulating lead levels and lower urinary excretion result in greater lead accumulation in CKD, with simultaneous greater risk of clinically meaningful disease. Recent studies suggest that levels of lead found commonly in the United States drinking water supply, and currently permissible by the Environmental Protection Agency, associate with hematologic toxicity in those with advanced CKD. Whether environmental lead contamination may have additional negative health impact among this at-risk population, including cardiovascular and neurocognitive disease, warrants further study.</p><p><strong>Summary: </strong>The underlying pathophysiology of kidney disease synergizes the susceptibility to environmental lead toxicity for those with CKD. Low levels of exposure, as found commonly in the United States water supply, may have adverse health impact in CKD. Further research will be needed to determine if more stringent environmental regulations are warranted to protect the health of all.</p>","PeriodicalId":10960,"journal":{"name":"Current Opinion in Nephrology and Hypertension","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-05-24DOI: 10.1097/MNH.0000000000001004
Raghunandan Konda, Arun Rajasekaran, Dana V Rizk
Purpose of review: This review focuses on latest developments in managing antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), a systemic autoimmune condition characterized by inflammation and necrosis of small blood vessels due to circulating autoantibodies that target neutrophilic granules.
Recent findings: Our understanding of AAV pathogenesis has evolved in the past decades highlighting the central pathogenic roles of autoantibodies and complement activation. In parallel, the appreciation for glucocorticoid toxicity has led the research on crucial steroid-sparing therapeutic alternatives. Complement inhibitors (like avacopan) that have emerged are associated with better preservation of kidney function in AAV patients with severe kidney impairment. The role of plasma-exchange (PLEX) was revisited in updated guidelines that recommended its potential use in the context of diffuse alveolar hemorrhage associated hypoxia and severe kidney involvement, particularly with a serum creatinine level above 3.4 mg/dl. The ANCA Kidney Risk Score risk prediction and Glucocorticoid Toxicity Index score aid in identifying high-risk patients and individualizing management plans.
Summary: Kidney involvement in AAV requires prompt diagnosis and initiation of immunosuppression to prevent irreversible nephron loss. Newer therapeutic targets are on the horizon and offer hope for personalized treatment strategies.
{"title":"Antineutrophil cytoplasmic antibody-associated vasculitis.","authors":"Raghunandan Konda, Arun Rajasekaran, Dana V Rizk","doi":"10.1097/MNH.0000000000001004","DOIUrl":"10.1097/MNH.0000000000001004","url":null,"abstract":"<p><strong>Purpose of review: </strong>This review focuses on latest developments in managing antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), a systemic autoimmune condition characterized by inflammation and necrosis of small blood vessels due to circulating autoantibodies that target neutrophilic granules.</p><p><strong>Recent findings: </strong>Our understanding of AAV pathogenesis has evolved in the past decades highlighting the central pathogenic roles of autoantibodies and complement activation. In parallel, the appreciation for glucocorticoid toxicity has led the research on crucial steroid-sparing therapeutic alternatives. Complement inhibitors (like avacopan) that have emerged are associated with better preservation of kidney function in AAV patients with severe kidney impairment. The role of plasma-exchange (PLEX) was revisited in updated guidelines that recommended its potential use in the context of diffuse alveolar hemorrhage associated hypoxia and severe kidney involvement, particularly with a serum creatinine level above 3.4 mg/dl. The ANCA Kidney Risk Score risk prediction and Glucocorticoid Toxicity Index score aid in identifying high-risk patients and individualizing management plans.</p><p><strong>Summary: </strong>Kidney involvement in AAV requires prompt diagnosis and initiation of immunosuppression to prevent irreversible nephron loss. Newer therapeutic targets are on the horizon and offer hope for personalized treatment strategies.</p>","PeriodicalId":10960,"journal":{"name":"Current Opinion in Nephrology and Hypertension","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141087302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-05-01DOI: 10.1097/MNH.0000000000000998
Henrik Dimke
Purpose of review: Activation of the calcium-sensing receptor (CASR) in the parathyroid gland suppresses the release of parathyroid hormone (PTH). Furthermore, activation of the renal CASR directly increases the urinary excretion of calcium, by inhibiting transepithelial calcium transport in the nephron. Gain-of-function mutations in the CASR gene lead to autosomal dominant hypocalcemia 1 (ADH1), with inappropriately low PTH levels and hypocalcemia, indicative of excessive activation of the parathyroid CASR. However, hypercalciuria is not always observed. The reason why the manifestation of hypercalciuria is not uniform among ADH1 patients is not well understood.
Recent findings: Direct activation of the CASR in the kidney has been cumbersome to study, and an indirect measure to effectively estimate the degree of CASR activation following chronic hypercalcemia or genetic gain-of-function CASR activation has been lacking. Studies have shown that expression of the pore-blocking claudin-14 is strongly stimulated by the CASR in a dose-dependent manner. This stimulatory effect is abolished after renal Casr ablation in hypercalcemic mice, suggesting that claudin-14 abundance may gauge renal CASR activation. Using this marker has led to unexpected discoveries regarding renal CASR activation.
Summary: These new studies have informed on renal CASR activation thresholds and the downstream CASR-regulated calcium transport mechanisms.
{"title":"New insights into renal calcium-sensing receptor activation.","authors":"Henrik Dimke","doi":"10.1097/MNH.0000000000000998","DOIUrl":"10.1097/MNH.0000000000000998","url":null,"abstract":"<p><strong>Purpose of review: </strong>Activation of the calcium-sensing receptor (CASR) in the parathyroid gland suppresses the release of parathyroid hormone (PTH). Furthermore, activation of the renal CASR directly increases the urinary excretion of calcium, by inhibiting transepithelial calcium transport in the nephron. Gain-of-function mutations in the CASR gene lead to autosomal dominant hypocalcemia 1 (ADH1), with inappropriately low PTH levels and hypocalcemia, indicative of excessive activation of the parathyroid CASR. However, hypercalciuria is not always observed. The reason why the manifestation of hypercalciuria is not uniform among ADH1 patients is not well understood.</p><p><strong>Recent findings: </strong>Direct activation of the CASR in the kidney has been cumbersome to study, and an indirect measure to effectively estimate the degree of CASR activation following chronic hypercalcemia or genetic gain-of-function CASR activation has been lacking. Studies have shown that expression of the pore-blocking claudin-14 is strongly stimulated by the CASR in a dose-dependent manner. This stimulatory effect is abolished after renal Casr ablation in hypercalcemic mice, suggesting that claudin-14 abundance may gauge renal CASR activation. Using this marker has led to unexpected discoveries regarding renal CASR activation.</p><p><strong>Summary: </strong>These new studies have informed on renal CASR activation thresholds and the downstream CASR-regulated calcium transport mechanisms.</p>","PeriodicalId":10960,"journal":{"name":"Current Opinion in Nephrology and Hypertension","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140862386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-02-28DOI: 10.1097/MNH.0000000000000977
Orly Tabachnikov, Karl Skorecki, Etty Kruzel-Davila
Purpose of review: More than a decade ago, apolipoprotein L1 ( APOL1 ) risk alleles designated G1 and G2, were discovered to be causally associated with markedly increased risk for progressive kidney disease in individuals of recent African ancestry. Gratifying progress has been made during the intervening years, extending to the development and clinical testing of genomically precise small molecule therapy accompanied by emergence of RNA medicine platforms and clinical testing within just over a decade.
Recent findings: Given the plethora of excellent prior review articles, we will focus on new findings regarding unresolved questions relating mechanism of cell injury with mode of inheritance, regulation and modulation of APOL1 activity, modifiers and triggers for APOL1 kidney risk penetrance, the pleiotropic spectrum of APOL1 related disease beyond the kidney - all within the context of relevance to therapeutic advances.
Summary: Notwithstanding remaining controversies and uncertainties, promising genomically precise therapies targeted at APOL1 mRNA using antisense oligonucleotides (ASO), inhibitors of APOL1 expression, and small molecules that specifically bind and inhibit APOL1 cation flux are emerging, many already at the clinical trial stage. These therapies hold great promise for mitigating APOL1 kidney injury and possibly other systemic phenotypes as well. A challenge will be to develop guidelines for appropriate use in susceptible individuals who will derive the greatest benefit.
{"title":"APOL1 nephropathy - a population genetics success story.","authors":"Orly Tabachnikov, Karl Skorecki, Etty Kruzel-Davila","doi":"10.1097/MNH.0000000000000977","DOIUrl":"10.1097/MNH.0000000000000977","url":null,"abstract":"<p><strong>Purpose of review: </strong>More than a decade ago, apolipoprotein L1 ( APOL1 ) risk alleles designated G1 and G2, were discovered to be causally associated with markedly increased risk for progressive kidney disease in individuals of recent African ancestry. Gratifying progress has been made during the intervening years, extending to the development and clinical testing of genomically precise small molecule therapy accompanied by emergence of RNA medicine platforms and clinical testing within just over a decade.</p><p><strong>Recent findings: </strong>Given the plethora of excellent prior review articles, we will focus on new findings regarding unresolved questions relating mechanism of cell injury with mode of inheritance, regulation and modulation of APOL1 activity, modifiers and triggers for APOL1 kidney risk penetrance, the pleiotropic spectrum of APOL1 related disease beyond the kidney - all within the context of relevance to therapeutic advances.</p><p><strong>Summary: </strong>Notwithstanding remaining controversies and uncertainties, promising genomically precise therapies targeted at APOL1 mRNA using antisense oligonucleotides (ASO), inhibitors of APOL1 expression, and small molecules that specifically bind and inhibit APOL1 cation flux are emerging, many already at the clinical trial stage. These therapies hold great promise for mitigating APOL1 kidney injury and possibly other systemic phenotypes as well. A challenge will be to develop guidelines for appropriate use in susceptible individuals who will derive the greatest benefit.</p>","PeriodicalId":10960,"journal":{"name":"Current Opinion in Nephrology and Hypertension","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-06DOI: 10.1097/mnh.0000000000001000
Mythri Shankar, Sehrish Ali, Silvi Shah
We discuss the sex-based differences in the pharmacokinetics and pharmacodynamics of kidney protective medications and their implications on women's health.
我们讨论了保护肾脏药物的药代动力学和药效学方面的性别差异及其对女性健康的影响。
{"title":"Women's health and kidney protective medications.","authors":"Mythri Shankar, Sehrish Ali, Silvi Shah","doi":"10.1097/mnh.0000000000001000","DOIUrl":"https://doi.org/10.1097/mnh.0000000000001000","url":null,"abstract":"We discuss the sex-based differences in the pharmacokinetics and pharmacodynamics of kidney protective medications and their implications on women's health.","PeriodicalId":10960,"journal":{"name":"Current Opinion in Nephrology and Hypertension","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140837115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01Epub Date: 2024-02-23DOI: 10.1097/MNH.0000000000000980
Jennifer S Lees, June Fabian, Michael G Shlipak
Purpose of review: In this report, we summarize why the availability of cystatin C is important across a variety of clinical scenarios, the recent literature on when, why and in whom cystatin C testing should be considered, and how nephrologists can take practical steps to incorporate cystatin C testing into their practice.
Recent findings: Large intra-individual discrepancies between estimated glomerular filtration rate by creatinine (eGFRcr) and estimated glomerular filtration rate by creatinine eGFRcys (known as eGFRdiff) are observed in at least 1 in 4 people. These differences are seen more commonly among more vulnerable individuals: older adults, females, non-White individuals and those living with multiple medical conditions. A large eGFRdiff, where eGFRcys is lower than eGFRcr, is associated with a plethora of adverse outcomes, including medication-associated adverse events, acute kidney injury, cardiovascular disease, kidney failure and all-cause mortality. Among studies that have measured GFR, eGFRcr-cys usually provides the most accurate estimation of kidney function compared to mGFR, including among participants with large discrepancies between eGFRcr and eGFRcys.
Summary: Cystatin C improves sensitivity and specificity of chronic kidney disease diagnosis, improves detection of harmful acute and chronic changes in kidney function, improves precision of treatment eligibility and safety, and may reduce healthcare inequalities. Better education, curiosity, and motivation among nephrologists could substantially improve the availability and utilization of cystatin C.
综述目的:在本报告中,我们总结了为什么胱抑素 C 的可用性在各种临床情况下都很重要,最近关于何时、为何以及对哪些人应考虑进行胱抑素 C 检测的文献,以及肾病学家如何采取实际措施将胱抑素 C 检测纳入其临床实践:每 4 个人中至少有 1 人存在肌酐估算肾小球滤过率(eGFRcr)与肌酐估算肾小球滤过率 eGFRcys(即 eGFRdiff)之间的巨大个体差异。这些差异更常见于较脆弱的人群:老年人、女性、非白人和患有多种疾病的人。较大的 eGFRdiff,即 eGFRcys 低于 eGFRcr,与许多不良后果有关,包括药物相关不良事件、急性肾损伤、心血管疾病、肾衰竭和全因死亡率。总结:胱抑素 C 可提高慢性肾脏病诊断的敏感性和特异性,改善对肾功能有害的急性和慢性变化的检测,提高治疗资格和安全性的精确性,并可减少医疗不平等。加强对肾科医生的教育、提高他们的好奇心和积极性,可以大大提高胱抑素 C 的可用性和利用率。
{"title":"Cystatin C should be routinely available for estimating kidney function.","authors":"Jennifer S Lees, June Fabian, Michael G Shlipak","doi":"10.1097/MNH.0000000000000980","DOIUrl":"10.1097/MNH.0000000000000980","url":null,"abstract":"<p><strong>Purpose of review: </strong>In this report, we summarize why the availability of cystatin C is important across a variety of clinical scenarios, the recent literature on when, why and in whom cystatin C testing should be considered, and how nephrologists can take practical steps to incorporate cystatin C testing into their practice.</p><p><strong>Recent findings: </strong>Large intra-individual discrepancies between estimated glomerular filtration rate by creatinine (eGFRcr) and estimated glomerular filtration rate by creatinine eGFRcys (known as eGFRdiff) are observed in at least 1 in 4 people. These differences are seen more commonly among more vulnerable individuals: older adults, females, non-White individuals and those living with multiple medical conditions. A large eGFRdiff, where eGFRcys is lower than eGFRcr, is associated with a plethora of adverse outcomes, including medication-associated adverse events, acute kidney injury, cardiovascular disease, kidney failure and all-cause mortality. Among studies that have measured GFR, eGFRcr-cys usually provides the most accurate estimation of kidney function compared to mGFR, including among participants with large discrepancies between eGFRcr and eGFRcys.</p><p><strong>Summary: </strong>Cystatin C improves sensitivity and specificity of chronic kidney disease diagnosis, improves detection of harmful acute and chronic changes in kidney function, improves precision of treatment eligibility and safety, and may reduce healthcare inequalities. Better education, curiosity, and motivation among nephrologists could substantially improve the availability and utilization of cystatin C.</p>","PeriodicalId":10960,"journal":{"name":"Current Opinion in Nephrology and Hypertension","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01Epub Date: 2024-03-13DOI: 10.1097/MNH.0000000000000983
Pongpratch Puapatanakul, Jeffrey H Miner
Purpose of review: With the latest classification, variants in three collagen IV genes, COL4A3 , COL4A4 , and COL4A5 , represent the most prevalent genetic kidney disease in humans, exhibiting diverse, complex, and inconsistent clinical manifestations. This review breaks down the disease spectrum and genotype-phenotype correlations of kidney diseases linked to genetic variants in these genes and distinguishes "classic" Alport syndrome (AS) from the less severe nonsyndromic genetically related nephropathies that we suggest be called "Alport kidney diseases".
Recent findings: Several research studies have focused on the genotype-phenotype correlation under the latest classification scheme of AS. The historic diagnoses of "benign familial hematuria" and "thin basement membrane nephropathy" linked to heterozygous variants in COL4A3 or COL4A4 are suggested to be obsolete, but instead classified as autosomal AS by recent expert consensus due to a significant risk of disease progression.
Summary: The concept of Alport kidney disease extends beyond classic AS. Patients carrying pathogenic variants in any one of the COL4A3/A4/A5 genes can have variable phenotypes ranging from completely normal/clinically unrecognizable, hematuria without or with proteinuria, or progression to chronic kidney disease and kidney failure, depending on sex, genotype, and interplays of other genetic as well as environmental factors.
{"title":"Alport syndrome and Alport kidney diseases - elucidating the disease spectrum.","authors":"Pongpratch Puapatanakul, Jeffrey H Miner","doi":"10.1097/MNH.0000000000000983","DOIUrl":"10.1097/MNH.0000000000000983","url":null,"abstract":"<p><strong>Purpose of review: </strong>With the latest classification, variants in three collagen IV genes, COL4A3 , COL4A4 , and COL4A5 , represent the most prevalent genetic kidney disease in humans, exhibiting diverse, complex, and inconsistent clinical manifestations. This review breaks down the disease spectrum and genotype-phenotype correlations of kidney diseases linked to genetic variants in these genes and distinguishes \"classic\" Alport syndrome (AS) from the less severe nonsyndromic genetically related nephropathies that we suggest be called \"Alport kidney diseases\".</p><p><strong>Recent findings: </strong>Several research studies have focused on the genotype-phenotype correlation under the latest classification scheme of AS. The historic diagnoses of \"benign familial hematuria\" and \"thin basement membrane nephropathy\" linked to heterozygous variants in COL4A3 or COL4A4 are suggested to be obsolete, but instead classified as autosomal AS by recent expert consensus due to a significant risk of disease progression.</p><p><strong>Summary: </strong>The concept of Alport kidney disease extends beyond classic AS. Patients carrying pathogenic variants in any one of the COL4A3/A4/A5 genes can have variable phenotypes ranging from completely normal/clinically unrecognizable, hematuria without or with proteinuria, or progression to chronic kidney disease and kidney failure, depending on sex, genotype, and interplays of other genetic as well as environmental factors.</p>","PeriodicalId":10960,"journal":{"name":"Current Opinion in Nephrology and Hypertension","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10990029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}