Sodium/Glucose Cotransporter 2 Inhibitors and Magnesium Homeostasis: A Review.

Magnesium (Mg2+), also known as "the forgotten ion," is the second most abundant intracellular cation and is essential in a broad range of intracellular physiological and biochemical reactions. Its deficiency, hypomagnesemia (Mg2+<1.8mg/dL), is a prevalent condition and routinely poses challenges in its management in clinical practice. Sodium/glucose cotransporter 2 (SGLT2) inhibitors have emerged as a new class of drugs with treating hypomagnesemia as their unique extraglycemic benefit. The beneficial effect of SGLT2 inhibitors on magnesium balance in patients with diabetes with or without hypomagnesemia has been noted as a class effect in recent meta-analysis data from randomized clinical trials. Some reports have demonstrated their role in treating refractory hypomagnesemia in patients with or without diabetes. Moreover, studies on animal models have attempted to illustrate the effect of SGLT2 inhibitors on Mg2+homeostasis. In this review, we discuss the current evidence and possible pathophysiological mechanisms, and we provide directions for further research. We conclude by suggesting the effect of SGLT2 inhibitors on Mg2+homeostasis is a class effect, with certain patients gaining significant benefits. Further studies are needed to examine whether SGLT2 inhibitors can become a desperately needed novel class of medicines in treating hypomagnesemia.

American Board of Internal Medicine Nephrology Procedure Requirements for Initial Certification: Time for a Change and Pursuing Consensus in the Nephrology Community.

In 1988, the American Board of Internal Medicine (ABIM) defined essential procedural skills in nephrology, and candidates for ABIM certification were required to present evidence of possessing the skills necessary for placement of temporary dialysis vascular access, hemodialysis, peritoneal dialysis, and percutaneous renal biopsy. In 1996, continuous renal replacement therapy was added to the list of nephrology requirements. These procedure requirements have not been modified since 1996 while the practice of nephrology has changed dramatically. In March 2021, the ABIM Nephrology Board embarked on a policy journey to revise the procedure requirements for nephrology certification. With the guidance of nephrology diplomates, training program directors, professional and patient organizations, and other stakeholders, the ABIM Nephrology Board revised the procedure requirements to reflect current practice and national priorities. The approved changes include the Opportunity to Train standard for placement of temporary dialysis catheters, percutaneous kidney biopsies, and home hemodialysis which better reflects the current state of training in most training programs, and the new requirements for home dialysis therapies training will align with the national priority to address the underuse of home dialysis therapies. This perspective details the ABIM process for considering changes to the certification procedure requirements and how ABIM collaborated with the larger nephrology community in considering revisions and additions to these requirements.

Emerging Viral Infections and the Potential Impact on Hypertension, Cardiovascular Disease, and Kidney Disease.

Viruses are ubiquitous in the environment and continue to have a profound impact on human health and disease. The COVID-19 pandemic has highlighted this with impressive morbidity and mortality affecting the world's population. Importantly, the link between viruses and hypertension, cardiovascular disease, and kidney disease has resulted in a renewed focus and attention on this potential relationship. The virus responsible for COVID-19, SARS-CoV-2, has a direct link to one of the major enzymatic regulatory systems connected to blood pressure control and hypertension pathogenesis, the renin-angiotensin system. This is because the entry point for SARS-CoV-2 is the ACE2 (angiotensin-converting enzyme 2) protein. ACE2 is one of the main enzymes responsible for dampening the primary effector peptide Ang II (angiotensin II), metabolizing it to Ang-(1-7). A myriad of clinical questions has since emerged and are covered in this review. Several other viruses have been linked to hypertension, cardiovascular disease, and kidney health. Importantly, patients with high-risk apolipoprotein L1 (APOL1) alleles are at risk for developing the kidney lesion of collapsing glomerulopathy after viral infection. This review will highlight several emerging viruses and their potential unique tropisms for the kidney and cardiovascular system. We focus on SARS-CoV-2 as this body of literature in regards to cardiovascular disease has advanced significantly since the COVID-19 pandemic.

Effect of Low-Dose Methotrexate on eGFR and Kidney Adverse Events: A Randomized Clinical Trial.

BACKGROUND: Low-dose methotrexate (LD-MTX) is contraindicated in advanced CKD, but kidney safety in normal kidney function or mild-to-moderate CKD is less clear. METHODS: We performed a secondary analysis for eGFR and kidney AEs using the randomized double-blind, placebo-controlled Cardiovascular Inflammation Reduction Trial. Adults with cardiovascular disease and diabetes and/or metabolic syndrome were randomly allocated to oral LD-MTX (target dose 15-20 mg/week) or placebo. All participants took folic acid 1 mg 6 days/week. Exclusion criteria included systemic rheumatic disease and creatinine clearance <40 ml/min. The least-squares mean Δ eGFR from baseline was calculated at each study visit; the difference in eGFR between LD-MTX and placebo was compared. We used Cox proportional hazard models to compare rates of kidney AEs for LD-MTX versus placebo. RESULTS: A total of 2391 participants were randomized to LD-MTX and 2395 to placebo. At baseline, the mean age was 66 years, 19% were female, and mean eGFR was 80.0 ml/min per 1.73 m 2 (54% had Stage 2 CKD and 18% had Stage 3 CKD). Median follow-up was 23 months. The LD-MTX group had less decline in eGFR than placebo (difference in least-squares mean ΔeGFR from baseline to on-treatment visits: 0.93 ml/min per 1.73 m 2 , 95% confidence interval [95% CI], 0.45 to 1.40, P <0.001). There were 138 (incidence rate [IR], 2.97 per 100 person-years) kidney AEs in the LD-MTX group and 184 (IR, 3.99 per 100 person-years) among placebo (hazard ratio [HR] 0.73, 95% confidence interval [95% CI], 0.59 to 0.91) during safety laboratory monitoring. CONCLUSIONS: These results demonstrate the kidney safety of LD-MTX among patients with normal kidney function or mild-to-moderate CKD at baseline.

Vascular control of kidney epithelial transporters.

A major pathway in hypertension pathogenesis involves direct activation of ANG II type 1 (AT1) receptors in the kidney, stimulating Na+ reabsorption. AT1 receptors in tubular epithelia control expression and stimulation of Na+ transporters and channels. Recently, we found reduced blood pressure and enhanced natriuresis in mice with cell-specific deletion of AT1 receptors in smooth muscle (SMKO mice). Although impaired vasoconstriction and preserved renal blood flow might contribute to exaggerated urinary Na+ excretion in SMKO mice, we considered whether alterations in Na+ transporter expression might also play a role; therefore, we carried out proteomic analysis of key Na+ transporters and associated proteins. Here, we show that levels of Na+-K+-2Cl- cotransporter isoform 2 (NKCC2) and Na+/H+ exchanger isoform 3 (NHE3) are reduced at baseline in SMKO mice, accompanied by attenuated natriuretic and diuretic responses to furosemide. During ANG II hypertension, we found widespread remodeling of transporter expression in wild-type mice with significant increases in the levels of total NaCl cotransporter, phosphorylated NaCl cotransporter (Ser71), and phosphorylated NKCC2, along with the cleaved, activated forms of the α- and γ-epithelial Na+ channel. However, the increases in α- and γ-epithelial Na+ channel with ANG II were substantially attenuated in SMKO mice. This was accompanied by a reduced natriuretic response to amiloride. Thus, enhanced urinary Na+ excretion observed after cell-specific deletion of AT1 receptors from smooth muscle cells is associated with altered Na+ transporter abundance across epithelia in multiple nephron segments. These findings suggest a system of vascular-epithelial in the kidney, modulating the expression of Na+ transporters and contributing to the regulation of pressure natriuresis.NEW & NOTEWORTHY The use of drugs to block the renin-angiotensin system to reduce blood pressure is common. However, the precise mechanism for how these medications control blood pressure is incompletely understood. Here, we show that mice lacking angiotensin receptors specifically in smooth muscle cells lead to alternation in tubular transporter amount and function. Thus, demonstrating the importance of vascular-tubular cross talk in the control of blood pressure.

Pannexin 1 channels control the hemodynamic response to hypoxia by regulating O2-sensitive extracellular ATP in blood.

Pannexin 1 (Panx1) channels export ATP and may contribute to increased concentration of the vasodilator ATP in plasma during hypoxia in vivo. We hypothesized that Panx1 channels and associated ATP export contribute to hypoxic vasodilation, a mechanism that facilitates the matching of oxygen delivery to metabolic demand of tissue. Male and female mice devoid of Panx1 (Panx1-/-) and wild-type controls (WT) were anesthetized, mechanically ventilated, and instrumented with a carotid artery catheter or femoral artery flow transducer for hemodynamic and plasma ATP monitoring during inhalation of 21% (normoxia) or 10% oxygen (hypoxia). ATP export from WT vs. Panx1-/-erythrocytes (RBC) was determined ex vivo via tonometer experimentation across progressive deoxygenation. Mean arterial pressure (MAP) was similar in Panx1-/- (n = 6) and WT (n = 6) mice in normoxia, but the decrease in MAP in hypoxia seen in WT was attenuated in Panx1-/- mice (-16 ± 9% vs. -2 ± 8%; P < 0.05). Hindlimb blood flow (HBF) was significantly lower in Panx1-/- (n = 6) vs. WT (n = 6) basally, and increased in WT but not Panx1-/- mice during hypoxia (8 ± 6% vs. -10 ± 13%; P < 0.05). Estimation of hindlimb vascular conductance using data from the MAP and HBF experiments showed an average response of 28% for WT vs. -9% for Panx1-/- mice. Mean venous plasma ATP during hypoxia was 57% lower in Panx1-/- (n = 6) vs. WT mice (n = 6; P < 0.05). Mean hypoxia-induced ATP export from RBCs from Panx1-/- mice (n = 8) was 82% lower than that from WT (n = 8; P < 0.05). Panx1 channels participate in hemodynamic responses consistent with hypoxic vasodilation by regulating hypoxia-sensitive extracellular ATP levels in blood.NEW & NOTEWORTHY Export of vasodilator ATP from red blood cells requires pannexin 1. Blood plasma ATP elevations in response to hypoxia in mice require pannexin 1. Hemodynamic responses to hypoxia are accompanied by increased plasma ATP in mice in vivo and require pannexin 1.

A20 in Myeloid Cells Protects Against Hypertension by Inhibiting Dendritic Cell-Mediated T-Cell Activation.

RATIONALE: The ubiquitin-editing protein A20 in dendritic cells (DCs) suppresses NF-κB (nuclear factor-κB) signaling and constrains DC-mediated T-cell stimulation, but the role of A20 in modulating the hypertensive response requires elucidation. OBJECTIVE: Here, we tested the hypothesis that A20 in CD11c-expressing myeloid cells mitigates Ang II (angiotensin II)-induced hypertension by limiting renal T-cell activation. METHODS AND RESULTS: Mice with heterozygous deletion of A20 in CD11c-expressing myeloid cells (DC ACT[Cd11c-Cre+A20flox/wt]) have spontaneous DC activation but have normal baseline blood pressures. In response to low-dose chronic Ang II infusion, DC ACT mice compared with WT (wild type) controls had an exaggerated hypertensive response and augmented proportions of CD62LloCD44hi effector memory T lymphocytes in the kidney lymph node. After 10 days of Ang II, DC ACT kidneys had increased numbers of memory effector CD8+, but not CD4+ T cells, compared with WTs. Moreover, the expressions of TNF-α (tumor necrosis factor-α) and IFN-γ (interferon-γ) were upregulated in the DC ACT renal CD8+ T cells but not CD4+ T cells. Saline challenge testing revealed enhanced renal fluid retention in the DC ACT mice. DC ACT kidneys showed augmented protein expression of γ-epithelial sodium channel and NHE3 (sodium-hydrogen antiporter 3). DC ACT mice also had greater reductions in renal blood flow following acute injections with Ang II and enhanced oxidant stress in the vasculature as evidenced by higher circulating levels of malondialdehyde compared with WT controls. To directly test whether enhanced T-cell activation in the DC ACT cohort was responsible for their exaggerated hypertensive response, we chronically infused Ang II into lymphocyte-deficient DC ACT Rag1 (recombination activating protein 1)-deficient (Rag1-/-) mice and WT (Cd11c-Cre-A20flox/wt) Rag1-/- controls. The difference in blood pressure elevation accruing from DC activation was abrogated on the Rag1-/- strain. CONCLUSIONS: Following stimulation of the renin-angiotensin system, A20 suppresses DC activation and thereby mitigates T-cell-dependent blood pressure elevation.

Back off baclofen when the kidneys don't work.

Medication adverse events are common and often preventable. Patients with diminished kidney function are particularly susceptible to adverse events, especially if the medication's primary means of elimination is through the kidneys. Neurotoxicity from baclofen (80% excreted by the kidneys) is increasingly being recognized in patients with diminished kidney function. Chauvin et al. performed a large population-based retrospective cohort study in patients with end-stage kidney disease (ESKD) and showed a high rate of encephalopathy with hospitalizations shortly after baclofen exposure. This commentary discusses the high rate of altered mental status after baclofen exposure in patients with ESKD, potential reasons for the continued reports of this adverse event, and strategies to educate the health care community.

Therapeutic options for chronic kidney disease-associated pulmonary hypertension.

PURPOSE OF REVIEW: Pulmonary hypertension is a common and devastating complication of chronic kidney disease (CKD). Traditionally considered a consequence of volume overload, recent findings now expand this paradigm. These novel mechanisms herald new treatment options. This review summarizes the current evidence to provide a theoretical model of the contributing factors for CKD-associated pulmonary hypertension. Along this framework, we highlight current and emerging therapeutic strategies for each putative factor. RECENT FINDINGS: A series of retrospective studies of right heart catheterization data provide insights into the potential hemodynamic profile of CKD-associated pulmonary hypertension. These studies suggest that elevated pulmonary vascular resistance may commonly contribute to pulmonary hypertension. In addition, preclinical models implicate an increasing array of CKD-associated factors which influence pulmonary vascular biology. Many of these factors also adversely affect kidney function and CKD progression. Clinical trial and other prospective data for treatments of CKD-associated pulmonary hypertension remain limited. SUMMARY: Volume overload and left-ventricular dysfunction are the predominant focus of CKD-associated pulmonary hypertension treatment for most patients. However, new findings suggest that treatments targeting pulmonary vascular vasoconstriction and remodeling may be promising treatment options for select patients. Clinical trials are needed for all therapeutic strategies for CKD-associated pulmonary hypertension.

Pulmonary Hypertension Subtypes and Mortality in CKD.

RATIONALE & OBJECTIVE: Pulmonary hypertension (PH) contributes to cardiovascular disease and mortality in patients with chronic kidney disease (CKD), but the pathophysiology is mostly unknown. This study sought to estimate the prevalence and consequences of PH subtypes in the setting of CKD. STUDY DESIGN: Observational retrospective cohort study. SETTING & PARTICIPANTS: We examined 12,618 patients with a right heart catheterization in the Duke Databank for Cardiovascular Disease from January 1, 2000, to December 31, 2014. EXPOSURES: Baseline kidney function stratified by CKD glomerular filtration rate category and PH subtype. OUTCOMES: All-cause mortality. ANALYTICAL APPROACH: Multivariable Cox proportional hazards analysis. RESULTS: In this cohort, 73.4% of patients with CKD had PH, compared with 56.9% of patients without CKD. Isolated postcapillary PH (39.0%) and combined pre- and postcapillary PH (38.3%) were the most common PH subtypes in CKD. Conversely, precapillary PH was the most common subtype in the non-CKD cohort (35.9%). The relationships between mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure with mortality were similar in both the CKD and non-CKD cohorts. Compared with those without PH, precapillary PH conferred the highest mortality risk among patients without CKD (HR, 2.27; 95% CI, 2.00-2.57). By contrast, in those with CKD, combined pre- and postcapillary PH was associated with the highest risk for mortality in CKD in adjusted analyses (compared with no PH, HRs of 1.89 [95% CI, 1.57-2.28], 1.87 [95% CI, 1.52-2.31], 2.13 [95% CI, 1.52-2.97], and 1.63 [95% CI, 1.12-2.36] for glomerular filtration rate categories G3a, G3b, G4, and G5/G5D). LIMITATIONS: The cohort referred for right heart catheterization may not be generalizable to the general population. Serum creatinine data in the 6 months preceding catheterization may not reflect true baseline CKD. Observational design precludes assumptions of causality. CONCLUSIONS: In patients with CKD referred for right heart catheterization, PH is common and associated with poor survival. Combined pre- and postcapillary PH was common and portended the worst survival for patients with CKD.

Tackling acid-base disorders, one Twitter poll at a time.

Understanding and interpretation of acid-base disorders is an important clinical skill that is applicable to the majority of physicians. Although this topic is taught early in medical school, acid-base disturbances have been described as challenging by postgraduate trainees. We describe the use of Twitter, an online microblogging platform, to augment education in acid-base disturbances by using polls in which the user is shown laboratory values and then asked to select the most likely etiology of the disorder. The answer and a brief explanation are then shared in a subsequent tweet. Both polling questions and answers are shared from the account for the online, mobile-optimized, nephrology teaching tool NephSIM (https://www.nephsim.com/). An anonymous survey was administered to assess attitudes toward these polls. Using Twitter as an approach to enhance teaching of acid-base disturbances was both feasible and an engaging way to teach a challenging topic for trainees and physicians. Moreover, the coronavirus disease 2019 (COVID-19) pandemic has demonstrated the importance of incorporating virtual learning opportunities in all levels of medical education.

Renin-angiotensin system inhibition in advanced chronic kidney disease: how low can the kidney function go?

PURPOSE OF REVIEW: To present the available data on the risks and benefits for ACEi/ARB usage in patients with advanced CKD. RECENT FINDINGS: It has been well established that ACEi/ARB use is beneficial in patients with mild-to-moderate CKD, especially in patients with proteinuria. The majority of available data includes patients with diabetes mellitus. However, data in individuals with advanced CKD are limited. Additionally, data available for this subset of patients is conflicting and the definition of advanced CKD varies across clinical trials. SUMMARY: On the basis of our literature review, evidence suggests continuing ACEi/ARB therapy in patients with advanced CKD (eGFR less than 15 ml/min/1.73 m) unless hyperkalemia ensues unresponsive to therapy, hypotension develops or have unusually rapid worsening of eGFR (not usual progressive decline). These patients should be monitored closely. There is not enough data to support starting ACEi/ARBs de novo in patients with advanced CKD (eGFR less than 15 ml/min/1.73 m). If RAS blockade is started de novo in this subgroup, we recommend close monitoring.

Vascular type 1 angiotensin receptors control blood pressure by augmenting peripheral vascular resistance in female mice.

Angiotensin II (ANG II) is a major mediator of hypertension pathogenesis. In addition, there are well-documented differences in expression of the renin-angiotensin system (RAS) components and ANG II responses between males and females, which may explain sex differences in blood pressure (BP) and hypertension epidemiology. We previously showed that type 1A angiotensin (AT1A) receptors in vascular smooth muscle cells (VSMCs) play a critical role in BP regulation and hypertension pathogenesis, but these studies were carried out in male mice. Therefore, the major goal of the current studies was to examine the impact of VSMC AT1A receptors on BP and hypertension pathogenesis in female mice. We found that elimination of VSMC AT1A receptors in female mice reduced (≈8 mmHg) baseline BP without altering sodium sensitivity. The severity of ANG II-induced hypertension was diminished (≈33% reduction in BP), particularly during the last 2 wk of chronic ANG II infusion, compared with controls, but natriuresis was not altered during the first 5 days of ANG II infusion. Urinary norepinephrine levels were enhanced in female SMKO compared with control mice. There was a virtually complete elimination of ANG II-induced kidney hemodynamic responses with attenuation of acute vasoconstrictor responses in the systemic vasculature. These findings demonstrate that direct vascular actions of AT1A receptors play a prominent role in BP control and hypertension pathogenesis in female mice.

Baclofen Toxicity in Kidney Disease.

Baclofen, a commonly prescribed muscle relaxant, is primarily excreted via the kidneys; toxicity is a potentially serious adverse outcome in patients with decreased kidney function. We describe a patient with end-stage kidney disease receiving hemodialysis who developed neurotoxicity and hemodynamic instability after receiving baclofen for muscle spasms. In this case, prompt recognition of baclofen toxicity and urgent hemodialysis were effective in reversing this toxicity. This case is used to examine the pharmacokinetics and pathophysiology of baclofen toxicity and discuss appropriate diagnosis and management of baclofen toxicity. We recommend reducing the baclofen dose in patients who have moderately reduced kidney function (estimated glomerular filtration rate, 30-60mL/min/1.73m2) and avoiding use in patients with severely reduced kidney function (estimated glomerular filtration rate < 30mL/min/1.73m2) or on renal replacement therapy.

Podocyte-specific knockout of cyclooxygenase 2 exacerbates diabetic kidney disease.

Enhanced expression of cyclooxygenase 2 (COX2) in podocytes contributes to glomerular injury in diabetic kidney disease, but some basal level of podocyte COX2 expression might be required to promote podocyte attachment and/or survival. To investigate the role of podocyte COX2 expression in diabetic kidney disease, we deleted COX2 specifically in podocytes in a mouse model of Type 1 diabetes mellitus (Akita mice). Podocyte-specific knockout (KO) of COX2 did not affect renal morphology or albuminuria in nondiabetic mice. Albuminuria was significantly increased in wild-type (WT) and KO Akita mice compared with nondiabetic controls, and the increase in albuminuria was significantly greater in KO Akita mice compared with WT Akita mice at both 16 and 20 wk of age. At the 20-wk time point, mesangial expansion was also increased in WT and KO Akita mice compared with nondiabetic animals, and these histologic abnormalities were not improved by KO of COX2. Tubular injury was seen only in diabetic mice, but there were no significant differences between groups. Thus, KO of COX2 enhanced albuminuria and did not improve the histopathologic features of diabetic kidney disease. These data suggest that 1) KO of COX2 in podocytes does not ameliorate diabetic kidney disease in Akita mice, and 2) some basal level of podocyte COX2 expression in podocytes is necessary to attenuate the adverse effects of diabetes on glomerular filtration barrier function.

The Evolution of the Journal Club: From Osler to Twitter.

Journal clubs have typically been held within the walls of academic institutions and in medicine have served the dual purpose of fostering critical appraisal of literature and disseminating new findings. In the last decade and especially the last few years, online and virtual journal clubs have been started and are flourishing, especially those harnessing the advantages of social media tools and customs. This article reviews the history and recent innovations of journal clubs. In addition, the authors describe their experience developing and implementing NephJC, an online nephrology journal club conducted on Twitter.

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI.

Inappropriate activation of the renin-angiotensin system (RAS) contributes to many CKDs. However, the role of the RAS in modulating AKI requires elucidation, particularly because stimulating type 1 angiotensin II (AT1) receptors in the kidney or circulating inflammatory cells can have opposing effects on the generation of inflammatory mediators that underpin the pathogenesis of AKI. For example, TNF-α is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF-α is suppressed or enhanced by AT1 receptor signaling in T lymphocytes or the distal nephron, respectively. In this study, cell tracking experiments with CD4-Cre mT/mG reporter mice revealed robust infiltration of T lymphocytes into the kidney after cisplatin injection. Notably, knockout of AT1 receptors on T lymphocytes exacerbated the severity of cisplatin-induced AKI and enhanced the cisplatin-induced increase in TNF-α levels locally within the kidney and in the systemic circulation. In contrast, knockout of AT1 receptors on kidney epithelial cells ameliorated the severity of AKI and suppressed local and systemic TNF-α production induced by cisplatin. Finally, disrupting TNF-α production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF-α levels induced by cisplatin. These results illustrate discrepant tissue-specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatory mediators produced by renal parenchymal cells may influence the function of remote organs by altering systemic cytokine levels. Our findings suggest selective inhibition of AT1 receptors within the nephron as a promising intervention for protecting patients from cisplatin-induced nephrotoxicity.