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Clinical Journal of the American... Jan 2023Acid-base disorders are common in the intensive care unit. By utilizing a systematic approach to their diagnosis, it is easy to identify both simple and mixed...
Acid-base disorders are common in the intensive care unit. By utilizing a systematic approach to their diagnosis, it is easy to identify both simple and mixed disturbances. These disorders are divided into four major categories: metabolic acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. Metabolic acidosis is subdivided into anion gap and non-gap acidosis. Distinguishing between these is helpful in establishing the cause of the acidosis. Anion gap acidosis, caused by the accumulation of organic anions from sepsis, diabetes, alcohol use, and numerous drugs and toxins, is usually present on admission to the intensive care unit. Lactic acidosis from decreased delivery or utilization of oxygen is associated with increased mortality. This is likely secondary to the disease process, as opposed to the degree of acidemia. Treatment of an anion gap acidosis is aimed at the underlying disease or removal of the toxin. The use of therapy to normalize the pH is controversial. Non-gap acidoses result from disorders of renal tubular H + transport, decreased renal ammonia secretion, gastrointestinal and kidney losses of bicarbonate, dilution of serum bicarbonate from excessive intravenous fluid administration, or addition of hydrochloric acid. Metabolic alkalosis is the most common acid-base disorder found in patients who are critically ill, and most often occurs after admission to the intensive care unit. Its etiology is most often secondary to the aggressive therapeutic interventions used to treat shock, acidemia, volume overload, severe coagulopathy, respiratory failure, and AKI. Treatment consists of volume resuscitation and repletion of potassium deficits. Aggressive lowering of the pH is usually not necessary. Respiratory disorders are caused by either decreased or increased minute ventilation. The use of permissive hypercapnia to prevent barotrauma has become the standard of care. The use of bicarbonate to correct the acidemia is not recommended. In patients at the extreme, the use of extracorporeal therapies to remove CO 2 can be considered.
Topics: Humans; Bicarbonates; Critical Illness; Acidosis; Acid-Base Equilibrium; Acid-Base Imbalance; Alkalosis
PubMed: 35998977
DOI: 10.2215/CJN.04500422 -
Frontiers in Medicine 2022Alport syndrome (AS) is a hereditary kidney disease associated with proteinuria, hematuria and progressive kidney failure. It is characterized by a defective glomerular... (Review)
Review
Alport syndrome (AS) is a hereditary kidney disease associated with proteinuria, hematuria and progressive kidney failure. It is characterized by a defective glomerular basement membrane caused by mutations in type IV collagen genes which result in defective type IV collagen α3, α4, or α5 chains, respectively. Alport syndrome has three different patterns of inheritance: X-linked, autosomal and digenic. In a study of CKD of unknown etiology type IV collagen gene mutations accounted for the majority of the cases of hereditary glomerulopathies which suggests that AS is often underrecognized. The natural history and prognosis in patients with AS is variable and is determined by genetics and environmental factors. At present, no preventive or curative therapies exist for AS. Current treatment includes the use of renin-angiotensin-aldosterone system inhibitors which slow progression of kidney disease and prolong life expectancy. Ramipril was found in retrospective studies to delay the onset of ESKD and was recently demonstrated to be safe and effective in children and adolescents, supporting that early initiation of Renin Angiotensin Aldosterone System (RAAS) blockade is very important. Mineralocorticoid receptor blockers might be favorable for patients who develop "aldosterone breakthrough." While the DAPA-CKD trial suggests a beneficial effect of SGLT2 inhibitors in CKD of non-metabolic origin, only a handful of patients had Alport in this cohort, and therefore conclusions can't be extrapolated for the treatment of AS with SGLT2 inhibitors. Advances in our understanding on the pathogenesis of Alport syndrome has culminated in the development of innovative therapeutic approaches that are currently under investigation. We will provide a brief overview of novel therapeutic targets to prevent progression of kidney disease in AS. Our review will include bardoxolone methyl, an oral NRf2 activator; lademirsen, an anti-miRNA-21 molecule; sparsentan, dual endothelin type A receptor (ETAR) and angiotensin 1 receptor inhibitor; atrasentan, oral selective ETAR inhibitor; lipid-modifying agents, including cholesterol efflux transporter ATP-binding cassette A1 (ABCA1) inducers, discoidin domain receptor 1 (DDR1) inhibitors and osteopontin blocking agents; the antimalarial drug hydroxychloroquine; the antiglycemic drug metformin and the active vitamin D analog paricalcitol. Future genomic therapeutic strategies such as chaperone therapy, genome editing and stem cell therapy will also be discussed.
PubMed: 35547199
DOI: 10.3389/fmed.2022.848389 -
International Journal of Molecular... Feb 2023Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines.... (Review)
Review
Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the endothelin receptor type A (ET) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ET receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment.
Topics: Humans; Angiotensin II Type 1 Receptor Blockers; Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Kidney; Kidney Diseases; Proteinuria; Receptor, Endothelin A
PubMed: 36834836
DOI: 10.3390/ijms24043427 -
Nephrology, Dialysis, Transplantation :... Oct 2020The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium-glucose... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials.
METHODS
In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol).
RESULTS
Overall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n = 2510) were ischaemic/hypertensive nephropathy (n = 687) and chronic glomerulonephritis (n = 695), of which immunoglobulin A nephropathy (n = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR).
CONCLUSIONS
Participants with a wide range of underlying kidney diseases receiving renin-angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2-4 and increased albuminuria, with and without T2D.
Topics: Aged; Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Glomerular Filtration Rate; Glucosides; Humans; Male; Prognosis; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 32862232
DOI: 10.1093/ndt/gfaa234 -
JAMA Cardiology Oct 2021Coronary artery disease (CAD) and coronary microvascular dysfunction (CMD) may contribute to the pathophysiologic characteristics of heart failure with preserved...
IMPORTANCE
Coronary artery disease (CAD) and coronary microvascular dysfunction (CMD) may contribute to the pathophysiologic characteristics of heart failure with preserved ejection fraction (HFpEF). However, the prevalence of CAD and CMD have not been systematically studied.
OBJECTIVE
To examine the prevalence of CAD and CMD in hospitalized patients with HFpEF.
DESIGN, SETTING, AND PARTICIPANTS
A total of 106 consecutive patients hospitalized with HFpEF were evaluated in this prospective, multicenter, cohort study conducted between January 2, 2017, and August 1, 2018; data analysis was performed from March 4 to September 6, 2019. Participants underwent coronary angiography with guidewire-based assessment of coronary flow reserve, index of microvascular resistance, and fractional flow reserve, followed by coronary vasoreactivity testing. Cardiac magnetic resonance imaging was performed with late gadolinium enhancement and assessment of extracellular volume. Myocardial perfusion was assessed qualitatively and semiquantitatively using the myocardial-perfusion reserve index.
MAIN OUTCOMES AND MEASURES
The prevalence of obstructive epicardial CAD, CMD, and myocardial ischemia, infarction, and fibrosis.
RESULTS
Of 106 participants enrolled (53 [50%] women; mean [SD] age, 72 [9] years), 75 had coronary angiography, 62 had assessment of coronary microvascular function, 41 underwent coronary vasoreactivity testing, and 52 received cardiac magnetic resonance imaging. Obstructive epicardial CAD was present in 38 of 75 participants (51%, 95% CI, 39%-62%); 19 of 38 (50%; 95% CI, 34%-66%) had no history of CAD. Endothelium-independent CMD (ie, coronary flow reserve <2.0 and/or index of microvascular resistance ≥25) was identified in 41 of 62 participants (66%; 95% CI, 53%-77%). Endothelium-dependent CMD (ie, abnormal coronary vasoreactivity) was identified in 10 of 41 participants (24%; 95% CI, 13%-40%). Overall, 45 of 53 participants (85%; 95% CI, 72%-92%) had evidence of CMD and 29 of 36 (81%; 95% CI, 64%-91%) of those without obstructive epicardial CAD had CMD. Cardiac magnetic resonance imaging findings included myocardial-perfusion reserve index less than or equal to 1.84 (ie, impaired global myocardial perfusion) in 29 of 41 patients (71%; 95% CI, 54%-83%), visual perfusion defect in 14 of 46 patients (30%; 95% CI, 19%-46%), ischemic late gadolinium enhancement (ie, myocardial infarction) in 14 of 52 patients (27%; 95% CI, 16%-41%), and extracellular volume greater than 30% (ie, diffuse myocardial fibrosis) in 20 of 48 patients (42%; 95% CI, 28%-56%). Patients with obstructive CAD had more adverse events during follow-up (28 [74%]) than those without obstructive CAD (17 [46%]).
CONCLUSIONS AND RELEVANCE
In this cohort study, 91% of patients with HFpEF had evidence of epicardial CAD, CMD, or both. Of those without obstructive CAD, 81% had CMD. Obstructive epicardial CAD and CMD appear to be common and often unrecognized in hospitalized patients with HFpEF and may be therapeutic targets.
Topics: Aged; Coronary Angiography; Coronary Occlusion; Coronary Vessels; Female; Follow-Up Studies; Fractional Flow Reserve, Myocardial; Heart Failure; Heart Ventricles; Humans; Magnetic Resonance Imaging, Cine; Male; Microcirculation; Prevalence; Prospective Studies; Stroke Volume; Time Factors; United Kingdom; Ventricular Function, Left
PubMed: 34160566
DOI: 10.1001/jamacardio.2021.1825 -
Cureus Feb 2023Chronic kidney disease (CKD) is a debilitating progressive illness that affects more than 10% of the world's population. In this literature review, we discussed the... (Review)
Review
Chronic kidney disease (CKD) is a debilitating progressive illness that affects more than 10% of the world's population. In this literature review, we discussed the roles of nutritional interventions, lifestyle modifications, hypertension (HTN) and diabetes mellitus (DM) control, and medications in delaying the progression of CKD. Walking, weight loss, low-protein diet (LPD), adherence to the alternate Mediterranean (aMed) diet, and Alternative Healthy Eating Index (AHEI)-2010 slow the progression of CKD. However, smoking and binge alcohol drinking increase the risk of CKD progression. In addition, hyperglycemia, altered lipid metabolism, low-grade inflammation, over-activation of the renin-angiotensin-aldosterone system (RAAS), and overhydration (OH) increase diabetic CKD progression. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend blood pressure (BP) control of <140/90 mmHg in patients without albuminuria and <130/80 mmHg in patients with albuminuria to prevent CKD progression. Medical therapies aim to target epigenetic alterations, fibrosis, and inflammation. Currently, RAAS blockade, sodium-glucose cotransporter-2 (SGLT2) inhibitors, pentoxifylline, and finerenone are approved for managing CKD. In addition, according to the completed Study of Diabetic Nephropathy with Atrasentan (SONAR), atrasentan, an endothelin receptor antagonist (ERA), decreased the risk of renal events in diabetic CKD patients. However, ongoing trials are studying the role of other agents in slowing the progression of CKD.
PubMed: 36874334
DOI: 10.7759/cureus.34572 -
Kidney International Jul 2023Doubling of serum creatinine (equivalent to a 57% decline in the estimated glomerular filtration rate (eGFR)) is an accepted component of a composite kidney endpoint in...
Doubling of serum creatinine (equivalent to a 57% decline in the estimated glomerular filtration rate (eGFR)) is an accepted component of a composite kidney endpoint in clinical trials. Smaller declines in eGFR (40%, 50%) have been applied in several recently conducted clinical trials. Here, we assessed the effects of newer kidney protective agents on endpoints including smaller proportional declines in eGFR to compare relative event rates and the magnitude of observed treatment effects. We performed a post hoc analysis of 4401 patients in the CREDENCE, 4304 in the DAPA-CKD, 5734 in the FIDELIO-DKD, and 3668 in the SONAR trials, which assessed the effects of canagliflozin, dapagliflozin, finerenone and atrasentan in patients with chronic kidney disease. Effects of active therapies versus placebo on alternative composite kidney endpoints incorporating different eGFR decline thresholds (40%, 50%, or 57% eGFR reductions from baseline) with kidney failure or death due to kidney failure were compared. Cox-proportional hazards regression models were used to assess and compare treatment effects. During follow-up, event rates were higher for endpoints incorporating smaller versus larger eGFR decline thresholds. Compared to the treatment effects on kidney failure or death due to kidney failure, the magnitude of relative treatment effects was generally similar when considering composite endpoints incorporating smaller declines in eGFR. Hazard ratios for the four interventions ranged from 0.63 to 0.82 for the endpoint incorporating 40% eGFR decline and 0.59 to 0.76 for the endpoint incorporating 57% eGFR decline. Clinical trials incorporating a 40% eGFR decline in a composite endpoint would require approximately half the number of participants compared to a 57% eGFR decline with equivalent statistical power. Thus, in populations at high risk of CKD progression, the relative effects of newer kidney protective therapies appear generally similar across endpoints based on varying eGFR decline thresholds.
Topics: Humans; Renal Insufficiency, Chronic; Canagliflozin; Glomerular Filtration Rate; Kidney; Diabetes Mellitus, Type 2
PubMed: 37119876
DOI: 10.1016/j.kint.2023.03.037 -
Kidney International Supplements Jan 2018Over the past 30 years there have been many complementary therapies developed to achieve glycemic control and have an impact on cardiovascular outcomes, as well as... (Review)
Review
Over the past 30 years there have been many complementary therapies developed to achieve glycemic control and have an impact on cardiovascular outcomes, as well as reduce the risk of microvascular disease. The 2 most notable new entries have been the sodium-glucose cotransporter 2 (SGLT2) inhibitors and the glucagon-like peptide-1 (GLP-1) agonists. Both these classes of agents have demonstrated reductions in cardiovascular event rates as well as reductions in blood pressure and weight. Moreover, while both have demonstrated a benefit in slowing nephropathy progression, the SGLT2 inhibitors appear to have a significantly greater effect compared with the GLP-1 agents. There is an ongoing trial specifically powered for renal disease progression, CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy). Additionally, there are 2 other classes of agents being tested to slow nephropathy progression, a selective endothelin-1 receptor antagonist, atrasantan, in the SONAR (Study of Diabetic Nephropathy With Atrasentan) trial and a nonsteroidal mineralocorticoid receptor antagonist, finerenone, in the FIDELIO (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus) trial. These and other studies are discussed.
PubMed: 30675435
DOI: 10.1016/j.kisu.2017.10.005 -
Cardiovascular Diabetology Sep 2023Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest...
BACKGROUND
Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD.
METHODS
We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25-75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300-5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model.
RESULTS
In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9).
CONCLUSIONS
More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR.
TRIAL REGISTRATION
RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.
Topics: Humans; Atrasentan; Diabetes Mellitus, Type 2; Insulin Resistance; Kidney; Renal Insufficiency, Chronic; Endothelin Receptor Antagonists
PubMed: 37716952
DOI: 10.1186/s12933-023-01964-8 -
Kidney International Jul 2018Drug repurposing, is the re-tasking of known medications for new clinical indications. Advantages, compared to de novo drug development, include reduced cost and time to... (Review)
Review
Drug repurposing, is the re-tasking of known medications for new clinical indications. Advantages, compared to de novo drug development, include reduced cost and time to market plus the added benefit of a known pharmacokinetic and safety profiles. Suitable drug candidates are identified through serendipitous observations, data mining, or increased understanding of disease mechanisms. This review highlights drugs suited for repurposing in kidney disease. The main cause of mortality in patients with chronic kidney disease is cardiovascular disease. Hence, we have included CV endpoints for the drugs. This review begins with candidates in acute kidney injury: vasodilators levosimendan and vitamin D, followed by candidates in CKD, with particular focus on diabetic kidney disease, autosomal dominant polycystic kidney disease, and focal segmental glomerulosclerosis. Examples include glucose-lowering drugs (sodium glucose co-transporter 2 inhibitors, glucagon-like peptide 1 agonists, and metformin), which have mechanistic potential for cardiac and/or renal protection beyond glucose lowering, with broader applicability to the nondiabetic population; xanthine oxidase inhibitors (allopurinol, febuxostat), selective endothelin receptor A antagonist (atrasentan), Janus kinase inhibitor (baricitinib), selective costimulation modulator (abatacept), pentoxyfylline, and the DNA demethylating agent/vasodilator (hydralazine).
Topics: Cardiovascular Diseases; Clinical Trials as Topic; Drug Repositioning; Endothelin A Receptor Antagonists; Gout Suppressants; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Renal Insufficiency, Chronic; Vasodilator Agents
PubMed: 29628139
DOI: 10.1016/j.kint.2017.12.026