The time to offer treatments for COVID-19.

Background: COVID-19 has several overlapping phases. Treatments to date have focused on the late stage of disease in hospital. Yet, the pandemic is by propagated by the viral phase in out-patients. The current public health strategy relies solely on vaccines to prevent disease.Methods: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results.Results: As of 2/15/2021, we found 111 publications reporting findings on 14 classes of agents, and 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care. Remdesivir and high titer convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries.Expert Opinion: Vaccines and antibodies are highly antigen specific, and new SARS-Cov-2 variants are appearing. We call on public health authorities to authorize treatments with known low-risk and possible benefit for outpatients in parallel with universal vaccination.

The Importance of Understanding the Stages of COVID-19 in Treatment and Trials.

COVID-19, caused by SARS-CoV-2, continues to be a major health problem since its first description in Wuhan, China, in December 2019. Multiple drugs have been tried to date in the treatment of COVID-19. Critical to treatment of COVID-19 and advancing therapeutics is an appreciation of the multiple stages of this disease and the importance of timing for investigation and use of various agents. We considered articles related to COVID-19 indexed on PubMed published January 1, 2020-November 15, 2020, and considered papers on the medRxiv preprint server. We identified relevant stages of COVID-19 including three periods: pre-exposure, incubation, and detectable viral replication; and five phases: the viral symptom phase, the early inflammatory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. This common terminology should serve as a framework to guide when COVID-19 therapeutics being studied or currently in use is likely to provide benefit rather than harm.

The unresolved epidemic of chronic kidney disease of uncertain origin (CKDu) around the world: A review and new insights.

EPIDEMIOLOGY: An increasing number of inhabitants of Central America have developed a form of chronic kidney disease of unknown cause, named Mesoamerican nephropathy (MeN). Because similar epidemics have been reported in other parts of the world, such as Sri Lanka, India, Egypt, and Tunisia, this condition is currently called chronic kidney disease of uncertain origin (CKDu). CLINICAL PRESENTATION: This disease is characterized by minimal proteinuria, leukocyturia, hyperuricemia, hypokalemia reduced glomerular filtration rate, and renal tubular dysfunctions. Pathology: The kidneys manifest tubulo-interstitial nephritis and glomerulosclerosis. Electron microscopy shows large dimorphic lysosomes with dark electron-dense aggregates. Potential causes: The cause(s) of this disease remain largely unknown. Several hypotheses have been proposed including infections, dehydration, global warming, hyperuricemia, exposure to agro-chemicals or heavy metals, and genetic susceptibility. This review addresses a mounting body of evidence suggesting that the disease may be the result of exposure to a variety of water contaminants combined with volume depletion. THERAPY: Absent a clear understanding of the causes of the disease, no specific therapeutic interventions can be recommended. Preliminary studies suggest that reduction of working hours, frequent rest in shaded area, and administration of purified water may reduce the risk of CKDu.

Hypertension in High School Students: Genetic and Environmental Factors: The HYGEF Study.

Hypertension and obesity in the young population are major risk factors for renal and cardiovascular events, which could arise in adulthood. A candidate-gene approach was applied in a cohort observational study, in which we collected data from 2638 high school adolescent students. Participants underwent anthropometric and blood pressure (BP) measurements, as well as saliva and urine sample collection for genomic DNA extraction and renal function evaluation, respectively. We tested whether candidate genes previously implicated in salt-sensitive hypertension in adults impact BP also among adolescents. Since inflammatory mechanisms may be involved in pathophysiology of hypertension and in endothelial dysfunction and atherosclerosis through reactive oxygen species, the baseline urinary excretion of inflammatory and oxidative stress markers in a subgroup of adolescents stratified according to ADD1(alpha adducin) rs4961 genotypes was assessed. Regression analysis of BP values with genetic polymorphisms, highlighted an association with a missense variant of LSS (lanosterol synthase, rs2254524), a gene coding for an enzyme involved in endogenous ouabain synthesis. Higher diastolic and systolic BP were associated with LSS A allele (P=0.011 and P=0.023, respectively). BP resulted associated with 5 more SNPs. The KL (klotho) rs9536314 missense variant was associated with 24 hour urinary Na+ excretion (P=0.0083). Urinary protein tests showed a greater excretion of IL1ß (interleukin 1ß) and interleukin 10 (P<0.0001) in carriers of the ADD1 rs4961 T allele. In conclusion, 3 missense gene variants already implicated in adult hypertension impact BP or Na+ excretion among adolescents, and, together with activated pro-inflammatory pathways, might predispose to early cardiovascular damage.

Renovascular disease: Is there still a role for revascularization?
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There are substantial doubts pertaining to the clinical usefulness of radiological and surgical interventions in the management of renovascular disease, particularly in patients with diffuse atherosclerotic vascular disease. This article reviews the current knowledge on advantages and limitations of interventional techniques in the management of patients with atherosclerotic renovascular disease.
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Acute Declines in Renal Function during Intensive BP Lowering: Implications for Future ESRD Risk.

The magnitude of decline in renal function that should be tolerated during intensive BP lowering and its association with risk of ESRD are unclear. To determine whether the acute declines in kidney function in the intensive BP lowering arm of two trials in CKD associated with higher risk of ESRD, we performed a retrospective study of 899 African American Study of Kidney Disease and Hypertension (AASK) and 761 Modification of Diet in Renal Disease (MDRD) Trial participants previously randomized to strict versus usual BP control. The predictor was the percentage decline in eGFR (<5%, 5% to <20%, or ≥20%) between randomization and months 3 and 4 of the trial (time to achieve BP goals). ESRD was the outcome of interest. Compared with a <5% eGFR decline in the usual BP arm, a 5% to <20% eGFR decline during intensive BP lowering did not associate with a higher risk of ESRD in the AASK (adjusted hazard ratio [aHR], 1.19; 95% confidence interval [95% CI], 0.84 to 1.68) or the MDRD Trial (aHR, 1.08; 95% CI, 0.84 to 1.40). However, a 5% to <20% eGFR decline in the usual BP arm associated with higher risk of ESRD in AASK (aHR, 1.83; 95% CI, 1.30 to 2.57) and MDRD Trial (aHR, 1.62; 95% CI, 1.25 to 2.11). A ≥20% eGFR decline associated with higher risk of ESRD in both strict and usual BP arms. Thus, acute eGFR declines ≥20% during intensive BP lowering identified a subset of patients at higher risk for adverse outcomes.

Con: Mesoamerican nephropathy: is the problem dehydration or rehydration?

In recent years, an increasing number of inhabitants of Central America have developed a form of chronic kidney disease, now named Mesoamerican nephropathy. This disease is characterized by minimal proteinuria, hyperuricemia, hypokalemia and reduced glomerular filtration rate. Histologically the kidneys manifest tubulointerstitial nephritis. The cause(s) of this disease remain unknown. Some have proposed that dehydration, in combination with hyperuricemia, may be primarily responsible for Mesoamerican nephropathy. In this article, I propose the hypothesis that the disease may be largely due to rehydration with large amounts of contaminated water, whereas dehydration would play only a contributing role.

Measurement of Cardiac Output and Blood Volume During Hemodialysis with Fluorescent Dye Dilution Technique.

Intradialytic hypotensive events (IDH) accompanied by deleterious decreases of the cardiac output complicate up to 25% of hemodialysis treatments. Monitoring options available to track hemodynamic changes during hemodialysis have been found ineffective to anticipate the occurrence of IDH. We have assembled opto-electronic instrumentation that uses the fluorescence of a small bolus of indocyanine green dye injected in the hemodialysis circuit to estimate cardiac output and blood volume based on indicator dilution principles in patients receiving hemodialysis. The instrument and technique were tested in 24 adult end-stage renal failure subjects during 64 hemodialysis sessions. A single calibration factor could be used across subjects and across time. Intra-subject variability of the measurements over time was <10%. Stroke volume index (SVI) (mean ± SEM = 34 ± 1 vs. 39 ± 2 mL m-2) and central blood volume (CBV) index (783 ± 36 vs. 881 ± 33 mL m-2) were lower at the beginning of the sessions in which IDH eventually occurred. Cardiac index, SVI, and CBV index decreased with hemodialysis in all treatment sessions but the decrease was more intense in the IDH sessions. We conclude that hemodynamic monitoring can be implemented in patients receiving hemodialysis with minimal disruption of the treatment and could help understand intradialytic hypotension.

Electrophysiological and clinical consequences of hyperkalemia.

Despite the potentially life-threatening consequences of hyperkalemia, symptoms are often absent or mild. However, when hyperkalemia has been recognized, evaluation of vital signs is essential for determining hemodynamic stability and identifying the presence of cardiac arrhythmias related to the hyperkalemia. Quite commonly, and depending on the severity and rapidity of onset, hyperkalemia may be associated with substantial electrocardiographic (EKG) changes that can lead to death if proper interventions are not instituted. Through its effects on the resting membrane potential and threshold potential of excitable cells, hyperkalemia is a potentially life-threatening disorder. Symptoms and physical examination findings are often absent. Once identified, the entire clinical picture must be taken into account, including an assessment of hemodynamic stability, the presence of other electrolyte abnormalities, and an EKG evaluation. While there is a typical progression of EKG findings based on hyperkalemia severity, EKG manifestations are myriad and their evolution may be unpredictable.

The Challenges of Blood Pressure Control in Dialysis Patients.

Hypertension is very prevalent among patients with chronic kidney disease (CKD) and end-stage kidney disease (ESRD). However, there are still several unsolved issues pertaining to the definition, variability, diagnosis and management of hypertension in these patients. This manuscript critically reviews the current challenges in clinical practice in defining, diagnosing and treating hypertension in CKD and ESRD patients. Moreover, the manuscript reviews the pharmacokinetics, pharmacodynamics and safety of most anti-hypertensive drugs used in the management of these patients.

Pathophysiology of resistant hypertension in chronic kidney disease.

Hypertension associated with chronic kidney diseases often is resistant to drug treatment. This review deals with two main aspects of the management of CKD patients with hypertension: the role of sodium/volume and the need for dietary salt restriction, as well as appropriate use of diuretics and what currently is called sequential nephron blockade; the second aspect that is addressed extensively in this review is the role of the sympathetic nervous system and the possible clinical use of renal denervation.

Effect of high-dose atorvastatin on renal function in subjects with stroke or transient ischemic attack in the SPARCL trial.

BACKGROUND AND PURPOSE: Higher low-density lipoprotein cholesterol is associated with more rapid chronic kidney disease progression; reduction in cholesterol with statins, in conjunction with statins' pleiotropic effects, such as decreasing inflammation, may be renoprotective. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial assessed the effect of statin treatment on the risk of nonfatal and fatal stroke in subjects with a noncardioembolic stroke or transient ischemic attack, no known coronary heart disease, and low-density lipoprotein cholesterol between 2.6 and 4.9 mmol/L (100-190 mg/dL). METHODS: We explored the effect of randomization to atorvastatin 80 mg/d or placebo on the change in estimated glomerular filtration rate (eGFR; using the 4-component Modification of Diet in Renal Disease Study equation) in SPARCL subjects (n=4731) with (eGFR, <60 mL/min per 1.73 m2; n=3119) and without (eGFR, ≥60 mL/min per 1.73 m2; n=1600) chronic kidney disease overall and by glycemic status at baseline. RESULTS: Mean baseline eGFR was similar between treatment groups (65.5±0.26 versus 65.6±0.26 mL/min per 1.73 m2 atorvastatin versus placebo; 33% versus 34% had chronic kidney disease, respectively; P=0.55). After 60 months, eGFR increased 3.46±0.33 mL/min per 1.73 m2 in those randomized to atorvastatin versus 1.42±0.34 mL/min per 1.73 m2 in those randomized to placebo (P<0.001) independent of baseline renal function. In the subgroup with diabetes mellitus at randomization, eGFR increased 1.12±0.92 mL/min per 1.73 m2 in the atorvastatin group and decreased 1.69±0.92 mL/min per 1.73 m2 in placebo group during a period of 60 months (P=0.016). CONCLUSIONS: This post hoc analysis suggests that atorvastatin treatment may improve renal function in patients with prior stroke or transient ischemic attack with and without chronic kidney disease, and that atorvastatin treatment may prevent eGFR decline in patients with stroke and diabetes mellitus. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00147602.

Dyslipidemia and progression of kidney disease: role of lipid-lowering drugs.

HMG-CoA reductase inhibitors (statins) have been shown to reduce cardiovascular morbidity in patients with normal and abnormal kidney function but not in patients with end-stage kidney disease. Evidence supports a role for statins in delaying the progression of kidney disease in a variety of experimental models in animals. However, the evidence that statins may retard CKD progression in humans is scant. In this review, we critically consider the available data supporting a role for statins in CKD progression in humans and the possibility that there might be differences among statins in regards to effects on the kidneys. Finally, we review the evidence that statins may increase the risk of acute kidney injury.