Familial hyperkalemic hypertension (FHHt) can be mainly attributed to increased activity of the renal Na:Cl cotransporter (NCC), which is caused by altered expression and regulation of the with-no-lysine (K) 1 (WNK1) or WNK4 kinases. The WNK1 gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK/STE20-proline-alanine rich kinase (SPAK)/NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces remarkable activation and phosphorylation of SPAK and NCC. The effect of KS-WNK1 was abrogated by eliminating a WNK-WNK-interacting domain and by a specific WNK inhibitor, WNK463, indicating that the activation of SPAK/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under control conditions in oocytes, the activating serine 335 of the WNK4 T loop is not phosphorylated. In contrast, this serine becomes phosphorylated when the intracellular chloride concentration ([Cl]) is reduced or when KS-WNK1 is coexpressed with WNK4. KS-WNK1-mediated activation of WNK4 is not due to a decrease of the [Cl]. Coimmunoprecipitation analysis revealed that KS-WNK1 and WNK4 interact with each other and that WNK4 becomes autophosphorylated at serine 335 when it is associated with KS-WNK1. Together, these observations suggest that WNK4 becomes active in the presence of KS-WNK1, despite a constant [Cl].

Fatigue is a commonly reported and debilitating symptom among patients with CKD, yet little is known about its epidemiology, pathogenesis, and treatment. Various measurement tools have been used in published studies to identify and quantify fatigue. These include several single-item measures embedded in longer questionnaires for assessing depression, quality of life, or symptom burden in patients with kidney disease. Approximately 70% of patients with CKD report fatigue, with up to 25% reporting severe symptoms. Patient-reported fatigue is associated with death, dialysis initiation, and hospitalization among individuals with CKD. The pathophysiology is multifactorial and likely includes decreased oxygen delivery and increased reliance on anaerobic metabolism, thus generating lactic acidosis in response to exertion; the effects of chronic metabolic acidosis and hyperphosphatemia on skeletal muscle myocytes; protein-energy wasting and sarcopenia; and depression. Physical activity has been shown to improve fatigue in some small but promising trials, and so should be recommended, given the additional benefits of exercise. Targeting higher hemoglobin levels with erythropoiesis-stimulating agents may improve fatigue, but potential adverse cardiovascular effects preclude their use to solely treat fatigue without the presence of another indication. Current guidelines recommend cautious individualization of hemoglobin targets for those at low cardiovascular risk who still experience fatigue or functional limitation despite a hemoglobin level of 10 g/dl. Sodium bicarbonate supplementation for the treatment of metabolic acidosis may also improve functional status. Selective serotonin reuptake inhibitors have not been consistently shown to improve fatigue in patients with kidney disease, but an ongoing trial will evaluate the effect of alternative antidepressant drug and behavioral activation therapy on fatigue in patients with CKD. Overall, more research is needed to further clarify underlying mechanisms of fatigue and identify effective, targeted treatments for patients with CKD.

The COVID-19 outbreak has had substantial effects on the incidence and management of kidney diseases, including acute kidney injury (AKI), End-Stage Kidney Disease (ESKD), glomerulonephritis, and kidney transplantation. Initial reports from China suggested a lower AKI incidence in patients with COVID-19, but more recent studies from North America reveal a much higher incidence, likely due to higher prevalence of comorbid conditions such as hypertension, diabetes, and chronic kidney disease (CKD). AKI in this setting is associated with worse outcomes, including requirement for vasopressors or mechanical ventilation and death. Performing renal replacement therapy in those with AKI poses challenges such as limiting exposure of staff, preserving PPE, coagulopathy, and hypoxemia due to Acute Respiratory Distress Syndrome. Continuous Renal Replacement Therapy is the preferred modality, with sustained low-efficiency dialysis also an option, both managed without 1:1 hemodialysis nursing support. Regional citrate is the preferred anticoagulation, but systemic unfractionated heparin may be used in cases of coagulopathy. Ultrafiltration rate has to be set carefully, taking into consideration hypotension, hypoxemia, and responsiveness to presser and ventilatory support. Chance of transmission puts in-center chronic hemodialysis and other immunosuppressed patients at particularly increased risk. Limited data show that patients with CKD are also at increased risk for more severe disease if infected. Little is known about the virus's effects on immunocompromised patients with glomerular diseases and kidney transplants, which introduces challenges for management of immunosuppressant regimens. While there are no standardized guidelines regarding the management of immunosuppression, several groups recommend stopping the anti-metabolite in hospitalized transplant patients and continuing a reduced dose of calcineurin inhibitors. This comprehensive review critically appraises the best available evidence regarding the effect of COVID-19 on the incidence and management of kidney diseases. Where evidence is lacking, current expert opinion and clinical guidelines are reviewed and knowledge gaps worth investigation are identified.

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