Gender-specific risk factors and outcomes of hyperkalemia in CKD patients: smoking as a driver of hyperkalemia in men.

Background: Hyperkalemia is common among patients with chronic kidney disease (CKD) but there is scarce information on differential risk factors and outcomes for men and women. For instance, smoking has been suggested to be a risk factor for hyperkalemia, but specific analysis of the sex-specific impact of smoking on hyperkalemia in CKD is lacking. Methods: We studied serum potassium levels in 2891 participants from the NEFRONA cohort: 483 controls (47% women) and 2408 CKD patients (38% women) without prior cardiovascular disease (CVD), assessing whether smoking is a risk factor for hyperkalemia, and if hyperkalemia is associated with outcomes separately for men and women. Results: Median potassium levels and prevalence of hypo and hyperkalemia were higher in CKD participants than in controls. Serum potassium levels were higher and hyperkalemia and severe hyperkalemia more prevalent in men than in women with non-dialysis CKD (G3-G5). The highest prevalence of hyperkalemia for each gender was found in CKD G4-G5 and hemodialysis patients for men (46%) and in hemodialysis (54%) for women. Gender-specific etiological multivariate analysis identified current smoking as a risk factor for hyperkalemia only in men. Hyperkalemia was independently associated with stopping RAASi, an outcome which was more common in women. Hyperkalemia was also associated to higher risk of cardiovascular events within 4 years in men. In conclusion, hyperkalemia is common among men and women with CKD, but the prevalence, risk factors and outcomes may differ by gender. Specifically, current smoking is a driver of hyperkalemia in men.

Increased expression of SCARF genes favoring SARS-CoV-2 infection in key target organs in CKD.

Background: Chronic kidney disease (CKD), especially diabetic CKD, is the condition that most increases the risk of lethal coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the underlying molecular mechanisms are unclear. SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) regulate coronavirus cell entry and/or replication. We hypothesized that CKD may alter the expression of SCARF genes. Methods: A literature search identified 34 SCARF genes of which we selected 21 involved in interactions between SARS-CoV/SARS-CoV-2 and host cells, and assessed their mRNA expression in target tissues of COVID-19 (kidneys, lungs, aorta and heart) in mice with adenine-induced CKD. Results: Twenty genes were differentially expressed in at least one organ in mice with CKD. For 15 genes, the differential expression would be expected to favor SARS-CoV-2 infection and/or severity. Of these 15 genes, 13 were differentially expressed in the kidney and 8 were validated in human CKD kidney transcriptomics datasets, including those for the most common cause of CKD, diabetic nephropathy. Two genes reported to protect from SARS-CoV-2 were downregulated in at least two non-kidney target organs: Ifitm3 encoding interferon-induced transmembrane protein 3 (IFITM3) in lung and Ly6e encoding lymphocyte antigen 6 family member 6 (LY6E) in aorta. Conclusion: CKD, including diabetic CKD, is associated with the differential expression of multiple SCARF genes in target organs of COVID-19, some of which may sensitize to SARS-CoV-2 infection. This information may facilitate developing therapeutic strategies aimed at decreasing COVID-19 severity in patients with CKD.

Interaction of Fabry Disease and Diabetes Mellitus: Suboptimal Recruitment of Kidney Protective Factors.

Fabry disease is a lysosomal disease characterized by globotriaosylceramide (Gb3) accumulation. It may coexist with diabetes mellitus and both cause potentially lethal kidney end-organ damage. However, there is little information on their interaction with kidney disease. We have addressed the interaction between Fabry disease and diabetes in data mining of human kidney transcriptomics databases and in Fabry (Gla-/-) and wild type mice with or without streptozotocin-induced diabetes. Data mining was consistent with differential expression of genes encoding enzymes from the Gb3 metabolic pathway in human diabetic kidney disease, including upregulation of UGCG, the gene encoding the upstream and rate-limiting enzyme glucosyl ceramide synthase. Diabetic Fabry mice displayed the most severe kidney infiltration by F4/80+ macrophages, and a lower kidney expression of kidney protective genes (Pgc1α and Tfeb) than diabetic wild type mice, without a further increase in kidney fibrosis. Moreover, only diabetic Fabry mice developed kidney insufficiency and these mice with kidney insufficiency had a high expression of Ugcg. In conclusion, we found evidence of interaction between diabetes and Fabry disease that may increase the severity of the kidney phenotype through modulation of the Gb3 synthesis pathway and downregulation of kidney protective genes.

Approach to Pregnancy in Patients With Lupus Nephritis.

Active lupus nephritis (LN) in pregnancy is strongly associated with poor maternal and fetal outcomes and, therefore, has implications on the planning, timing, and management. Prepregnancy evaluation is essential for all LN patients with childbearing potential to ensure pregnancies proceed in a safe and timely manner. Both maternal and fetal risks are communicated to patient during the evaluation. Stratification into different risk profile groups is then made based on disease activity and organ impairment severity. Patients with LN are generally divided into 3 main groups. Patients with LN who become pregnant receive treatments that are nonteratogenic and optimal for fetal and maternal outcomes. Throughout the pregnancy period, these patients are monitored closely under surveillance by a multidisciplinary team of clinicians. The management of patients with LN in pregnancy can be challenging both diagnostically (distinguishing LN from pre-eclampsia and determining the role and timing of kidney biopsy) and therapeutically (LN flares during pregnancy and managing a newly diagnosed LN during pregnancy).

SCARF Genes in COVID-19 and Kidney Disease: A Path to Comorbidity-Specific Therapies.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has killed ~7 million persons worldwide. Chronic kidney disease (CKD) is the most common risk factor for severe COVID-19 and one that most increases the risk of COVID-19-related death. Moreover, CKD increases the risk of acute kidney injury (AKI), and COVID-19 patients with AKI are at an increased risk of death. However, the molecular basis underlying this risk has not been well characterized. CKD patients are at increased risk of death from multiple infections, to which immune deficiency in non-specific host defenses may contribute. However, COVID-19-associated AKI has specific molecular features and CKD modulates the local (kidney) and systemic (lung, aorta) expression of host genes encoding coronavirus-associated receptors and factors (SCARFs), which SARS-CoV-2 hijacks to enter cells and replicate. We review the interaction between kidney disease and COVID-19, including the over 200 host genes that may influence the severity of COVID-19, and provide evidence suggesting that kidney disease may modulate the expression of SCARF genes and other key host genes involved in an effective adaptive defense against coronaviruses. Given the poor response of certain CKD populations (e.g., kidney transplant recipients) to SARS-CoV-2 vaccines and their suboptimal outcomes when infected, we propose a research agenda focusing on CKD to develop the concept of comorbidity-specific targeted therapeutic approaches to SARS-CoV-2 infection or to future coronavirus infections.

Cognitive disorders in patients with chronic kidney disease: Approaches to prevention and treatment.

BACKGROUND: Cognitive impairment is common in patients with chronic kidney disease (CKD), and early intervention may prevent the progression of this condition. METHODS: Here, we review interventions for the complications of CKD (anemia, secondary hyperparathyroidism, metabolic acidosis, harmful effects of dialysis, the accumulation of uremic toxins) and for prevention of vascular events, interventions that may potentially be protective against cognitive impairment. Furthermore, we discuss nonpharmacological and pharmacological methods to prevent cognitive impairment and/or minimize the latter's impact on CKD patients' daily lives. RESULTS: A particular attention on kidney function assessment is suggested during work-up for cognitive impairment. Different approaches are promising to reduce cognitive burden in patients with CKD but the availabe dedicated data are scarce. CONCLUSIONS: There is a need for studies assessing the effect of interventions on the cognitive function of patients with CKD.

Tirzepatide and prevention of chronic kidney disease.

Tirzepatide is a twincretin recently approved to improve glycemic control in type 2 diabetes mellitus (T2DM). More specifically, tirzepatide is an agonist of both the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide-1 (GLP1) receptors. In recent clinical trials in persons with obesity or overweight with associated conditions, tirzepatide decreased body weight and other cardiorenal risk factors (blood pressure, low-density lipoprotein cholesterol, glycated hemoglobin and albuminuria). Moreover, in a post hoc analysis of the SURPASS-4 randomized clinical trial, tirzepatide decreased albuminuria and total estimated glomerular filtration rate (eGFR) slopes and nearly halved the risk of a pre-specified composite kidney endpoint (eGFR decline ≥40%, renal death, kidney failure or new-onset macroalbuminuria) in participants with T2DM and high cardiovascular risk when compared with insulin glargine. Similar to other kidney-protective drugs, tirzepatide, alone or combined with sodium-glucose co-transporter 2 inhibitors, caused an early dip in eGFR. Moreover, tirzepatide also decreased eGFR slopes in participants with eGFR >60 mL/min/1.73 m2 or with normoalbuminuria. We now review the potential kidney health implications of tirzepatide, addressing its structure and function, relationship to current GLP1 receptor agonists, impact of recent results for the treatment and prevention of kidney disease, and expectations for the future.

Sodium zirconium cyclosilicate and metabolic acidosis: Potential mechanisms and clinical consequences.

Metabolic acidosis is frequent in chronic kidney disease (CKD) and is associated with accelerated progression of CKD, hypercatabolism, bone disease, hyperkalemia, and mortality. Clinical guidelines recommend a target serum bicarbonate ≥ 22 mmol/L, but metabolic acidosis frequently remains undiagnosed and untreated. Sodium zirconium cyclosilicate (SZC) binds potassium in the gut and is approved to treat hyperkalemia. In clinical trials with a primary endpoint of serum potassium, SZC increased serum bicarbonate, thus treating CKD-associated metabolic acidosis. The increase in serum bicarbonate was larger in patients with more severe pre-existent metabolic acidosis, was associated to decreased serum urea and was maintained for over a year of SZC therapy. SZC also decreased serum urea and increased serum bicarbonate after switching from a potassium-binding resin in normokalemic individuals. Mechanistically, these findings are consistent with SZC binding the ammonium ion (NH4+) generated from urea by gut microbial urease, preventing its absorption and, thus, preventing the liver regeneration of urea and promoting the fecal excretion of H+. This mechanism of action may potentially result in benefits dependent on corrected metabolic acidosis (e.g., improved well-being, decreased catabolism, improved CKD mineral bone disorder, better control of serum phosphate, slower progression of CKD) and dependent on lower urea levels, such as decreased protein carbamylation. A roadmap is provided to guide research into the mechanisms and clinical consequences of the impact of SZC on serum bicarbonate and urate.

The transcription factor Fosl1 preserves Klotho expression and protects from acute kidney injury.

Increased expression of AP-1 transcription factor components has been reported in acute kidney injury (AKI). However, the role of specific components, such as Fosl1, in tubular cells or AKI is unknown. Upstream regulator analysis of murine nephrotoxic AKI transcriptomics identified AP-1 as highly upregulated. Among AP-1 canonical components, Fosl1 was found to be upregulated in two transcriptomics datasets from nephrotoxic murine AKI induced by folic acid or cisplatin and from proximal tubular cells exposed to TWEAK, a cytokine mediator of AKI. Fosl1 was minimally expressed in the kidneys of control uninjured mice. Increased Fosl1 protein was localized to proximal tubular cell nuclei in AKI. In human AKI, FOSL1 was found present in proximal tubular cells in kidney sections and in urine along with increased urinary FOSL1 mRNA. Selective Fosl1 deficiency in proximal tubular cells (Fosl1Δtub) increased the severity of murine cisplatin- or folate-induced AKI as characterized by lower kidney function, more severe kidney inflammation and Klotho downregulation. Indeed, elevated AP-1 activity was observed after cisplatin-induced AKI in Fosl1Δtub mice compared to wild-type mice. More severe Klotho downregulation preceded more severe kidney dysfunction. The Klotho promoter was enriched in Fosl1 binding sites and Fosl1 bound to the Klotho promoter in cisplatin-AKI. In cultured proximal tubular cells, Fosl1 targeting increased the proinflammatory response and downregulated Klotho. In vivo, recombinant Klotho administration protected Fosl1Δtub mice from cisplatin-AKI. Thus, increased proximal tubular Fosl1 expression during AKI is an adaptive response, preserves Klotho, and limits the severity of tubular cell injury and AKI.

Gain-of-function TLR7 and loss-of-function A20 gene variants identify a novel pathway for Mendelian lupus and lupus nephritis.

Systemic lupus erythematosus (SLE) is a chronic and inflammatory autoimmune disease of unknown origin that may cause kidney disease, i.e. lupus nephritis (LN). Within a wider trend towards an expanding field of genetic causes of kidney disease, two recent reports have emphasized the role of Mendelian autoimmune disorders in causing LN both in children and in young adults. Loss-of-function (LOF) variants of tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and gain of function (GOF) variants of Toll-like receptor 7 (TLR7) cause SLE and LN, respectively. Interestingly, both genes regulate the same signaling route, as A20, the protein encoded by TNFAIP3, inhibits nuclear factor ĸB (NF-ĸB) activation while TLR7 promoted NF-ĸB activation. Moreover, TNFAIP3 and TLR7 variants are relatively frequent, potentially contributing to polygenic risk for LN. Finally, they both may be expressed by kidney cells, potentially contributing to the severity of kidney injury in persons who have already developed autoimmunity. The fact that both genes regulate the same pathway may lead to novel therapeutic approaches targeting the shared molecular pathway.

Who killed Bruce Lee? The hyponatraemia hypothesis.

Bruce Lee brought attention to martial arts in the Western world and popularized the quote 'Be water, my friend'. Lee died at the age of 32 years in Hong Kong on 20 July 1973, under mysterious circumstances. The cause of death is unknown, although numerous hypotheses have been proposed, from assassination by gangsters to the more recent suggestion in 2018 that he died from heatstroke. The necropsy showed cerebral oedema. A prior episode was diagnosed as cerebral oedema 2 months earlier. We now propose, based on an analysis of publicly available information, that the cause of death was cerebral oedema due to hyponatraemia. In other words, we propose that the kidney's inability to excrete excess water killed Bruce Lee. In this regard, Lee had multiple risk factors for hyponatraemia that may have included high chronic fluid intake, factors that acutely increase thirst (marijuana) and factors that decrease the ability of the kidneys to excrete water by either promoting secretion of antidiuretic hormone (ADH) or interfering with water excretion mechanisms in kidney tubules: prescription drugs (diuretics, non-steroidal anti-inflammatory drugs, opioids, antiepileptic drugs), alcohol, chronic low solute intake, a past history of acute kidney injury and exercise.

Impact of different COVID-19 waves on kidney replacement therapy epidemiology and mortality: REMER 2020.

BACKGROUND: Kidney replacement therapy (KRT) confers the highest risk of death from coronavirus disease 2019 (COVID-19). However, most data refer to the early pandemic waves. Whole-year analysis compared with prior secular trends are scarce. METHODS: We present the 2020 REMER Madrid KRT registry, corresponding to the Spanish Region hardest hit by COVID-19. RESULTS: In 2020, KRT incidence decreased 12% versus 2019, while KRT prevalence decreased by 1.75% for the first time since records began and the number of kidney transplants (KTs) decreased by 16%. Mortality on KRT was 10.2% (34% higher than the mean for 2008-2019). The 2019-2020 increase in mortality was larger for KTs (+68%) than for haemodialysis (+24%) or peritoneal dialysis (+38%). The most common cause of death was infection [n = 419 (48% of deaths)], followed by cardiovascular [n = 200 (23%)]. Deaths from infection increased by 167% year over year and accounted for 95% of excess deaths in 2020 over 2019. COVID-19 was the most common cause of death (68% of infection deaths, 33% of total deaths). The bulk of COVID-19 deaths [209/285 (73%)] occurred during the first COVID-19 wave, which roughly accounted for the increased mortality in 2020. Being a KT recipient was an independent risk factor for COVID-19 death. CONCLUSIONS: COVID-19 negatively impacted the incidence and prevalence of KRT, but the increase in KRT deaths was localized to the first wave of the pandemic. The increased annual mortality argues against COVID-19 accelerating the death of patients with short life expectancy and the temporal pattern of COVID-19 mortality suggests that appropriate healthcare may improve outcomes.

Wasp stings and plasma exchange.

Invasive species related to climate change and/or globalization may be associated with novel forms of kidney disease. This is the case for wasps. Several species of Asian wasps are increasingly found in America (e.g. Asian giant hornet, Vespa mandarinia) and Europe (e.g. yellow-legged Asian hornet, V. velutina; black shield hornet, V. bicolor; and Oriental hornet, V. orientalis). Some of these species have been associated with human deaths and acute kidney injury. The literature on wasps and acute kidney injury is scarce and mostly originates from Asia, so nephrologists outside Asia are not familiar with this health problem. In a recent issue of ckj, Liu et al. describe a simple, four-item Wasp Sting Severity Score (WSS) developed from 1131 wasp sting patients. Vespa mandarinia and V. velutina were among those causing hospitalization, although most cases were caused by the black-bellied hornet (V. basalis). Liu et al. propose that a WSS ≥3 should guide early (<24 h after stings) plasma exchange, as plasma exchange was associated with lower mortality in severely affected patients but continuous venovenous haemofiltration and haemoperfusion were not. The WSS will require external validation. This manuscript should raise awareness about the potentially fatal consequences of stings by wasp species making their way into America and Europe.

Stopping kidney protection in the elderly following acute kidney injury: think mortality.

Chronic kidney disease (CKD) is projected to become the fifth most common global cause of death by 2040. This illustrates a key consequence of CKD, i.e. premature mortality. Since nephroprotective drugs such as renin-angiotensin system (RAS) blockers and sodium-glucose transport protein 2 (SGLT2) inhibitors decrease glomerular hyperfiltration, they may be stopped following an episode of acute kidney injury (AKI). This may theoretically modify the risks of subsequent events, ranging from hyperkalaemia to CKD progression to cardiovascular events, but the evidence so far has been inconsistent. Roemer et al. have now addressed the shortcomings of prior studies. In a population of mostly elderly (median age 78 years) prevalent users of RAS blockers with an indication for this therapy and who survived for at least 3 months after discharge following a hospitalization characterized by moderate to severe AKI, roughly 50% had stopped RAS blockade at 3 months. Stopping RAS blockade was associated with an increased risk of a primary composite outcome of death, myocardial infarction and stroke, of which a large majority (80%) of events were deaths. In contrast, the risk of hyperkalaemia was reduced and the risk of repeated AKI, CKD progression or heart failure hospitalization was unchanged in patients who stopped RAS blockers. These findings call for a re-evaluation of the practice of stopping RAS blockers in the long-term following AKI and suggest that studies are needed regarding similar practices for SGLT2 inhibitors.

Solving the riddle of Aguascalientes nephropathy: nephron number, environmental toxins and family clustering.

Aguascalientes, Mexico, has a high incidence and prevalence of advanced chronic kidney disease (CKD). CKD is especially frequent in young people ages 20-40 years in whom the cause of CKD was unknown, although kidney biopsies frequently showed focal segmental glomerulosclerosis (FSGS) and glomerulomegaly. Macias-Diaz et al. have now pursued this lead by screening teenagers in Calvillo, one of the hardest hit municipalities. They uncovered clinical, laboratory, kidney biopsy and exposure findings that define a new entity, Aguascalientes nephropathy, and are consistent with familial exposure to common environmental toxins, potentially consisting of pesticides. They hypothesize that prenatal exposure to these toxins may decrease nephron number. The young age of persons with FSGS would be consistent with a novel environmental toxin introduced more than 50 years ago but not present in the environment before. Key takeaways from this research are the need to screen teenagers for albuminuria, to provide kidney-protective strategies to patients identified as having CKD and for the research community to support Aguascalientes nephrologists and health authorities to unravel the cause and potential solutions for this CKD hotspot. In this regard, the screening approach and the cohort generated by Macias-Diaz et al. represent a giant step forward. The next steps should be to screen younger children for albuminuria and kidney size and to identify the putative toxins.

Blood pressure targets in CKD 2021: the never-ending guidelines debacle.

In 2021, two updated clinical guidelines were published, providing guidance on blood pressure (BP) targets for people with chronic kidney disease (CKD). Kidney Disease: Improving Global Outcomes (KDIGO) updated its 2012 Clinical Practice Guideline for the Management of BP in CKD. Different systolic blood pressure (SBP) and diastolic blood pressure (DBP) targets for CKD (<130/80 and <140/90 mmHg, respectively, for people with a urinary albumin: creatinine ratio >30 mg/g or without pathological albuminuria) were replaced by a single number: an SBP target of <120 mmHg is suggested, when tolerated. This represents a major decrease in the SBP target and the abandonment of DBP targets. The European Society of Cardiology (ESC) also published a 2021 Clinical Guideline on Cardiovascular Disease Prevention in Clinical Practice that updates a prior 2016 guideline on prevention and the 2018 ESC/European Society of Hypertension Clinical Practice Guidelines for the Management of Arterial Hypertension. The 2021 ESC guideline was endorsed by 12 European scientific societies. The recommended office BP targets for people with CKD are <140-130 mmHg SBP (lower SBP is acceptable if tolerated) and <80 mmHg DBP. The question is: What should the practicing physician do now: treat hypertension in people with CKD to an SBP target of <120 mmHg or to a target of <140-130 mmHg? Major guideline bodies are aware of the activities of other major players. There is an urgent need for guideline bodies to establish communication channels, search consensus on major issues that impact the health of hundreds of millions of people worldwide and end individualism in guidelines generation.

The last pre-pandemic European Renal Association Registry report: age at start of kidney replacement therapy in Europe.

The European Renal Association (ERA) Registry Annual Report 2019 will be its last pre-pandemic report. From 2020 on, registry data will incorporate any potential impact of coronavirus disease 2019 (COVID-19) on kidney replacement therapy (KRT) practices in Europe. The 2019 report focussed on age comparisons and found substantial differences in the distribution of primary renal disease, treatment modality, kidney donor type and the survival probabilities for different age categories. The report presents data that support a correlation (R 2 = 0.43, P < 0.00001) between the incidence of KRT per million population (pmp) and the median age at the start of KRT in the different regions and countries, suggesting that initiating KRT at an older median age may be a determinant of KRT incidence. The causes of the lower age at KRT in some countries should be explored. These may include, but are not limited to, KRT not being offered to the elderly or the elderly refusing KRT. In this regard, there was a correlation between the median age at the start of KRT and per capita gross domestic product (GDP) (R 2 = 0.26, P < 0.0046), suggesting that the availability of resources may be a factor that limits the offer of KRT to the elderly. The UK may represent a case to study these issues. Both age at initiation of KRT and KRT incidence are below the European median and lower than that expected for GDP. Furthermore, there are differences between the various countries within the UK, as well as documented racial differences, the latter being a piece of information missing for most European countries.