Calcineurin inhibitor-related hyperkalemia is caused by hyporeninemic hypoaldosteronism and fludrocortisone is an effective treatment: Report of a case series and review of the literature.

INTRODUCTION: Calcineurin inhibitors (CNIs) are widely used in transplantation. Although CNI-related hyperkalemia is common (10%-60.6%), the underlying pathogenetic mechanism is not well-elucidated and may lead to dose adjustment or treatment withdrawal. OBJECTIVE: The aim of this study is to describe CNI-related hyperkalemia due to hyporeninemic hypoaldosteronism in pediatric transplant recipients who were successfully treated with fludrocortisone. METHOD: In a total of 55 hematopoietic stem cell (HSCT) and 35 kidney transplant recipients followed according to institutional immunosuppression protocols, recipients diagnosed with CNI-related hyperkalemia were reviewed. Recipients who were receiving intravenous fluid, potassium, or were diagnosed with hemolysis, acute graft rejection, or had an eGFR < 30 mL/min/1.73m2, were excluded. A detailed analysis of clinical history as well as biochemical studies was carried out to reveal possible pathophysiology. RESULTS: Three pediatric transplant recipients (one HSCT, two kidney transplantation) with findings of hyperkalemia, hyponatremia, and a mild elevation in blood urea nitrogen while on CNIs were recruited. Urinary potassium excretion was diminished while sodium excretion was increased. Plasma aldosterone levels were low, and renin was not increased in response. Primary adrenal insufficiency was ruled out, and hyporeninemic hypoaldosteronism was diagnosed. CNI-related hyperkalemia was detected earlier in case 1, who had HSCT (22 days), than in the second and third cases, who had kidney transplantation (24 and 30 months post-transplantation, respectively). The discrepancy was hypothesized to be explained by higher overall CNI dose due to higher serum target CNI used in HSCT than kidney transplantation. Electrolyte imbalance was reversed upon administration of physiologic dose fludrocortisone (0.05 mg, daily), while fludrocortisone was ceased after CNI withdrawal in case 1, which is additional evidence for the etiological association of CNIs and hyporeninemic hypoaldosteronism. CONCLUSION: Our three cases strengthen the premise that CNI-related hyperkalemia may be due to hyporeninemic hypoaldosteronism, and the timing and severity may be related to CNI dose. Fludrocortisone is a safe and effective treatment in CNI-related hyperkalemia, providing maintenance of CNIs, which are one of the essential therapeutic agents for pediatric transplantation.

Acquired hyperkalaemia leading to periodic paralysis: an emergency department perspective.

Hyperkalaemia is one of the common electrolyte imbalances dealt with in the emergency department and is caused by extracellular accumulation of potassium ions above normal limits usually greater than 5.0-5.5 mmol/L. It is found in a total of 1-10% of hospitalised patients usually associated with chronic kidney disease and heart failure. The presentation can range from being asymptomatic to deadly arrhythmias. The appearance of symptoms depends on the rate of change rather than just the numerical values. The rare presentation includes periodic paralysis characterised by the sudden onset of short-term muscle weakness, stiffness or paralysis. Management goals are directed towards reducing potassium levels in emergency settings and later on avoiding the triggers for future attacks. In this case, we present a man in his 50s with the generalised weakness later on diagnosed as hyperkalaemic periodic paralysis secondary to tumour lysis syndrome. Emergency physicians dealing with common electrolyte imbalances should keep a sharp eye on their rare presentation and their precipitating factors and should act accordingly.

Myelotoxicity and kidney dysfunction related to the use of trimethoprim-sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia: a case report of severe adverse events with a common drug.

Trimethoprim-sulfamethoxazole (TMP-SMX) is the primary therapeutic option for Pneumocystis jirovecii pneumonia (PCP). Gastrointestinal symptoms and cutaneous rash are common side effects, with hyperkalemia being uncommon in patients without kidney dysfunction, and myelotoxicity being even rarer. We present the case of a male patient with hypertension and a recent diagnosis of non-Hodgkin lymphoma, undergoing rituximab treatment for two months. He was admitted to the intensive care unit due to dyspnea, tachypnea, and pleuritic pain, requiring mechanical ventilation. Chest computed tomography showed bilateral and multilobed ground-glass opacities, compromising more than 80% of the lung parenchyma. Pulmonary tuberculosis and COVID-19 were ruled out. An angiotomography and Doppler ultrasound revealed an extensive pulmonary thrombus and deep venous thrombosis. Empiric treatment with TMP-SMX for PCP was initiated, but within four days, the patient experienced metabolic acidosis and severe hyperkalemia, necessitating hemodialysis. He also presented with progressive pancytopenia and critical levels of leukopenia and thrombocytopenia. The hypothesis of TMP-SMX-induced myelotoxicity was suspected. Considering the unavailability of an alternative treatment, it was opted to continue TMP-SMX and initiate a granulocyte-colony-stimulating factor. However, the patient maintained medullary deterioration, becoming refractory to the transfusion of blood derivates. On the 17th day of treatment, a clinical decision was made to suspend TMP-SMX, leading to improvements within 48 hours in marrow and kidney functions, metabolic acidosis, and hyperkalemia. Despite all efforts, the patient died after 35 days of hospitalization due to hospital-acquired infections. This case highlights the importance of clinicians recognizing potential myelotoxicity with TMP-SMX and promptly discontinuing the drug if necessary.

A rare case of essential thrombocythemia with pseudo-hyperkalemia.

Essential thrombocythemia (ET) is a rare clonal stem cell disorder that affects the production of platelets in the bone marrow. This condition causes an overproduction of platelets, which can lead to blood clots and other complications. Potassium, on the other hand, is an essential mineral that plays a vital role in various bodily functions, including nerve impulses and muscle contractions. Here, in this case report, we investigated a case of pseudo-hyperkalemia caused by essential thrombocythemia in a 77-year-old woman with very high platelet counts. Moreover, this case report, which has no similar examples in the literature review, is important for clinicians.

Severe Hyperkalemia During a Robot-Assisted Total Radical Prostatectomy in a Patient with Stage 3a Chronic Kidney Disease: A Case Report.

A 63-year-old man with stage 3a chronic kidney disease (CKD) and mild hyperkalemia was scheduled for a robot-assisted prostatectomy. He was being treated with lisinopril. Owing to mild hyperkalemia (6.2 mmol/L), lisinopril was discontinued, and sodium polystyrene sulfonate was administered on the day before surgery. Three hours after incision, electrocardiographic signs of hyperkalemia manifested with the serum potassium concentration rising to 8 mmol/L. Although hyperkalemia is a common and well-documented side effect of angiotensin-converting enzyme inhibitors in patients with CKD, we report an extreme increase in potassium within a very short time period despite prior drug discontinuation.

Acceptability, Adherence, Safety and Experiences of Low Energy Diets in People With Obesity and Chronic Kidney Disease: A Mixed Methods Study.

OBJECTIVES: Obesity is a modifiable risk factor for chronic kidney disease (CKD) progression. Low energy diets (LEDs) have not been adequately studied in people with CKD. This study aimed to explore acceptability, adherence, safety, and experiences of two LED prescriptions in adults living with obesity and CKD. DESIGN AND METHODS: In a mixed-methods study, obese adults with CKD were prescribed two LEDs (∼800 to 1000 kcal/day each), in a randomised order for 2 weeks each. One diet consisted of four meal replacement products daily (Optifast®, Nestlé Health Science) and the other two pre-prepared frozen meals (Lite n' Easy®, Mitchell's Quality Foods). Participants received weekly dietitian support, completed daily adherence checklists (converted to % of provided meals/replacements consumed) and participated in post-intervention semi-structured interviews to capture their experience. RESULTS: Nine participants were included (mean age 46.5 ± 14.3 years, estimated glomerular filtration rate 64 ± 26 mL/min/1.73 m2, 4/9 male). Mean self-reported adherence was 88 ± 11% and mean 4-week weight change was -7.3 ± 5.6 kg. Two participants withdrew at week two. Most frequently reported side effects were hunger and headaches. Adverse events of interest included one episode each of hyperkalaemia and hypoglycaemia. No serious adverse events occurred. Four overarching themes of patient experiences were identified: strategies used to adapt, disruption to the norm, individual preferences, and influences on acceptability. CONCLUSIONS: LEDs were found to be acceptable and safe with high self-reported adherence rates. Future LED trials should include specialist diabetes management, close monitoring for hyperkalaemia and adequate support to assist with managing side effects and dietary and social adjustments.

Potassium levels in women with polycystic ovary syndrome using spironolactone for long-term.

OBJECTIVE: Spironolactone (SPL) has been used to manage hyperandrogenic manifestations in women with polycystic ovary syndrome (PCOS), but data on the risk of hyperkalemia in this population are scarce. The aim of this study was to evaluate the incidence of hyperkalemia in women with PCOS using SPL in the long term. DESIGN: Single-centre retrospective study. PATIENTS: Inclusion and analysis of 98 treatment periods in 78 women with PCOS (20 of whom were duplicates, returning after treatment interruption for a mean of 38 months) who received SPL for a minimum of 12 months and had at least three measurements of potassium levels over time. MEASUREMENTS: Clinical and hormonal profiles before and during SPL treatment. RESULTS: Mean age was 29.1 (SD: 9.6) years, and body mass index was 32.2 (SD: 8.1) kg/m². Nine patients had diabetes, and 22 had prediabetes. SPL was used in combination with combined oral contraceptive pills in 55 participants and progestin-only pills/long-acting reversible contraception in 28; metformin was added in 35, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in 15. Median SPL dose was 100 (range: 50-150) mg. A total of 327 serum potassium measurements were obtained (84 pre-exposure and 243 postexposure). Four potassium measurements were above the reference range before exposure and 19 during exposure. All potassium measurements above the reference range during follow-up were classified as mild hyperkalemia (5.1-5.5 mEq/L). CONCLUSIONS: The present findings suggest that women with PCOS, without kidney or heart disease, using SPL combined with hormonal contraception for managing clinical hyperandrogenism have a low incidence of hyperkalemia and well-tolerated minor adverse effects.

Overview of research progress on the association of dietary potassium intake with serum potassium and survival in hemodialysis patients, does dietary potassium restriction really benefit hemodialysis patients?

For the general population, increasing potassium intake can reduce the incidence of cardiovascular and cerebrovascular diseases. However, since hyperkalemia is a common and life-threatening complication in maintenance hemodialysis patients, which can increase the risk of malignant arrhythmia and sudden death, the current mainstream of management for hemodialysis patients is dietary potassium restriction in order to prevent hyperkalemia. Hemodialysis patients are usually advised to reduce dietary potassium intake and limit potassium-rich fruits and vegetables, but there is limited evidence to support this approach can reduce mortality and improve quality of life. There is still no consistent conclusion on the association between dietary potassium intake and serum potassium and survival in hemodialysis patients. According to the current small observational studies, there was little or even no association between dietary potassium intake and serum potassium in hemodialysis patients when assurance of adequate dialysis and specific dietary patterns (such as the plant-based diet mentioned in the article) are being followed, and excessive dietary potassium restriction may not benefit the survival of hemodialysis patients. Additionally, when assessing the effect of diet on serum potassium, researchers should not only focus on the potassium content of foods, but also consider the type of food and the content of other nutrients. However, more large-scale, multi-center clinical trials are required to provide high-quality evidence support. Besides, further research is also needed to determine the optimal daily potassium intake and beneficial dietary patterns for hemodialysis patients.

[Hyponatremia and Electrolyte Disorders in Cancer Patients].

Onconephrology is a rising and rapidly expanding field of medicine in which nephrology and oncology meet each other. Besides multidisciplinary meetings, oncologists and nephrologists often discuss on timing of the treatment, dosage, and side effects management. Cancer patients often encounter different electrolyte disorders. They are mostly secondary to the tumor itself or consequences of its treatment. In the last years, the great efforts to find new therapies like targeted, immune, and cell-based led us to many new side effects. Hyponatremia, hypokalemia, hyperkalemia, hypercalcemia, and hypomagnesemia are among the most common electrolyte disorders. Data have shown a worse prognosis in patients with electrolytic imbalances. Additionally, they cause a delay in chemotherapy or even an interruption. It is important to diagnose promptly these complications and treat them. In this review, we provide a special focus on hyponatremia and its treatment as the most common electrolytes disorder in cancer patients, but also on newly described cases of hypo- and hyperkalemia and metabolic acidosis.

Tumor lysis syndrome in premature infant prompting early resection of a large sacrococcygeal teratoma: a case report.

BACKGROUND: Sacrococcygeal teratomas (SCTs) are the most common congenital neoplasm and often require resection soon after birth. There are rare reports of cardiac arrest during surgery due to manipulation of the tumor triggering secondary necrosis and hyperkalemia. CASE PRESENTATION: This case describes a very preterm infant with a SCT who develops spontaneous preoperative tumor lysis syndrome (TLS). The medical team utilized rasburicase and the patient underwent total gross resection at 40 h of life. CONCLUSIONS: We emphasize the importance of the early recognition and management of tumor lysis syndrome in SCT with rasburicase, aggressive management of hyperkalemia and consideration of early resection of SCTs even in the case of a very premature infant.

Acute flaccid paralysis due to multifactorial hyperkalaemia.

A male patient in his late 30s with a history of Lynch syndrome and colorectal cancer relapse, which recently started chemotherapy, was admitted to the emergency department with acute lower limb weakness that had progressed to all limbs and resulted in complete flaccid paresis with general areflexia. Blood tests showed severe hyperkalaemia, severe acute kidney injury and hyperuricaemia. Ultrasound showed bilateral hydronephrosis due to pelvic mass obstruction. Hyperkalaemia correction measurements were started as well as rasburicase with the assumption of tumour lysis syndrome and postrenal kidney injury. The patient showed a favourable clinical response with complete return of limb movement in the following hours and progressive recovery of renal function in the following days. This case highlights the need for prompt diagnosis and correction of severe hyperkalaemia, and its multiple possible causes, as it can lead to acute flaccid paralysis and a fatal outcome.

Brugada syndrome uncovered in patient with pseudohypoaldosteronism due to hyperkalaemia.

Brugada syndrome is a rare sodium channelopathy that predisposes to an increased risk of malignant arrythmias and sudden cardiac death. Previous studies have reported that metabolic disturbances can uncover a Brugada ECG pattern. Given the risk of malignant arrhythmias, it is important to correctly diagnose and treat Brugada syndrome. We report a case of Brugada syndrome uncovered by hyperkalaemia precipitated in a patient with pseudohypoaldosteronism.

Medication-Related Adverse Events and Discordancies in Cystatin C-Based vs Serum Creatinine-Based Estimated Glomerular Filtration Rate in Patients With Cancer.

Importance: Serum creatinine-based estimated glomerular filtration rate (eGFRcr) may overestimate the glomerular filtration rate (GFR) in patients with cancer. Cystatin C-based eGFR (eGFRcys) is an alternative marker of GFR. Objective: To determine whether the therapeutic drug levels and adverse events (AEs) associated with renally cleared medications were higher in patients with cancer whose eGFRcys was more than 30% lower than their eGFRcr. Design, Setting, and Participants: This cohort study analyzed adult patients with cancer at 2 major academic cancer centers in Boston, Massachusetts. These patients had their creatinine and cystatin C measured on the same day between May 2010 and January 2022. The date of the first simultaneous eGFRcr and eGFRcys measurement was considered to be the baseline date. Exposure: The primary exposure was eGFR discordance, defined as an eGFRcys that was more than 30% lower than the eGFRcr. Main Outcomes and Measures: The primary outcome was risk of the following medication-related AEs within 90 days of the baseline date: (1) supratherapeutic vancomycin trough level greater than 30 µg/mL, (2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5 mEq/L), (3) baclofen toxic effect, and (4) supratherapeutic digoxin level (>2.0 ng/mL). For the secondary outcome, a multivariable Cox proportional hazards regression model was used to compare 30-day survival of those with vs without eGFR discordance. Results: A total of 1869 adult patients with cancer (mean [SD] age, 66 [14] years; 948 males [51%]) had simultaneous eGFRcys and eGFRcr measurement. There were 543 patients (29%) with an eGFRcys that was more than 30% lower than their eGFRcr. Patients with an eGFRcys that was more than 30% lower than their eGFRcr were more likely to experience medication-related AEs compared with patients with concordant eGFRs (defined as eGFRcys within 30% of eGFRcr), including vancomycin levels greater than 30 µg/mL (43 of 179 [24%] vs 7 of 77 [9%]; P = .01), trimethoprim-sulfamethoxazole-related hyperkalemia (29 of 129 [22%] vs 11 of 92 [12%]; P = .07), baclofen toxic effects (5 of 19 [26%] vs 0 of 11; P = .19), and supratherapeutic digoxin levels (7 of 24 [29%] vs 0 of 10; P = .08). The adjusted odds ratio for vancomycin levels more than 30 µg/mL was 2.59 (95% CI, 1.08-7.03; P = .04). Patients with an eGFRcys more than 30% lower than their eGFRcr had an increased 30-day mortality (adjusted hazard ratio, 1.98; 95% CI, 1.26-3.11; P = .003). Conclusions and relevance: Results of this study suggest that among patients with cancer with simultaneous assessment of eGFRcys and eGFRcr, supratherapeutic drug levels and medication-related AEs occurred more commonly in those with an eGFRcys more than 30% lower than their eGFRcr. Future prospective studies are needed to improve and personalize GFR estimation and medication dosing in patients with cancer.

Prolonged postoperative hypoaldosteronism related to hyperkalemia in patients with aldosterone-producing adenoma.

Hyperkalemia is developed in a part of patients with aldosterone-producing adenoma (APA) after adrenalectomy, suspected to be due to the insufficiency of aldosterone secretion. The purpose of this study is to determine the frequency and characteristics of prolonged postoperative hypoaldosteronism (PPHA) using chemiluminescent enzyme immunoassay (CLEIA). We studied 58 patients with APA with long time after adrenalectomy and whose PAC was measured using a CLEIA kit. The PAC value measured using CLEIA was significantly lower than that of using RIA between two consecutive visits before and after the shift of measuring method of PAC (median [interquantile range], 123.0 [99.8-164.0] vs. 39.5 [15.8-64.2] pg/mL, p < 0.01). PAC was below the minimum limit of quantification (4.0 pg/mL) of the CLEIA kit at least once in nine patients (15.5%) who had PPHA. The PPHA group were older (mean ± standard deviation, 61.3 ± 8.5 vs. 50.5 ± 10.1 years, p < 0.01) and had lower eGFR (60.3 ± 14.0 vs. 82.3 ± 22.8 mL/min/1.73 m2, p < 0.01) than the non-PPHA group. The frequency of postoperative hyperkalemia (maximum serum potassium >5.5 mEq/L) was higher in the PPHA group than in the non-PPHA group (55.6% vs. 8.2%, p < 0.01). In conclusion, a few patients with APA long time after adrenalectomy had unmeasurable PAC using CLEIA. PPHA is likely to develop in patients with APA after adrenalectomy who are older and have impaired renal function. Additionally, PPHA is related to the occurrence of postoperative hyperkalemia.

Pseudohyperkalemia in chronic lymphocytic leukemia: Prevalence, impact, and management challenges.

The term pseudohyperkalemia refers to a false elevation in serum potassium levels due to potassium release from cells in vitro. Falsely elevated potassium levels have been reported in patients with thrombocytosis, leukocytosis, and hematologic malignancies. This phenomenon has been particularly described in chronic lymphocytic leukemia (CLL). Leukocyte fragility, extremely high leukocyte counts, mechanical stress, higher cell membrane permeability related to an interaction with lithium heparin in plasma blood samples, and metabolite depletion due to a high leukocyte burden have been reported to contribute to pseudohyperkalemia in CLL. The prevalence of pseudohyperkalemia is up to 40%, particularly in the presence of a high leukocyte count (>50 × 109/L). The diagnosis of pseudohyperkalemia is often overlooked, which may result in unnecessary and potentially harmful treatment. The use of whole blood testing and point-of-care blood gas analysis, along with thorough clinical evaluation, may help differentiate between true and pseudohyperkalemic episodes.

Long-term effect of eplerenone treatment in children with chronic allograft nephropathy.

BACKGROUND: Literature supports the protective role of mineralocorticoid antagonist (MRA) against the renal injury induced by aldosterone in kidney transplant recipients. However, there is limited data available regarding the safety and efficacy of MRAs in pediatric renal transplant patients. Therefore, we aimed to investigate the effect of long-term eplerenone administration in children with chronic allograft nephropathy (CAN). METHODS: Twenty-six renal transplant children with biopsy-proven CAN, an estimated glomerular filtration rate (eGFR ) > 40 mL/min per 1.73 m2 and with a significant proteinuria were included. Selected patients were randomly divided into two groups as follows; Group 1 (n = 10) patients received 25 mg/day eplerenone and Group 2 (n = 16) patients did not receive eplerenone for 36 months. Patients were examined in the renal transplant outpatient clinic biweekly for the first month and once a month thereafter. The primary outcome of the patients was compared. RESULTS: Mean eGFR stayed stable in group 1 patients, but significantly decreased in group 2 at 36 months (57.53 ± 7.53 vs. 44.94 ± 8.04 mL/min per 1.73 m2 , p = .001). Similarly, spot protein-creatinine ratio was significantly lower in group 1 compared to group 2 patients at 36 months (1.02 ± 7.53 vs. 3.61 ± 0.53, p < .001). Eplerenone associated hyperkalemia was not observed in group 1 patients (4.6 ± 0.2 vs. 4.56 ± 0.3, p = .713). CONCLUSION: The long-term eplerenone administration blunted the chronic allograft nephropathy by maintaining a stable eGFR levels and decreasing urine protein-creatinine ratio. Eplerenone associated hyperkalemia was not observed in our study.

Calcineurin regulates aldosterone production via dephosphorylation of NFATC4.

The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic inhibition of protein phosphatase 3 (calcineurin, Cn) results in inappropriately low plasma aldosterone levels despite concomitant hyperkalemia and hyperreninemia. We tested the hypothesis that Cn participates in the signal transduction pathway regulating aldosterone synthesis. Inhibition of Cn with tacrolimus abolished the potassium-stimulated (K+-stimulated) expression of aldosterone synthase, encoded by CYP11B2, in the NCI-H295R human adrenocortical cell line as well as ex vivo in mouse and human adrenal tissue. ZG-specific deletion of the regulatory Cn subunit CnB1 diminished Cyp11b2 expression in vivo and disrupted K+-mediated aldosterone synthesis. Phosphoproteomics analysis identified nuclear factor of activated T cells, cytoplasmic 4 (NFATC4), as a target for Cn-mediated dephosphorylation. Deletion of NFATC4 impaired K+-dependent stimulation of CYP11B2 expression and aldosterone production while expression of a constitutively active form of NFATC4 increased expression of CYP11B2 in NCI-H295R cells. Chromatin immunoprecipitation revealed NFATC4 directly regulated CYP11B2 expression. Thus, Cn controls aldosterone production via the Cn/NFATC4 pathway. Inhibition of Cn/NFATC4 signaling may explain low plasma aldosterone levels and hyperkalemia in patients treated with tacrolimus, and the Cn/NFATC4 pathway may provide novel molecular targets to treat primary aldosteronism.