Hyperkalemia in chronic kidney disease: a focus on potassium lowering pharmacotherapy.

INTRODUCTION: Hyperkalemia is one of the most common electrolyte disorders in chronic kidney disease (CKD) and is associated with serious adverse outcomes. Hyperkalemia risk is even greater when CKD patients also have additional predisposing conditions such as diabetes or heart failure. Renin-angiotensin-aldosterone-system blockers are first-line treatments for cardio- and nephroprotection, but their use is often limited due to K+ elevation, resulting in high rates of discontinuation. AREAS COVERED: This article provides an overview of factors interfering with K+ homeostasis and discusses recent data on newer therapeutic agents used for the treatment of hyperkalemia. A detailed literature search was performed in two major databases (PubMed/MEDLINE and Scopus) up to April 2023. EXPERT OPINION: Major clinical trials have tested new and promising kidney protective therapies such as sodium/glucose-cotransporter-2 inhibitors and mineralocorticoid-receptor-antagonists, with promising results. Until recently, the only treatment option for hyperkalemia was the cation-exchanging resin sodium-polystyrene-sulfonate. However, despite its common use, the efficacy and safety data of this drug in the long-term management of hyperkalemia are scarce. During the last decade, two novel orally administered K+-exchanging compounds (patiromer and sodium-zirconium-cyclosilicate) have been approved for the treatment of adults with hyperkalemia, as they both effectively reduce elevated serum K+ and maintain chronically K+ balance within the normal range with an excellent tolerability and no serious adverse events.

Prospective Analysis of B Lymphocyte Subtypes, before and after Initiation of Dialysis, in Patients with End-Stage Renal Disease.

End-stage renal disease (ESRD) is followed by alterations in adaptive immunity. The aim of this study was to evaluate B lymphocyte subtypes in ESRD patients before and after hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). PATIENTS AND METHODS: CD5, CD27, BAFF, IgM and annexin were evaluated by flow cytometry on CD19+ cells in ESRD patients (n = 40), at time of initiating HD or CAPD (T0) and 6 months later (T6). RESULTS: A significant reduction in ESRD-T0 compared to controls was noticed for CD19+, 70.8 (46.5) vs. 171 (249), p < 0.0001, CD19+CD5-, 68.6 (43) vs. 168.9 (106), p < 0.0001, CD19+CD27-, 31.2 (22.1) vs. 59.7 (88.4), p < 0.0001, CD19+CD27+, 42.1 (63.6) vs. 84.3 (78.1), p = 0.002, CD19+BAFF+, 59.7 (37.8) vs. 127.9 (123.7), p < 0.0001 and CD19+IgM+ cells, 48.9 (42.8) vs. 112.5 (81.7) (K/µL), p < 0.0001. The ratio of early/late apoptotic B lymphocytes was reduced (16.8 (10.9) vs. 110 (25.4), p = 0.03). CD19+CD5+ cells were the only cell type with an increased proportion in ESRD-T0 patients (2.7 (3.7) vs. 0.6 (1.1), p < 0.0001). After 6 months on CAPD or HD, CD19+CD27-(%) and early apoptotic lymphocytes were reduced further. The HD patients also showed a significant increase in late apoptotic lymphocytes, from 1.2 (5.7) to 4.2 (7.2) K/mL, p = 0.02. CONCLUSIONS: B cells and most of their subtypes were significantly reduced in ESRD-T0 patients compared to controls, the only exception being CD19+CD5+ cells. Apoptotic changes were prominent in ESRD-T0 patients and were exacerbated by HD.

Serum OPG and RANKL Levels as Risk Factors for the Development of Cardiovascular Calcifications in End-Stage Renal Disease Patients in Hemodialysis.

Cardiovascular calcifications (CVC) are frequently observed in chronic kidney disease (CKD) patients and contribute to their cardiovascular mortality. The aim of the present study was to investigate the impact of osteoprotegerin (OPG)/Receptor Activator of NF-κΒ (RANK)/RANK ligand (RANKL) pathway in the development and evolution of CVCs in hemodialysis patients. In total, 80 hemodialysis patients were assessed for the presence of vascular (abdominal aorta and muscular arteries) calcifications and results were correlated to serum OPG and RANKL levels and the OPG/RANKL ratio. Traditional cardiovascular risk factors and mineral bone disease parameters were also estimated. The presence of VCs was also evaluated 5 years after the initiation of the study, and results were correlated to the initial serum OPG levels. Age, diabetes mellitus, coronary artery disease and OPG levels (p < 0.001) were associated with VCs, whereas RANKL levels were not. Multivariate analysis though revealed that only OPG levels were significantly associated with abdominal aorta calcifications (p = 0.026), but they were not correlated with the progression of VCs. Serum OPG levels are positively and independently associated with VCs in HD patients, but not with their progression. RANKL levels did not show any associations, whereas further studies are needed to establish the significance of OPG/RANKL ratio.

A Rare Case of Extensive Eggshell Intestinal Wall Peritoneal Calcification in a Long-Term Continuous Peritoneal Dialysis Patient.

Encapsulating peritoneal sclerosis (EPS) is a rare but rather serious complication of long-term peritoneal dialysis. The etiology of EPS is multifactorial, with long-term peritoneal dialysis, multiple peritonitis episodes, and uncontrolled hyperparathyroidism considered to be major risk factors for this often life-threatening condition. We report a case of a 55-year-old female patient with Down syndrome and end-stage renal disease (ESRD) on long-term peritoneal dialysis (PD) with extensive intestinal peritoneal calcifications and a rather uncomplicated long follow-up.

Clustering of End Stage Renal Disease Patients by Dimensionality Reduction Algorithms According to Lymphocyte Senescence Markers.

End stage renal disease (ESRD) engenders detrimental effects in the Immune system, manifested as quantitative alterations of lymphocyte subpopulations, akin, albeit not identical to those observed during the ageing process. We performed dimensionality reduction of an extended lymphocyte phenotype panel of senescent and exhaustion related markers in ESRD patients and controls with Principal Component Analysis (PCA) and Uniform Manifold Approximation and Projection (UMAP). The plane defined by the first two principal components of PCA showed two fuzzy clusters, for patients and controls, respectively, with loadings of non-senescent markers pointing towards the controls' centroid. Naive lymphocytes were reduced in ESRD patients compared to controls (CD4+CD45RA+CCR7+ 200(150-328) vs. 426(260-585cells/µl respectively, P = 0.001, CD19+IgD+CD27- 54(26-85) vs. 130(83-262)cells/µl respectively, P < 0.001). PCA projections of the multidimensional ESRD immune phenotype suggested a more senescent phenotype in hemodialysis compared to hemodiafiltration treated patients. Lastly, clustering based on UMAP revealed three distinct patient groups, exhibiting gradual changes for naive, senescent, and exhausted lymphocyte markers. Machine learning algorithms can distinguish ESRD patients from controls, based on their immune-phenotypes and also, unveil distinct immunological groups within patients' cohort, determined possibly by dialysis prescription.

Validation of the International IgA Nephropathy Prediction Tool in the Greek Registry of IgA Nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is among the commonest glomerulonephritides in Greece and an important cause of end-stage kidney disease (ESKD) with an insidious chronic course. Thus, the recently published International IgAN prediction tool could potentially provide valuable risk stratification and guide the appropriate treatment module. This study aimed to externally validate this prediction tool using a patient cohort from the IgAN registry of the Greek Society of Nephrology. METHODS: We validated the predictive performance of the two full models (with or without race) derived from the International IgAN Prediction Tool study in the Greek Society of Nephrology registry of patients with IgAN using external validation of survival prediction models (Royston and Altman). The discrimination and calibration of the models were tested using the C-statistics and stratified analysis, coefficient of determination ( R D 2 ) for model fit, and the regression coefficient of the linear predictor (ßPI), respectively. RESULTS: The study included 264 patients with a median age of 39 (30-51) years where 65.2% are men. All patients were of Caucasian origin. The 5-year risk of the primary outcome (50% reduction in estimated glomerular filtration rate or ESKD) was 8%. The R D 2 for the full models with and without race when applied to our cohort was 39 and 35%, respectively, and both were higher than the reported R D 2 for the models applied to the original validation cohorts (26.3, 25.3, and 35.3%, respectively). Harrel's C statistic for the full model with race was 0.71, and for the model without race was 0.70. Renal survival curves in the subgroups (<16th, ~16 to <50th, ~50 to <84th, and >84th percentiles of linear predictor) showed adequate separation. However, the calibration proved not to be acceptable for both the models, and the risk probability was overestimated by the model. CONCLUSIONS: The two full models with or without race were shown to accurately distinguish the highest and higher risk patients from patients with low and intermediate risk for disease progression in the Greek registry of IgAN.

End stage renal disease has an early and continuous detrimental effect on regulatory T cells.

End stage renal disease (ESRD) is followed by disturbed adaptive immunity, together with alterations in T cell subsets, including CD4+CD25+FoxP3+ cells (Tregs). In the present study, we assessed the effect of haemodialysis (HD) on the Treg population. CD3+CD4+, CD3+CD8+ and CD4+CD25+FoxP3+ cells were estimated by flow cytometry in 142 ESRD patients (45 ESRD-preHD, 97 on HD) and 30 healthy controls (HC). Patients on HD were classified into three groups according to time on dialysis (HD vintage - HDV): A < 2 years, B: 2-5 years and C: >5 years on HD. The mean age of patients on HD (M/F 53/44) was 54.8 ± 14 years and the median HDV 58 (78) months. We observed a significant progressive reduction in the percentage and count of lymphocytes (p < .001, p < .001, respectively), CD3+CD4+ (p = .003 and, p < .001, respectively) and Tregs (p = .001 and, p < .001, respectively), between HC, ESRD-preHD and HD patients. HDV had a significant inverse correlation with total lymphocyte, CD3+CD4+ and Treg cell counts (p = .001, p < .001, p < .001, respectively) and, the percentage of lymphocytes and CD3+CD4+ cells (p = .005, p = .01, respectively). Furthermore, we stratified patients on HD into three groups according to HDV: A < 2 years, B: 2-5 years and C: >5 years on HD. Total lymphocytes and Tregs were significantly different among the three vintage groups (Kruskal-Wallis H test, p < .001, p < .001 respectively). CD3+CD4+ and CD3+CD8+ cells were also significantly affected (p < .001 and p = .001, respectively), after at least 2 years of HD. Tregs show prompt and significant reduction at the pre-dialysis stage, and continue to decrease gradually even after long-term HD, in a context of total lymphocyte reduction.

Prospective De Novo Donor-Specific Antibody Monitoring in Renal Transplant Patients.

BACKGROUND: De novo donor-specific antibodies (dnDSA) are associated with antibody-mediated rejection leading to kidney transplant failure. However, many transplant patients are stable with no signs of graft dysfunction at the time of dnDSA detection at screening test. METHODS: We prospectively studied 26 kidney transplant patients for 3 years, with dnDSA detected using the Luminex single-antigen bead assay in a routine test. Proteinuria and estimated glomerular filtration rate were evaluated along with dnDSA monitoring at least annually. RESULTS: Graft loss associated with dnDSA occurred in 8 (31%) patients, 14 ± 11 months after the initial detection of dnDSA. These patients had more frequently multiple dnDSA (P = .004) and remarkable proteinuria, more than 1 g daily (P < .001). The remaining 18 patients were followed for 38 ± 15 months and considered stable as there was no deterioration regarding estimated glomerular filtration rate and proteinuria. In 7 (39%) of these patients, dnDSA waned and were not detected anymore at follow-up. Antibodies against HLA class I had a significantly (P < .001) lower mean fluorescence intensity (MFI) (2603 ± 1098) compared with those against HLA class II (11,109 ± 6414). In regression analysis, they were predictive of dnDSA wane (P = .043; odds ratio, 0.18; 95% confidence interval, 0.04-0.94). Despite fluctuations during follow-up, there was no significant change in MFI for those who retained the dnDSA. CONCLUSIONS: The presence of dnDSA is transient in a significant proportion of stable renal transplant patients, especially in those with antibodies against HLA class I and a low MFI. Multiple dnDSA and severe proteinuria adversely affect renal graft survival.

Transient Hyperphosphatasemia in an Adolescent and an Adult Renal Transplant Patient.

BACKGROUND: In renal transplant patients receiving immunosuppression, a significant increase in alkaline phosphatase (ALP) might be indicative of liver or bone diseases caused by many factors. In infancy and early childhood, a transient and therefore benign increase in ALP often has been described, usually during a course of infectious disease. Rarely, transient hyperphosphatasemia occurs in adults. We herein present 2 cases of transient hyperphosphatasemia in an adolescent and an adult renal transplant recipient, respectively. CASE REPORT: In the first case, a 17-year-old adolescent presented with an ALP value up to 2451 U/L, reporting no symptoms. In the second case, a 56-year-old woman with a second well-functioning kidney transplant presented with an ALP value up to 1532 U/L, without symptoms. In both cases, the biochemical profile and ultrasound study were negative for liver disease while no viral or other type of infection was detected. Bone scanning was within normal range and parathyroid hormone was also normal. However, bone ALP was measured at 8.9 and 11.9 times, respectively, above reference values. ALP electrophoresis had a characteristic pattern with involvement of both liver and bone-specific isoforms. About 6 weeks after their peak, ALP values gradually returned to normal range. CONCLUSION: Benign transient hyperphosphatasemia, although rare, should be considered in the differential diagnosis of isolated ALP increase, even in adult patients with kidney transplant. Electrophoresis of ALP could narrow the diagnostic procedure in cases when neither liver nor bone disease is clinically apparent.

CD28null and Regulatory T Cells Are Substantially Disrupted in Patients with End-Stage Renal Disease Due to Diabetes Mellitus.

BACKGROUND: End-stage renal disease (ESRD) is associated with alterations in T-cell immunity, including increased CD28null and reduced regulatory T cells (Tregs). However, whether immune disturbances are due to ESRD or primary disease is not yet clear. As diabetes mellitus is the leading cause of ESRD, we evaluated its impact on the immune profile of ESRD patients. METHODS: CD28null, Tregs, and natural killer cells were initially analyzed by flow cytometry in 30 predialysis ESRD patients due to diabetes (DM), 30 non-DM (NDM), and 25 healthy controls. Measurements were repeated after 6 months on hemodialysis (HD) or peritoneal dialysis (CAPD). RESULTS: The percentage of CD4 + CD28null cells, CD8 + CD28null cells, and Tregs showed significant differences in DM, NDM, and controls; mean rank 33.71 vs. 25.68 vs. 18.88, p = 0.006, 37.79 vs. 28.82 vs. 17.08, p = 0.008, and 20.79 vs. 26.12 vs. 41.33, p = 0.001, respectively. DM vs. NDM had increased CD4 + CD28null and CD8 + CD28null cells, 11.5% (1.5%-24%) vs. 4.1% (0-42.3%), p = 0.02 and 61.3% (24%-76%) vs. 43% (5.7%-85%), p = 0.04, respectively. After 6 months on HD but not CAPD, DM showed a significant further increase in CD4 + CD28null cells, from 30 (14-100) to 52.7 (15-203), p = 0.02; and CD8 + CD28null cells, from 137 (56-275) to 266 (103-456), p = 0.01. CONCLUSIONS: Diabetes mellitus affects T-cell subtypes even at predialysis stage, though changes become more prominent after commencement on HD.

Influence of end stage renal disease on CD28 expression and T-cell immunity.

BACKGROUND: T-cell immunity is affected in end stage renal disease (ESRD). However, whether this happens at pre- or post-dialysis stage and what is the impact of different renal replacement methods, remains unclear. We investigated the alterations of T-cell subtypes in patients at pre-dialysis ESRD and their further changes during dialysis. METHODS: CD4+, CD8+, CD4 + CD28null and CD8 + CD28null T-cells were analysed in 40 ESRD patients at two different time points, (a) the day started on dialysis (ESRD-T0) and (b) 6 months later (ESRD-T6), while being on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Twenty-five age matched healthy volunteers served as controls. RESULTS: CD4+ and CD8+ T-cells were significantly reduced in ESRD-T0 patients compared to controls, 604 (105-3551) vs 943 (584-1867)µ/L, P = .001, and 352 (103-1561) vs 422.4 (263-1453)µ/L, P = .05, respectively. However, proportions of CD4 + CD28null and CD8 + CD28null cells were significantly increased, 6.4 (0.3-30)% vs 2.7 (0.1-7.8)%, P = .04 and 58.2 (12.8-85.4)% vs 39 (7.8-57.1)%, P = .01, respectively. Proportion of CD4 + CD28null cells showed significant correlation with serum CRP (r = .4, P = .04) and albumin levels (r = -.5, P = .007) in ERSD patients. ESRD-T0 patients with cardiovascular disease (CVD) had increased CD4 + CD28null and CD8 + CD28null proportions, 8.6 (1-30)% vs 2.1 (0.1-19.8)%, P = .04 and 62.5 (12.8-85.4)% vs 45.5 (5.7-73.7)%, P = .02, respectively, compared to those without. Six months later, both CD4 + CD28null and CD8 + CD28null T-cells were increased in HD compared to CAPD patients, by +110.11 (-27.1 to 311.4)% vs -28.1 (-100 to 30)%, P = .003 and +55.23 (-29.06 to 197.93)% vs -8.34 (-54.99 to 66.72)%, P = .05, respectively. CONCLUSIONS: CD4 + CD28null and CD8 + CD28null T-cells are increased at pre-dialysis ESRD, and correlate with chronic inflammatory markers and the presence of CVD. Dialysis methods seem to have different impact on these subpopulations.

Severe euglycemic diabetic ketoacidosis of multifactorial etiology in a type 2 diabetic patient treated with empagliflozin: case report and literature review.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a relatively novel class of oral medications for the treatment of Type 2 DM with a generally acceptable safety profile. However, these agents have been associated with rare events of a serious and potentially life-threatening complication named euglycemic diabetic ketoacidosis (euDKA). euDKA is not identical with the typical diabetic ketoacidosis, as it often presents with serious metabolic acidosis but only mild to moderate glucose and anion gap elevation. CASE PRESENTATION: We report a case of a 51-year old female with Type 2 DM treated with an SGLT-2 inhibitor, developing severe metabolic acidosis with only mild blood glucose elevation after a routine surgery. A careful evaluation of involved factors led to the diagnosis of euDKA, followed by cautious application of simple therapeutic measures that resulted in complete restoration of acidosis and glycemic control in less than 48-h. CONCLUSIONS: Euglycemic ketoacidosis is a rare but rather serious complication of SGLT-2 inhibitors use, often with a multifactorial etiology. Its atypical presentation requires a high level of awareness by physicians as early recognition of this complication can quickly and safely restore acid-base balance.

Euglycaemic diabetic ketoacidosis as a complication of SGLT-2 inhibitors: epidemiology, pathophysiology, and treatment.

INTRODUCTION: Sodium-glucose co-transporters 2 (SGLT-2) inhibitors are a relatively novel class of oral medications for the treatment of Type 2 Diabetes Mellitus, which lower plasma glucose by inhibiting glucose reabsorption in the proximal renal tubule. Apart from their hypoglycemic action, recent data suggest these agents have additional major cardioprotective and nephroprotective properties. AREAS COVERED: This review summarizes the existing data on epidemiology, pathophysiology, and treatment of euglycaemic ketoacidosis (euDKA) as a complication of SGLT-2 inhibitor use. EXPERT OPINION: Although SGLT-2 inhibitors have a relatively good adverse event profile, they have been associated with the serious and potentially life-threatening metabolic complication of euDKA. Data from major outcome trials suggest that the rate of DKA is quite low. However, the rate of DKA could be generally underestimated in clinical trials due to the atypical presentation of ketoacidosis, and even more so in real-life conditions. Management of this serious metabolic complication requires a proper understanding of its pathophysiology as well as increased awareness and early recognition of the potential risk factors involved. Following this, the institution of an array of simple supportive measures, could safely restore normal acid-base balance in most patients.

Chronic Therapy with Sucroferric Oxyhydroxide Does Not Affect Iron and Anemia Markers in Dialysis Patients.

INTRODUCTION: Sucroferric oxyhydroxide (SOH) is an iron-based phosphate binder (PB), and its use has been widely expanded since its initial approval in 2014. Based on the existing data, however, it remains yet unclear whether its long-term administration is followed by iron overload in dialysis patients. The purpose of this observational study was to evaluate the longstanding effects of SOH on the anemia and iron indices in patients on dialysis. METHODS: A total of 110 patients from 3 dialysis centers were included in the study; 49 were under chronic treatment with SOH (cohort A), while 61 were either receiving other PB or no treatment for hyperphosphatemia (cohort B). We initially compared the hematologic profile of patients in 2 cohorts (phase I), and subsequently, we evaluated modifications of the above parameters in the SOH treated patients over a period of 6 months (phase II). RESULTS: There were no statistically significant differences between 2 cohorts in terms of hemoglobin (Hb; 11.4 ± 1.3 vs. 11.6 ± 0.9 g/dL, p = 0.375), ferritin (473 ± 230 vs. 436 ± 235 ng/mL, p = 0.419) and transferrin saturation (TSAT;26.6 ± 13.2 vs. 26.5 ± 10.6%, p = 0.675), serum phosphate concentration (4.57 ± 1.05 vs. 4.3 ± 0.96 mg/dL, p = ns), and intact PTH (286 ± 313 vs. 239 ± 296 pg/mL, p = ns). Marginally, but significantly higher calcium levels were found in cohort A compared to cohort B (9.18 ± 0.58 vs. 8.9 ± 0.51 mg/dL, respectively, p = 0.008). In phase II, no significant changes were observed in hematological parameters after a 6-month treatment with SOH (Hb: from 11.5 ± 1.1 to 11.4 ± 1.3 g/dL, p = 0.4, serum ferritin levels: from 475 ± 264 to 473 ± 230 ng/mL, p = 0.951, TSAT: from 26.5 ± 16.7 to 26.6 ± 13.2%, p = 0.933). There were also no significant changes in the administration of iron supplements or erythropoietin dose during this period. CONCLUSIONS: SOH is an effective PB, and its long-term use is not complicated by iron overload.

Impact of Τh1 and Τh2 cytokines in the progression of idiopathic nephrotic syndrome due to focal segmental glomerulosclerosis and minimal change disease.

BACKGROUND: Differential diagnosis between primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is sometimes difficult as nephrotic syndrome is the main clinical symptom in both diseases. OBJECTIVES: This study has attempted to evaluate the urinary excretion of Th1 and Th2 cytokines as potential biomarkers in distinguishing the two types of nephrotic syndrome, and predicting outcome of renal function. PATIENTS AND METHODS: Thirty-six patients with FSGS (M/F 22/14, Age; 41.9 ± 17 years, SCr=1.7 ± 0.8 mg/dL, UProt=4.7 ± 5.5 g/24 h), and 21 with MCD (M/F 5/16, Age; 41.4 ± 15 years, SCr = 1 ± 0.4 mg/dL, UProt = 7.9 ± 9.3 g/24 h) were included in the study. Τh1 (IL-2, IL-12, GM-CSF, INF-γ, TNF-α) and Th2 cytokines (IL-4, IL-5, IL-10, IL-13) were measured by multiple cytokine assay, Luminex technology, in first morning urinary samples collected at the day of renal biopsy. RESULTS: No significant differences in urinary excretion of all cytokines were found between FSGS and MCD patients. In FSGS however, IL-12 urinary levels were independent factor correlated with both global sclerosis (R = 0.5, P = 0.009) and interstitial fibrosis (R = 0.5, P = 0.02). Th1 cytokines (IL-2 and GM-CSF) were significantly increased in FSGS patients who did not respond to treatment (P = 0.03 and P = 0.007, respectively). Th2 cytokines (IL-4, IL-5, IL-10, IL-13) were significantly increased in MCD patients with frequent relapses (P = 0.05, P = 0.001, P = 0.01, P = 0.03). CONCLUSIONS: Urinary excretion of Th1 and Th2 cytokines cannot discriminate FSGS from MCD. Th1 cytokines, especially IL-12, IL-2 and GM-CSF, may be involved in pathology and progression of FSGS, while Th2 cytokines are implicated in frequent relapses of nephrotic syndrome in MCD.