Immunomodulation Driven by Theranova Filter during a Single HD Session.

Background: Patients with end-stage kidney disease (ESKD) have altered immunity. Patients on hemodialysis (HD) present a coexistence of immunodeficiency and activation of the immune system. We evaluated the immunophenotypic profile induced by the medium cut-off of Theranova filter during a single HD session in the same individual. Methods: This pilot observational study explored 11 patients (75 ± 8 years and 73% male). Blood samples were collected prior to (predialytic, PRE) and after 4 h (postdialytic, POST) standard HD session with a medium cut-off, polyarylethersulfone and polyvinylpyrrolidone blend, BPA-free membrane. We performed an immunophenotyping characterization by using flow cytometry. We evaluated eryptosis RBCs and HLA-DR expression on monocytes and Treg cells. Results: The percentages of eryptosis in lymphocytes (CD3+), lymphocyte T helper (CD3+ and CD4+) cells, and monocytes (CD45+ and CD14+) were similar pre- and post-HD. On the contrary, HLA-DR expression and Treg cell numbers significantly decreased after HD. Conclusions: Many studies have focused on the comparison between healthy volunteers and HD patients, but very few have focused on the changes that occur after an HD session in the same individual. With this pilot observational study, we have revealed an immunomodulation driven by HD treatment with Theranova filter. Our preliminary results can be considered to be a hypothesis, generating and stimulating further studies with better designs and larger populations.

[Lymphocytic leukopenia in two patients affected by polycystic kidney disease waiting for renal transplantation].

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, responsible for 10% of patients on renal replacement therapy. The disease is well known to be associated with many extrarenal manifestations. Leukopenia may also be present, even if it is not commonly identified as a typical extrarenal manifestation. Herein we describe two case reports of ADPKD patients with leukopenia. The first case is about a 47-year-old patient affected by ADPKD, regularly treated with peritoneal dialysis, who showed a progressive reduction of white blood cell count, mostly of lymphocytes. Lymphocytic leukopenia was so severe that, when he was called for transplantation from a deceased donor, he was considered temporarily not eligible. We then describe a second ADPKD patient regularly treated with peritoneal dialysis, who had stable lymphopenia for years. Six years after starting PD, it was necessary to perform bone marrow aspirate to investigate the simultaneous presence of hypogammaglobulinemia together with M-protein and to exclude monoclonal gammopathy. All the exams performed did not show any significant results, the patients were re-included in the waiting list and one of them was transplanted. Given our experience and what is reported in the literature, there seems to be enough evidence to consider leukopenia as an extrarenal manifestation of ADPKD. However, the clinical significance of leukopenia in ADPKD patients is not known. It could be interesting to investigate the leucocytes' function and if ADPKD patients with leukopenia are more susceptible to infection, or not. Moreover, it would be very useful to analyze the relationship between such manifestation and genotype/phenotype.

Relationship between Residual Urine Output and Type of Dialysis with FGF23 Levels.

Several studies investigated the role of fibroblast growth factor 23 (FGF23) in the regulation of renal phosphate excretion in chronic kidney disease (CKD). However, patients with residual urine output (UO) seem to control their serum phosphorus levels better. Our aim was to determine whether FGF23 levels are influenced by dialysis modality and UO. We performed a cross-sectional study in hemodialysis (HD) and peritoneal dialysis (PD) patients. The C-terminal FGF23 (cFGF23) levels were determined in plasma with a two-site enzyme-linked immunosorbent assay. The UO collection referred to an mL/day measurement. All p values were two-sided, and the statistical significance was set at p < 0.05. We enrolled 133 patients (58 HD, 75 PD, UO 70%). The median cFGF23 was significantly higher in HD vs. PD patients (p = 0.0017) and not significantly higher in patients without UO (p = 0.12). We found a negative correlation between cFGF23 and the UO volume (p = 0.0250), but the correlation was not significant when considering the type of dialysis treatment. Phosphorus (ß = 0.21677; p = 0.0007), type of dialysis (ß = −0.68392; p = 0.0003), and creatinine (ß = 0.08130; p = 0.0133) were significant and independent predictors of cFGF23 levels. In conclusion, cFGF23 was significantly higher in HD than in PD patients. We found a significant negative correlation between cFGF23 and the residual UO volume, but the correlation was not significant considering the type of dialysis. Our study reveals that dialysis modality is an independent predictor of FGF23 levels. In particular, PD is associated with lower FGF23 levels than HD.

[Slowing progression of chronic kidney disease in polycistic kidney disease patients with tolvaptan: from guidelines to clinical practice].

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and accounts for∼10% of patients on renal replacement therapy. In the last decade, no specific treatment was available and only preventive measures could be put in place to delay the onset of ESRD. Following the results of the TEMPO 3:4 study, tolvaptan was approved in many countries, for the purpose of slowing the progression of renal insufficiency. In Italy tolvaptan is available since 2016 for patients with chronic kidney disease (CKD) stage 1-3, and since 2020 for patients with CKD stage 4, who fulfil the criteria of "rapid disease progression", according to the European recommendations. After this approval, Italian nephrology units have had to change their organization to be able to identify the patients eligible for the drug and to guarantee frequent patient monitoring. In this paper, we present our three-year experiences with tolvaptan, focusing on its safety profile and tolerability, but also on the high burden of care that such therapy represents not only for doctors, but also for patients. Strategies to implement remote monitoring may be useful to reduce the burden of assistance on one side, and the medicalization of ADPKD patients in the early stage of the disease, on the other.

Differential effects of peritoneal and hemodialysis on circulating regulatory T cells one month post initiation of renal replacement therapy.

Backgroundː Chronic kidney disease stage G5 (CKD G5) patients show an activated but impaired immune system. One function of the FOXP3+ regulatory T (Treg) cells is to preserve tolerance to self while maintaining the ability to fight infectious agents. The aim of this pilot study is to evaluate longitudinal changes in Treg cells before and 1 month after the first dialysis treatment. Materials and methodsː CKD G5 patients not yet on dialysis were enrolled and started on hemodialysis (HD) or peritoneal dialysis (PD). Tregs were analyzed by flow cytometry at two time points: T0 (before the first dialysis treatment) and T1 (1 month after the first dialysis session). Wilcoxon test for dependent samples was used to compare the mean percentage difference between T0 and T1: Δ% = 100 × [(T1 - T0) / T0]. Resultsː 21 patients were enrolled: 8 on HD and 13 on PD. The proportion of total lymphocytes (low side scatter lymphocyte gate) and T lymphocytes (in the CD3+CD4+ gate) did not change significantly 1 month after the start of dialysis in both groups. Treg cells (as CD25+FOXP3+, FOXP3+, or CD25+CD127-), analyzed as percentage of the lymphocyte gate, showed a significant increase post PD (CD25+FOXP3+: median = 35.92; p = 0.0425; FOXP3+: median = 30.85; p = 0.0479 and CD25+CD127-: median = 23.71; p = 0.0215). The same populations, did not change 1 month after the first dialysis session. Conclusionː Our study is the first to evaluate longitudinal effects of dialysis on Treg cells in uremia and suggests that PD was more effective in increasing Treg levels 1 month post initiation of dialysis and may contribute to improvement of inflammatory status. Thus, PD may contribute to better outcomes for patients with renal dysfunction, also maintaining homeostasis of peritoneal and renal tissues.

Combination of biomarker with clinical risk factors for prediction of severe acute kidney injury in critically ill patients.

BACKGROUND: Acute kidney injury (AKI) occurs commonly in the intensive care unit (ICU). Insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2), known as [TIMP-2] x [IGFBP7] (NephroCheck), have been identified as novel biomarkers for the prediction of AKI risk. However, the effective use of disease biomarkers is indispensable from an appropriate clinical context. We conducted a retrospective cohort study to find risk factors and assess the performance of the combination of NephroCheck with risk factors, so as to provide feasible information for AKI prediction. METHODS: All patients who were admitted in the ICU (from June 2016 to July 2017) participated in the study. The primary outcome was the detection of severe AKI within the first 7 days after patients being admitted to the ICU. The predictors were separated into three categories: chronic risk factors, acute risk factors and biochemical indicators. RESULTS: The study included 577 patients. 96 patients developed to severe AKI (16.6%) within 7 days. In addition to NephroCheck (+) (OR = 2.139, 95% CI (1.260-3.630), P = 0.005), age > 65 years (OR = 1.961, 95% CI (1.153-3.336), P = 0.013), CKD (OR = 2.573, 95% CI (1.319-5.018), P = 0.006) and PCT (+)(OR = 3.223, 95% CI (1.643-6.321), P = 0.001) were also the independent predictors of severe AKI within 7 days. Compared to NephroCheck (+) only (AUC = 0.66, 95% CI:0.60-0.72), the combination of NephroCheck (+) and risk factors (age > 65 years, CKD and PCT positive) (AUC = 0.75, 95% CI:0.70-0.81) led to a significant increase in the area under ROC curve for severe AKI prediction within 7 days. CONCLUSIONS: Although NephroCheck is an effective screening tool for recognizing high-risk patients, we found that combination with biomarker and risk factors (age > 65 years, CKD, procalcitonin positive) for risk assessment of AKI has the greatest significance to patients with uncertain disease trajectories.

Urinary [TIMP-2] × [IGFBP7] and serum procalcitonin to predict and assess the risk for short-term outcomes in septic and non-septic critically ill patients.

BACKGROUND: Biomarkers can play a critical role by facilitating diagnosis and stratification of disease, as well as assessment or prediction of disease severity. Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 product ([TIMP-2] × [IGFBP7]) predict the development and progression of AKI and recently procalcitonin (PCT), a widely used biomarker for sepsis diagnosis and management, has been associated with AKI occurrence in ICU patients. To assess combinations of [TIMP-2] × [IGFBP7] and PCT results for prediction and risk stratification of short-term outcomes in septic and non-septic patients, a retrospective cohort analysis of critically ill patients was performed in a multidisciplinary ICU. ROC curve analysis was used in order to evaluate predictive performance of combined results of [TIMP-2] × [IGFBP7] and PCT at the time of admission for AKI development. To verify the utility of adding [TIMP-2] × [IGFBP7] and PCT results for risk assessment, we evaluated the predictive value of having a single-marker positivity compared to a double-marker positivity using the widely used cut-off of 0.3 (ng/mL)2/1000 for [TIMP-2] × [IGFBP7] and 0.5 µg/L for PCT. Risk assessment for AKI occurrence within 48 h, acute kidney disease (AKD) and mortality at 7 days was performed by logistic/Cox regression analysis. RESULTS: 433 patients were analysed, of whom 168 had AKI within 48 h (93 septic and 65 non-septic patients). Combination of [TIMP-2] × [IGFBP7] and PCT showed a good predictive ability for AKI occurrence (AUC 0.81, 95% CI 0.77-0.86, p < 0.001, Sens 78%, Spec 73%). Combinations of biomarkers increased the odd ratios (OR) considerably. A single-marker positivity showed a fourfold risk increase, while the double-marker positivity a 26-fold risk increase for AKI occurrence. Moreover, the double-marker positivity showed an elevated risk for AKD at 7 days in non-septic patients (OR 15.9, 95% CI 3,21-73,57, p < 0.001) and for mortality within 7 days in septic patients (HR 4.1, 95% CI 1.4-11.8, p = 0.001). CONCLUSIONS: Although combining the results of [TIMP-2] × [IGFBP7] and PCT may be a useful tool to identify and stratify ICU patients at high risk for septic AKI and short-term adverse outcomes, data should be confirmed in a large prospective study.

Acute rejection in kidney transplantation and the evaluation of associated polymorphisms (SNPs): the importance of sample size.

Background Acute rejection (AR) is one of the most frequent complications after kidney transplantation (KT). Scientific evidence reports that some single-nucleotide polymorphisms (SNPs) located in genes involved in the immune response and in the pharmacokinetics and pharmacodynamics of immunosuppressive drugs are associated with rejection in renal transplant patients. The aim of this study was to evaluate some SNPs located in six genes: interleukin-10 (IL-10), tumor necrosis factor (TNF), adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1), uridine diphosphate glucuronosyltransferase family 1 member A9 (UGT1A9), inosine monophosphate dehydrogenase 1 (IMPDH1) and IMPDH2. Methods We enrolled cases with at least one AR after KT and two groups of controls: patients without any AR after KT and healthy blood donors. Genetic analysis on DNA was performed. The heterozygosity (HET) was determined and the Hardy-Weinberg equilibrium (HWE) test was performed for each SNP. The sample size was calculated using the QUANTO program and the genetic associations were calculated using the SAS program (SAS Institute Inc., Cary, NC, USA). Results In our previous preliminary study (sample size was not reached for cases), the results showed that patients with the C allele in the SNP rs1045642 and the A allele in the SNP rs2032582 of the ABCB1 gene had more frequent AR. In contrast, with the achievement of sample size, the trend of the previous data was not confirmed. Conclusions Our study highlights a fundamental aspect of scientific research that is generally presumed, i.e. the sample size of groups enrolled for a scientific study. We believe that our study will make a significant contribution to the scientific community in the discussion of the importance of the analysis and the achievement of sample size to evaluate the associations between SNPs and the studied event.

A New Series of Sorbent Devices for Multiple Clinical Purposes: Current Evidence and Future Directions.

Adsorption is an extracorporeal technique utilized for blood purification. It complements convection and diffusion (the main modalities of solute removal). It involves the passage of blood (or plasma) through an adsorption cartridge, where solutes are removed by direct binding to the sorbent material. Over the years, new adsorption cartridges, with improved characteristics have been developed. Furthermore, the therapeutic applications of adsorption have expanded. These now involve the treatment of inflammatory conditions, chronic uremic symptoms, and autoimmune disease, in addition to intoxication, which was once considered the classical indication for adsorption therapy. HA130, HA230, and HA330 (Jafron, Zhuhai City, China) are among the widely used adsorption cartridges in China. There has been sufficient body of evidence to support their effectiveness and safety. In this review, we aim to highlight their main clinical applications.

Persistent decrease of renal functional reserve in patients after cardiac surgery-associated acute kidney injury despite clinical recovery.

Background: Cardiac surgery is a leading cause of acute kidney injury (AKI). Such AKI patients may develop progressive chronic kidney disease (CKD). Others, who appear to have sustained no permanent loss of function (normal serum creatinine), may still lose renal functional reserve (RFR). Methods: We extended the follow-up in the observational 'Preoperative RFR Predicts Risk of AKI after Cardiac Surgery' study from hospital discharge to 3 months after surgery for 86 (78.2%) patients with normal baseline estimated glomerular filtration rate (eGFR), and re-measured RFR with a high oral protein load. The primary study endpoint was change in RFR. Study registration at clinicaltrials.gov Identifier: NCT03092947, ISRCTN Registry: ISRCTN16109759. Results: At 3 months, three patients developed new CKD. All remaining patients continued to have a normal eGFR (93.3 ± 15.1 mL/min/1.73 m2). However, when stratified by post-operative AKI and cell cycle arrest (CCA) biomarkers, AKI patients displayed a significant decrease in RFR {from 14.4 [interquartile range (IQR) 9.5 - 24.3] to 9.1 (IQR 7.1 - 12.5) mL/min/1.73 m2; P < 0.001} and patients without AKI but with positive post-operative CCA biomarkers also experienced a similar decrease of RFR [from 26.7 (IQR 22.9 - 31.5) to 19.7 (IQR 15.8 - 22.8) mL/min/1.73 m2; P < 0.001]. In contrast, patients with neither clinical AKI nor positive biomarkers had no such decrease of RFR. Finally, of the three patients who developed new CKD, two sustained AKI and one had positive CCA biomarkers but without AKI. Conclusions: Among elective cardiac surgery patients, AKI or elevated post-operative CCA biomarkers were associated with decreased RFR at 3 months despite normalization of serum creatinine. Larger prospective studies to validate the use of RFR to assess renal recovery in combination with biochemical biomarkers are warranted.

Biocompatibility and Cytotoxic Evaluation of New Sorbent Cartridges for Blood Hemoperfusion.

BACKGROUND/AIMS: The use of adsorption cartridges for hemoperfusion (HP) is rapidly evolving. For these devices, the potential induced cytotoxicity is an important issue. The aim of this study was to investigate potential in vitro cytotoxic effects of different sorbent cartridges, HA130, HA230, HA330, HA380 (Jafron, China), on U937 monocytes. METHODS: Monocytes were exposed to the sorbent material in static and dynamic manners. In static test, cell medium samples were collected after 24 h of incubation in the cartridges. In dynamic test, HP modality has been carried out and samples at 30, 60, 90, and 120 min were collected. RESULTS: Compared to control samples, there was no evidence of increased necrosis or apoptosis in monocytes exposed to the cartridges both in the static and dynamic tests. CONCLUSION: Our in vitro testing suggests that HA cartridges carry an optimal level of biocompatibility and their use in HP is not associated with adverse reactions or signs of cytotoxicity.

Usefulness of glycated albumin as a biomarker for glucose control and prognostic factor in chronic kidney disease patients on dialysis (CKD-G5D).

In chronic kidney disease patients on dialysis (CKD-G5D) accurate assessment of glycemic control is vital to improve their outcome and survival. The best glycemic marker for glucose control in these patients is still debated because several clinical and pharmacological factors may affect the ability of the available biomarkers to reflect the patient's glycemic status properly. This review discusses the role of glycated albumin (GA) both as a biomarker for glucose control and as a prognostic factor in CKD-G5D; it also looks at the pros and cons of GA in comparison to the other markers and its usefulness in hemodialysis and peritoneal dialysis.

Preoperative Renal Functional Reserve Predicts Risk of Acute Kidney Injury After Cardiac Operation.

BACKGROUND: Although acute kidney injury (AKI) frequently complicates cardiac operations, methods to determine AKI risk in patients without underlying kidney disease are lacking. Renal functional reserve (RFR) can be used to measure the capacity of the kidney to increase glomerular filtration rate under conditions of physiologic stress and may serve as a functional marker that assesses susceptibility to injury. We sought to determine whether preoperative RFR predicts postoperative AKI. METHODS: We enrolled 110 patients with normal resting glomerular filtration rates undergoing elective cardiac operation. Preoperative RFR was measured by using a high oral protein load test. The primary end point was the ability of preoperative RFR to predict AKI within 7 days of operation. Secondary end points included the ability of a risk prediction model, including demographic and comorbidity covariates, RFR, and intraoperative variables to predict AKI, and the ability of postoperative cell cycle arrest markers at various times to predict AKI. RESULTS: AKI occurred in 15 patients (13.6%). Preoperative RFR was lower in patients who experienced AKI (p < 0.001) and predicted AKI with an area under the receiver operating characteristic curve (AUC) of 0.83 (95% confidence interval [CI]: 0.70 to 0.96). Patients with preoperative RFRs not greater than 15 mL · min-1 · 1.73 m-2 were 11.8 times more likely to experience AKI (95% CI: 4.62 to 29.89 times, p < 0.001). In addition, immediate postoperative cell cycle arrest biomarkers predicted AKI with an AUC of 0.87. CONCLUSIONS: Among elective cardiac surgical patients with normal resting glomerular filtration rates, preoperative RFR was highly predictive of AKI. A reduced RFR appears to be a novel risk factor for AKI, and measurement of RFR preoperatively can identify patients who are likely to benefit from preventive measures or to select for use of biomarkers for early detection. Larger prospective studies to validate the use of RFR in strategies to prevent AKI are warranted. ClinicalTrials.gov identifier: NCT03092947, ISRCTN Registry: ISRCTN16109759.

Predictors of rapid disease progression in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases with a reported prevalence of 1:400 to 1:1000. Since the intact kidneys can compensate for the loss of glomerular filtration in ADPKD patients, renal insufficiency usually remains undetected until almost the fourth decade of life. Hereafter, reliable diagnostic and prognostic biomarkers to identify ADPKD progression are urgently needed. Several studies and systematic reviews tried to identify markers or predictors of rapid disease progression of ADPKD. The aim of this study is to review predictors of rapid disease progression of ADPKD that can be useful to the clinician. We will describe several factors associated with rapid progression of ADPKD derived from retrospective or cross-sectional studies, suggesting the best and most useful predictors that may help to patients management in clinical practice. We will attempt to identify the most useful predictors of rapid disease progression of ADPKD: established TKV growth rate >5% per year, annual estimated glomerular filtration rate decline >5 mL/min/1.73 m2, truncating PKD1 mutations and elevated plasma copeptin level. The combination of several factors that can predict the rapid ADPKD progression is more accurate than a single-marker strategy. The "PRO-PKD" risk scoring system combined with TKV, can be useful in order to evaluate the ADPKD patients and they appear to be appropriate predictors of progression disease. Moreover levels of copeptin and some urinary markers can be matched to these factors for improved patient assessment in rapid progression.

The Influence of Hemodialysis on T Regulatory Cells: A Meta-Analysis and Systematic Review.

AIMS: The study aimed to determine whether the available literature supports a positive or negative influence of dialysis on regulatory T-cells (Tregs). METHODS: We performed a systematic search and a meta-analysis. Mean differences in Tregs number of chronic kidney disease stages G5 on dialysis patients (CKD G5D) and healthy controls (HCs) were compared. Random effects model was applied. The software used was general package for meta-analysis (version 4.3-0, depends R (≥2.9.1)). RESULTS: Five studies were included in the meta-analysis. The mean difference in percentage of Tregs on CD4+ T-cells between CKD G5D and HCs was not statistically different. Moreover, CKD GFR stages G5 not on dialysis (CKD G5) versus HC (p = 0.002; mean difference in Treg percentage was -2.47% in CKD G5 vs. HC) and CKD G5 versus CKD G5D (not significant). CONCLUSION: This meta-analysis demonstrates an association between the uremic state and lower Tregs, and supports the hypothesis that hemodialysis alter Tregs. Our findings highlight the need for new clinical studies. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=449242.

Copeptin levels and kidney function in ADPKD: case-control study.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Studies have suggested a possible prognostic role of copeptin in determining the rate of progressive kidney function decline in ADPKD patients. However, it remains unresolved whether the changes in copeptin levels are specific for ADPKD or merely reflect a decline in glomerular filtration rate (GFR) regardless of the etiology of chronic kidney disease (CKD). METHODS: We performed a case-control study in ADPKD and non-ADPKD (control) patients. Patients were categorized based on the GFR-category (G-stage, KDIGO). We evaluated urea, creatinine, cystatin C, and copeptin in plasma and correlated these levels with estimated glomerular filtration rate (eGFR) (CKD-EPI). All p-values were two sided, and p < 0.05 was considered as statistically significant. RESULTS: We enrolled 112 ADPKD and 112 control patients. The median copeptin level was 10.72 (interquartile range (IQR) 5.21 - 26.21) pmol/L in the ADPKD group and 12.32 (IQR 4.47 - 30.73) pmol/L in the control group. The median copeptin level increased according to the G-stage in a progressive fashion and remained statistically significant across all G-stages and in both groups. Copeptin levels were not significantly different between ADPKD and control groups. We found a significant inverse correlation between copeptin level and eGFR (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) in the ADPKD, r = -0.81 (p < 0.001), and in the control group, r = -0.76 (p < 0.001). CONCLUSIONS: Copeptin levels seem to be strongly correlated with renal function rather than the presence of ADPKD. Further prospective studies need to evaluate its role as a prognostic marker in the early stage of CKD for ADPKD progression.