Efficacy and Safety of the Use of SGLT2 Inhibitors in Patients on Incremental Hemodialysis: Maximizing Residual Renal Function, Is There a Role for SGLT2 Inhibitors?

SGLT-2i are the new standard of care for diabetic kidney disease (DKD), but previous studies have not included patients on kidney replacement therapy (KRT). Due to their high risk of cardiovascular, renal complications, and mortality, these patients would benefit the most from this therapy. Residual kidney function (RKF) conveys a survival benefit and cardiovascular health among hemodialysis (HD) patients, especially those on incremental hemodialysis (iHD). We retrospectively describe the safety and efficacy of SGLT2i regarding RKF preservation in seven diabetic patients with different clinical backgrounds who underwent iHD (one or two sessions per week) during a 12-month follow-up. All patients preserved RKF, measured as residual kidney urea clearance (KrU) in 24 h after the introduction of SGLT2i. KrU levels improved significantly from 4.91 ± 1.14 mL/min to 7.28 ± 1.68 mL/min at 12 months (p = 0.028). Pre-hemodialysis blood pressure improved 9.95% in mean systolic blood pressure (SBP) (p = 0.015) and 10.95% in mean diastolic blood pressure (DBP) (p = 0.041); as a result, antihypertensive medication was modified. Improvements in blood uric acid, hemoglobin A1c, urine albumin/creatinine ratio (UACR), and 24 h proteinuria were also significant. Regarding side effects, two patients developed uncomplicated urinary tract infections that were resolved. No other complications were reported. The use of SGLT2i in our sample of DKD patients starting iHD on a 1-2 weekly regimen appears to be safe and effective in preserving RKF.

Validation of formulas calculating normalized protein catabolic rate in patients undergoing home hemodialysis.

Depner and Daugirdas developed a simplified formula to estimate the normalized protein catabolic rate in patients on twice- or thrice-weekly hemodialysis (JASN, 1996). The aim of our work was to establish formulas in more frequent schedules and validate them in home-based hemodialysis patients. We realized that the structure of Depner and Daugirdas' normalized protein catabolic rate formulas has a general meaning and can be expressed as PCRn = C0/[a + b*(Kt/V) + c/(Kt/V)] + d, where C0 is pre-dialysis blood urea nitrogen, Kt/V is dialysis dose, a, b, c, d are the specific coefficients for each combination of home-based hemodialysis schedules and the day of blood sampling. The same applies to the formula that adjusts C0 (C'0) for residual kidney clearance of blood water urea (Kru) and urea distribution volume (V): C'0 = C0*[1 + (a1 + b1/(Kt/V))*Kru/V]. On this basis, we computed the six coefficients (a, b, c, d, a1, b1) for each of the 50 possible combinations and simulated a total of 24,000 weekly dialysis cycles using the Daugirdas Solute Solver software recommended by the KDOQI 2015 guidelines. From the associated statistical analyses we obtained 50 sets of coefficient values, which were validated comparing the paired normalized protein catabolic rate values (i.e., those estimated with our formulas with those modeled with Solute Solver) in 210 datasets of 27 patients on home-based hemodialysis. The mean values ± SD were 1.06 ± 0.262 and 1.07 ± 0.283 g/kg/day, respectively, with a mean difference of 0.004 ± 0.034 g/kg/day (p = 0.11). The paired values were highly correlated (R2 = 0.99). In conclusion, even if the coefficient values were validated in a relatively small sample of patients, they allow an accurate estimation of normalized protein catabolic rate in home-based hemodialysis patients.

Could incremental haemodialysis be a new standard of care? A suggestion from a long-term observational study.

Introduction: The term incremental haemodialysis (HD) means that both dialysis dose and frequency can be low at dialysis inception but should be progressively increased, to compensate for any subsequent reduction in residual kidney function. Policy of the Matera Dialysis Center is to attempt an incremental start of HD without a strict low-protein diet in all patients choosing HD and with urine output (UO) >500 ml/day. The present study aimed at analyzing the results of this policy over the last 20 years. Subjects and methods: The dataset of all patients starting HD between January 1st, 2000 and December 31st, 2019 was retrieved from the local electronic database. Exclusion criteria were: urine output <500 ml/day or follow-up <3 months after the start of the dialysis treatment. Results: A total of 266 patients were retrieved; 64 of them were excluded from the study. The remaining 202 patients were enrolled into the study and subdivided into 3 groups (G1, G2 and G3) according to the frequency of treatment at the start of dialysis: 117 patients (57.9%) started with once-a-week (1HD/wk) (G1); 46 (22.8%) with twice-a-week (2HD/wk) (G2); 39 (19.3%) with thrice-a-week (3HD/wk) dialysis regimen (G3). Patients of G1 remained on 1HD/wk for 11.9 ±14.8 months and then transferred to 2HD/wk for further 13.0 ±20.3 months. Patients of G2 remained on 2HD/wk for 16.7 ±23.2 months. Altogether, 25943 sessions were administered during the less frequent treatment periods instead of 47988, that would have been delivered if the patients had been on 3HD/wk, thus saving 22045 sessions (45.9%). Gross mortality of the entire group was 12.6%, comparable to the mean mortality of the Italian dialysis population (16.2%). Survival at 1 and 5 years was not significantly different among the 3 groups: 94% and 61% (G1); 83% and 39% (G2); 84% and 46% (G3). Conclusions: Our long-term observational study suggests that incremental HD is a valuable option for incident patients. For most of them (80.7%) it is viable for about 1-2 years, with obvious socio-economic benefits and survival rates comparable to that of the Italian dialysis population. However, randomized controlled trials are lacking and therefore urgently needed. If they will confirm observational data, incremental HD will be a new standard of care.

Does delivering more dialysis improve clinical outcomes? What randomized controlled trials have shown.

Some randomized controlled trials (RCTs) have sought to determine whether different dialysis techniques, dialysis doses and frequencies of treatment are able to improve clinical outcomes in end-stage kidney disease (ESKD). Virtually all of these RCTs were enacted on the premise that 'more' haemodialysis might improve clinical outcomes compared to 'conventional' haemodialysis. Aim of the present narrative review was to analyse these landmark RCTs by posing the following question: were their intervention strategies (i.e., earlier dialysis start, higher haemodialysis dose, intensive haemodialysis, increase in convective transport, starting haemodialysis with three sessions per week) able to improve clinical outcomes? The answer is no. There are at least two main reasons why many RCTs have failed to demonstrate the expected benefits thus far: (1) in general, RCTs included relatively small cohorts and short follow-ups, thus producing low event rates and limited statistical power; (2) the designs of these studies did not take into account that ESKD does not result from a single disease entity: it is a collection of different diseases and subtypes of kidney dysfunction. Patients with advanced kidney failure requiring dialysis treatment differ on a multitude of levels including residual kidney function, biochemical parameters (e.g., acid base balance, serum electrolytes, mineral and bone disorder), and volume overload. In conclusion, the different intervention strategies of the RCTs herein reviewed were not able to improve clinical outcomes of ESKD patients. Higher quality studies are needed to guide patients and clinicians in the decision-making process. Future RCTs should account for the heterogeneity of patients when considering inclusion/exclusion criteria and study design, and should a priori consider subgroup analyses to highlight specific subgroups that can benefit most from a particular intervention.

The spectrum of kidney dysfunction requiring chronic dialysis therapy: Implications for clinical practice and future clinical trials.

Staging to capture kidney function and pathophysiologic processes according to severity is widely used in chronic kidney disease or acute kidney injury not requiring dialysis. Yet the diagnosis of "end-stage kidney disease" (ESKD) considers patients as a single homogeneous group, with negligible kidney function, in need of kidney replacement therapy. Herein, we review the evidence behind the heterogeneous nature of ESKD and discuss potential benefits of recasting the terminology used to describe advanced kidney dysfunction from a monolithic entity to a disease with stages of ascending severity. We consider kidney assistance therapy in lieu of kidney replacement therapy to better reconcile all available types of therapy for advanced kidney failure including dietary intervention, kidney transplantation, and dialysis therapy at varied schedules. The lexicon "kidney dysfunction requiring dialysis" (KDRD) with stages of ascending severity based on levels of residual kidney function (RKF)-that is, renal urea clearance-and manifestations related to uremia, fluid status, and other abnormalities is discussed. Subtyping KDRD by levels of RKF could advance dialysis therapy as a form of kidney assistance therapy adjusted based on RKF and clinical symptoms. We focus on intermittent hemodialysis and underscore the need to personalize dialysis treatments and improve characterization of patients included in clinical trials.

Patiromer in a Patient with Severe Hyperkalemia on Incremental Hemodialysis with 1 Session per Week: A Case Report and Literature Review.

Hyperkalemia is common in patients with ESRD, undergoing hemodialysis (HD), and is associated with an increase in hospitalization and mortality. Residual kidney function in long-term dialysis patients is associated with lower morbidity and mortality in HD patients. Although the 2015 National Kidney Foundation-Kidney Disease Outcomes Quality Initiate (NKD-KDOQI) guidelines allow the reduction in the weekly HD dose for patients with a residual kidney urea clearance (Kur) >3 mL/min/1.73 m2, very few centers adjust the dialysis dose based on these criteria. In our center, the pattern of incremental hemodialysis (iHD) with once-a-week schedule (1 HD/W) has been an option for a group of patients showing very good results. This pattern is maintained as long as residual diuresis is >1,000 mL/24 h, Kur is >4 mL/min, and there is no presence of edema or volume overload, as well as no analytical parameters persistently outside the advisable range (serum phosphorus >6 mg/dL or potassium [K+] >6.5 mmol/L). Management of hyperkalemia in HD patients includes reduction of dietary intake, dosing of medications that contribute to hyperkalemia, and use of cation-exchange resins such as calcium or sodium polystyrene sulfonate. Two newer potassium binders, patiromer sorbitex calcium and sodium zirconium cyclosilicate, have been safely used for potassium imbalance treatment in patients with ESRD in HD with a conventional regimen of thrice weekly, but has not yet been studied in 1 HD/W schedules. We present the case of a 76-year-old woman in iHD (1 HD/W) treated with patiromer for severe HK and describe her clinical characteristics and outcomes. In addition, we review the corresponding literature. Based on these data, it can be anticipated that the use of patiromer may overcome the risk of hyperkalemia in patients with incident ESRD treated with less-frequent HD regimens.

Routine assessment of kidney urea clearance, dialysis dose and protein catabolic rate in the once-weekly haemodialysis regimen.

BACKGROUND: The dialysis dose (Kt/V) and normalized protein catabolic rate (PCRn) are the most useful indices derived from the urea kinetic model (UKM) in haemodialysis (HD) patients. The kidney urea clearance (Kru) is another important UKM parameter which plays a key role in the prescription of incremental HD. Ideally, the three kinetic parameters should be assessed using the complex software Solute Solver based on the double pool UKM. In the clinical setting, however, the three indices are estimated with simplified formulae. The recently introduced software SPEEDY assembles the aforementioned equations in a plain spreadsheet, to produce quite accurate results of Kru, Kt/V and PCRn. Unfortunately, specific equations to compute Kt/V and PCRn for patients on a once-weekly HD regimen (1HD/wk) were not available at the time SPEEDY was built-up. We devised a new version of SPEEDY (SPEEDY-1) and an even simpler variant (SPEEDY-1S), using two recently published equations for the 1HD/wk schedule . Moreover, we also added a published equation to estimate the equivalent renal clearance (EKR) normalized to urea distribution volume (V) of 35 L (EKR35) from Kru and Kt/V . Aim of the present study was to compare the results obtained using the new methods (SPEEDY-1 and SPEEDY-1S) with those provided by the reference method Solute Solver. SUBJECTS AND METHODS: One hundred historical patients being treated with the once-weekly HD regimen were enrolled. A total of 500 HD sessions associated to the availability of monthly UKM studies were analysed in order to obtain Kru, single pool Kt/V (spKt/V), equilibrated Kt/V (eKt/V), V, PCRn and EKR35 values by using Solute Solver, SPEEDY-1 and SPEEDY-1S. RESULTS: When comparing the paired values of the above UKM parameters, as computed by SPEEDY-1 and Solute Solver, respectively, all differences but one were statistically significant at the one-sample t-test; however, the agreement limits at Bland-Altman analysis showed that all differences were negligible. When comparing the paired values of the above UKM parameters, as computed by SPEEDY-1S and Solute Solver, respectively, all differences were statistically significant; however, the agreement limits showed that the differences were negligible as far as Kru, spKt/V and eKt/V are concerned, though much larger regarding V, PCRn and EKR35. CONCLUSIONS: We implemented SPEEDY with a new version specific for the once-weekly HD regimen, SPEEDY-1. It provides accurate results and is presently the best alternative to Solute Solver. Using SPEEDY-1S led to a larger difference in PCRn and EKR35, which could be acceptable for clinical practice if SPEEDY-1 is not available.

Improving the "second generation Daugirdas equation" to estimate Kt/V on the once-weekly haemodialysis schedule.

INTRODUCTION: The haemodialysis (HD) dose, as expressed by Kt/V urea, is currently routinely estimated with the second generation Daugirdas (D2) equation (Daugirdas in J Am Soc Nephrol 4:1205-1213, 1993). This equation, initially devised for a thrice-weekly schedule, was modified to be used for all dialysis schedules (Daugirdas et al. in Nephrol Dial Transplant 28:2156-2160, 2013), by adopting a variable factor that adjusts for the urea generation (GFAC) over the preceding inter-dialysis interval (PIDI, days). This factor was set at 0.008 for the mid-week session of the standard thrice-weekly HD schedule. In theory, by setting PIDI = 7, one could get GFAC = 0.0025, to be used in patients on the once-weekly (1HD/wk) schedule, but actually this has never been tested. Moreover, GFAC was derived not taking into account the residual kidney urea clearance (Kru). Aim of the present study was to provide a specific value of GFAC for patients on  a once-weekly hemodialysis schedule. SUBJECTS AND METHODS: The equation to predict GFAC (GFAC-1) in the 1HD/wk schedule was established in a group of 80 historical Italian patients (group 1) and validated in a group of 100 historical Spanish patients (group 2), by comparing the Kt/V computed using GFAC-1 (Kt/VGFAC-1) with the reference Kt/V (Kt/VSS) values, as computed with the web-based Solute-Solver software (SS) (Daugirdas et al. in Am J Kidney Dis 54:798-809, 2009). Three more sets of Kt/V (Kt/V0.008, Kt/V0.0025 and Kt/V0.0035) values were computed using the GFAC of the original D2 equation (0.008), the GFAC predicted by PIDI/7 (0.0025) and the mean observed GFAC-1 (0.0035), respectively. They were compared with the reference Kt/VSS values. RESULTS: The predicting equation obtained from group 1 was: GFAC-1 = 0.0022 + 0.0105 × Kru/V (R2 = 0.93). Mean Kt/VSS in the group 2 was 1.54 ± 0.29 SD (N = 500 HD sessions). The mean percent differences for Kt/V0.008, Kt/V0.0025, Kt/VGFAC-1, and Kt/V0.0035 were 5.1 ± 1.0%, - 1.4 ± 0.7%, 0.0 ± 0.3%, - 0.3 ± 0.7%, respectively. No statistically significant difference was found between Kt/V values, except for Kt/V0.008. CONCLUSION: A linear relationship was found between GFAC and Kru/V in patients on the 1HD/wk schedule. Such a relationship is able to improve the "second generation Daugirdas equation" for an accurate estimate of the single pool Kt/V in this setting. However, a simple replacement in the D2 equation of 0.008 with the mean observed GFAC (0.0035) could suffice in the clinical practice.

IHDIP: a controlled randomized trial to assess the security and effectiveness of the incremental hemodialysis in incident patients.

BACKGROUND: Most people who make the transition to renal replacement therapy (RRT) are treated with a fixed dose thrice-weekly hemodialysis réegimen, without considering their residual kidney function (RKF). Recent papers inform us that incremental hemodialysis is associated with preservation of RKF, whenever compared with conventional hemodialysis. The objective of the present controlled randomized trial (RCT) is to determine if start HD with one sessions per week (1-Wk/HD), it is associated with better patient survival and other safety parameters. METHODS/DESIGN: IHDIP is a multicenter RCT experimental open trial. It is randomized in a 1:1 ratio and controlled through usual clinical practice, with a low intervention level and non-commercial. It includes 152 incident patients older than 18 years, with a RRF of ≥4 ml/min/1.73 m2, measured by renal clearance of urea (KrU). The intervention group includes 76 patients who will start with incremental HD (1-Wk/HD). The control group includes 76 patients who will start with thrice-weekly hemodialysis régimen. The primary outcome is assessing the survival rate, while the secondary outcomes are the morbidity rate, the clinical parameters, the quality of life and the efficiency. DISCUSSION: This study will enable to know the number of sessions a patient should receive when starting HD, depending on his RRF. The potentially important clinical and financial implications of incremental hemodialysis warrant this RCT. TRIAL REGISTRATION: U.S. National Institutes of Health, ClinicalTrials.gov . Number: NCT03239808 , completed 13/04/2017. SPONSOR: Foundation for Training and Research of Health Professionals of Extremadura.

Justificación y diseño de DiPPI: un ensayo controlado aleatorizado para evaluar la seguridad y la efectividad de la hemodiálisis progresiva en pacientes incidentes / Rationale and design of DiPPI: A randomized controlled trial to evaluate the safety and effectiveness of progressive hemodialysis in incident patients

INTRODUCCIÓN: La hemodiálisis (HD) progresiva es una modalidad de inicio del tratamiento renal sustitutivo adaptada a las necesidades individuales de cada paciente. Está condicionada fundamentalmente por la función renal residual (FRR). En ella, la frecuencia de sesiones con las que el paciente inicia HD (una o 2 sesiones por semana) es menor que en la HD convencional (3 por semana). Dicha frecuencia aumenta (de una a 2, y de 2 a 3) con el declinar de la FRR. Metodología/diseño: DiPPI es un estudio abierto, multicéntrico, experimental, aleatorizado 1:1 y controlado con procedimiento de práctica clínica habitual, de bajo nivel de intervención y no comercial. Incluye 152 pacientes mayores de 18 años, con enfermedad renal crónica estadio 5, que inician HD como tratamiento renal sustitutivo; y la FRR, medida por aclaramiento renal de urea (KrU) es ≥ 4ml/min/1,73 m2. El estudio se basa en un grupo de intervención con 76 pacientes que iniciarán HD con una sola sesión por semana (modalidad progresiva) y un grupo control con 76 pacientes que comenzarán con 3 sesiones por semana. El objetivo primario es evaluar la supervivencia y los objetivos secundarios son la morbilidad (hospitalizaciones), los parámetros clínicos habituales, la calidad de vida y la eficiencia. DISCUSIÓN: Este estudio permitirá conocer, con la máxima evidencia científica, cuántas sesiones debe recibir un paciente al inicio del tratamiento con HD, dependiendo de su FRR. Registro: Registrado en U.S. National Institutes of Health, ClinicalTrials.gov con número NCT03239808

INTRODUCTION: Progressive haemodialysis (HD) is a starting regime for renal replacement therapy (RRT) adapted to each patient's necessities. It is mainly conditioned by the residual renal function (RRF). The frequency of sessions with which patients start HD (one or two sessions per week), is lower than that for conventional HD (three times per week). Such frequency is increased (from one to two sessions, and from two to three sessions) as the RRF declines. Methodology/DESIGN: IHDIP is a multicentre randomised experimental open trial. It is randomised in a 1:1 ratio and controlled through usual clinical practice, with a low intervention level and non-commercial. It includes 152 patients older than 18 years with chronic renal disease stage 5 and start HD as RRT, with an RRF of ≥ 4 ml/min/1.73 m2, measured by renal clearance of urea (KrU). The intervention group includes 76 patients who will start with one session of HD per week (progressive HD). The control group includes 76 patients who will start with three sessions per week (conventional HD). The primary purpose is assessing the survival rate, while the secondary purposes are the morbidity rate (hospital admissions), the clinical parameters, the quality of life and the efficiency. DISCUSSION: This study will enable us to know, with the highest level of scientific evidence, the number of sessions a patient should receive when starting the HD treatment, depending on his/her RRF. Trial registration: Registered at the U.S. National Institutes of Health, ClinicalTrials.gov under the number NCT03239808

Rationale and design of DiPPI: A randomized controlled trial to evaluate the safety and effectiveness of progressive hemodialysis in incident patients. / Justificación y diseño de DiPPI: un ensayo controlado aleatorizado para evaluar la seguridad y la efectividad de la hemodiálisis progresiva en pacientes incidentes.

INTRODUCTION: Progressive haemodialysis (HD) is a starting regime for renal replacement therapy (RRT) adapted to each patient's necessities. It is mainly conditioned by the residual renal function (RRF). The frequency of sessions with which patients start HD (one or two sessions per week), is lower than that for conventional HD (three times per week). Such frequency is increased (from one to two sessions, and from two to three sessions) as the RRF declines. METHODOLOGY/DESIGN: IHDIP is a multicentre randomised experimental open trial. It is randomised in a 1:1 ratio and controlled through usual clinical practice, with a low intervention level and non-commercial. It includes 152 patients older than 18 years with chronic renal disease stage 5 and start HD as RRT, with an RRF of ≥4ml/min/1.73m2, measured by renal clearance of urea (KrU). The intervention group includes 76 patients who will start with one session of HD per week (progressive HD). The control group includes 76 patients who will start with three sessions per week (conventional HD). The primary purpose is assessing the survival rate, while the secondary purposes are the morbidity rate (hospital admissions), the clinical parameters, the quality of life and the efficiency. DISCUSSION: This study will enable us to know, with the highest level of scientific evidence, the number of sessions a patient should receive when starting the HD treatment, depending on his/her RRF. TRIAL REGISTRATION: Registered at the U.S. National Institutes of Health, ClinicalTrials.gov under the number NCT03239808.

Very low doses of direct intravenous iron in each session as maintenance therapy in hemodialysis patients.

BACKGROUND: Intravenous (IV) iron supplementation is widely used in hemodialysis (HD) patients to treat their periodic losses. However, the ideal dose and frequency is unknown. The goal of the study is to see if a 20 mg dose of iron IV at the end of each session of HD as iron maintenance is better than the iron prior therapy. We analyze the erythropoiesis activity (EA) and functional iron (FI) after four weeks of treatment. METHODS: In 36 patients, we measure reticulocyte count and content of hemoglobin reticulocyte (CHr) as EA and FI markers, respectively, before and after the treatment. Before the study, 23 patients received another different therapy with IV iron as maintenance therapy. RESULTS: Reticulocyte count: 49.7 ± 23.8 × 10(3) before and 47.2 ± 17.2 × 10(3) after the treatment (p= 0.51). The CHr: 34.8 ± 3.7 pg and 34.4 ± 3.5 pg, respectively, (p= 0.35), showing an excellent correlation with the other FI markers (serum iron r = 0.6; p = 0.001; saturation transferrin r = 0.49; p = 0.004); that is not shown with the serum ferritin (r = 0.23; p = 0.192) or the hepcidin levels (r = 0.22; p = 0.251). There was not a correlation between the C-Reactive Protein, reticulocyte count, and CHr. The 13 patients who did not receive the iron prior to the study showed high FI levels, but not an increased of the serum ferritin or the serum hepcidin levels. CONCLUSIONS: The administration of a small quantity of iron at the end of every HD session keeps the EA and the FI levels and allows reducing the iron overload administered and/or decreasing the iron stores markers in some patients.