Early Eculizumab Withdrawal in Patients With Atypical Hemolytic Uremic Syndrome in Native Kidneys Is Safe and Cost-Effective: Results of the CUREiHUS Study.

Introduction: The introduction of eculizumab has improved the outcome in patients with atypical hemolytic uremic syndrome (aHUS). The optimal treatment strategy is debated. Here, we report the results of the CUREiHUS study, a 4-year prospective, observational study monitoring unbiased eculizumab discontinuation in Dutch patients with aHUS after 3 months of therapy. Methods: All pediatric and adult patients with aHUS in native kidneys and a first-time eculizumab treatment were evaluated. In addition, an extensive cost-consequence analysis was conducted. Results: A total of 21 patients were included in the study from January 2016 to October 2020. In 17 patients (81%), a complement genetic variant or antibodies against factor H were identified. All patients showed full recovery of hematological thrombotic microangiopathy (TMA) parameters after the start of eculizumab. A renal response was noted in 18 patients. After a median treatment duration of 13.6 weeks (range 2.1-43.9), eculizumab was withdrawn in all patients. During follow-up (80.7 weeks [0.0-236.9]), relapses occurred in 4 patients. Median time to first relapse was 19.5 (14.3-53.6) weeks. Eculizumab was reinitiated within 24 hours in all relapsing patients. At last follow-up, there were no chronic sequelae, i.e., no clinically relevant increase in serum creatinine (sCr), proteinuria, and/or hypertension in relapsing patients. The low sample size and event rate did not allow to determine predictors of relapse. However, relapses only occurred in patients with a likely pathogenic variant. The cost-effectiveness analysis revealed that the total medical expenses of our population were only 30% of the fictive expenses that would have been made when patients received eculizumab every fortnight. Conclusion: It is safe and cost-effective to discontinue eculizumab after 3 months of therapy in patients with aHUS in native kidneys. Larger data registries are needed to determine factors associated with suboptimal kidney function recovery during eculizumab treatment, factors to predict relapses, and long-term outcomes of eculizumab discontinuation.

Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective.

BACKGROUND: Eculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient. METHODS: We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) [classical pathway (CP) activity levels] of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modelling was performed with non-linear mixed-effects modelling. The final model was used to develop improved dosing strategies. RESULTS: A PK model with parallel linear and non-linear elimination rates best described the data with the parameter estimates clearance 0.163 L/day, volume of distribution 6.42 L, maximal rate 29.6 mg/day and concentration for 50% of maximum rate 37.9 mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0 mg/L and  Hill coefficient 5.42. A weight-based loading dose, followed by PK-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity <10%), compared with 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in ∼33% of the population by means of individualized dosing. With a fixed-dose 4-week dosing interval to allow for holidays, treatment costs will increase by 7.1% and we predict 91% of the patients will reach the efficacy target. CONCLUSIONS: A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.

Cost-effectiveness of eculizumab treatment after kidney transplantation in patients with atypical haemolytic uraemic syndrome.

Background: Kidney transplantation in patients with atypical haemolytic uraemic syndrome (aHUS) is frequently complicated by recurrence of aHUS, often resulting in graft loss. Eculizumab prophylaxis prevents recurrence, improving graft survival. An alternative treatment strategy has been proposed where eculizumab is administered upon recurrence. We combined available evidence and performed a cost-effectiveness analysis of these competing strategies. Methods: A cost-effectiveness analysis using a decision analytical approach with Markov chain analyses was used to compare alternatives for aHUS patients with end-stage renal disease (ESRD): (i) dialysis treatment, (ii) kidney transplantation, (iii) kidney transplantation with eculizumab therapy upon recurrence of aHUS, (iv) kidney transplantation with eculizumab induction consisting of 12 months of prophylaxis and (v) kidney transplantation with lifelong eculizumab prophylaxis. We assumed that all patients received a graft from a living donor and that recurrence probability was 28.4% within the first year of transplantation. Results: At 8.34 quality-adjusted life years (QALYs) gained and a cost of €402 412, kidney transplantation without eculizumab was the least costly alternative. By comparison, dialysis was more costly and resulted in fewer QALYs gained. Eculizumab upon recurrence resulted in 9.55 QALYs gained at a cost of €425 097. The incremental cost-effectiveness ratio (ICER) was €18 748 per QALY. Both eculizumab induction and lifelong eculizumab were inferior to eculizumab upon recurrence, as both resulted in fewer QALYs gained and higher costs. Conclusions: Kidney transplantation is more cost effective than dialysis to treat ESRD due to aHUS. Adding eculizumab treatment results in a substantial gain in QALYs. When compared with eculizumab upon recurrence, neither eculizumab induction nor lifelong eculizumab prophylaxis resulted in more QALYs, but did yield far higher costs. Therefore, eculizumab upon recurrence of aHUS is more acceptable.

Drug therapy management in patients with renal impairment: how to use creatinine-based formulas in clinical practice.

PURPOSE: The use of estimated glomerular filtration rate (eGFR) in daily clinical practice. METHODS: eGFR is a key component in drug therapy management (DTM) in patients with renal impairment. eGFR is routinely reported by laboratories whenever a serum creatinine testing is ordered. In this paper, we will discuss how to use eGFR knowing the limitations of serum creatinine-based formulas. RESULTS: Before starting a renally excreted drug, an equally effective drug which can be used more safely in patients with renal impairment should be considered. If a renally excreted drug is needed, the reliability of the eGFR should be assessed and when needed, a 24-h urine creatinine clearance collection should be performed. After achieving the best approximation of the true GFR, we suggest a gradual drug dose adaptation according to the renal function. A different approach for drugs with a narrow therapeutic window (NTW) is recommended compared to drugs with a broad therapeutic window. For practical purposes, a therapeutic window of 5 or less was defined as a NTW and a list of NTW drugs is presented. Considerations about the drug dose may be different at the start of the therapy or during the therapy and depending on the indication. Monitoring effectiveness and adverse drug reactions are important, especially for NTW drugs. Dose adjustment should be based on an ongoing assessment of clinical status and risk versus the benefit of the used regimen. CONCLUSION: When determining the most appropriate dosing regimen serum creatinine-based formulas should never be used naively but always in combination with clinical and pharmacological assessment of the individual patient.

Membranous nephropathy in the older adult: epidemiology, diagnosis and management.

Membranous nephropathy is the most important cause of the nephrotic syndrome in elderly patients (aged >65 years). The clinical presentation is similar in older and younger patients, although elderly patients more often present with renal failure. Notably, glomerular filtration rate (GFR) is usually lower in the elderly due to the physiological decline in GFR after the age of 30 years. Secondary causes, especially malignancies, are more common in older patients with membranous nephropathy. Therefore, elderly patients should undergo a thorough examination to exclude a secondary cause. The prognosis of elderly patients with idiopathic membranous nephropathy is not very different from that of younger patients. All elderly patients should receive symptomatic treatment aimed at reducing hypertension, oedema, proteinuria and hyperlipidaemia. It is recommended that elderly patients with a low serum albumin (<2 g/dL) receive prophylactic anticoagulation because of a high risk for thrombosis. Immunosuppressive therapy should be reserved for elderly patients at high risk of progression to end-stage renal disease because the elderly are particularly prone to the adverse effects and infectious complications of immunosuppressive therapy. High-risk elderly patients are characterised by renal insufficiency (GFR <45 mL/min/1.73m(2)), an increase in serum creatinine of >25% or a severe persistent nephrotic syndrome not responding to symptomatic treatment. In addition, elderly patients with a relatively normal GFR (>or=45 mL/min/1.73m(2)) and high urinary excretion of beta(2)-microglobulin and IgG are also at increased risk of developing end-stage renal disease; however, the deterioration in renal function is usually a slow process. Therefore, such patients benefit from immunosuppressive therapy only if their life expectancy is good. If immunosuppressive therapy is started, first-line treatment consists of prednisone and cyclophosphamide. If cyclophosphamide is contraindicated or fails to induce a remission, ciclosporin could be used. Treatment with ciclosporin should be limited to patients with a relatively normal renal function (GFR >60 mL/min/1.73m(2)) in view of its nephrotoxicity in patients with renal dysfunction.

Assessment of glomerular filtration rate in healthy subjects and normoalbuminuric diabetic patients: validity of a new (MDRD) prediction equation.

BACKGROUND: Based on the data derived from the Modification of Diet in Renal Disease (MDRD) study, a new equation was developed for the estimation of glomerular filtration rate (GFR). This equation, which takes into account body weight, age, sex, serum creatinine, race, serum urea, and serum albumin, provided a more accurate estimation of GFR in patients with renal insufficiency. However, this prediction equation has not been validated in subjects with normal or supra-normal GFR. METHODS: In a cross-sectional study, we measured GFR by inulin clearance in 46 healthy controls and 46 non-complicated type 1 diabetic patients. In this study population, GFR was predicted by measured creatinine clearance, the Cockcroft-Gault formula, and the MDRD equation. RESULTS: In the healthy subjects, mean GFR (+/-SD) was 107+/-11 as compared to 122+/-18 ml/min per 1.73 m(2) in the diabetic patients. This difference in GFR was reflected by a lower serum creatinine (76+/-8 vs 71+/-8 micro mol/l) in the diabetic patients. In the healthy controls, median absolute differences (and the 50th-75th-90th percentile of percentage absolute differences) between predicted and measured GFR were 5.2 ml/min per 1.73 m(2) (4.9-9.8-18.5%) for creatinine clearance, 9.0 ml/min per 1.73 m(2) (8.6-14.3-24.6%) for the Cockcroft-Gault formula, and 10.7 ml/min per 1.73 m(2) (10.9-16.3-25.5%) for the MDRD equation. In the diabetic patients, these differences were 8.3 ml/min per 1.73 m(2) (7.6-9.3-13.0%) for creatinine clearance; 11.8 ml/min per 1.73 m(2) (10.1-16.0-22.5%) for the Cockcroft-Gault formula, and 18.8 ml/min per 1.73 m(2) (16.0-24.2-31.9%) for the MDRD equation. CONCLUSIONS: In subjects with a normal or increased GFR, the new MDRD-prediction equation of GFR is less accurate than creatinine clearance or the Cockcroft-Gault formula, and offers no advantage.