Ravulizumab drug monitoring has not been explored for maintenance therapy in patients with complement-mediated (atypical) hemolytic uremic syndrome (aHUS). Phase III trials suggest the standard dosing regimen provides troughs about threefold higher than needed to suppress complement activity. We describe the use of ravulizumab in pediatric patients with aHUS in remission, exploring potential modified dosing strategies based on serum drug levels and complement markers. This single-center, retrospective cohort study included pediatric patients with aHUS in remission receiving outpatient ravulizumab infusions between June 30, 2023, and March 31, 2024, with at least one ravulizumab trough. Patients received a standard (SR) or a modified (MR) regimen, determined by the nephrologist. The primary outcome was to describe troughs and corresponding AH50 for patients on at least two equal doses. Secondary outcomes included comparison of troughs by regimen, intra-patient variability, possible adverse drug events (pADE), and drug costs. Nine patients were included. The mean ravulizumab trough level was 399.1 (± 107.3) mcg/mL. All patients exceeded the goal of 175 mcg/mL and achieved AH50 < 10

Primary hyperoxaluria type 1 (PH1) is a genetic disorder resulting in excess hepatic oxalate production, potentially leading to urolithiasis, nephrocalcinosis (NC), and ultimately, chronic kidney disease, kidney failure, and systemic oxalosis. Lumasiran, the first liver-directed RNA interference therapeutic administered to infants and toddlers, is approved in several countries, including those of the European Union and the United States, for treatment of PH1 to lower urinary oxalate (UOx) and plasma oxalate (POx) levels in pediatric and adult patients. Lumasiran demonstrated sustained efficacy with an acceptable safety profile over 30 months in infants and young children age <6 years with PH1 participating in ILLUMINATE-B (NCT03905694). We evaluated efficacy and safety outcomes through Month (M) 60 of ILLUMINATE-B. ILLUMINATE-B was a Phase 3, multinational, open-label, single-arm study. Eligibility included a confirmed PH1 diagnosis, age <6 years at study entry, an estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2 if age ≥12 months or normal serum creatinine if age <12 months, and a UOx:creatinine ratio (UOx:Cr) greater than the upper limit of normal (ULN). Lumasiran was administered subcutaneously using weight-based dosing. An extension period (EP) of up to 54 months followed the 6-month primary analysis. The primary endpoint was percentage change in spot UOx:Cr from baseline to M6. Secondary endpoints included change from baseline in UOx excretion, proportion of patients with UOx excretion ≤ULN and ≤1.5 × ULN for age, and changes from baseline in POx and in eGFR. Exploratory endpoints included changes in NC and kidney stone event rates. All 18 patients who enrolled in ILLUMINATE-B entered the EP and completed the study at M60. At consent, the median (range) age was 50.1 (3–72) months; the median age at diagnosis was 16.3 months. The median (range) exposure to lumasiran was 55.5 (54.5–56.1) months. The mean spot UOx:Cr actual values were 0.63 mmol/mmol at baseline and 0.11 mmol/mmol at M60 (Fig. 1A); the mean percentage change from baseline in the spot UOx:Cr was −74% at M60 (Fig. 1B). Overall, 100% of patients had a spot UOx:Cr value that was ≤ULN at ≥1 post-baseline visit. The mean POx decreased from 13.24 μmol/L at baseline to 8.21 μmol/L at M60 (ULN: 12.11 μmol/L), a mean percentage change from baseline of −25%. The eGFR remained stable over time, with a mean (SEM) of 112.8 (6.9) mL/min/1.73 m2 at baseline and 109.8 (5.7) mL/min/1.73 m2 at M60 (Fig. 2). The mean (SEM) annual rate of change in eGFR was 0.26 (0.8) mL/min/1.73 m²/y, calculated using simple linear regression. In the 2 patients who had CKD stage 2 at baseline, the mean (SEM) eGFR was 70.2 (5.6) mL/min/1.73 m2 at baseline and mean (SEM) change from baseline at M60 was −3.5 (4.3) mL/min/1.73 m2. Among 14 patients with medullary NC at baseline, NC grade was improved at M60 in 12 (86%; 10 had complete resolution and 2 did not), stable in 1 (7%), and indeterminate in 1 (7%). The 4 patients without NC at baseline remained stable, with no NC at M60. During the study, the rate of kidney stone events per person-year was 0.11 (95% confidence interval, 0.06–0.21); 14 (78%) patients had 0 kidney stone events. Overall, 5 (28%) patients had adverse events (AEs) considered related to lumasiran by the investigator. The most common lumasiran-related AEs were mild, transient injection site reactions, which affected 3 patients (17%; 7 events in 410 total administered doses); symptoms included erythema, discoloration, hematoma, urticaria, and pain at the injection site. There were no AEs leading to treatment discontinuation or study withdrawal, and no deaths. In this final analysis of long-term data from ILLUMINATE-B, infants and young children with PH1 had reductions in UOx and POx that were sustained over 60 months of lumasiran treatment. Kidney function was stable throughout long-term treatment. Medullary NC grade improved in most patients, and kidney stone event rates were low. The safety profile remained acceptable; the most common lumasiran-related AEs were mild, transient injection site reactions. Alnylam Pharmaceuticals.

BACKGROUNDCytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid organ transplant recipients. Pre-emptive treatment of patients with CMV viraemia using antiviral agents has been suggested as an alternative to routine prophylaxis to prevent CMV disease. This is an update of a Cochrane review first published in 2005.OBJECTIVESThis review was conducted to evaluate the efficacy of pre-emptive treatment with antiviral medications in preventing symptomatic CMV disease.SEARCH METHODSFor this update, we searched the Cochrane Renal Group's Specialised Register (to 16 January 2013) through contact with the Trials' Search Co-ordinator using search terms relevant to this review.SELECTION CRITERIAWe included randomised controlled trials (RCTs) of pre-emptive treatment compared with placebo, no specific treatment or with antiviral prophylaxis in solid organ transplant recipients.DATA COLLECTION AND ANALYSISFour authors assessed the quality and extracted all data. Analyses used a random-effects model and results were expressed as risk ratio (RR) and 95% confidence intervals (CI).MAIN RESULTSWe identified 15 eligible studies (1098 participants). Of these, six investigated pre-emptive treatment versus placebo or treatment of CMV when disease occurred (standard care), eight looked at pre-emptive treatment versus antiviral prophylaxis, and one reported on oral versus intravenous pre-emptive treatment.Assessment of risk of bias identified that the processes reported for sequence generation and allocation concealment were at low risk of bias in only five and three studies, respectively. All studies were considered to be at low risk of attrition bias, and seven studies were considered to be at low risk of bias for selective reporting. Only one study reported adequate blinding of participants and personnel; no study reported blinding of outcome assessment.Compared with placebo or standard care, pre-emptive treatment significantly reduced the risk of CMV disease (6 studies, 288 participants: RR 0.29, 95% CI 0.11 to 0.80) but not acute rejection (3 studies, 185 participants: RR 1.21, 95% CI 0.69 to 2.12) or all-cause mortality (3 studies, 176 participants: RR 1.23, 95% CI 0.35 to 4.30). Comparative studies of pre-emptive therapy versus prophylaxis showed no significant differences in preventing CMV disease between pre-emptive and prophylactic therapy (7 studies, 753 participants: RR 1.00, 95% CI 0.36 to 2.74) but there was significant heterogeneity (I² = 63%). Leucopenia was significantly less common with pre-emptive therapy compared with prophylaxis (6 studies, 729 participants: RR 0.42, 95% CI 0.20 to 0.90). Other adverse effects did not differ significantly or were not reported. There were no significant differences in the risks of all-cause mortality, graft loss, acute rejection and infections other than CMV.AUTHORS' CONCLUSIONSFew RCTs have evaluated the effects of pre-emptive therapy to prevent CMV disease. Pre-emptive therapy is effective compared with placebo or standard care. Despite the inclusion of five additional studies in this update, the efficacy of pre-emptive therapy compared with prophylaxis to prevent CMV disease remains unclear due to significant heterogeneity between studies. Additional head-to-head studies are required to determine the relative benefits and harms of pre-emptive therapy and prophylaxis to prevent CMV disease in solid organ transplant recipients.

Background Ravulizumab drug monitoring has not been explored for maintenance therapy in patients with atypical hemolytic uremic syndrome (aHUS). Phase III trials suggest standard dosing regimen provides troughs about 3-fold higher than needed to suppress complement activity. We describe the use of ravulizumab in pediatric patients with aHUS in remission, exploring potential modified dosing strategies based on serum drug level and complement markers. Methods This single-center, retrospective cohort study included pediatric patients with aHUS in remission receiving outpatient ravulizumab infusions between June 30, 2023 and March 31, 2024 with at least one ravulizumab trough. Patients received a standard (SR) or a modified (MR) regimen, determined by the nephrologist. The primary outcome was to describe troughs and corresponding AH50 for patients on at least two equal doses. Secondary outcomes included comparison of troughs by regimen, intra-patient variability, possible adverse drug events (pADE), and drug costs. Results Nine patients were included. The mean ravulizumab trough level was 399.1 (± 107.3) mcg/mL. All patients exceeded goal of 175 mcg/mL and achieved AH50 < 10%. Four patients (44%) received ravulizumab according to a MR. No difference was observed in ravulizumab trough levels between SR and MR groups (p = 0.67). Patients with multiple troughs showed low intra-patient variability (CV < 25%). pADE rates were similar across regimens, and MR was associated with lower drug costs. Conclusion Individualized maintenance regimens of ravulizumab based on trough and complement monitoring appears safe and effective while reducing drug costs. Further study is needed to define optimal ravulizumab maintenance dosing strategy.

The primary hyperoxalurias (PH 1, 2, and 3) are rare autosomal recessive disorders of glyoxylate metabolism resulting in hepatic overproduction of oxalate. Clinical presentations that should prompt consideration of PH include kidney stones, nephrocalcinosis, and kidney failure of unknown etiology, especially with echogenic kidneys on ultrasound. PH1 is the most common and severe of the primary hyperoxalurias with a high incidence of kidney failure as early as infancy. Until the recent availability of a novel RNA interference (RNAi) agent, PH care was largely supportive of eventual need for kidney/liver transplantation in PH1 and PH2. Together with the Oxalosis and Hyperoxaluria Foundation, the authors developed a diagnostic algorithm for PH1 and in this report outline best clinical practices related to its early diagnosis, supportive treatment, and long-term management, including the use of the novel RNAi. PH1-focused approaches to dialysis and kidney/liver transplantation for PH patients with progression to chronic kidney disease/kidney failure and systemic oxalosis are suggested. Therapeutic advances for this devastating disease heighten the importance of early diagnosis and informed treatment.

BackgroundPrimary hyperoxaluria type 1 (PH1) is a genetic disorder resulting in overproduction of hepatic oxalate, potentially leading to recurrent kidney stones, nephrocalcinosis, chronic kidney disease, and kidney failure. Lumasiran, the first RNA interference therapeutic approved for infants and young children, is a liver-directed treatment that reduces hepatic oxalate production. Lumasiran demonstrated sustained efficacy with an acceptable safety profile over 12 months in infants and young children (age <6 years) with PH1 in ILLUMINATE-B (clinicaltrials.gov: NCT03905694), an ongoing, Phase 3, multinational, open-label, single-arm study.MethodsHere, we report interim efficacy and safety findings from ILLUMINATE-B following 30 months of lumasiran treatment. Eligible patients had an estimated glomerular filtration rate (eGFR) >45 ml/min/1.73 m2 if ≥12 months old or normal serum creatinine if <12 months old, and a urinary oxalate to creatinine ratio (UOx:Cr) greater than the upper limit of normal. All 18 patients enrolled in ILLUMINATE-B completed the 6-month primary analysis period, entered an extension period of up to 54 months, and continue to participate in the study.ResultsAt Month 30, mean percent change from baseline in spot UOx:Cr was −76%, and mean percent change in plasma oxalate was −42%. eGFR remained stable through Month 30. In 14 patients (86%) with nephrocalcinosis at baseline, nephrocalcinosis grade improved at Month 24 in 12; no patient worsened. In the 4 patients without baseline nephrocalcinosis, nephrocalcinosis was absent at Month 24. Kidney stone event rates were ≤0.25 per person-year through Month 30. Mild, transient injection site reactions were the most common lumasiran-related adverse events (17% of patients).ConclusionIn infants and young children with PH1, long-term lumasiran treatment resulted in sustained reductions in urinary and plasma oxalate that were sustained for 30 months, with an acceptable safety profile. Kidney function remained stable, low kidney stone event rates were observed through Month 30, and nephrocalcinosis grade improvements were observed through Month 24. Clinical Trial Registrationhttps://clinicaltrials.gov, identifier NCT03905694.

Rationale & Objective: Lumasiran reduces uri-nary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease.Study Design: Phase 3, open-label, single-arm trial.Setting & Participants: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate <= 45 mL/min/1.73 m2 (if age >= 12 months) or increased serum creatinine level (if age <12 months), and POx >= 20 mu mol/ L at screening, including patients with or without systemic oxalosis.Intervention: Lumasiran administered subcuta-neously; 3 monthly doses followed by monthly or quarterly weight-based dosing.Outcome: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enroll-ment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); abso-lute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. Results: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient.Limitations: Single-arm study without placebo control.Conclusions: Lumasiran resulted in substantial reductions in POx with acceptable safety in pa-tients with PH1 who have advanced kidney dis-ease, supporting its efficacy and safety in this patient population.Funding: Alnylam Pharmaceuticals.Trial Registration: Registered at Clinical-Trials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17.

Diagnosing genetic kidney disease has become more accessible with low-cost, rapid genetic testing. The study objectives were to determine genetic testing diagnostic yield and examine predictors of genetic diagnosis in children with nephrolithiasis/nephrocalcinosis (NL/NC). This retrospective multicenter cross-sectional study was conducted on children ≤ 21 years old with NL/NC from pediatric nephrology/urology centers that underwent the Invitae Nephrolithiasis Panel 1/1/2019–9/30/2021. The diagnostic yield of the genetic panel was calculated. Bivariate and multiple logistic regression were performed to assess for predictors of positive genetic testing. One hundred and thirteen children (83 NL, 30 NC) from 7 centers were included. Genetic testing was positive in 32

Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate. Lumasiran demonstrated efficacy and safety in the 6-month primary analysis period of the phase 3, multinational, open-label, single-arm ILLUMINATE-B study of infants and children < 6 years old with PH1 (ClinicalTrials.gov: NCT03905694 (4/1/2019); EudraCT: 2018–004,014-17 (10/12/2018)). Outcomes in the ILLUMINATE-B extension period (EP) for patients who completed ≥ 12 months on study are reported here. Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed ≥ 6 additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7–20.5) months). Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72% at month 6, which was maintained at 72% at month 12; mean month 12 reductions in prespecified weight subgroups were 89%, 68%, and 71% for patients weighing < 10 kg, 10 to < 20 kg, and ≥ 20 kg, respectively. The mean reduction from baseline in plasma oxalate level was reported to be 32% at month 6, and this improved to 47% at month 12. Additional improvements were also seen in nephrocalcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related adverse events were mild, transient injection-site reactions (3 patients (17%)). Lumasiran treatment provided sustained reductions in urinary and plasma oxalate through month 12 across all weight subgroups, with an acceptable safety profile, in infants and young children with PH1. A higher resolution version of the Graphical abstract is available as Supplementary information

Children with chronic kidney disease (CKD) generally have worse educational and psychosocial outcomes compared with their healthy peers. This can impair their ability to manage their treatment, which in turn can have long-term health consequences through to adulthood. We attempted to capture the experiences of children with CKD and to describe the perspectives of their parents and caregivers on access to educational and psychosocial support.Children with CKD (n = 34) and their caregivers (n = 62) were sampled via focus groups from pediatric hospitals in Australia, Canada, and the USA. Sixteen focus groups were convened and the transcripts were analyzed thematically.We identified four themes: disruption to self-esteem and identity (emotional turmoil of adolescence, wrestling with the sick self, powerlessness to alleviate child's suffering, balancing normality and protection); disadvantaged by lack of empathy and acceptance (alienated by ignorance, bearing the burden alone); a hidden and inaccessible support system (excluded from formal psychological support, falling behind due to being denied special considerations); and building resilience (finding partners in the journey, moving towards acceptance of the illness, re-establishing childhood).Children with CKD and their caregivers encountered many barriers in accessing psychosocial and educational support and felt extremely disempowered and isolated as a consequence. Improved availability and access to psychosocial and educational interventions are needed to improve the wellbeing and educational advancement of children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Abstract BACKGROUND AND AIMS Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterised by hepatic oxalate overproduction that leads to progressive kidney disease. As kidney function declines, oxalate elimination is compromised and plasma oxalate (POx) increases, leading to systemic oxalosis. In chronic kidney disease (CKD) stages 3b–5, elevated POx is directly related to the pathophysiology of oxalosis, and reduction of POx is a relevant clinical trial endpoint. Lumasiran, an RNA interference therapeutic designed to reduce hepatic oxalate production, is indicated for the treatment of PH1 in all age groups. Data from the ILLUMINATE-C trial (EudraCT: 2019–0 013 346-17) demonstrated substantial reductions in POx and acceptable safety in patients with PH1 with impaired kidney function, including patients on haemodialysis (HD), who received lumasiran for 6 months. In Cohorts A (no HD) and B (on HD), respectively, lumasiran led to 33.33% [95% confidence interval (95% CI): −15.16 to 81.82] and 42.43% (95% CI: 34.15–50.71) least-squares (LS) mean reductions in POx from baseline to Month 6 (the primary endpoint). Here, we present METHOD ILLUMINATE-C is an ongoing Phase 3, single-arm study with two cohorts, Cohort A (N = 6; no HD at study start) and Cohort B (N = 15; on HD). The 6-month primary analysis period is followed by an extension period (EP) of up to 54 months. Key inclusion criteria include genetically confirmed PH1, eGFR ≤ 45 mL/min/1.73 m2 and POx ≥ 20 μmol/L. Patients received weight-based dosing of subcutaneous lumasiran. Outcomes of interest for the current analysis included assessments of cardiac oxalosis using echocardiography, medullary nephrocalcinosis by kidney ultrasound, kidney stone events and burdensome symptoms of PH1. RESULTS All 21 patients [43% female; 76% white; median age 8 (range 0–59) years] completed the 6-month primary analysis period. Among patients with abnormal left ventricular ejection fraction (LVEF; abnormal defined as LVEF < 55%) at baseline, 1/1 patient in Cohort A and 2/4 patients in Cohort B showed ≥ 5% improvement at Month 6. Among patients with abnormal global longitudinal strain (GLS, a measure of LV contractility more sensitive than LVEF for predicting outcomes; abnormal defined as |GLS| <15%) at baseline, 1/1 patient in Cohort A and 3/3 patients in Cohort B showed ≥ 2% improvement at Month 6. In Cohort A, 5/6 patients had nephrocalcinosis at baseline, 2 remained stable, none worsened, and 3 improved (2 unilateral and 1 bilateral improvement) at Month 6. In Cohort A, 1 patient did not have nephrocalcinosis at baseline and had bilateral worsening at Month 6. In Cohort B, 2/11 patients had nephrocalcinosis at baseline; both improved (1 unilateral and 1 bilateral improvement). In Cohort A, the rate of kidney stone events per person-year was 3.20 (95% CI: 1.96–5.22) in the 12 months prior to consent and 1.48 (95% CI: 0.55–3.92) during the first 6 months of lumasiran treatment. For patients in both cohorts, the most burdensome symptoms at baseline, including fatigue, nausea/decreased appetite, bone pain and decreased mobility, improved or remained stable at Month 6; none of the symptoms worsened. CONCLUSION Lumasiran treatment resulted in substantial reductions in POx in patients of all ages with PH1 and advanced kidney disease. The observations regarding cardiac measures that reflect systemic oxalosis, together with the kidney stone event and nephrocalcinosis results, are consistent with mobilisation of oxalate from systemic stores. Data on these long-term outcomes will continue to be collected and further evaluated in the EP. These results, along with previous reports from ILLUMINATE-A and ILLUMINATE-B, provide evidence supporting the effectiveness of lumasiran across the full spectrum of patients affected by PH1.