Liver Transplantation in Childhood: A 2-Year Single Center Experience.

ObjectivePrimary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder caused by AGXT mutations, leading to hepatic oxalate overproduction, nephrolithiasis, and progressive renal failure. This study aims to evaluate the therapeutic potential of base editors delivered via lipid nanoparticles (LNPs) for treating PH1.MethodsWe utilized LNPs to deliver the base editor variant spG‐ABE8e into a PH1 rat model. A single‐dose injection of LNP‐ABE was administered to assess its efficacy in correcting the pathogenic Agxt point mutation.ResultsTreatment with LNP‐ABE achieved highly efficient correction of the Agxt mutation, which resulted in the normalization of urinary oxalate excretion, prevention of calcium oxalate deposits, and reversal of renal injury‐associated gene expression profiles in PH1 rats. Furthermore, this study identified the minimum Agxt correction efficiency required for urinary oxalate normalization.ConclusionOur findings demonstrate that LNP‐mediated delivery of base editors can effectively correct AGXT pathogenic mutations and ameliorate disease phenotypes in PH1, providing critical preclinical benchmarks for future clinical translation.Key pointsThe base editor precisely corrected the Agxt gene with high efficiency in PH1 rats.LNP‐delivered Adenine Base Editor (ABE) normalized urinary oxalate levels and prevented calculus formation.This study identified the minimal Agxt correction efficiency required for urinary oxalate normalization.

BackgroundPrimary hyperoxaluria (PH) is a rare inherited disorder characterized by excessive oxalate accumulation in blood and urine due to defects in glyoxylate metabolism, leading to significant clinical consequences. As genetic and phenotypic heterogeneity contribute to the morbidity of PH, this study examined the phenotypes and genotypes of PH among confirmed pediatric patients (< 18 years) diagnosed with PH at a tertiary care center in Saudi Arabia between 2014 and 2023.ResultsTwenty-one patients from 14 families, including 10 boys (47.6%) and 11 girls (52.4%), were included. Six families had more than one affected child. The median age at diagnosis was 36 months (interquartile range = 6–84). All but one patient had PH type 1 [due to alanine–glyoxylate aminotransferase gene variant (AGXT)], with the remaining patient having PH type 2 [associated with glyoxylate and hydroxypyruvate reductase gene (GRHPR)]. The most frequent variant in the AGXT gene was NM_000030.3: c.33dup (p.Lys12GlnfsTer156), which was detected in 38.1% of patients. High parental consanguinity (90.5%) and positive family history (81%) were notable. The major clinical manifestations were kidney stones (71.4%), nephrocalcinosis (47.6%), failure to thrive (38.1%), stage V chronic kidney disease (42.9%), and hematuria (33.3%). All patients received conservative management, in addition to liver transplantation in eight patients and combined liver–kidney transplantation in two patients. The mortality rate was 14.3% (3/21). AGXT variants such as NM_000030.3:c.481G > A(p.(Gly161Ser) and NM_000030.3: c.346G > A (p.(Gly116Arg) displayed potential trends with worse renal prognosis.ConclusionsPH type 1 is the predominant form of hyperoxaluria among Saudi patients. High consanguinity might contribute to its disease burden. Early diagnosis and intervention are critical for improving outcomes. Recently approved RNA interference-based therapies offer promising outcomes, potentially reducing the need for organ transplantation in patients with PH type 1.Clinical trail numberNot applicable.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13023-025-04082-8.

Safety and efficacy of small interfering RNA agents (lumasiran) in therapy for primary hyperoxaluria type 1: A systematic review

Abstract Background and Aims Primary hyperoxaluria type 1 (PH1) is a rare disorder (prevalence: 1–3 cases per million individuals), caused by mutations in the AGXT gene leading to an enzymatic deficit, resulting in altered metabolism and oxalate accumulation. It is often underdiagnosed due to limited awareness of the condition and inadequate diagnostic tools. Although rare, PH1 is a cause of nephrolithiasis and end-stage chronic kidney disease. PH1 can account for 3–10% of ESRD cases in patients who have recurrent kidney stones or early onset kidney failure. Its symptoms can overlap with those of other renal conditions, making it challenging to accurately determine its true prevalence in hemodialyzed populations. Method We conducted from September 2023 to September 2024, a collaborative project among eight hemodialysis centers in Tuscany, aimed at screening hemodialysis patients with at least one of specific clinical and anamnestic characteristics (Table 1). Selected patients underwent buccal swab testing for AGXT gene variants. Results A total of 176 patients on hemodialysis were screened, with the following characteristics: 70% male, 87% Caucasian ethnicity, chronic kidney disease onset between the ages of 40 and 65 years (mean age: 52 years), 99% without consanguinity in their pedigree, and 16% with obesity (BMI &amp;gt;25). Among these patients, 9% reported a family history of chronic kidney disease, and 3% had a family history of nephrolithiasis. At the time of screening, 9% had active kidney stones, with 30% of these cases involving bilateral stones. Nephrocalcinosis was present in 2% of the cases. Only 7 out of 176 patients had confirmed calcium oxalate stone composition. Notably, 78% of the dialysis population had no defined etiology for their chronic kidney disease (CKDu). Additionally, 15% were on hemodialysis following renal transplant failure. Patients underwent buccal swabs to screen for AGXT mutations. No cases of PH1 were identified, although five patients were found to be carrier of heterozygous AGXT gene variants. Conclusion The genetic screening conducted on our selected case series did not identify any cases of PH1, confirming the rarity of the disease. However, the negative result of this screening test does not exclude the diagnosis of other forms of primary hyperoxaluria (types 2 and 3). The project allowed us to reassess the medical histories of our patients, from which it emerged that in a significant number of cases there is no clear diagnosis of the renal condition, opening the possibility for further diagnostic investigations aimed at obtaining an accurate diagnosis.

Abstract Background and Aims Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive genetic disorder caused by mutations in the AGXT gene, resulting in dysfunction of the enzyme alanine-glyoxylate aminotransferase (AGT) and leading to hepatic overproduction of oxalate. PH1 is an underdiagnosed condition, and its identification profoundly alters transplantation strategies due to the need to address the primary cause of the disease, which is the hepatic metabolic defect. The aim of this study was to evaluate the prevalence of PH1 among patients with chronic kidney disease (CKD) of unknown etiology who are candidates for kidney transplantation. Method Patients with CKD of unknown etiology who were candidates for kidney transplantation were evaluated across six Brazilian centers. These patients were selected based on the presence of nephrocalcinosis, recurrent or bilateral nephrolithiasis, recurrent urinary tract infections, unexplained graft loss, or a family history of PH1. The assessment included measurement of serum oxalate levels and genetic analysis using a lithiasis-related gene panel consisting of 40 genes, covering primary hyperoxaluria types 1, 2, and 3. Results A total of 39 patients were evaluated, with a median age of 48 (39–53) years; 54% female, and 87% Caucasian. Recurrent urinary tract infections were observed in 26%, nephrocalcinosis in 21%, staghorn calculi in 8%, and nephrolithiasis in 92%. Among the sample, 18% had a prior renal graft loss. Overall, 33% of the cases had positive genetic variants (n = 13), including: PH1 (n = 6), cystinuria (n = 2), Dent disease (n = 1), Hypomagnesemia (CLDN19) (n = 1), Familial Hypocalciuric Hypercalcemia (FHH1) (n = 1), Nephronophthisis (NPHP1) (n = 1), and CLDN19 deletion (n = 1). Patients with PH1 were more frequently diagnosed in the context of nephrocalcinosis (50% vs 15%, P = 0.08), retransplant evaluation (50% vs 12%, P = 0.05), and with higher plasma oxalate levels (14 vs 78 µmol/L, P = 0.014). Conclusion Among CKD patients, the frequency of undiagnosed genetic disorders related to nephrolithiasis was high (33%), with the most common being PH1 (15%) and cystinuria (5%). Elevated plasma oxalate, nephrocalcinosis, and prior graft loss were more commonly associated with PH1, a severe condition impacting both pre- and post-transplant management. Systematic screening for CKD of unknown etiology, combined with nephrolithiasis, revealed a high rate of positive genetic findings and should be considered in pre-transplant evaluations

Abstract Background and Aims Hyperoxaluria arises from either genetic defect in glyoxylate metabolism (primary) or increased intestinal oxalate absorption (secondary). It can cause calcium oxalate supersaturation, leading to urolithiasis and oxalate nephropathy. This is characterized by tubulointerstitial oxalate deposits along with an interstitial inflammatory reaction. Method This study aimed to assess the epidemiological and clinical characteristics of hyperoxaluria diagnosed through renal biopsy. We conducted a retrospective study of cases diagnosed via renal biopsy between January 2004 and December 2024. Results A total of 31 cases of hyperoxaluria were identified, including 12 children and 19 adults, with a male-to-female ratio of 0.7. The mean age at diagnosis was 21.5 ± 6.4 years. Parental consanguinity was noted in 20 cases (64.5%), a family history of chronic kidney disease in 15 patients (48.3%), and a personal history of urinary lithiasis in 11 cases (35.4%). Hypertension was present in 5 patients, Hematuria in 10 cases while Proteinuria (range: 1.2–1.9 g/24 h) was noted in 14 patients. Renal biopsy confirmed the diagnosis in all cases. The main indication for biopsy was renal failure with a mean serum creatinine level of 648.3 ± 106.5 μmol/L. In two patients, hyperoxaluria was diagnosed following early recurrence in a kidney graft. Primary hyperoxaluria was identified in 28 cases, while three cases were secondary: two of our patients have short bowel syndrome as a result of ileocolic resection following an operation for a complication of their inflammatory bowel disease, and another patient has been diagnosed with exocrine pancreatic insufficiency. Conclusion Diagnosing hyperoxaluria in patients with renal failure is a difficult task. When clinical and radiological findings are inconclusive, renal biopsy remains a crucial tool for reaching a definitive diagnosis.

Abstract Background and Aims Monogenic kidney stone diseases are reported to be present in up to 15% of patients attending specialised metabolic kidney stone clinics. This is relevant as many of these disorders are actionable, guiding personalised treatment to reduce future stone formation. This study evaluated the medical and family history of patients who had already received a genetic test, to look for pre-existing factors that may suggest the presence of a genetic disorder related to kidney stones. The aim was to ascertain which clinical factors, in patients attending a metabolic kidney stone clinic, are most likely to predict a positive genetic diagnosis. Hence, certain categories of stone forming patients can be prioritised for future genetic testing. Method We analysed all patients attending the Royal Free Hospital's metabolic stone clinic from September 2022 to September 2024 who had genetic testing either with next generation sequencing or whole genome sequencing with a focused exome analysis using the nephrolithiasis and nephrocalcinosis gene panel (R256) provided by the NHS Genomic Medicine Service. Patients had been tested over this time period on the basis of either clinical suspicion of a specific diagnosis, or because clinical and biochemical analysis had not yielded a diagnosis. We therefore retrospectively analysed this cohort against clinical criteria known to be associated with underlying genetic diagnoses in stone forming patients. 35 patients were tested during the selected period. Patients with a confirmed genetic mutation (“positive,” n = 6) and the remainder with no mutation found (“negative,” n = 29), were compared using a t-test to look for differences between the two groups in certain relevant parameters. These were age at the time of the test, sex, family history of kidney stones, age at the time of first stone, presence of nephrocalcinosis, rate of recurrence of kidney stones, and eGFR at the time of the test. In addition, an arbitrarily weighted scoring system, based on widely accepted risk factors for monogenic stone disease (Fig. 1), was used to generate a cumulative score for each patient. Results We found three parameters that were significantly different between the “positive” genetic test group compared to the “negative” group. These factors were: first episode of stone at age &amp;lt;18 y.o. (P = 0.0107), presence of nephrocalcinosis (P = 0.0040) and having a higher cumulative score (P = 0.0073). 6 out of 35 patients received a positive genetic diagnosis: two cases of Bartter syndrome, and one case each of cystinuria, primary hyperoxaluria type 1, primary hyperoxaluria type 3, and hereditary hypophosphataemic rickets with hypercalciuria. Conclusion Although based on a small and highly selected sample of patients, this study highlights that genetic testing is more likely to yield a positive outcome in patients who form stones at young age and/or have nephrocalcinosis. A composite score, which combines and weights multiple parameters, may also be a clinically useful method of prioritising those patients who should receive the R256 genomic medicine test. This is important because determining the sensitivity of genetic screening in all stone formers would require the entire cohort to be tested, which is neither practical nor cost effective. Meanwhile, our data support the idea that clinicians should enquire about age of first stone in all stone formers.

Abstract Background Incremental Peritoneal Dialysis (PD) is a strategy for initiating PD that aims to reduce dialysis burden and, consequently, improve patients’ therapy acceptance and quality of life. Incremental PD may help to preserve diuresis, reduce costs and minimize plastic waste, with no observed difference in mortality compared to standard PD. Almost all PD fluids exploit glucose as an osmotic agent that rapidly diffuses across the peritoneal membrane, potentially resulting in metabolic abnormalities such as hyperglycemia, hyperinsulinemia, obesity, and hyperlipidemia. Moreover, glucose itself induces significant morphological and functional changes in the peritoneum leading to ultrafiltration failure. Xylitol and L-carnitine have been proposed as potential alternatives to glucose and, after successful preclinical testing, are now in phase III of clinical development (ELIXIR study, EU CT n° 2024-513562-19-00). Here we report the design of EXCITE, the first pilot study to assess the safety and efficacy of PolyCore, a bimodal PD solution formulated as a ternary combination of xylitol, L-carnitine and Polydextrin, in ESKD patients treated with incremental PD. Study design EXCITE is a single-arm, pilot, multicenter study to evaluate the safety and efficacy of PolyCore, a ternary combination of xylitol, l-carnitine and polydextrin, to treat end-stage kidney disease patients starting peritoneal dialysis. The study shall enroll ESKD patients, in stable clinical conditions, incident to IPD or who have been receiving IPD for no more than 6 months, with GFR ≥ 5 ml/min/1.73 m2, Kt/V urea ≥ 1.7, and being treated with two PD exchanges per day encompassing one Icodextrin (7.5%)-based solution and a Glucose (up to 1.5%)-based. Main exclusion criteria are having experienced a peritonitis in the three months preceding screening, severe pulmonary/cardiac/hepatic insufficiency and clinically significant abnormal liver function. Enrolled patients shall enter a 28-day run-in period starting or continuing their pre-study incremental PD. The run-in period shall allow to verify the PD treatment adequacy and to genetically test patients for primary hyperoxaluria type 1 and 2. After the run-in period, patients will be switched to PolyCore for 28 days according to the following schedule: - PolyCore, two extended duration exchanges [8–12 hours] or- PolyCore, one extended duration exchange [8–12 hours] and one short dwell exchange [4–6 hours] Patients who need to transition to a full dose of PD treatment during the study will drop out of the study. The primary endpoints, related to safety, include the evaluation of Adverse Events, blood chemistry and hematology, 24 h diuresis and dialysate analyses, weekly Kt/V and residual kidney function. Secondary endpoints, related to efficacy, include peritoneal ultrafiltration, sodium removal, glycemic and lipidic parameters, peritoneal clearances and quality of life by KDQOL-SF. Given the nature of the study, single-arm and pilot without formal formulation of the hypotheses to be tested, 28 patients, including drop-outs, will be enrolled. This number is sufficient to obtain sufficiently valid summary measures of efficacy estimates to allow a formal calculation for the design of a proof of efficacy study. Conclusions Osmo-metabolic agents, currently in Phase III trials, offer a promising alternative to the many adverse effects of glucose. The EXCITE study, a pilot trial, aims to provide the first scientific insights into the use of osmo-metabolic agents in combination with polydextrin, a key component of existing glucose-free alternatives, with the aim of yielding a single product for incremental peritoneal dialysis, combining the local and systemic biocompatibility of xylitol and L-carnitine with ultrafiltration performance of Polydextrin.

Abstract Background and Aims 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 &amp;lt;6 years with PH1 participating in ILLUMINATE-B (NCT03905694). We evaluated efficacy and safety outcomes through Month (M) 60 of ILLUMINATE-B. Method ILLUMINATE-B was a Phase 3, multinational, open-label, single-arm study. Eligibility included a confirmed PH1 diagnosis, age &amp;lt;6 years at study entry, an estimated glomerular filtration rate (eGFR) &amp;gt;45 mL/min/1.73 m2 if age ≥12 months or normal serum creatinine if age &amp;lt;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. Results 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. Conclusion 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. Source of Funding Alnylam Pharmaceuticals.

Primary hyperoxaluria (PH) is a family of three rare, autosomal recessive genetic disorders that can result in recurrent kidney stones, progressive chronic kidney disease (CKD), and kidney failure. PH prevalence is underestimated due to its varying presentation and lack of awareness; delays in diagnosis can lead to substantial burdens on the healthcare system. This retrospective, observational claims analysis evaluated disease burden and cost of care in patients who had PH, PH with CKD, or CKD alone. Data from the Merative MarketScan Commercial Claims and Encounters databases and the Centers for Medicare and Medicaid Services Medicare Fee-for-Service Limited Data Set were assessed during the study period of January 1, 2017, to December 31, 2021. PH prevalence was calculated based on the sample population within each data source. The study sample included 326 patients who had PH; applying projection factors to the US population, an estimated 4500 patients had a diagnosis of PH in 2021. Among these patients, 37% were estimated to have PH with CKD (65% of whom had early CKD, 33% had advanced CKD, and 2% had stage reported as unknown). Patients who had CKD alone (n = 845) were matched with patients who had PH with CKD (n = 169). Patients who had PH with CKD were significantly more burdened with kidney stones (p < 0.01) than patients who had CKD alone. Higher rates of pharmacotherapy and medical treatments were observed in patients who had PH with CKD versus patients who had CKD alone. Median semi-annual total all-cause healthcare costs were greater in patients who had PH with CKD than in patients with CKD alone, regardless of CKD stage ($54,154 in patients who had PH with advanced CKD vs. $35,016 in patients with advanced CKD alone; $9,784 in patients who had PH with early CKD vs. $5,572 in patients with early CKD alone). CKD stage progression among patients who had PH is associated with increasing all-cause costs, suggesting that early diagnosis and treatment of PH to limit the progression to advanced CKD could represent an opportunity to alleviate not only PH symptoms, but also the healthcare cost burden.

Primary hyperoxaluria is a severe autosomal recessive disorder that leads to chronic kidney disease and often necessitates renal replacement therapy in childhood. Some patients with primary hyperoxaluria type 1 respond to pyridoxine therapy, whereas patients with types 2 and 3 receive only citrate therapy. In recent years, a targeted drug – lumasiran – has become available for treating 1 type primary hyperoxaluria. Its mechanism is based on reducing glioxylate production and, consequently, oxalate formation. To date, no published data exist on the efficacy of lumasiran in Russian patients.Materials: Since 2014, 14 children with primary hyperoxaluria have been followed in the Nephrology Department of the National Research Center for Children’s Health: 12 with 1 type and 2 with type 3. Among the 12 children type 1 patients, 5 received pathogenetic therapy with lumasiran. The duration of treatment ranged from 9 months to 3 years, with a mean 26 months (SD 13 months).Results: After 12 months of therapy, no patients showed worsening of nephrocalcinosis or decline in kidney function. Four patients achieved marked reduction in urinary oxalate excretion (90%, 88%, 89% and 74%). One child had been on treatment for less than one year.Conclusions: Early treatment initiation of treatment for primary hyperoxaluria – particularly type 1 – significantly improve not only renal but also overall survival.

Defective hepatic alanine-glyoxylate aminotransferase (AGT) leads to oxalate overproduction in primary hyperoxaluria type 1 (PH1). Nedosiran and lumasiran are RNA interference (RNAi) agents inhibiting oxalate production. In PH1 patients with kidney failure isolated kidney transplantation (iKTx) might be possible with RNAi medication. We report on 17 PH1 patients on hemodialysis, who received lumasiran (8 patients, 1-68 years, 6 females), lumasiran post nedosiran (2 patients, both 6.5 years, male), double RNAi (dRNAi) (4 patients, 37 years, 3 infants, all male) and nedosiran (4 patients, 11-58 years, 2 female). Plasma oxalate (Pox) pre-HD was measured and systemic oxalate grading (SOG) was evaluated mainly by bone MRI and speckle echocardiography before start and repeatedly during treatment. In 4 patients iKTx was performed, being successful or with recurrence in 2 patients each. In others, development of Pox values under RNAi treatment and thus SOG increment and clinical deterioration were profound arguments for transplant decisions. Based on that iKTx is now planned in 5 and liver/kidney Tx in 4 patients (one liver already transplanted). Three patients have died. Pox should not be the sole parameter to decide on Tx procedure. In patients with minor oxalate deposition, no SOG deterioration and sensitivity to vitamin B6 or under efficacious RNAi treatment, iKTx can be considered. Severe (and deteriorating) systemic oxalosis, high Pox during RNAi treatment and maximum dialysis, makes us reconsider combined or sequential LKTx rather than iKTx. Patients with severe systemic oxalosis at time of diagnosis still have a high mortality rate.

Continuous kidney replacement therapy (CKRT) can influence pharmacokinetics (PK), including clearance (CL) of antibiotics like piperacillin (PIP). Both CKRT intensity, or "dialysis dose," and residual kidney function can alter PIP PK and pharmacodynamic (PD) target attainment (TA), defined by the percentage of time free PIP concentrations exceed the minimum inhibitory concentration (% fT > MIC). In existing reports, children receiving PIP and CKRT are usually oligoanuric, so PIP PK/PD in non-oligoanuric patients receiving high-intensity CKRT is unknown. This report analyzes free PIP PK/PD in a child with robust kidney function who received 30-minute infusions of 100 mg/kg PIP-tazobactam every 6 hours while on high-intensity CKRT after liver-kidney transplant for primary hyperoxaluria. Model-informed PK software was used to estimate PK/PD parameters for periods on and off CKRT. PIP CL on CKRT was 66% higher than off CKRT (5.59 L/hr vs 3.36 L/hr). Nearly 100% fT > 1xMIC (using 8 mg/L for Enterobacterales) was achieved whether on or off CKRT, but only 60% fT > 4xMIC was achieved on CKRT. CKRT CL was 40% of total CL on CKRT and 51% of the CKRT dialysis dose, suggesting PIP elimination was mostly renal despite high-intensity dialysis. Monitoring of free PIP concentrations may help ensure proper TA in non-oligoanuric patients receiving high-dose CKRT.

Final 60-Month Efficacy, Safety, and Kidney Stone Outcomes of a Phase 3 Trial of Lumasiran for Primary Hyperoxaluria Type 1 in Infants and Young Children

Normal urinary oxalate excretion in 4-hydroxy-2-oxo-glutarate aldolase 1 (HOGA1) deficient mice with AGT expression in peroxisomes and not in mitochondria.

Background: Primary hyperoxaluria is a rare genetic disorder of hepatic oxalate over production. Standard of care was largely supportive with hyperhydration, urinary alkalinization and pyridoxine. RNA interference therapies have recently shown promising results. Material and Methods: The systematic review was prospectively registered with PROSPERO and followed PRISMA guidelines. Pubmed, EMBASE and CENTRAL were searched from January 1974 to July 2024 for randomized controlled trials and single arm intervention studies on use of RNAi therapies in primary hyperoxaluria. Results: We found 127 records across the databases, with 12 of them included in the final analysis. A total of 140 patients were enrolled in Lumasiran (9 trials) and Nedosiran (3 trials). Most studies demonstrated a significant reduction in the oxalate burden. Injection site reaction was the most common adverse event with a largely acceptable safety profile. Quality of studies assessed through ROB-2 and ROBINS-I showed a low risk of bias. Conclusion: This systematic review emphasizes the effectiveness and safety of RNA interference therapies, Lumasiran and Nedosiran, in treating primary hyperoxaluria by lowering urinary and plasma oxalate levels.

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder of hepatic oxalate overproduction leading to kidney failure and systemic oxalosis. Lumasiran is an RNA interference therapeutic approved for lowering urinary oxalate (UOx) and plasma oxalate (POx) in PH1. This Phase 2 open-label extension (OLE) study evaluated the safety and efficacy of long-term lumasiran treatment (up to 54 months) in patients with PH1 who had completed the Phase 1/2 parent study. The Phase 2 OLE (NCT03350451) included patients with PH1 6 to 64 years old, 24-hour UOx excretion>0.7mmol/1.73m2/day, and estimated glomerular filtration rate (eGFR)>45mL/min/1.73m2 who enrolled within 12 months of parent study completion. Patients initiated subcutaneous lumasiran at parent study dosage. Endpoints included adverse event (AE) incidence (primary) and change over time in efficacy measures, including 24-hour UOx and eGFR. All 20 patients (median age 11.5 years; 65% female) who completed the parent study entered and completed the Phase 2 OLE. Of 21 treatment-related AEs over 427 doses, 13 were transient injection site reactions (ISRs), affecting 8/20 patients (40%); all ISRs were mild in severity. After Month (M) 18 through M51 (last dosing), no ISRs were reported. No treatment-related severe or serious AEs were reported. Lumasiran treatment led to a substantial mean reduction in 24h UOx from baseline to M54 of-1.5mmol/24h/1.73m2. At visits M42 through M54, 24-hour UOx was≤1.5×ULN in 89-94% of patients at each visit. The mean annual change in eGFR was-0.4mL/min/1.73m2/year overall; eGFR was also stable in those patients with baseline eGFR<90mL/min/1.73m2. These data represent the longest published follow-up of lumasiran-treated patients with PH1 (ages: 6-43 years) to date. Long-term lumasiran treatment for PH1 had acceptable safety and led to sustained and substantial reduction of UOx with preservation of kidney function.

THE AIM: To evaluate clinical and genotypic features, renal prognosis in orphan tubulopathies with nephrocalcinosis and cys- tine calculi in 22 pediatric patients. PATIENTS AND METHODS: The study included 22 patients (from 1 year 4 months to 17 years 11 months) with orphan tubulopathies with nephrocalcinosis (22) and cystinuria, cystine stones (2). Of the 22 probands, there were 14 (63.6 %) boys and 8 (36.4 %) girls. Clinical, biochemical, imaging, and molecular genetic diagnostic methods were used. The severity of chronic kidney disease was stratified according to the K/DOQI classification (2002). RESULTS: A genetic study of 22 children with nephrocalcinosis revealed primary hyperoxaluria of types I, II, III (AGXT, GRHPR, HOGA1) in 5; familial hypomagnesemia with hypercalciuria and nephrocalcinosis (CLDN16) in 5; hypophosphatemic rickets with hypercal- ciuria and nephrocalcinosis (SLC34A3) in 3; Bartter type I syndrome (SLC12A1) in 1 and Bartter syndrome type IV (BSND) in 1, Dent1 disease (CLCN5) in 1, Dent disease 2 (OCRL) in 1, idiopathic infantile hypercalcemia type I (SLC34A1) in 1 and type II (CYP24A1) in 2. Based on the detection of mutations in the SLC3A1 and SLC7A9 genes, 2 probands were diagnosed with type I and non type I cystinuria. The features of gene mutation variants in 22 children with orphan tubulopathies with nephrocalci- nosis and cystinuria, and cystine nodules were identified. A study of kidney function in 22 children over the age of 2 years with nephrocalcinosis and cystinuria revealed CKD C1 with normal glomerular filtration rate (17), CKD C2, C3, C4 (5). A girl with familial hypomagnesemia with hypercalciuria and nephrocalcinosis due to a mutation of the CLDN16 gene, progression CKD of С1 to C4, underwent kidney transplantation at the age of 18 before starting dialysis. CONCLUSION: Features of the clinical phenotype and variants of mutations of genes of orphan tubulopathies with nephrocalcinosis and cystinuria, cystine stones in 22 children were established. Progression of CKD from C1 with normal glomerular filtration rate to C2, C3, C4 was ascertained from 22 in 5 children (25) % with primary hyperoxaluria type1 (1), hypomagnesemia with calciuria and nephrocalcinosis (3), Dent-2 Disease (1). Identification of gene mutations in molecular genetic studies in children with nephrocalcinosis and cys- tinuria establishes a clinical and genetic diagnosis, the pathogenesis of an orphan tubulopathy, and determines personalized management based on individual genetic characteristics.

In primary hyperoxaluria (PH), clinical manifestations can initiate during early childhood. Given the high prevalence of urinary lithiasis and chronic kidney disease (CKD) among adult population, in which clinical manifestations of PH after childhood, diagnosis becomes more difficult. This guide was developed to improve the diagnostic and therapeutic fields of PH in adult patients for clinicians. PH can cause (i) kidney stones and (ii) calcium oxalate crystal deposition within the kidney tissue (oxalate nephropathy). Clinical criteria for suspected PH in adults include the following: (i) Recurrent stone disease (in children, however, it should be suspected in the first episode); (ii) Nephrocalcinosis that is particularly associated with decreased glomerular filtration rate (GFR); (iii) Presence of oxalate crystals (calcium oxalate monohydrate and whewellite) in any biological fluid or tissue. To the above, the following can be added: (iv) Hyperoxaluria without clear cause of secondary hyperoxaluria; (v) Oxalate urinary excretion >1.0 mmol/1.73 m2 body surface area in two samples; (vi) Kidney transplant recipients with previous CKD of unknown aetiology or previous history of recurrent urolithiasis and presenting graft nephrocalcinosis and GFR drop with no other clear cause. Routine PH screening of all adult patients with hyperoxaluria is costly strategy and therefore not recommended. Suspected PH in adults should be guided in accordance with clinical criteria. In patients with a confirmed PH diagnosis, all efforts should be directed towards adequate genetic and biochemical characterisation given that each patient can benefit from various therapeutic strategies.