Simultaneous or sequential kidney-liver transplantation in primary hyperoxaluria

Simultaneous or sequential kidney-liver transplantation in primary hyperoxaluria | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Simultaneous or sequential kidney-liver transplantation in primary hyperoxaluria Maria Arena, Raffaella Labbadia, Andrea Cappoli, Gionata Spagnoletti, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4138380/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Primary hyperoxaluria type 1 is responsible for pediatric kidney failure in 1 to 2% of cases. Novel therapies based on RNA interference are changing the natural history of the disease. However, for those who will progress to kidney failure, and for patients living in countries that cannot afford these expensive therapies, liver-kidney transplantation may remain the only efficient therapy. The aim of the study was to evaluate the outcome of patients with primary hyperoxaluria type 1 who received simultaneous or sequential liver-kidney transplantation. We retrospectively evaluated 10 patients, five patients received a simultaneous transplantation, and five underwent sequential transplantation with a median postponement of the kidney transplantation of 8 months (range 4–20). Median follow up was 3.2 years (range 1.6–11). Median estimated glomerular filtration rate at 6 and 12 months was 81.2 (range: 45.7-108.8) and 79.3 ml/min/1.73m 2 (range 54.7-112.1) in patients who underwent simultaneous transplantation, and 45.7 (range 34.5–86.7) and 38.3 ml/min/1.73m 2 (range 29.9–77.5) in those with sequential transplantation (p:NS). Biopsies performed at 6 and 12 months showed precipitation of calcium oxalate crystals in all patients except one, demonstrating the recurrence of deposition despite the delay between liver and kidney transplantation. No differences in kidney function or in post-transplant renal oxalate precipitations were observed between patients that underwent bilateral nephrectomy and those who did not. None of the patients has lost the kidney graft at the last follow-up. Our study shows that adapting the transplant strategy to individual cases, patients with primary hyperoxaluria type 1 can be successfully treated. Sequential liver-kidney transplantation simultaneous liver-kidney transplantation primary hyperoxaluria oxalate nephrectomy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Primary hyperoxaluria type 1 (PH1) is a rare inborn autosomal-recessive disease, caused by mutation of the AGTX gene, responsible for derangement of vitamin B6-dependent hepatic-specific peroxisomal alanine:glyoxylate aminotransferase (AGT). AGT disfunction leads to accumulation of glyoxylate and overproduction of glycolate and oxalate. PH1 is the most frequent subtype of primary hyperoxaluria, and accounts for 70–80% the cases( 1 ). PH1 is responsible for kidney failure in 1–2% of children in Europe, United States and Japan( 2 ). The most frequent clinical presentation in children is kidney stones, nephrocalcinosis and kidney failure( 3 ). Oxalate excretion decreases with the reduction of kidney function resulting in oxalate supersaturation and deposition in various organs including the retina, bones, kidneys, skin, myocardium, vessel walls, and central nervous system( 4 ). As soon as PH1 is diagnosed, it is recommended to start conservative therapy, which consist in high fluid intake (at least 3 L/m 2 ), alkalization of urines, diet modifications and vitamin B6 (pyridoxine) supplementation( 5 ). However, only patients carrying specific AGTX pathogenic variants, namely the Gly170Arg and Phe152Ile mutations, are likely to respond to pharmacological doses of pyridoxine( 6 , 7 ). Recently, novel therapies based on RNA interference, have emerged( 8 ). Lumasiran, which is currently the most studied molecule, decreases liver oxalate production by targeting the mRNA of the HAO1 gene, which encodes for the hepatic glycolate oxidase enzyme. Three phase III studies have been conducted to evaluate the efficacy and safety of the drug in different populations, resulting in a substantial reduction of urine and plasma oxalate levels with an acceptable safety profile( 9 – 11 ). Lumasiran has been approved for medical use by the Food and Drug Administration in the US and by the European Medicine Agency in 2020. The follow-up of patients treated with RNA interference is currently too limited to assess if this novel approach will replace in the future the need for liver transplantation. Only few case reports are available. Stone et al.( 12 ) have described a child who was diagnosed with PH1 only after kidney transplantation; he received aggressive renal replacement therapy and lumasiran, which prevented graft loss. A second report describes five PH1 patients that have undergone isolated kidney transplantation under lumasiran therapy; despite limited follow-up, this report suggests that this strategy could be safe and is efficient in maintaining plasma oxalate levels below 80–90 µmol/L( 13 ). However, in another case report, an adult patient was treated with lumasiran pre-transplant and underwent isolated kidney transplantation once serum oxalate levels had normalized; however he developed acute rejection and possibly a recurrence of oxalate nephropathy 25 days after transplantation( 14 ). It is unquestionable that new therapeutic approaches based on RNA silencing are changing the natural history of PH1 and will reduce the number of patients that will progress to kidney failure. However, for those that will progress to kidney failure, and certainly for patients living in countries that cannot afford these expensive therapies, liver-kidney transplantation remains an option, if not the only efficient therapy. Isolated kidney transplantation is associated with poor graft and patient survival in these patients( 15 ). The choice between simultaneous or sequential liver-kidney transplantation is still debated. Simultaneous transplantation is mostly performed in patients with chronic kidney disease (CKD) stage 4, whereas in patients with CKD stage 5, the sequential modality is usually preferred, starting with the liver, while the kidney transplantation is postponed and performed only after a period of intensive hemodialysis to reduce serum oxalate levels( 3 , 5 ). Unfortunately, the rarity of the disease limits the number of patients included in different studies, preventing to draw conclusions. The aim of our study was to retrospectively evaluate the outcome of PH1 patients that have been treated with simultaneous or sequential liver-kidney transplantation at our center. Patients and Methods Between 2012 and 2018, ten patients with PH1 received a liver-kidney transplantation at the Bambino Gesù Children’s Hospital in Rome. The study was conducted in accordance with the guidelines for Good Clinical Practice and all patients already enrolled in the Certain study which was approved by Bambino Gesu’ Children’s Hospital’s ethics committee. The following parameters were retrospectively retrieved from the medical charts for each patient: - demographic characteristics (age, sex, nationality, height and body weight at the time of transplant) - clinical presentation of the disease - duration of follow up - dialysis modality (hemodialysis or peritoneal dialysis) before transplantation - waiting time on dialysis before transplantation - type of combined transplant received (simultaneous or sequential) and in case of sequential transplantation, time between liver and kidney transplantation. The choice between simultaneous or sequential liver-kidney transplantation was made on a case-by-case basis considering the severity of systemic oxalates deposition that increased with the duration of dialysis prior to transplantation. Patients with more signs of systemic oxalosis, more prolonged kidney failure, and higher serum oxalate levels received a sequential transplant; those with no or limited systemic involvement, lower serum oxalate levels, CKD stage 3 or 4 or CKD 5 with short time on dialysis received simultaneous transplantation. - type of donor (living or deceased, related or not) - hemodialysis treatment during and after transplant surgery - renal function at 6 and 12 months - signs of systemic involvement including: - bone status, based on XR evaluation, - cardiac involvement based on electrocardiogram and echocardiogram evaluations - retinal involvement, based on fundus evaluation - bone marrow involvement, based the responsiveness of anemia to erythropoietin and other cytopenias - immunosuppressive therapy - uni- or bilateral nephrectomy and timing of surgery - serum and urinary oxalates levels - histological examinations of protocol kidney biopsies performed at 6 and 12 months. One patient died soon after surgery, secondary to hemorrhagic complications and was removed from the analyses. Results All patients received a diagnosis of primary hyperoxaluria in the first months of life, which was confirmed as PH1 by genetic analysis. Demographic and clinical characteristics are summarized in Table 1. The median age at kidney transplantation was 5.6 years (range: 2.3-17.0). Clinical presentation ranged from nephrocalcinosis discovered by renal ultrasound soon after birth to acute renal failure or chronic kidney disease. The median follow-up was 3.2 years (range 1.6-11) and the median time between the start of dialysis and kidney transplantation was 10,8 months (range 2,5-57,4). In 4 patients from low-income countries, peritoneal dialysis was performed as the initial renal replacement therapy, while hemodialysis was performed in the remaining 6 patients. Once admitted to our Institution, all patients initially treated with peritoneal dialysis were shifted to hemodialysis to improve oxalate clearance. On hemodialysis, all patients were treated intensively with 6 intermittent hemodialysis (IHD) treatments per week until kidney transplantation. Five patients received a simultaneous liver-kidney transplantation and five underwent sequential transplantation, with a median postponement of the kidney transplantation of 8 months (range 4-20). All patients were treated with continuous veno-venous hemodiafiltration (CVVHDF) during the entire duration of the renal transplantation procedure. In the post-operative period, CVVHDF was performed in 4 patients in the simultaneous group for a duration ranging 2 to 15 days. One patient was switched from CVVHDF to IHD for a total period of 15 days. In the sequential group, one patient was treated with CVVHDF for 24 hours and one patient underwent IHD twice a day for 10 days after kidney transplantation. Table 1. Demographic and clinical characteristics of PH1 patients. Patient Sex Nationality Type of dialysis Months on dialysis prior to transplant Age at liver/kidney transplantation (months) Weight at transplantation (Kg) Type of Transplant Kidney donor type Liver donor type 1 F Moroccan HD 3.6 82 17 Simultaneous D D 2 F Italian HD 10.8 152 45.5 Simultaneous D D 3 F Italian HD 7.1 117 23.1 Simultaneous D D 4 F Lebanese HD 2.5 73 16.3 Simultaneous L L 5 F Russian PD/HD 57.4 53/61 13.6 Sequential L L 6 F Lebanese PD/HD 21.2 197/204 43.8 Sequential L D 7 M Lebanese PD/HD 37 35/39 11 Sequential L L 8 M Lebanese PD/HD 10 20/27 9.4 Sequential L L 9 M Italian HD 32.2 17/36 12.8 Sequential D D HD: hemodialysis, PD: peritoneal dialysis, D: Deceased, L: Living In patients who underwent simultaneous transplant, the median estimated GFR (eGFR) at 6 and 12 months post-transplant was 81.2 (range: 45.7-108.8) and 79.3 ml/min/1.73m 2 (range 54.7-112.1), respectively. In children treated with sequential transplant the median eGFR was 45.7 (range 34.5-86.7) and 38.3 ml/min/1.73m 2 (range: 29.9-77.5), respectively (p=NS). Four patients received both organs from deceased donors (3 in the simultaneous transplantation group and 1 in the sequential transplantation group). Four patients received both organs from consanguineous living-related donors (1 in the simultaneous transplantation group and 3 in the sequential transplantation group). In one case treated sequentially, the living-related donor was different (liver transplant from the father and kidney transplant from the grandmother). One patient in the sequential transplantation group, received kidney from a consanguineous living-related donor and the liver from a cadaveric donor. Bilateral nephrectomy was performed in 5 patients. The second kidney was removed at the time of kidney transplantation to preserve diuresis during dialysis. In children with sequential transplant, serum oxalates showed a median drop of 51% (range 14-73%) between liver and kidney transplantation. There were no differences in the immunosuppressive regimen. All patients received a triple maintenance therapy with tacrolimus, mycophenolate mofetil and corticosteroid. One patient needed to replace mycophenolate mofetil with azathioprine due to gastro-intestinal side effects. One patient was switched from mycophenolate mofetil to everolimus for persistent EBV infection and was treated with low dose tacrolimus for histologic evidence of calcineurin inhibitor toxicity. Urinary oxalate excretion (Ox / CrU) one year after kidney transplantation was available in 6 patients, 3 in the simultaneous transplantation group and 3 in the sequential transplantation group. The Ox / CrU values were not statistically different based on the transplant strategy (p<0.067). No correlation between bilateral nephrectomy and Ox / CrU at 1-year post-transplant was observed (Table 2). Table 2. Post-transplant urinary oxalate excretion in relation to the type of transplant and bilateral nephrectomy Patient Ox/CrU Type of Tx Bilateral Nephrectomy 2 0.23 Simultaneous No 3 0.07 Simultaneous Yes 4 0.09 Simultaneous No 5 0.52 Sequential No 7 0.21 Sequential Yes 8 0.55 Sequential Yes The protocol biopsies performed at 6 and 12 months showed precipitation of calcium oxalate (CaOx) crystals in all patients except one who had been treated sequentially. At the last follow-up, none of the patients has lost the kidney graft. Discussion The best transplant approach in patients with PH1 is still debated. In our limited cohort, we did not observe a substantial difference in kidney function outcome between patients that underwent simultaneous or sequential liver-kidney transplantation. Data from the literature are conflicting. Some authors reported similar results ( 19 , 21 ), whereas others have observed more frequently a eGFR < 50 ml/min/1.73 m 2 in patients treated with sequential transplantation( 17 ). These latter authors observed no difference between simultaneous and preemptive transplantation. Most likely, the observed differences are related to differences in the oxalate burden before transplantation and the consequent attitude, in most centers, to sequentially transplant the most severe patients. These patients usually have higher oxalate levels and more systemic involvement( 5 , 18 ) and longer duration of dialysis prior to transplantation( 4 , 19 ). Nonetheless, the most recent data from the OxalEurope registry show comparable outcomes of simultaneous and sequentially liver-kidney transplantation( 20 ). A kidney protective effect of the liver graft has been reported in patients transplanted from the same donor, mostly in non-sensitized patients( 21 – 23 ). Furthermore, a positive role has been suggested in HLA matching between the liver and the kidney( 21 , 24 ). The role of native kidney nephrectomy is also debated. During disease progression, the kidneys filter and accumulate huge amounts of oxalate, which potentially may become a major source of oxalates released in the circulation after transplantation. For that reason, systematic bilateral nephrectomy has been advocated but its benefit has not been clearly demonstrated( 25 , 26 ). In 1997, Mizusawa et al.( 27 ) reported that in combined transplantation, the urinary excretion of oxalates was lower in patients undergoing bilateral nephrectomy compared to patients who did not. However, no differences in kidney function and serum oxalate values were reported after transplantation between the two populations. Recently, Villani et al.( 28 ) reported a faster reduction in plasma oxalate levels and more rapid normalization of urinary oxalate excretion combining bilateral nephrectomy to intensive hemodialysis after transplantation. Similar data have also been reported by Lee et al.( 29 ) in a larger patient population. In our cohort, five patients underwent bilateral nephrectomy. We did not observe significant differences in eGFR or in post-transplant renal oxalate precipitations between patients that underwent bilateral nephrectomy and those who did not. However, urinary oxalate excretion was higher after kidney transplantation in patients undergoing sequential transplantation, regardless of the nephrectomy status, most likely related to a more severe systemic oxalosis. Few reports have described the evolution of serum oxalates between the liver and the kidney transplantation in patients that underwent a sequential procedure( 30 ). On average, we observed a 51% reduction in serum oxalate levels after liver transplantation, although in some patients a prolonged period of intensive hemodialysis is required. Furthermore, oxalate reduction did not prevent oxalate precipitation in the newly transplanted kidneys. Bergstralh et al.( 31 ) have shown that urinary oxalate excretion remains elevated for up to 3 years after transplantation. We routinely perform two protocol biopsies after kidney transplantation, at 6 and 12 months. Oxalate crystal precipitations was observed in all biopsies except one. Cornell et al.( 32 ) observed CaOx crystals recurrence on surveillance biopsies in 41% of patients treated with simultaneous transplantation. Higher urine oxalate levels after transplant were associated with a higher CaOx crystal index( 32 ). No significant differences were observed between patients receiving isolated kidney transplantation or simultaneous liver-kidney transplantation, highlighting the importance of reducing systemic calcium oxalate depositions before and after transplantation. To our knowledge, no study has compared deposition of CaOx crystals between simultaneous and sequential transplantation; we did not observe substantial differences. This study has limitations related to its retrospective nature, the limited duration of the follow-up and to the small size of the cohort. Nonetheless, it adds information to the current knowledge limited because of the rarity of the disease. Fortunately, the natural history of PH1 is changing, thanks to the new therapies that are being developed. Nonetheless, liver transplantation may still be advantageous in patients that accumulate significant amounts of systemic oxalates and will still be mandatory in all patients living in countries that cannot afford these new therapies. Despite its limitations, our study shows that patients with PH1 can be successfully treated adapting the transplant strategy to individual cases and to the availability of living-related donors. Every effort should be made to reduce the systemic oxalate burden before kidney transplantation and urinary oxalate concentrations after kidney transplantation. Declarations Acknowledgments I would also like to extend my deepest gratitude to Dr. Luca Dello Strologo for his stimulating and supportive guide during my training period and for all that he has taught us. Funding and Competing interests This work was supported also by the Italian Ministry of Health with Current Research funds. 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Am J Transpl Off J Am Soc Transpl Am Soc Transpl Surg November 10(11):2493–2501 Cornell LD, Amer H, Viehman JK, Mehta RA, Lieske JC, Lorenz EC et al (2021) Posttransplant recurrence of calcium oxalate crystals in patients with primary hyperoxaluria: Incidence, risk factors, and effect on renal allograft function. Am J Transpl Off J Am Soc Transpl Am Soc Transpl Surg. 26 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4138380","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":286507161,"identity":"3f7ded4f-e70a-4892-b7a6-676c0d5dbeb3","order_by":0,"name":"Maria 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Bambino Gesu","correspondingAuthor":false,"prefix":"","firstName":"Isabella","middleName":"","lastName":"Guzzo","suffix":""}],"badges":[],"createdAt":"2024-03-20 15:57:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4138380/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4138380/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54176974,"identity":"3470cc94-e66c-497a-a47f-cc76b540540e","added_by":"auto","created_at":"2024-04-05 16:04:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":85658,"visible":true,"origin":"","legend":"\u003cp\u003eRenal function in two groups at 6 and 12 months\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4138380/v1/b5458e08b28fc4c7f74ab38b.png"},{"id":54176976,"identity":"3a3ba3cd-f04b-4142-84c5-5ed250010ac1","added_by":"auto","created_at":"2024-04-05 16:04:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":85846,"visible":true,"origin":"","legend":"\u003cp\u003eDifference in serum oxalate values before liver transplant and before kidney transplant in patients undergoing sequential transplantation\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4138380/v1/251a490e30cde4457b1513b0.png"},{"id":54176977,"identity":"19091d81-a8aa-42f5-8733-977390a71239","added_by":"auto","created_at":"2024-04-05 16:04:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":56921,"visible":true,"origin":"","legend":"\u003cp\u003eOx / CrU values in patients with sequential and simultaneous transplant\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4138380/v1/3869a54cc5b9c4ea8fac0ded.png"},{"id":54176979,"identity":"c258eb90-ec7a-4fc4-8a01-afc84912cd58","added_by":"auto","created_at":"2024-04-05 16:04:49","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2609925,"visible":true,"origin":"","legend":"\u003cp\u003eIntratubular crystals on hematoxylin and eosin under standard light microscopy as small rounded radiated concretions\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4138380/v1/d3b3258fd40f18158bcf4e90.png"},{"id":54176975,"identity":"afb4e93d-d7ce-4edb-ab41-6e7bb04b62c8","added_by":"auto","created_at":"2024-04-05 16:04:48","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2285430,"visible":true,"origin":"","legend":"\u003cp\u003eMulticolored birefringence of CaOx deposits under polarized light\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4138380/v1/fa7455642b4534eba1e4b587.png"},{"id":55243895,"identity":"96c58232-94c2-453d-8bf8-cfe0a81b2142","added_by":"auto","created_at":"2024-04-24 15:38:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2762668,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4138380/v1/1589b747-6fc0-4d0f-be20-a5547c36950c.pdf"}],"financialInterests":"","formattedTitle":"Simultaneous or sequential kidney-liver transplantation in primary hyperoxaluria","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrimary hyperoxaluria type 1 (PH1) is a rare inborn autosomal-recessive disease, caused by mutation of the \u003cem\u003eAGTX\u003c/em\u003e gene, responsible for derangement of vitamin B6-dependent hepatic-specific peroxisomal alanine:glyoxylate aminotransferase (AGT). AGT disfunction leads to accumulation of glyoxylate and overproduction of glycolate and oxalate. PH1 is the most frequent subtype of primary hyperoxaluria, and accounts for 70\u0026ndash;80% the cases(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). PH1 is responsible for kidney failure in 1\u0026ndash;2% of children in Europe, United States and Japan(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The most frequent clinical presentation in children is kidney stones, nephrocalcinosis and kidney failure(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Oxalate excretion decreases with the reduction of kidney function resulting in oxalate supersaturation and deposition in various organs including the retina, bones, kidneys, skin, myocardium, vessel walls, and central nervous system(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs soon as PH1 is diagnosed, it is recommended to start conservative therapy, which consist in high fluid intake (at least 3 L/m\u003csup\u003e2\u003c/sup\u003e), alkalization of urines, diet modifications and vitamin B6 (pyridoxine) supplementation(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, only patients carrying specific \u003cem\u003eAGTX\u003c/em\u003e pathogenic variants, namely the Gly170Arg and Phe152Ile mutations, are likely to respond to pharmacological doses of pyridoxine(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Recently, novel therapies based on RNA interference, have emerged(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Lumasiran, which is currently the most studied molecule, decreases liver oxalate production by targeting the mRNA of the \u003cem\u003eHAO1\u003c/em\u003e gene, which encodes for the hepatic glycolate oxidase enzyme. Three phase III studies have been conducted to evaluate the efficacy and safety of the drug in different populations, resulting in a substantial reduction of urine and plasma oxalate levels with an acceptable safety profile(\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Lumasiran has been approved for medical use by the Food and Drug Administration in the US and by the European Medicine Agency in 2020. The follow-up of patients treated with RNA interference is currently too limited to assess if this novel approach will replace in the future the need for liver transplantation. Only few case reports are available. Stone et al.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) have described a child who was diagnosed with PH1 only after kidney transplantation; he received aggressive renal replacement therapy and lumasiran, which prevented graft loss. A second report describes five PH1 patients that have undergone isolated kidney transplantation under lumasiran therapy; despite limited follow-up, this report suggests that this strategy could be safe and is efficient in maintaining plasma oxalate levels below 80\u0026ndash;90 \u0026micro;mol/L(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). However, in another case report, an adult patient was treated with lumasiran pre-transplant and underwent isolated kidney transplantation once serum oxalate levels had normalized; however he developed acute rejection and possibly a recurrence of oxalate nephropathy 25 days after transplantation(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is unquestionable that new therapeutic approaches based on RNA silencing are changing the natural history of PH1 and will reduce the number of patients that will progress to kidney failure. However, for those that will progress to kidney failure, and certainly for patients living in countries that cannot afford these expensive therapies, liver-kidney transplantation remains an option, if not the only efficient therapy. Isolated kidney transplantation is associated with poor graft and patient survival in these patients(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The choice between simultaneous or sequential liver-kidney transplantation is still debated. Simultaneous transplantation is mostly performed in patients with chronic kidney disease (CKD) stage 4, whereas in patients with CKD stage 5, the sequential modality is usually preferred, starting with the liver, while the kidney transplantation is postponed and performed only after a period of intensive hemodialysis to reduce serum oxalate levels(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Unfortunately, the rarity of the disease limits the number of patients included in different studies, preventing to draw conclusions.\u003c/p\u003e \u003cp\u003eThe aim of our study was to retrospectively evaluate the outcome of PH1 patients that have been treated with simultaneous or sequential liver-kidney transplantation at our center.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003eBetween 2012 and 2018, ten patients with PH1 received a liver-kidney transplantation at the Bambino Ges\u0026ugrave; Children\u0026rsquo;s Hospital in Rome. The study was conducted in accordance with the guidelines for Good Clinical Practice and all patients already enrolled in the Certain study which was approved by Bambino Gesu\u0026rsquo; Children\u0026rsquo;s Hospital\u0026rsquo;s ethics committee.\u003c/p\u003e\n\u003cp\u003eThe following parameters were retrospectively retrieved from the medical charts for each patient:\u003c/p\u003e\n\u003cp\u003e- demographic characteristics (age, sex, nationality, height and body weight at the time of transplant)\u003c/p\u003e\n\u003cp\u003e- clinical presentation of the disease\u003c/p\u003e\n\u003cp\u003e- duration of follow up\u003c/p\u003e\n\u003cp\u003e- dialysis modality (hemodialysis or peritoneal dialysis) before transplantation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e- waiting time on dialysis before transplantation\u003c/p\u003e\n\u003cp\u003e- type of combined transplant received (simultaneous or sequential) and in case of sequential transplantation, time between liver and kidney transplantation.\u003c/p\u003e\n\u003cp\u003eThe choice between simultaneous or sequential liver-kidney transplantation was made on a case-by-case basis considering the severity of systemic oxalates deposition that increased with the duration of dialysis prior to transplantation. Patients with more signs of systemic oxalosis, more prolonged kidney failure, and higher serum oxalate levels received a sequential transplant; those with no or limited systemic involvement, lower serum oxalate levels, CKD stage 3 or 4 or CKD 5 with short time on dialysis received simultaneous transplantation.\u003c/p\u003e\n\u003cp\u003e- type of donor (living or deceased, related or not)\u003c/p\u003e\n\u003cp\u003e- hemodialysis treatment during and after transplant surgery\u003c/p\u003e\n\u003cp\u003e- renal function at 6 and 12 months\u003c/p\u003e\n\u003cp\u003e- signs of systemic involvement including:\u003c/p\u003e\n\u003cp\u003e- bone status, based on XR evaluation,\u003c/p\u003e\n\u003cp\u003e- cardiac involvement based on electrocardiogram and echocardiogram evaluations\u003c/p\u003e\n\u003cp\u003e- retinal involvement, based on fundus evaluation\u003c/p\u003e\n\u003cp\u003e- bone marrow involvement, based the responsiveness of anemia to erythropoietin and other cytopenias\u003c/p\u003e\n\u003cp\u003e- immunosuppressive therapy\u003c/p\u003e\n\u003cp\u003e- uni- or bilateral nephrectomy and timing of surgery\u003c/p\u003e\n\u003cp\u003e- serum and urinary oxalates levels\u003c/p\u003e\n\u003cp\u003e- histological examinations of protocol kidney biopsies performed at 6 and 12 months.\u003c/p\u003e\n\u003cp\u003eOne patient died soon after surgery, secondary to hemorrhagic complications and was removed from the analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAll patients received a diagnosis of primary hyperoxaluria in the first months of life, which was confirmed as PH1 by genetic analysis.\u003c/p\u003e\n\u003cp\u003eDemographic and clinical characteristics are summarized in Table 1.\u003c/p\u003e\n\u003cp\u003eThe median age at kidney transplantation was 5.6 years (range: 2.3-17.0). Clinical presentation ranged from nephrocalcinosis discovered by renal ultrasound soon after birth to acute renal failure or chronic kidney disease.\u003c/p\u003e\n\u003cp\u003eThe median follow-up was 3.2 years (range 1.6-11) and the median time between the start of dialysis and kidney transplantation was 10,8 months (range 2,5-57,4).\u003c/p\u003e\n\u003cp\u003eIn 4 patients from low-income countries, peritoneal dialysis was performed as the initial renal replacement therapy, while hemodialysis was performed in the remaining 6 patients. Once admitted to our Institution, all patients initially treated with peritoneal dialysis were shifted to hemodialysis to improve oxalate clearance. On hemodialysis, all patients were treated intensively with 6 intermittent hemodialysis (IHD) treatments per week until kidney transplantation.\u003c/p\u003e\n\u003cp\u003eFive patients received a simultaneous liver-kidney transplantation and five underwent sequential transplantation, with a median postponement of the kidney transplantation of 8 months (range 4-20).\u003c/p\u003e\n\u003cp\u003eAll patients were treated with continuous veno-venous hemodiafiltration (CVVHDF) during the entire duration of the renal transplantation procedure.\u003c/p\u003e\n\u003cp\u003eIn the post-operative period, CVVHDF was performed in 4 patients in the simultaneous group for a duration ranging 2 to 15 days. One patient was switched from CVVHDF to IHD for a total period of 15 days. In the sequential group, one patient was treated with CVVHDF for 24 hours and one patient underwent IHD twice a day for 10 days after kidney transplantation.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 1.\u003c/strong\u003e Demographic and clinical characteristics of PH1 patients.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"769\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.672301690507152%\" valign=\"top\"\u003e\n \u003cp\u003ePatient\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.9414824447334205%\" valign=\"top\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.18335500650195%\" valign=\"top\"\u003e\n \u003cp\u003eNationality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.192457737321197%\" valign=\"top\"\u003e\n \u003cp\u003eType of dialysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.143042912873861%\" valign=\"top\"\u003e\n \u003cp\u003eMonths on dialysis prior to transplant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003eAge at liver/kidney transplantation (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003eWeight at transplantation\u003c/p\u003e\n \u003cp\u003e(Kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.263979193758127%\" valign=\"top\"\u003e\n \u003cp\u003eType of Transplant\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.45253576072822%\" valign=\"top\"\u003e\n \u003cp\u003eKidney donor type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.542262678803641%\" valign=\"top\"\u003e\n \u003cp\u003eLiver donor type\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.672301690507152%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.9414824447334205%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.18335500650195%\" valign=\"top\"\u003e\n \u003cp\u003eMoroccan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.192457737321197%\" valign=\"top\"\u003e\n \u003cp\u003eHD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.143042912873861%\" valign=\"top\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.263979193758127%\" valign=\"top\"\u003e\n \u003cp\u003eSimultaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.45253576072822%\" valign=\"top\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.542262678803641%\" valign=\"top\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.672301690507152%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.9414824447334205%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.18335500650195%\" valign=\"top\"\u003e\n \u003cp\u003eItalian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.192457737321197%\" valign=\"top\"\u003e\n \u003cp\u003eHD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.143042912873861%\" valign=\"top\"\u003e\n \u003cp\u003e10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e152\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e45.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.263979193758127%\" valign=\"top\"\u003e\n \u003cp\u003eSimultaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.45253576072822%\" valign=\"top\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.542262678803641%\" valign=\"top\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.672301690507152%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.9414824447334205%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.18335500650195%\" valign=\"top\"\u003e\n \u003cp\u003eItalian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.192457737321197%\" valign=\"top\"\u003e\n \u003cp\u003eHD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.143042912873861%\" valign=\"top\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e23.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.263979193758127%\" valign=\"top\"\u003e\n \u003cp\u003eSimultaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.45253576072822%\" valign=\"top\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.542262678803641%\" valign=\"top\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.672301690507152%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.9414824447334205%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.18335500650195%\" valign=\"top\"\u003e\n \u003cp\u003eLebanese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.192457737321197%\" valign=\"top\"\u003e\n \u003cp\u003eHD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.143042912873861%\" valign=\"top\"\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e16.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.263979193758127%\" valign=\"top\"\u003e\n \u003cp\u003eSimultaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.45253576072822%\" valign=\"top\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.542262678803641%\" valign=\"top\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.672301690507152%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.9414824447334205%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.18335500650195%\" valign=\"top\"\u003e\n \u003cp\u003eRussian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.192457737321197%\" valign=\"top\"\u003e\n \u003cp\u003ePD/HD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.143042912873861%\" valign=\"top\"\u003e\n \u003cp\u003e57.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e53/61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e13.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.263979193758127%\" valign=\"top\"\u003e\n \u003cp\u003eSequential\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.45253576072822%\" valign=\"top\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.542262678803641%\" valign=\"top\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.672301690507152%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.9414824447334205%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.18335500650195%\" valign=\"top\"\u003e\n \u003cp\u003eLebanese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.192457737321197%\" valign=\"top\"\u003e\n \u003cp\u003ePD/HD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.143042912873861%\" valign=\"top\"\u003e\n \u003cp\u003e21.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e197/204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e43.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.263979193758127%\" valign=\"top\"\u003e\n \u003cp\u003eSequential\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.45253576072822%\" valign=\"top\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.542262678803641%\" valign=\"top\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.672301690507152%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.9414824447334205%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.18335500650195%\" valign=\"top\"\u003e\n \u003cp\u003eLebanese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.192457737321197%\" valign=\"top\"\u003e\n \u003cp\u003ePD/HD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.143042912873861%\" valign=\"top\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e35/39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.263979193758127%\" valign=\"top\"\u003e\n \u003cp\u003eSequential\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.45253576072822%\" valign=\"top\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.542262678803641%\" valign=\"top\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.672301690507152%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.9414824447334205%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.18335500650195%\" valign=\"top\"\u003e\n \u003cp\u003eLebanese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.192457737321197%\" valign=\"top\"\u003e\n \u003cp\u003ePD/HD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.143042912873861%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e20/27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e9.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.263979193758127%\" valign=\"top\"\u003e\n \u003cp\u003eSequential\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.45253576072822%\" valign=\"top\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.542262678803641%\" valign=\"top\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.672301690507152%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.9414824447334205%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.18335500650195%\" valign=\"top\"\u003e\n \u003cp\u003eItalian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.192457737321197%\" valign=\"top\"\u003e\n \u003cp\u003eHD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.143042912873861%\" valign=\"top\"\u003e\n \u003cp\u003e32.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e17/36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.304291287386215%\" valign=\"top\"\u003e\n \u003cp\u003e12.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.263979193758127%\" valign=\"top\"\u003e\n \u003cp\u003eSequential\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.45253576072822%\" valign=\"top\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.542262678803641%\" valign=\"top\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eHD: hemodialysis, PD: peritoneal dialysis, D: Deceased, L: Living\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn patients who underwent simultaneous transplant, the median estimated GFR (eGFR) at 6 and 12 months post-transplant was 81.2 (range: 45.7-108.8) and 79.3 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e (range 54.7-112.1), respectively. In children treated with sequential transplant the median eGFR was 45.7 (range 34.5-86.7) and 38.3 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e (range: 29.9-77.5), respectively (p=NS).\u003c/p\u003e\n\u003cp\u003eFour patients received both organs from deceased donors (3 in the simultaneous transplantation group and 1 in the sequential transplantation group). Four patients received both organs from consanguineous living-related donors (1 in the simultaneous transplantation group and 3 in the sequential transplantation group). In one case treated sequentially, the living-related donor was different (liver transplant from the father and kidney transplant from the grandmother). One patient in the sequential transplantation group, received kidney from a consanguineous living-related donor and the liver from a cadaveric donor.\u003c/p\u003e\n\u003cp\u003eBilateral nephrectomy was performed in 5 patients. The second kidney was removed at the time of kidney transplantation to preserve diuresis during dialysis.\u003c/p\u003e\n\u003cp\u003eIn children with sequential transplant, serum oxalates showed a median drop of 51% (range 14-73%) between liver and kidney transplantation.\u003c/p\u003e\n\u003cp\u003eThere were no differences in the immunosuppressive regimen. All patients received a triple maintenance therapy with tacrolimus, mycophenolate mofetil and corticosteroid. One patient needed to replace mycophenolate mofetil with azathioprine due to gastro-intestinal side effects. One patient was switched from mycophenolate mofetil to everolimus for persistent EBV infection and was treated with low dose tacrolimus for histologic evidence of calcineurin inhibitor toxicity.\u003c/p\u003e\n\u003cp\u003eUrinary oxalate excretion (Ox / CrU) one year after kidney transplantation was available in 6 patients, 3 in the simultaneous transplantation group and 3 in the sequential transplantation group. The Ox / CrU values were not statistically different based on the transplant strategy (p\u0026lt;0.067).\u003c/p\u003e\n\u003cp\u003eNo correlation between bilateral nephrectomy and Ox / CrU at 1-year post-transplant was observed (Table 2).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 2.\u003c/strong\u003e Post-transplant urinary oxalate excretion in relation to the type of transplant and bilateral nephrectomy\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003ePatient\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eOx/CrU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eType of Tx\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eBilateral Nephrectomy\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eSimultaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eSimultaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eSimultaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eSequential\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eSequential\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eSequential\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe protocol biopsies performed at 6 and 12 months showed precipitation of calcium oxalate (CaOx) crystals in all patients except one who had been treated sequentially. At the last follow-up, none of the patients has lost the kidney graft.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe best transplant approach in patients with PH1 is still debated. In our limited cohort, we did not observe a substantial difference in kidney function outcome between patients that underwent simultaneous or sequential liver-kidney transplantation. Data from the literature are conflicting. Some authors reported similar results (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), whereas others have observed more frequently a eGFR\u0026thinsp;\u0026lt;\u0026thinsp;50 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e in patients treated with sequential transplantation(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). These latter authors observed no difference between simultaneous and preemptive transplantation. Most likely, the observed differences are related to differences in the oxalate burden before transplantation and the consequent attitude, in most centers, to sequentially transplant the most severe patients. These patients usually have higher oxalate levels and more systemic involvement(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) and longer duration of dialysis prior to transplantation(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Nonetheless, the most recent data from the OxalEurope registry show comparable outcomes of simultaneous and sequentially liver-kidney transplantation(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA kidney protective effect of the liver graft has been reported in patients transplanted from the same donor, mostly in non-sensitized patients(\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Furthermore, a positive role has been suggested in HLA matching between the liver and the kidney(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe role of native kidney nephrectomy is also debated. During disease progression, the kidneys filter and accumulate huge amounts of oxalate, which potentially may become a major source of oxalates released in the circulation after transplantation. For that reason, systematic bilateral nephrectomy has been advocated but its benefit has not been clearly demonstrated(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). In 1997, Mizusawa et al.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) reported that in combined transplantation, the urinary excretion of oxalates was lower in patients undergoing bilateral nephrectomy compared to patients who did not. However, no differences in kidney function and serum oxalate values were reported after transplantation between the two populations. Recently, Villani et al.(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) reported a faster reduction in plasma oxalate levels and more rapid normalization of urinary oxalate excretion combining bilateral nephrectomy to intensive hemodialysis after transplantation. Similar data have also been reported by Lee et al.(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) in a larger patient population. In our cohort, five patients underwent bilateral nephrectomy. We did not observe significant differences in eGFR or in post-transplant renal oxalate precipitations between patients that underwent bilateral nephrectomy and those who did not. However, urinary oxalate excretion was higher after kidney transplantation in patients undergoing sequential transplantation, regardless of the nephrectomy status, most likely related to a more severe systemic oxalosis.\u003c/p\u003e \u003cp\u003eFew reports have described the evolution of serum oxalates between the liver and the kidney transplantation in patients that underwent a sequential procedure(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). On average, we observed a 51% reduction in serum oxalate levels after liver transplantation, although in some patients a prolonged period of intensive hemodialysis is required. Furthermore, oxalate reduction did not prevent oxalate precipitation in the newly transplanted kidneys.\u003c/p\u003e \u003cp\u003eBergstralh et al.(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) have shown that urinary oxalate excretion remains elevated for up to 3 years after transplantation. We routinely perform two protocol biopsies after kidney transplantation, at 6 and 12 months. Oxalate crystal precipitations was observed in all biopsies except one. Cornell et al.(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e) observed CaOx crystals recurrence on surveillance biopsies in 41% of patients treated with simultaneous transplantation. Higher urine oxalate levels after transplant were associated with a higher CaOx crystal index(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). No significant differences were observed between patients receiving isolated kidney transplantation or simultaneous liver-kidney transplantation, highlighting the importance of reducing systemic calcium oxalate depositions before and after transplantation. To our knowledge, no study has compared deposition of CaOx crystals between simultaneous and sequential transplantation; we did not observe substantial differences.\u003c/p\u003e \u003cp\u003eThis study has limitations related to its retrospective nature, the limited duration of the follow-up and to the small size of the cohort. Nonetheless, it adds information to the current knowledge limited because of the rarity of the disease. Fortunately, the natural history of PH1 is changing, thanks to the new therapies that are being developed. Nonetheless, liver transplantation may still be advantageous in patients that accumulate significant amounts of systemic oxalates and will still be mandatory in all patients living in countries that cannot afford these new therapies. Despite its limitations, our study shows that patients with PH1 can be successfully treated adapting the transplant strategy to individual cases and to the availability of living-related donors. Every effort should be made to reduce the systemic oxalate burden before kidney transplantation and urinary oxalate concentrations after kidney transplantation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI would also like to extend my deepest gratitude to Dr. Luca Dello Strologo for his stimulating and supportive guide during my training period and for all that he has taught us.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding and Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported also by the Italian Ministry of Health with Current Research funds.\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMilliner DS, McGregor TL, Thompson A, Dehmel B, Knight J, Rosskamp R et al (2020) End Points for Clinical Trials in Primary Hyperoxaluria. Clin J Am Soc Nephrol CJASN 1 July 15(7):1056\u0026ndash;1065\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarambat J, van Stralen KJ, Espinosa L, Groothoff JW, Hulton SA, Cerkauskiene R et al (2012) Characteristics and outcomes of children with primary oxalosis requiring renal replacement therapy. Clin J Am Soc Nephrol CJASN March 7(3):458\u0026ndash;465\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCochat P, Rumsby G (2013) Primary hyperoxaluria. N Engl J Med 15 August 369(7):649\u0026ndash;658\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCochat P, Groothoff J (2013) Primary hyperoxaluria type 1: practical and ethical issues. Pediatr Nephrol Berl Ger Dec 28(12):2273\u0026ndash;2281\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCochat P, Hulton SA, Acquaviva C, Danpure CJ, Daudon M, De Marchi M et al (May 2012) Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment. 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Eur Ren Assoc 13 Febr 38(2):517\u0026ndash;521\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJoher N, Moktefi A, Grimbert P, Pagot E, Jouan N, El Karoui K et al (2022) Early post-transplant recurrence of oxalate nephropathy in a patient with primary hyperoxaluria type 1, despite pretransplant lumasiran therapy. Kidney Int January 101(1):185\u0026ndash;186\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMetry EL, van Dijk LMM, Peters-Sengers H, Oosterveld MJS, Groothoff JW, Ploeg RJ et al (2021) Transplantation outcomes in patients with primary hyperoxaluria: a systematic review. Pediatr Nephrol Berl Ger August 36(8):2217\u0026ndash;2226\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiang J, Chen Z, Xu F, Mei S, Li Z, Zhou J et al (July 2020) Outcomes of liver\u0026ndash;kidney transplantation in patients with primary hyperoxaluria: an analysis of the scientific registry of transplant recipients database. 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Transplantation 15 May 87(9):1415\u0026ndash;1421\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGroothoff JW, Metry E, Deesker L, Garrelfs S, Acquaviva C, Almardini R et al (2023) Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope. Nat Rev Nephrol March 19(3):194\u0026ndash;211\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRana A, Robles S, Russo MJ, Halazun KJ, Woodland DC, Witkowski P et al (2008) The combined organ effect: protection against rejection? Ann Surg November 248(5):871\u0026ndash;879\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOpelz G, Margreiter R, D\u0026ouml;hler B (2002) Prolongation of long-term kidney graft survival by a simultaneous liver transplant: the liver does it, and the heart does it too. Transplantation 27 November 74(10):1390\u0026ndash;1394 discussion 1370\u0026ndash;1371\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrenda R, Kaliciński P (2018) Combined and sequential liver-kidney transplantation in children. Pediatr Nephrol Berl Ger Dec 33(12):2227\u0026ndash;2237\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimpson N, Cho YW, Cicciarelli JC, Selby RR, Fong TL (2006) Comparison of renal allograft outcomes in combined liver-kidney transplantation versus subsequent kidney transplantation in liver transplant recipients: Analysis of UNOS Database. Transplantation 27 November 82(10):1298\u0026ndash;1303\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKavuk\u0026ccedil;u S, T\u0026uuml;rkmen M, Soylu A, Kasap B, Ozt\u0026uuml;rk Y, Karademir S et al (2008) February. Combined liver-kidney transplantation and follow-up in primary hyperoxaluria treatment: report of three cases. Transplant Proc. ;40(1):316\u0026ndash;9\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDevresse A, Cochat P, Godefroid N, Kanaan N (2020) Transplantation for Primary Hyperoxaluria Type 1: Designing New Strategies in the Era of Promising Therapeutic Perspectives. Kidney Int Rep 24 September 5(12):2136\u0026ndash;2145\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMizusawa Y, Parnham AP, Falk MC, Burke JR, Nicol D, Yamanaka J et al (1997) Potential for bilateral nephrectomy to reduce oxalate release after combined liver and kidney transplantation for primary hyperoxaluria type 1. Clin Transpl Oct 11(5 Pt 1):361\u0026ndash;365\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVillani V, Gupta N, Elias N, Vagefi PA, Markmann JF, Paul E et al (2017) Bilateral native nephrectomy reduces systemic oxalate level after combined liver-kidney transplant: A case report. Pediatr Transpl May ;21(3)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee E, Ramos-Gonzalez G, Rodig N, Elisofon S, Vakili K, Kim HB (May 2018) Bilateral native nephrectomy to reduce oxalate stores in children at the time of combined liver-kidney transplantation for primary hyperoxaluria type 1. Pediatr Nephrol Berl Ger. 33(5):881\u0026ndash;887\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeal R, Costa J, Santos T, Galv\u0026atilde;o A, Santos L, Rom\u0026atilde;zinho C et al (2017) Combined liver and kidney transplantation in two women with primary hyperoxaluria: Different roads led to different outcomes. Nefrol Engl Ed 1 July 37(4):433\u0026ndash;434\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBergstralh EJ, Monico CG, Lieske JC, Herges RM, Langman CB, Hoppe B et al (2010) Transplantation outcomes in primary hyperoxaluria. Am J Transpl Off J Am Soc Transpl Am Soc Transpl Surg November 10(11):2493\u0026ndash;2501\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCornell LD, Amer H, Viehman JK, Mehta RA, Lieske JC, Lorenz EC et al (2021) Posttransplant recurrence of calcium oxalate crystals in patients with primary hyperoxaluria: Incidence, risk factors, and effect on renal allograft function. Am J Transpl Off J Am Soc Transpl Am Soc Transpl Surg. 26\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Sequential liver-kidney transplantation, simultaneous liver-kidney transplantation, primary hyperoxaluria, oxalate, nephrectomy","lastPublishedDoi":"10.21203/rs.3.rs-4138380/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4138380/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePrimary hyperoxaluria type 1 is responsible for pediatric kidney failure in 1 to 2% of cases. Novel therapies based on RNA interference are changing the natural history of the disease. However, for those who will progress to kidney failure, and for patients living in countries that cannot afford these expensive therapies, liver-kidney transplantation may remain the only efficient therapy. The aim of the study was to evaluate the outcome of patients with primary hyperoxaluria type 1 who received simultaneous or sequential liver-kidney transplantation. We retrospectively evaluated 10 patients, five patients received a simultaneous transplantation, and five underwent sequential transplantation with a median postponement of the kidney transplantation of 8 months (range 4\u0026ndash;20). Median follow up was 3.2 years (range 1.6\u0026ndash;11). Median estimated glomerular filtration rate at 6 and 12 months was 81.2 (range: 45.7-108.8) and 79.3 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e (range 54.7-112.1) in patients who underwent simultaneous transplantation, and 45.7 (range 34.5\u0026ndash;86.7) and 38.3 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e (range 29.9\u0026ndash;77.5) in those with sequential transplantation (p:NS). Biopsies performed at 6 and 12 months showed precipitation of calcium oxalate crystals in all patients except one, demonstrating the recurrence of deposition despite the delay between liver and kidney transplantation. No differences in kidney function or in post-transplant renal oxalate precipitations were observed between patients that underwent bilateral nephrectomy and those who did not. None of the patients has lost the kidney graft at the last follow-up.\u003c/p\u003e \u003cp\u003eOur study shows that adapting the transplant strategy to individual cases, patients with primary hyperoxaluria type 1 can be successfully treated.\u003c/p\u003e","manuscriptTitle":"Simultaneous or sequential kidney-liver transplantation in primary hyperoxaluria","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-05 16:04:43","doi":"10.21203/rs.3.rs-4138380/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c10a1e3c-e956-44ef-a9d5-80bdeb04d372","owner":[],"postedDate":"April 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-24T15:30:17+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-05 16:04:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4138380","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4138380","identity":"rs-4138380","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}