Isolated kidney transplantation under lumasiran therapy in primary hyperoxaluria type 1: a report of five cases Free

INTRODUCTION

Primary hyperoxaluria type 1 (PH1) is caused by a mutation in the AGXT gene, encoding the hepatic peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). Defects in AGT increase glyoxylate and oxalate production, the latter inducing kidney stones and nephrocalcinosis [1, 2]. Symptoms vary from recurrent bilateral kidney stones with moderate chronic kidney disease (CKD) to early kidney failure in infancy [1, 3, 4]. Until recently, the treatment of PH1 was only symptomatic [2], consisting of standard of care (SOC) with intensive hyperhydration, urine alkalinization and conservative CKD management, with the use of pyridoxine in patients with peculiar mutations [5]. Among patients who reach kidney failure, intensive hemodialysis should be performed; however, systemic oxalosis worsens despite intensive dialysis, and bone is the main compartment for oxalate storage. Combined or sequential double liver/kidney transplantation (CLKT) has been traditionally recommended, as kidney transplant (KTx) alone leads to graft loss due to oxalate deposits, except in B6-sensitive forms [6–8]. With such challenging technical procedures and long-term complications of immunosuppressive therapies, patients’ quality of life (QoL) and survival may be significantly impaired [6].

Novel therapeutic strategies have emerged, using RNA interference (RNAi) therapies: lumasiran was approved in Europe and in the USA in 2020. Phase 1 and 2 studies have shown the safety of lumasiran [9], and Phase 3 studies showed its efficacy to decrease urinary oxalate (UOx) in patients with moderate/advanced CKD [10], and plasma oxalate (POx) levels in advanced CKD and dialysis [11]. It remains questionable whether RNAi therapies may replace double liver/kidney transplantation by isolated kidney transplantation and lumasiran; only one case report has described this procedure so far [12]. Thus, our objective is to provide additional data on such a strategy that may become a real game-changer for patients in transplantation medicine.

CASES

At a median (range) age of 26 (3–45) years and after 13 (5–17) months on lumasiran therapy while on intensive hemodialysis, five genetically confirmed PH1 patients received isolated kidney transplant, as summarized in Table 1. Plasma oxalate (POx) levels continuously and significantly decreased, from 110 (20–150) at lumasiran initiation, to 53 (10–72) at the time of KTx and 7 (5–26) µmol/L 3 months after KTx (P < .05). An intensive postoperative management associating hyperhydration (3 L/m²/day), pyridoxine (5–20 mg/kg/day), lumasiran, and when tolerated potassium citrate, was proposed. In all patients, isolated KTx was successful with at least 6 months of follow-up. None of the patients displayed overt lactic acidosis under lumasiran.

In Patient 1, diagnosis of PH1 was delayed, and she developed in dialysis severe systemic oxalosis with stunting, fractures and severe anemia; she received blood transfusions every 4–6 weeks in dialysis before initiating lumasiran therapy, and did not require additional transfusions after the first dose of lumasiran. The timing of such a rapid improvement appears surprising, but nothing else changed in the management at that time. She was transplanted from a deceased donor. Dialysis was performed just before KTx and during the first 48 h after the surgical procedure as a “prophylaxis.” Intensive hyperhydration, pyridoxine and potassium citrate were started immediately after KTx. The early postoperative period was marked by an obstruction of the JJ tube due to oxalate crystallization, with transient acute renal failure requiring hemodialysis from Day 18 to 36 post-KTx. Kidney ultrasounds showed one lithiasis at Months 1 and 3, but no lithiasis at Month 6.

Patient 2 was transplanted from a living donor. Postoperative management consisted of hyperhydration and pyridoxine, but the patient had a poor tolerance and further compliance to citrate.

Patient 3 was transplanted from a deceased donor. Pyridoxine and hyperhydration were prescribed; however, citrate was postponed because of digestive status. At 1 month post-KTx, the patient displayed increased creatinine levels due to mechanical reason (lymphocele), the nadir of creatinine levels having been observed at Day 10 post-Ktx at 72 µmol/L. He underwent urological surgery with arterial thrombosis, hemorrhagic shock, acute renal failure and anuria. Thus, he transiently restarted daily hemodialysis for 14 days. Urine alkalinization by citrate of potassium could secondary be introduced at Month 4 with good tolerance and observance.

Patient 4 was transplanted from a living donor. Dialysis was performed during the first 36 h after the surgical procedure as “prophylaxis.” Postoperative management consisted of hyperhydration and potassium citrate, but no pyridoxine (because of the genetic profile). Between Months 2 and 3, the patient presented two episodes of acute renal injury. Biopsy showed no acute rejection and only one oxalate deposit. The management consisted of intensification of hyperhydration (oral and intravenous), and an off-label “loading” dose of lumasiran with 3 monthly injections (as proposed in the product information template). There was no objective evidence of inadequate lumasiran effect before Tx, but since it was a scheduled living donor with POx levels remaining far above the proposed POx thresholds previously published in the literature [13], a multi-collegial board of nephrologists decided to propose an additional dose of lumasiran to block as much as possible hepatic synthesis of oxalate during the first weeks post-transplantation in the context of two episodes of early acute kidney injury. With 6 months of follow-up, renal function is stable.

Patient 5 was transplanted from a living donor. Of note, at 1 month, 24-h urine creatinine clearance was higher than estimated glomerular filtration rate (60 mL/min versus 38 mL/min/1.73 m²). At 3.5 months post-KTx, kidney function declined and kidney graft biopsy showed BK virus nephropathy but no signs of oxalate nephropathy. After reduction in immunosuppression, kidney function recovered partially. Renal ultrasounds showed a normal aspect of the kidney transplant and no changes in the native kidneys.

ETHICS

By French law, this retrospective study was approved by the local IRB (Comité d'Ethique des Hospices Civils de Lyon, session 29/04/2 022, 22_818; Comité d'Ethique du CHU de Strasbourg, approval number DC-2013-1990). By Dutch law, retrospective studies do not need ethical approval, and the patient agreed to publication of data. Of note, Patients 1, 3 and 5 were included in the industry-sponsored ILLUMINATE-C trial, but data presented here correspond only to local results, and not to the centralized data obtained during the trial.

DISCUSSION

Here, we present five cases of isolated KTx in combination with lumasiran in PH1 patients, all showing no signs of recurrent oxalate nephropathy after a follow-up of at least 6 months. Three patients received a graft from a living donor, and one had a genetic profile of pyridoxine resistance.

Regardless the cause of kidney failure in non-PH1 patients, Pox levels are increased well above the upper normal limit in all patients undergoing maintenance hemodialysis: Pox levels in dialysis patients without PH1 are on average around 40–50 μmol/L (control levels below 5–6.8 μmol/L) [14–16]. In patients with PH1, hepatic oxalate over-production leads to levels 2–3 times higher than the rest of the dialysis population, i.e. between 80 and 250 μmol/L. Such high levels may cause systemic oxalosis, oxalate deposits inducing major morbidity and mortality. Given the poor oxalate clearance by dialysis, even with intensive regimens, systemic oxalosis could do nothing else than worsen in dialysis [2], at least before the era of RNAi therapies. This is the main reason why the 2012 guidelines proposed pre-emptive transplantation before kidney failure has occurred in PH1 patients, if possible [2]. However, the proposed thresholds of POx for a safe transplant procedure, namely around 20 µmol/L [13], appear quite optimistic and probably not attainable in most patients, keeping in mind the POx levels observed in dialysis in non-PH1 patients. Recent data from the industry-sponsored ILLUMINATE-C trial showed a reduction of POx levels by 42% in the cohort of 15 PH1 patients in dialysis between baseline and 6 months, with a plateau reached within 2 months around 70–75 µmol/L [11]. Notably, an important inter-individual variability was observed.

Conceptually, to avoid both short-term complications and mortality of liver transplantation (corresponding to 14% of deaths in the historical cohorts) as well as long-term complications of immunosuppressive therapies [6], it is tempting to propose RNAi therapies instead of liver transplantation before dialysis in PH1, and isolated KTx in patients having reached kidney failure. In that setting, several questions emerge. Can isolated KTx be performed under lumasiran therapy in such patients? What would be the thresholds of POx to safely perform isolated KTx? What should be the optimal timing of lumasiran injections? At least in case of living donation, should we propose a “loading dose” again? What should be the postoperative management and follow-up? What should we propose to patients with B6-sensitive mutations, or more precisely could we stop lumasiran therapy in such patients once POx have normalized? This last question is of utmost importance given both the absence of long-term safety data and the socioeconomic burden of this extremely expensive medication in the long-term. One may argue that the use of vitamin B6 in four patients may have blunted the results, and it is true that it is impossible to discriminate the respective effects of B6 and lumasiran on POx levels in such patients. However, we performed for the first time this innovative strategy, and we did not want to penalize patients. That being said, the B6 sensitivity was difficult to assess in Patients 1 and 3 since PH1 was diagnosed at the time of kidney failure, and in Patient 5, despite maximal B6 therapy at the time of conservative therapy, an important hyperoxaluria remained. Thus, we hypothesize that the effect of lumasiran to control oxalate levels after Tx was more important, but this will have to be proved in the future.

A first case of isolated KTx was recently reported in a 39-year-old PH1 woman. After 3 years of conventional hemodialysis, followed by 1 year of daily hemodialysis and additional lumasiran treatment for 7 months, she underwent KTx. At Day 25 post-KTx, creatinine levels increased. The biopsy showed severe T-cell-mediated rejection, and hardly any signs of oxalate nephropathy, with good clinical response to intensive anti-rejection treatment. The patient showed a satisfying response to lumasiran with normalization of POx levels before KTx [12]. In this patient, an early postoperative management was performed, including aggressive hyperhydration, alkalinization and pyridoxine in addition to lumasiran. By analogy with the knowledge acquired when performing CLKT in PH1 without RNAi therapies, the release of systemic oxalate mainly from bone after CLKT is inevitable, justifying early postoperative management until UOx normalization. This last step may take time, months and even years [7]. As such, patients and caregivers must be informed before Tx, since it may have a great impact on QoL. Hyperhydration is indeed a cornerstone to avoid oxalate deposition on the graft, as illustrated here with the biopsies showing no (or very scarce) oxalate deposits. It was traditionally said that the time of hyperhydration after CLKT should correspond to the time the patient spent on dialysis, but the onset of RNAi therapies may modify this concept. However, one should keep in mind that RNAi therapies decrease the liver over-production of oxalate, but does not affect oxalate release from bone. We may nevertheless hypothesize that the severity of systemic oxalosis will decrease with lumasiran, but this remains to be proved. This last point is challenging since there are no validated methods to adequately evaluate in routine bone and systemic oxalate deposition; however, the improvement in anemia control may be an interesting outcome to consider, as well as FDG-positron emission tomography/computed tomography scans [17].

Thus, although long-term follow-up is needed, our data indicate that isolated KTx under lumasiran therapy may be a safe strategy in PH1 patients with kidney failure if POx levels are below 80–90 µmol/L. As in CLKT, intensive postoperative management associating hyperhydration and alkalinization remains crucial in this setting to avoid recurrence of oxalate deposits on the renal graft, as long as UOx/creatinine remains elevated from bone release.

ACKNOWLEDGEMENTS

This work was supported by members (A.L.S.-L., E.M., J.G., J.B.) of the European Reference Network for Rare Kidney Diseases (ERK-Net).

FUNDING

Not applicable.

CONFLICT OF INTEREST STATEMENT

A.L.S.-L., B.M. and C.L. received speaker fees from Alnylam; J.B. received consulting, travel and speaker fees from Alnylam, and consulting fees from Dicerna and Biocodex. C.A.-B. received travelling fees from Alnylam. The results presented in this paper have not been published previously in whole or part, except in abstract format.

REFERENCES