Table 2 Recommended management and monitoring of patients with PH1 on RNAi therapy

From: Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope

Groupa

Start

Cessation criteria after 6 months of therapy

Six-monthly analyses for 5 years and cessation criteria

Group A (VB6−, eGFR >30)

We recommend starting therapy

Uox >1.5 UL or less than a 30% reduction in Uoxb or a deterioration of the clinical condition or evidence of a SAEc

SAE or deterioration in clinical condition related to RNAi therapyc

Group B (VB6+, eGFR >30)

We suggest starting therapy, based on patient characteristics (not fully VB6 responsive, severe disease)

Uox >1.5 UL or <30% reduction Uoxb; or deterioration of clinical condition or evidence of a SAEc

SAE or deterioration in clinical condition related to RNAi therapyc

Group C (VB6−, eGFR <30)

We recommend starting therapy

Decrease in Pox <20% from baseline or deterioration of clinical condition or evidence of a SAEc

Stop if decrease in Pox is <20%d,e from baseline: discuss options if the decrease in Pox is <30% from baselined,e. Also stop treatment if there is evidence of an SAE OR deterioration in clinical condition related to RNAi therapyc

Group D (VB6+, eGFR <30)

We suggest starting therapy based on patient characteristics (not fully VB6 sensitive, rapidly deteriorating kidney function in case of eGFR 20–30)

Decrease in Pox <20% from baselined,f or deterioration of clinical condition as assessed by a committee; or evidence of a SAEc

Stop therapy if the decrease in Pox is <20%2,4; discuss options if the decrease in Pox is <30%d,f. Also stop treatment if there is evidence of a SAE or deterioration in clinical condition related to RNAi therapyc

Group E (no genetic diagnosis, eGFR <30)

We recommend starting therapy with monthly monitoring of Pox levels

Decrease Pox <20% of baseline or deterioration of clinical condition as assessed by a committee; or evidence of a SAEc. Also stop therapy if the suspected PH diagnosis is not confirmed genetically

Not applicable

Group F (no ongoing clinical disease)

We suggest starting therapy in adults and recommend starting therapy in children

Uox >1.5 UL or <30% reduction Uox of baseline; or deterioration of clinical condition as assessed by a committee; or evidence of a SAEc

SAE or deterioration in clinical condition related to RNAi therapyc

Group G (full VB6+)

We do not recommend starting therapy

Not applicable

Not applicable

  1. eGFR, estimated glomerular filtration rate (units: ml/min/1.73 m2); PH, primary hyperoxaluria; Pox, plasma oxalate; RNAi, RNA interference; SAE, severe adverse event; UL, upper level reference value; Uox, urinary oxalate excretion; VB6, vitamin B6 (also known as pyridoxine). aGroup A patients are defined as patients of any age with (genetically established) PH1; and biochemically established non-responsiveness to pyridoxine therapy or with mutation consistent with pyridoxine unresponsiveness; and urinary oxalate excretion >1.5 times the upper reference limit (based on at least two samples); and a clinical phenotype of PH1, characterized by active stone disease and/or nephrocalcinosis and/or renal impairment (but with eGFR >30 ml/min/1.73 m2). Group B patients are defined as patients of any age with genetically established PH1; and biochemically established partial responsiveness to pyridoxine therapy (that is, urinary oxalate level 1.0–1.5 times the upper reference limit of normal while on pyridoxine treatment); and a clinical phenotype of PH1, characterized by active stone disease and/or nephrocalcinosis and/or renal impairment (but with eGFR >30 ml/min/1.73 m2). Group C patients are defined as patients of any age with genetically established PH1; and a mutation consistent with pyridoxine unresponsiveness and eGFR <30 ml/min/1.73 m2. Group D patients are defined as patients of any age with genetically established PH1; and a mutation consistent with pyridoxine responsiveness and eGFR <30 ml/min/1.73 m2. Group E patients are defined as patients with clinically suspected PH1 with stage 5 CKD based on elevated plasma oxalate levels (>80 µmol/l in those with stage 5D CKD; >10 µmol/l in patients not on dialysis) and plasma glycolate levels, but awaiting genetic confirmation. Group F patients are defined as patients of any age with genetically established PH1; and biochemically established non-responsiveness to pyridoxine therapy or with a mutation consistent with pyridoxine non-responsiveness; and urinary oxalate excretion >1.5 times the upper reference limit (based on at least two samples); and no ongoing clinical disease. Group G patients are defined as patients of any age with genetically established PH1; and biochemically established full pyridoxine responsiveness (urinary oxalate less than the upper reference limit of normal while on pyridoxine treatment); and a clinical phenotype of PH1, characterized by active stone disease and/or nephrocalcinosis and/or renal impairment (but eGFR >30 ml/min/1.73 m2). bUox per 24 h or Uox-to-creatinine ratio. cDeterioration should be evaluated in the context of the individual patient; recurrent attacks due to pre-existing stones are not a criterion for failure. Only consider SAEs that are potentially related to lumasiran. dEvaluated in patients on a stable dialysis regimen or in pre-dialysis patients with a stable eGFR; otherwise discussion. eIn patients who do not undergo kidney transplantation during therapy course. In patients who do undergo kidney transplantation, evaluate the response to RNAi therapy on Pox, taking into account the expected reduction in relation to eGFR and estimation of stored oxalate. High Uox levels after kidney transplantation may be the result of oxalate release from bone. fIn patients who have not undergone kidney transplantation; in patients who do undergo kidney transplantation, consider stopping lumasiran 3 months after kidney transplantation if Uox excretion is normalized; repeat measurement of Uox every month and restart lumasiran if Uox increases >1 UL.
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