HPE HPE 85 – Spring 2017 - Page 61

Practical therapeutics Issue 85 | Spring 2017 upper limit of normal compared with 1% in the placebo group. More importantly, in two patients (0.2%), transaminases were elevated accompanied by an increase in serum bilirubin, fulfilling the so-called Hy’s law laboratory criteria (characterised by a significant risk of potentially fatal drug induced liver injury). 15,16 V2-receptor is mainly restricted to epithelial cells of the distal renal tubules. 14 The major group of adverse events reported in TEMPO 3:4 are all linked to its mode of action with blockade of ADH-signalling preventing urine concentration and causing polyuria (Table 2). 15 Patients should be informed about how the drug works, and that polyuria – with around 4–6l of urine per day – is not to be regarded a side effect but rather a consequence of the drug’s action and that will occur in 100% of cases. Besides polyuria-associated events, hepatotoxicity is another major adverse event having an impact on clinical practice. In TEMPO 3:4, 4.4% of patients taking tolvaptan showed an alanine transaminase (ALT) increase >3 times the Table 3 Criteria and major predictors of rapid disease progression Criterion Total kidney volume Early onset of hypertension (<35 years of age) Early onset urological complications (flank pain, cyst infections or macrohaematuria <35 years of age) Rapid loss of GFR (>5ml/min/1.73m 2 for one year or >2.5ml/min/1.73m 2 for five years) Type of mutation (with truncating PKD1 mutations showing the fastest progression) Family history: early onset of end-stage renal disease Tools for a standardised use of these criteria Mayo classification; 19 ERA-EDTA position statement 17 PROPKD score; 20 ERA-EDTA position statement PROPKD score; ERA-EDTA position statement KDIGO CKD guideline; 21 ERA-EDTA position statement PROPKD score; ERA-EDTA position statement ERA-EDTA position statement Patient selection Selecting patients who may benefit from initiating tolvaptan and fall within the approval criteria requires assessing signs and indicators of rapid progression. Use of these indicators should ensure only patients at risk of developing end-stage renal disease are treated. In order to guide and assist patient selection, the Working Group on Inherited Kidney Diseases of the ERA-EDTA (The European Renal Association – European Dialysis and Transplant Associati on) published a position statement in 2016 that proposes a decision algorithm. 17 Criteria of rapid progression can be divided into two groups. The first is based on criteria that prove current rapid progression and the second is factors that predict rapid progression in the future. The first group is mainly based on past renal function data that assumes a loss of eGFR >5ml/min/year or 2.5ml/min/year over five years to indicate rapid progression. Although serial measurements of the total kidney volume can also prove rapid progression, this criterion will be used less often in practice due to the requirement of serial MRIs and a standardised approach to volumetry. Furthermore, eGFR loss lacks clinical value in assessing CKD stage 1 patients who would not yet show loss of renal function. Consequently, predictors of rapid progression can greatly help in both assessing the indication and counselling patients. These predictors include TKV, which was shown to be a major indicator of disease progression in the CRISP- cohort. 18 As ADPKD progresses with age, it is extremely important to use an age-adapted model to assess the predictive value of total kidney volume. An important tool that incorporates age into a model predicting eGFR loss is the Mayo classification that can be calculated based upon a one-time kidney volumetry 19 and has recently been confirmed in other cohorts (data presented at Kidney Week Chicago 2016). The PROPKD score – developed by analysing the French GENKYST cohort – adds another layer of hospitalpharmacyeurope.com 59