The hallmark of autosomal dominant polycystic kidney disease (ADPKD) is numerous, fluid-filled cysts that derive from the entire nephron located throughout the entire parenchyma. The cystic transformation of the kidneys is accompanied by a progressive loss of renal function. Mutations in two genes lead to ADPKD – PKD1 and PKD2.1 They both encode for proteins that concentrate in primary cilia – a hallmark of proteins mutated in cystic kidney diseases that are consequently considered to be ciliopathies.2 Loss of function in one of the two proteins leads to increased proliferation, defects in planar cell polarity and hyper-secretion of renal tubular cells. However, with cilia being present on nearly every cell of the human body it is clear that the phenotype in ADPKD is not limited to the kidney but accompanied by extra-renal symptoms such as cysts in other organs, intracranial aneurysms, diverticulosis and heart valve defects.1 ADPKD follows an autosomal dominant inheritance. Consequently, affected families will have individuals suffering from ADPKD in every generation.
Even though ADPKD is a genetic disease, the diagnosis does not require a genetic exam in the vast majority of patients but is based on clinical criteria. In patients with a positive family history, clear imaging criteria based upon the number of cysts per kidney in an age-dependent fashion have been formulated and validated.3,4 Renal ultrasound is generally sufficient to make the diagnosis in these patients. In addition to the number of cysts detected, attention should be paid to the enlargement of the kidneys and ubiquitous localisation of the cysts throughout the parenchyma that would be expected in ADPKD (Figure 1). Furthermore, extra-renal symptoms can help to distinguish ADPKD from other cystic kidney disease entities such as nephronophthisis or simple kidney cysts.5
Figure 1: T2-weighted MRI shows the massive enlargement of both kidneys with cysts distributed throughout the entire parenchyma as typical in ADPKD accompanying polycystic liver disease – as shown here – is one of the most common extra-renal manifestations of the disease. Image courtesy of Thorsten Persigehl MD, Department of Radiology, University of Cologne.
Until the TEMPO 3:4 trial, only supportive measures were available to influence the course of disease in ADPKD patients. These include salt restriction (<5–7g per day) and a sufficient fluid intake of above 3l per day. Furthermore, women taking hormone preparations (such as oral contraceptives) should be prescribed with formulations containing no (or low) oestrogen content.1,5 Oestrogens drive the growth of the liver, which can be a significant problem especially in young female patients. Nephrotoxic substances – for example NSAIDs – should be avoided and a healthy lifestyle (for example, Mediterranean diet, physical activity and refraining from smoking) should be adopted to lower the risk of cardiovascular disease resulting from chronic kidney disease and early onset of arterial hypertension. The HALT-PKD study highlighted clear benefits of controlled blood pressure and the use of an ACE-inhibitor or an angiotensin-receptor blocker.6 However, there is no indication for dual RAAS-blockade in ADPKD.7
Targeted drug therapy in ADPKD
In recent decades, an enormous body of work was performed in rodent models of ADPKD to identify signal transduction pathways altered in ADPKD.8 This work led to the identification of mechanistic target of rapamycin (mTOR) signalling being increased in renal tubular cells. This leads to an elevated proliferative potential. Treatment with mTOR inhibitors showed a tremendous potential to slow disease progression in rodent experiments.9 Consequently, two large studies were performed that evaluated this concept in ADPKD patients. Unfortunately, mTOR inhibition was shown to be of no benefit to ADPKD patients, a major disappointment in the search for the first targeted therapeutic strategy.10,11 Apart from increased mTOR signalling, epithelial cells lining cysts in ADPKD showed increased cAMP levels that mediate cyst growth both by increasing fluid secretion and cellular proliferation. One of the key pathways regulating cAMP levels in the kidney is vasopressin receptor signalling. Both knockout of anti-diuretic hormone (ADH) as well as pharmacological inhibition of the vasopressin V2 receptor were able to slow down cyst growth in several rodent models.12,13 Importantly, expression of the V2 receptor is primarily limited to epithelial cells of the distal renal tubular system, making off-target effects of a treatment blocking this pathway unlikely.14
The path to approval of tolvaptan in ADPKD
Consequently, a randomised double-blinded trial was set up to examine the effect of the V2-receptor antagonist tolvaptan – which was already in clinical use for the treatment of hyponatraemia – in ADPKD. The TEMPO 3:4 trial is a landmark study in ADPKD research and – enrolling close to 1500 patients aged 18–50 years – could show that tolvaptan slows down both kidney growth by 49% and loss of estimated glomerular filtration rate (eGFR) by 26% during a three-year period.15 Interestingly, episodes of kidney pain – a common symptom in ADPKD patients – were also significantly less frequent in the tolvaptan group. As a result, tolvaptan was approved for the treatment of ADPKD in 2015 by the European Medicines Agency (EMA). It is available and reimbursed in several European countries for ADPKD patients who fulfil two pre-requisites based on the inclusion criteria of the TEMPO 3:4 trial. First, only patients being in CKD-stages 1–3 (that is, showing an eGFR of ≥30ml/min) can be treated. Second, patients have to show signs of rapid progression that indicate a patient will reach end-stage renal disease (Table 2). The US Food and Drug Administration has not approved tolvaptan for ADPKD, and a follow-up trial (REPRISE) is underway to study the effects of tolvaptan in older patients and patients in early CKD stage 4. The results are expected to be published 2017/18.
Major extra-renal effects of tolvaptan are not to be expected as expression of the 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 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
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 Association) 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 volumetry19 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 data by focusing on clinical criteria (Table 3).20 However, the PROPKD score depends on the results of a genetic exam that is not available to the majority of patients, because sequencing of PKD1 and PKD2 is not necessary to make a diagnosis of ADPKD. Nonetheless, the mutation is one of the strongest predictors of the disease course. Obtaining a concise family history may give indications on the underlying mutation but does not provide sufficient information to calculate the PROPKD score.17
Initiation and management of tolvaptan
Careful patient selection (see above) and counselling before starting therapy is crucial to a successful treatment17 Only patients who show signs of rapid progression, therefore expecting to reach end-stage renal disease, should be initiated on tolvaptan. Furthermore, contraindications to this drug need to be excluded – including severe liver disease, hypernatraemia, trouble perceiving or responding to thirst, obstruction of the urinary tract as well as pregnancy and breast-feeding (for details, see Summary of Product Characteristics).
Patients need to be advised to drink sufficiently rather before getting thirsty and always carry along a bottle of water. It is crucial that patients on tolvaptan know in which situations they need to stop taking the drug, that is, all events associated with a risk of dehydration such as diarrhoea, lacking access to water, or surgery. The water deficit should preferentially be managed with non-sparkling water. Calorie-rich drinks – which would lead to a tremendous increase in calorie-intake per day – should be avoided. A salt-restricted diet that is not rich in protein may help avoid excessive urine volumes. Patients suffering from accompanying polycystic liver disease have to be informed that tolvaptan does not have any impact on liver cysts.
Tolvaptan is then started at a dose of 60mg/day divided into 45mg taken in the morning and 15mg taken eight hours later. According to the strategy employed in the TEMPO 3:4 trial (where more than 50% of patients reached and remained on the maximum dose) up-titration to the target dose of 120mg per day should be attempted in all patients (second dose: 60/30mg, third dose: 90/30mg) while the up-titration period can be extended depending on package size and prescribing frequency (for example, once monthly). If, however, the maximum dose is not tolerable, therapy can be continued returning to a lower dose. Because metabolism of tolvaptan involves CYP3A4, caution is required in patients who take moderate to strong inhibitors of CYP3A4 (for example, clarithromycin, fluconazole, verapamil etc.). In these cases, adaptations of the tolvaptan dose are required. Patients should also be counselled on the avoidance of grapefruit juice, another CYP34A inhibitor.
Because the cases of hepatotoxicity described above occurred during the first 18 months of treatment, monthly LFTs are required during this period (extending to three-monthly controls afterwards) and attention needs to be paid to clinical signs of liver injury.15,16 Despite incidence of polyuria, close to 80% of patients continued taking the drug in TEMPO 3:4, indicating an acceptable adherence to tolvaptan treatment in ADPKD.17 This was not only the case in this clinical trial but also appears to hold true in the real-life setting (unpublished observation of the authors).
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20 Cornec-Le Gall E et al. The PROPKD Score: A new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2016;27:942–51.
21 KDIGO. KDIGO 2010 clinical practice guideline for the evaluation and management of chronic kidney disease. http://kdigo.org/home/guidelines/ckd-evaluation-management/ (accessed March 2017).
Declaration of interest
The Dept II of Internal Medicine has received research funding from Otsuka Pharmaceuticals.