ADPKD diagnosis and management using PROPKD score and tolvaptan

19 Jan 2023

Autosomal dominant polycystic kidney disease (ADPKD) is a form of polycystic kidney disease caused by mutations in the PKD1 and PKD2 genes, which could be predicted using genetic testing and assessed with the PROPKD score.1,2 In April 2018, tolvaptan was approved by the United States (US) Food and Drug Administration (FDA) for treating ADPKD patients at the risk of rapid progression.2 In the ASN Kidney Week 2022, Dr. Meyeon Park from the University of California, San Francisco Polycystic Kidney Disease Center of Excellence, the US, discussed a clinical case regarding the total kidney volume (TKV) as a prediction tool. She also shared her view on the continuous tolvaptan treatment until dialysis or transplantation, as well as genetic testing with PROPKD score prognosis in tolvaptan users.1 

A case study focused on a 55-year-old woman with a medical and family history of ADPKD, as well as a current estimated glomerular filtration rate (eGFR) of approximately 35mL/min/1.73m2. Her kidney magnetic resonance imaging (MRI) and ultrasound evaluating TKV indicated as Mayo class 1C.2 Alternatives to TKV calculation include the ellipsoid method, which presented a height-adjusted TKV (htTKV) of 884mL/m, classified as having the same Mayo class of 1C.2 Individuals who conducted genetic testing have shown to have lower rates of family history (63%) compared with those who did not do the testing (80%).2 At first, this patient showed no interest in undergoing genetic testing because of her known family history.2 She was subsequently tested for a living donor evaluation of her son and showed a positive heterozygous PKD1 mutation, which was classified as pathogenic according to the ADPKD variant database.2 

Genetic testing is useful for computing the PROPKD score which assesses the effects of clinical and genetic influences on renal survival in ADPKD.2 A greater PROPKD score was associated with a greater positive predictive value (PPV) for end-stage kidney disease (ESKD) at the age <60 years.2 Truncating PKD1 mutations give the greatest number of points, while PKD2 mutations give 0 points.2 The total PROPKD score categorizes patients into the low, intermediate, and high-risk groups.2 A separate study based on the TEMPO 3:4 and REPRISE study further proved the predictive value of PROPKD score for rapid decrease in eGFR, which was mediated with the use of tolvaptan vs. placebo in the intermediate group [-2.69 vs. -3.49; p=0.0102; relative treatment effect (RTE)=22.9%] and the high-risk group (-2.86 vs. -4.04; p=0.0033; RTE=29.2%).2 

PKD1 mutation is more common and is associated with 60%-78% of all ADPKD, compared with 15%-26% in PKD2 mutation as observed by a study of the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease (eTGESP).2 On the other hand, there was no mutation detected in 10%-15% of patients establishing cystic phenotypes, while other cystic disease genes (i.e., GANAB and DNAJB11) accounted for <1% of patients.2 Another study of the eTGESP showed that copy number variations (CNV) may account for a percentage of next-generation negatively screened instances and early onset of ESKD.2 Both kidney imaging and genotype criteria are predictive of disease progression (i.e., cyst burden and onset of ESKD) and may overlap, regardless of the type of mutation (i.e., PKD2 mutation can still be classified as higher risk).2 

Mayo class, which is more commonly used in the US, can also predict the average eGFR reduction, which is -2.43mL/year (women) for this patient at Mayo class 1C.2 The patient’s actual eGFR reduction on tolvaptan was approximately 2.6mL/min/1.73m2 per year, with her eGFR falling below 20mL/min/1.73m2, allowing her to be eligible for transplant.2 Some US experts (grade C evidence) recommended continuing tolvaptan until requiring kidney transplant or the initiation of dialysis.2 She was thus continued with tolvaptan until the transplant, which helped with her symptoms and cyst infection frequency.2 

A study by Dahl, et al. showed a decrease in htTKV growth with tolvaptan in ADPKD which improved the population risk profile.2 Besides, a study by Nunna, et al. on the number needed to harm (NNH) analysis on the TEMPO 3:4 patient-level data, which included 961 patients in the tolvaptan group and 483 in the placebo group, showed that the NNHs for alanine aminotransferase (ALT) >3 times upper limit of normal (3 x ULN) were only 1.78 and 2.51 for every 100 patients treated with tolvaptan instead of placebo over 12 and 24 months, respectively.2 

In conclusion, TKV is useful for risk stratification and predicting ADPKD disease progression.2 Dr. Park provided an expert opinion that “tolvaptan can be resumed until dialysis or transplant in eligible individuals”.2 For individuals with known family history, genetic testing could still be effective, along with the prognostic PROPKD score, and even with the use of tolvaptan.2 

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