Assessing Risk of Progression in ADPKD

Patient Presentation

A 52-year-old woman is referred for a second opinion about whether she should be treated with tolvaptan for autosomal dominant polycystic kidney disease (ADPKD). She was diagnosed with ADPKD 15 years ago on ultrasonography performed in the workup of abdominal pain. This study demonstrated innumerable cysts in bilaterally enlarged kidneys, but the length of the kidneys was not reported. She has had no complications of ADPKD and denies history of macroscopic hematuria, nephrolithiasis, cyst infections, or significant flank or abdominal pain related to her ADPKD. Her estimated GFR (eGFR) is 58 ml/min per 1.73 m². She is otherwise healthy with no medical problems and is interested to learn if she is a candidate for tolvaptan therapy.

Introduction

ADPKD is the most common hereditary kidney disease with a median age of kidney failure of 55 and 72 in patients affected by PKD1 and PKD2, respectively. The selective arginine vasopressin V2 receptor antagonist, tolvaptan, is an oral agent that reduces the rate of increase in total kidney volume (TKV) and slows the decline in GFR, likely resulting in delay of kidney failure. Additional clinical benefits of tolvaptan include decreases in episodes of kidney cyst pain, nephrolithiasis, and urinary tract infections (1). However, the mechanism of action of tolvaptan leads to aquaresis, which can be troubling to patients.

Who Should I Treat with Tolvaptan?

The US Food and Drug Administration (FDA) prescribing information states tolvaptan “is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).” Other than the stipulation limiting the treatment to adults (18 and older), there is no minimum or maximum GFR limit and no upper age limit. The treating physician must therefore take into consideration the study populations from the two phase 3 clinical trials and expert guidance regarding patient selection and management (2). TEMPO 3:4 clinical trial included ADPKD patients aged 18–50, with creatinine clearance greater than 60 ml/min and TKV > 750 ml (1). The REPRISE study included individuals between 18 and 55 years of age with eGFR 25–65 ml/min per 1.73 m² and between 56 and 65 years of age with eGFR 25–44 ml/min per 1.73 m² with evidence of prior progression (3). Participants with the fastest progressing disease derived the most benefit, while patients >55 years of age with slower rates of progression did not achieve statistically significant benefit from tolvaptan.

How Do I Determine If My Patient Is at Risk of Rapid Progression?

The definition of risk of rapid progression of ADPKD has not been formalized by most regulatory authorities (such as the FDA, European Medicines Association, and Health Canada), with several exceptions (e.g., Japan and Australia). A series of guidelines and consensus statements from experts (2,4,5) have been devised, but there is significant inconsistency in the results obtained using different classification systems (2). The different systems can be broadly categorized as using a combination of eGFR or eGFR slope; clinical characteristics, and genotype in a point system (PROPKD score); and utilizing measurements of TKV, kidney volume growth, or kidney length. The Mayo imaging classification (6), which utilizes height-adjusted TKV of typical ADPKD kidneys as a function of age, has been extensively evaluated and validated as a prognostic biomarker for GFR decline (6,7) and as a predictive biomarker to classify study participants who benefited (versus those who did not) from clinical interventions in the TEMPO 3:4 (8) and HALT PKD studies (9). In order to utilize the Mayo imaging classification, one must first ascertain whether the cystic kidneys are typical (class 1), i.e., with diffuse distribution of cysts throughout the kidneys, or atypical (class 2), with unilateral, asymmetric, segmental, or lopsided cyst distributions or kidney atrophy. Class 2 disease progresses more slowly, and the prognostic calculator should not be used in these patients (6). Simple measurements of sagittal and coronal length, width, and depth are obtained from noncontrast computed tomography or magnetic resonance imaging and entered into an online calculator (https://www.mayo.edu/research/documents/pkd-center-adpkd-classification/doc-20094754, accessed September 4, 2021). In our experience, these measurements are readily obtained by the treating nephrologist or radiologist. We emphasize that it is extremely valuable for the treating nephrologist to directly review the imaging ordered on their patients so as to become familiar with the varied appearance of cystic kidneys.

Individuals between the ages of 18 and 55 with Mayo imaging classification 1C–E are the most straightforward candidates for tolvaptan (2). Moreover, because the benefit is cumulative, these young individuals with class 1C–E kidneys and preserved GFR will derive the most benefit, the latter estimated on average as a delay in reaching kidney failure by an average of 6–7 years if treatment has been started at young age and high GFR (2). Another group that bears further mention is those who are older than 55. The REPRISE study did not demonstrate a significant benefit to individuals aged 55–65 because of low progression rates. Kidney imaging was not obtained in the REPRISE study, so it is unclear how to utilize Mayo imaging classification for decision making in those older than 55 years of age. Our practice in those older than 55 years of age is to obtain imaging and to evaluate GFR progression rates using the criterion of average annual rate of decline in GFR. Those with a high risk Mayo imaging classification and rate of GFR decline exceeding 5 ml/min in 1 year or >2.5 ml/min per 1.73 m² per year over 5 years would seem to be reasonable candidates. Those with stable or slowly declining GFR are not likely to benefit from tolvaptan and will be exposed unnecessarily to the risks of hepatotoxicity and the burden of aquaresis.

In the United States, genotype is not routinely obtained. Several studies have clearly demonstrated that the Mayo imaging classification more accurately conveys risk of progression than genotype alone, although knowledge of genotype in concert with Mayo imaging classification may provide additional information about risk of progression (7).

Contraindications for Tolvaptan

Absolute contraindications for tolvaptan include underlying liver disease not due to polycystic liver disease, hypovolemia, uncorrected hypernatremia, urinary tract obstruction, inability to perceive/respond to thirst, pregnancy or breast feeding, and concomitant use of strong CYP3A inhibitors.

Patient Education

Patients should be educated about the aquaretic action of tolvaptan and the resulting importance of high intake of water to satiate thirst and to prevent dehydration. We educate patients to adjust the timing of dosing to avoid the aquaretic effects during events with limited bathroom access. The polyuria might also impact the mode of commuting transportation as well as necessitate enhanced access to bathroom facilities. A social history focused on family and work life is critical to ascertain the ability of a patient to tolerate the aquaretic effects, and some professions may not be amenable to tolvaptan use. Although the nocturia can be troubling to some, most patients acclimate to this without difficulty. To avoid dehydration, we educate patients to drink water at night upon awakening to void. Patients should be educated to avoid excessive dietary sodium or protein as these can potentiate the polyuria due to their osmotic content.

Assessment and Monitoring of Liver Biochemical Tests

Prescription of tolvaptan is governed in the United States by a strict risk evaluation and management strategy (REMS), which requires measurement of AST, ALT, and bilirubin at baseline, at 2 and 4 weeks, every month for 18 months, and every 3 months thereafter. Full details of the REMS are described in the product label and expert guidance (2). Similar monitoring is advised by comparable regulatory agencies in other nations. We generally advise minimizing alcohol intake and acetaminophen use. Treating clinicians should respond to small increases (<2× upper limit of normal) in liver biochemical test results by querying patients about changes in medicines, level of exercise, and alcohol consumption; if the elevated tests persist or increase on subsequent testing, tolvaptan should be held and other etiologies evaluated. Elevation to >2× upper limit of normal triggers immediate treatment discontinuation with repeat testing in 48–72 h as specified by REMS. If liver tests return to normal, tolvaptan can be restarted but with frequent monitoring of liver tests.

What Are the Expected Benefits of Tolvaptan?

The difference in the slope of decline in eGFR between tolvaptan-treated and placebo-treated participants is approximately 1 ml/min per 1.73 m² (1,3). A patient starting tolvaptan with an eGFR of approximately 60 ml/min per 1.73 m², as in the case presentation, might expect a 4.5-year delay in kidney failure with tolvaptan (2). Many patients would agree that the trade-off of frequent liver monitoring and aquaretic side effects are worth it for this benefit, but others would disagree. The question of whether the delay in progression to kidney failure might result in ADPKD patients “ageing out” from kidney transplantation candidacy has been raised, but this occurrence would be very infrequent and should not be a consideration in whether to initiate treatment or not (10). Additionally, the decrease in episodes of kidney cyst pain, nephrolithiasis, and urinary tract infections should be considered in weighing the benefits and risks of tolvaptan.

How Would We Advise the Patient in This Case?

This patient underwent magnetic resonance imaging without contrast and was found to have a height-adjusted TKV of 938 ml/m representing Mayo imaging classification class 1C and will qualify to initiate tolvaptan. Prior to starting tolvaptan, the patient was educated as described above, including detailed discussion of the tolvaptan REMS, and informed that current clinical trials preclude the concomitant use of tolvaptan. If she consents to begin tolvaptan, we would start 45 mg in the morning and 15 mg in the afternoon, approximately 8 hours after the morning dose. If the initial dose is tolerated, we increase to the maximally tolerated dose, following the protocols employed in the TEMPO 3:4 and REPRISE studies. An alternate strategy is to titrate to the lowest dose that achieves urine osmolality below 300 mOsm/kg in a fasting specimen obtained prior to the morning dose of tolvaptan (2). The basis for this is a post hoc analysis of TEMPO 3:4, which found that 81% of participants achieved urine osmolality <300 mOsm/kg and no additional benefit was derived from decreases in urine osmolality <250 mOsm/kg (11). Comparisons between these two dosing strategies currently do not exist. In young patients similar to the population enrolled in the HALT PKD study A (age 18–49 and eGFR >60 ml/min per 1.73 m²), we would additionally prescribe antihypertensive agents with a goal blood pressure of 95–110/60–75 mmHg.

Conclusions

The licensing of tolvaptan by regulatory authorities represents an important step forward in the management of ADPKD, but requires careful attention to determining which patients can expect benefits to outweigh harms. Patients at risk of rapid progression of ADPKD include those with Mayo imaging classes 1C, 1D, and 1E even with normal eGFR in younger individuals as well as those with declining eGFR. Attention should be paid to patient age in conjunction with eGFR to ensure a high likelihood that the benefits of tolvaptan outweigh the aquaretic side effects and potential hepatotoxicity. Selection of those at high risk of progression, however, identifies a patient population expected to derive significant benefit from therapy with significant delays in CKD progression.

Disclosures

C.E. Gordon reports receiving research funding from Alexion and Reata and receiving honoraria from Alexion and Otsuka. D.C. Miskulin reports employment with Dialysis Clinic Inc.; receiving research funding from Dialysis Clinic Inc., Reata, Inc., and Regulus Inc.; and serving as an Associate Editor of CJASN. R.D. Perrone reports consultancy agreements with Caraway, Navitor, Otsuka, Palladiobio, Reata, and Sanofi-Genzyme; receiving research funding from Kadmon, Palladiobio, Reata, and Sanofi; receiving honoraria from Otsuka and Sanofi-Genzyme; serving as a scientific advisor or steering committee member for Otsuka, PalladioBio, and Sanofi-Genzyme clinical trials; and other interests/relationships with PKD Foundation and UpToDate.

Funding

None.