First Posted by RFN: February 4, 2019

Updated: November 2020

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited (genetic) kidney disease, affecting 1/400 to 1/1000 live births and is the fourth leading cause of end-stage kidney disease in adults. Both types of ADPKD (1 and 2) typically have adult onset of signs and symptoms. PKD was first described in literature in 19^th century, but the first documented case was in King Leopold of Poland (1532-1582). The underlying genes for PKD1 and PKD2 were cloned in 1995 and 1996, respectively. ADPKD is mainly caused by variants in the PKD 1 and PKD 2 genes, with truncating PKD 1 variants causing the most severe phenotype. The incidence of the PKD 1 mutation, in several large scale global studies, ranges from 75-85% of the affected population. Therefore, the PKD 2 mutation occurs in 15-25% of identified individuals. Spontaneous mutations, both PKD 1 and PKD 2, based on no detectable family history, make up approximately 20% of PKD population.

In ADPKD, cysts are the disease and the mechanism of cyst formation and cyst growth has been an area of intense basic research and clinical investigation. Understanding the pathophysiology of cyst development and growth has the basis for several clinical landmark trials in this field. Here, we will review the more recent major trials which have helped shape our current approach towards management of this disease.

The major limitation in developing an effective therapeutic modality has been that creatinine rises late in the course of disease because of compensatory hypertrophy of viable kidney tissue as growing cysts progressively compress kidney parenchyma. While early sensitive biomarkers for disease progression are currently lacking, height adjusted total kidney volume (htTKV), calculated by the ellipsoid equation, has shown to be a surrogate marker of disease progression, as measured by glomerular filtration rate (GFR). The CRISP (Consortium of Radiologic Imaging Studies of Polycystic Kidney) study started in 2006, and is still ongoing, documented that kidney enlargement, due entirely to cyst growth, in ADPKD is continuous, quantifiable, and associated with the decline of kidney function. The larger the kidney size the more rapid the decrease in kidney function.

Some of the therapeutic strategies studied over the last decade, using htTKV and GFR as end points, are summarized.

1.mTOR inhibitors: There was much enthusiasm among the nephrology community for the use of mammalian target of rapamycin (mTOR) inhibitors for PKD. Data from experimental and observational studies suggested that the mTOR pathway plays a critical role in cyst growth and use of sirolimus or everolimus may slow cyst growth. Everolimus was studied in a 2010 randomized control trial, In a study with 433 patients, it did not show significant benefit on kidney volume or GFR at 2 years and unacceptable side effects of severe aphthous stomatitis were noted.

2. Lower blood pressure (BP) targets: This therapeutic approach was tested by HALT-PKD studies between 2006 and 2014 in 1054 patients with image documented PKD. The HALT A (patients with GFR >60) and HALT B (patients with GFR 25-60) trials studied the utility of lower BP target vs standard BP target and ACE+ARB vs ACE alone in ADPKD patients. The study documented that the lower the mean arterial BP (MAP) BP, on a continum , the greater the beneficial effect on kidney volume growth.  With lower BP, GFR dropped in the short term and recovered or marginally improved in long term. Both left-ventricular-mass index and urinary albumin excretion decreased with lower BP. As expected, dizziness and light-headedness more common with in the low BP group, but not to any significant degree that led to discontinuation of BP medications or dropping out of the study. Dual RAAS blockade was no better than monotherapy , with either ACEI or ARB being equally effective in achieving outcomes. Dual RAAS blockade did not cause hyperkalemia or acute kidney injury.

3. Tolvaptan: Tolvaptan is a competitive antagonist of Vasopressin (V2) receptor. The TEMPO 3:4 trial published in 2012 (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) was the first of the two large randomized control trials to demonstrate some benefit of tolvaptan in slowing PKD progression. In a 3 year study of 1445 patients with total Kidney Volume (tKV) > 750 ml and CrCl > 60 cc/min , use of tolvaptan lead to slower annual increase in kidney volume (2.8% vs 5.5%) and slower decline in kidney function. However, tolvaptan had more adverse events related to aquaresis and elevated liver function tests as well as a much higher discontinuation rate (23%, vs. 14). TEMPO 4:4 confirmed these results after 2 additional years of follow up. However, it was shown that if Tolvaptan was discontinued, cyst growth accelerated to a rate of trajectory noted before this V2 receptor antagonist was started.

REPRISE (Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD) published in 2017, studied tolvaptan in patients with reduced GFR. It demonstrated again the slower decline in GFR with tolvaptan as compared to placebo. This study lead to FDA approval of tolvaptan as the first line treatment to slow renal function decline in ADPKD patients. The long-term effectiveness and its beneficial role in decreasing mortality, progression to end stage kidney disease, and extra renal manifestations of ADPKD are yet to be determined. Tolvaptan has been demonstrated to have a positive impact on decreasing liver cyst growth in those with ADPKD.

Underway is a collaborative study comparing water intake alone to result in a daily urine output that mimics the results in the Tolvaptan trials., attempting to determine if Tolvaptan has a benefit on PKD progression independent of the achieved aquaresis. Additional studies with other drugs for ADPKD are also underway – (metformin, esevatinib, Metformin, Bardoxolone, MicroRNAse-17 inhibitor, Venglustat)

Find the Spanish version of this post here.

Post by: Priti Meena & Nikhil Agrawal

Reviewed by: Theodore Steinman, MD.