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New Options in ADPKD and How to Use them–the PROPKD Score and Beyond

Hansjrog Rothe*

Coburg University of Applied Sciences, Dialysepraxis Weißwasser, Germany

*Corresponding Author:
Hansjrog Rothe
Coburg University of Applied Sciences, Dialysepraxis Weißwasser, Germany
E-mail: [email protected] de

Received date: August 29, 2018; Accepted date: September 11, 2018; Published date: September 17, 2018

Citation: Hansjrög Rothe (2018) New Options in ADPKD and How to Use them–the PROPKD Score and Beyond. J Clin Exp Nephrol Vol.3 No.3: 16. DOI: 10.21767/2472-5056.100067

Copyright:©2018 Rothe H. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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In recent years we have not only learned about new therapy options to slow down cyst growth in ADPKD. PROPKD, a progression score which combines clinical with genetic data, has been validated, which is a tool for the nephrologist in making individual clinical decisions in favour or against (potentially harmful) long-term medications. Patient cohorts have been characterized in whom kidney size remains stable at a certain plateau for years. This article reviews the literature on these new options and discusses possible adjustments of the PROPKD score and treatment options specifically for East Asian patients. Also, a practical concept for the clinic is proposed regarding the best management of CKD patients with ADPKD, making use of the progression score and pharmacogenetic information.


ADPKD; Vasopressin receptor blockers; m-Tor inhibitors; Statins; Cyst growth; Progression score; Pharmacogenetics


Twenty-three years have passed since the identification of the PKD2 gene on chromosome 4 [1] in addition to the PKD1 gene on chromosome 16 which established the genetic correlate of at least two clinically distinct phenotypic progression patterns of autosomal-dominant polycystic kidney disease (ADPKD) in European families. Recent years have brought new insight regarding aetiology and progression as well as intervention studies with rapamycin, everolimus and tolvaptan aiming for slowing down cyst growth with long-term medication. Only for tolvaptan approval was achieved (2015 in Europe), however, its potential hepatotoxic adverse effects are cause for concern in many patients. This increase in treatment options on the one hand and concern about long-term side effects on the other hand means, that nephrologists call for better tools of genetic stratification and progress prediction of ADPKD-associated chronic kidney disease. Recently published trials provide new data in this regard, which will be discussed in this article. Moreover, alternative therapy options and a practical approach to the treatment of ADPKD patients are presented.

Post-hoc analyses of the HALT-PKD studies

Until recently only two different progression patterns had been known, with decline in glomerular filtration rates (GFR) being always linear but with different slopes associated with PKD1 or PKD2 mutations. The recently published [2] post-hoc analysis of the HALT-PKD studies suggest that another criterion plays a role: patient cohorts with non-linear GFR decline have been defined who may maintain intermittent stable GFR plateaus for years.

Characterization of these subgroups in genetic and clinical aspects could open new therapeutic approaches in coming years.

In this post-hoc analysis long-term follow-up data of patients were investigated who had been enrolled in one of the two “Halt Progression of Polycystic Kidney Disease” studies. 494 Patients from study A (younger patients with initially normal GFR) were included and 435 patients from study B (older, GFR already reduced at the start). Availability of progression data over at least 3 years as well as at least 7 GFR measurements per patient were inclusion criteria. In 22% of the younger study A patients and 13% of the older study B patients, periods of nonlinear GFR decline were recorded, in 15.5% and 6%, respectively (studies A and B) these intermittently stable phases without GFR decline lasted for at least 4.5 years. Two thirds of these plateau patients from both studies had weak, so-called “non-truncating” mutations. Clinically, the following differences were noted: In study A, plateau patients had significantly smaller kidney volumes, higher renal arterial perfusion rates, lower albuminuria and body mass indices both at the beginning and at the end of the study period. In study B, plateau patients were older than those with linear GFR decline.

Apart from showing that it is not only the question of PKD1 vs. PKD2 mutations, but also the difference between truncating and non-truncating mutations which carries important prognostic information for the nephrologist, this post-hoc analysis also provided clinical criteria (association of GFR plateaus for several years with lower BMI´s) despite the relatively short duration of the study.

Which ADPKD patients are at risk of an especially rapid decline of their GFR?

In summary of all genetic and clinical factors available at this point, a score was suggested and validated by the initiators of several multi-national ADPKD studies [3], which may assist in making the decision pro or contra additional therapeutic options such as Tolvaptan. This PROPKD score reflects the current literature and will likely be developed further in the years to come.

Tables 1 and 2 summarize the direct signs and predicting risk factors of rapid progression of ADPKD (modified after Muller, Haas and Sayer [4].

Rate of GFR decline ≥ 5 mL/min/1.73 m2 in 1 year
Average rate GFR decline ≥ 2.5 mL/min/1.73 m2 over 5 years
Rate of kidney volume increase (in MRI) ≥ 5% increase of total kidney volume (TKV) per year

Table 1: Direct evidence of rapid progression of ADPKD.

Genetics Truncating PKD1 mutations are associated with more rapid progression than non-truncating ones PKD2 mutations are associated with the lowest progression rates.
Initial kidney size/Mayo classification >16.5 cm in ultrasound may be associated with more rapid progression, depending on the age at presentation. Height adjusted total kidney volume (htTKV) >600 mL/m is associated with rapid progression.
(Mayo-classification: predicted progression based on one-timepoint measurement of htTKV and associated age).
Blood pressure Arterial hypertension, especially before the age of 35 years, predicts a more rapid progression of ADPKD.
Urological complications Early complications such as cyst haemorrhages, loin pain Flankenschmerz, episodes of makrohematurias or cyst infections, especially before the age of 35 years, predict a more rapid progression.
Sex Male ADPKD patients show a more rapid progression than females.
PROPKD Score Model which combines genetic information with clinical ones-first onset of urological complications and arterial hypertension, sex and age. A score >6 predicts end-stage kidney disease before the age of 60.

Table 2: Indirect predictors of rapid progression of ADPKD.

The ratio of PKD1 mutations being truncating or nontruncating may be assumed to be relatively stable in any geographical region. This is reflected by another approach, which should be mentioned here although it is hardly applicable to clinical routine practice: in a computer model, which takes age, sex and the region into account, increase of TKV and GFR (GFR) decline over time may be simulated [5]. As illustrated in (Figures 1 and 2), the parameters are translated into coefficients which need to be estimated for each region. Obviously there seems to be a degree of uncertainty due to unpredictable novel


Figure 1: TKV: Total kidney volume; ΔTKV: 1-year change in TKV; α: Age coefficient; β: TKV coefficient; γ: Female coefficient; δ: Age: LnTKV coefficient; λ: Intercept.


Figure 2: eGFR: Estimated glomerular filtration rate; ΔeGFR: 1-year change in eGFR; TKV: Total kidney volume; β: Ln (TKV) coefficient; λ: Intercept.

How safe is a long-term treatment with tolvaptan? The REPRISE-study

Due to concerns articulated by the US Food and Drug Administration in connection with the approval, a study about efficacy and safety of Tolvaptan treatment in patients with advanced chronic kidney disease (CKD) stages was performed. The results of REPRISE (Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy) [6], a placebo-controlled multi-centre study, have now been published. ADPKD patients with CKD stages 2-4 (mean estimated GFR=41 ml/min per 1.73 m2) were treated with initial doses of either 90 mg or 60 mg Tolvaptan in the morning and 30 mg in the evening over a period of one year. Progression of renal failure was slowed down in the Tolvaptan cohort to -2.3 ml/min per 1.73 m2 (95% confidence interval [95% CI], −2.8 bis−1.9) as compared to -3.6 ml/min per 1.73 m2 (95% CI, -4.1 to -3.1) in the placebo group. The difference between the groups was significant after one year and was estimated in average at 1.3 ml/min per 1.73 m2; 95% CI, 0.9 to 1.7; P value <0.001. Based on these data Torres et al. [7] calculated postponement of kidney replacement therapy by 6.2 to 9 years, provided the long-term Tolvaptan therapy had been started at a residual GFR of 41 ml/ min. They argue, that this is considerably longer than, forinstance, the postponement of kidney replacement therapy achievable by ACE blocker therapy in diabetic nephropathy which amounts to about 2 years. In 5.6% of the Tolvaptan group a (reversible) increase in serum alanine aminotransferase activity was noted, as compared with 1.2% in the placebo group. No case of severe liver failure was recorded.

Life style

As in all chronic diseases, life style factors which the patients can positively influence themselves are tremendously important. This includes salt restriction, high fluid intake of about 3l per day but also all measures of blood pressure optimization (reduction of body mass index, regular exercise, and meditation/relaxation techniques) as well as refraining from smoking. Especially these aspects which require the active input of the nephrologist for continuous motivation highlight his or her role as a person, while score results may in fact be calculated by computer algorithms of artificial intelligence alone [8]. Since increased fluid intake results in suppression of vasopressin this approach is patho-physiologically quite similar to tolvaptan therapy (vasopressin receptor blockade). A recently launched prospective trial aims at exactly this similarity [9]: in a randomized multi-centre trial 180 ADPKD patients with a residual GFR ≥ 30 mL/min/1.73 m2 will be treated with either standard therapy and uncontrolled fluid intake or standard therapy and an individualized, prescribed and controlled fluid intake strictly lowering the urine osmolality below 270 mOsmol/kg.

Other therapy options beyond tolvaptan

There are several papers with reports of successfully slowing down cyst growth in regional patient cohorts using compounds which may be associated with less severe risk of liver damage. Statins [10] need to be mentioned here, Octreotide [11] (in an Italian cohort, positive effect regarding liver cyst growth in ADPKD), or a compound from traditional Chinese medicine called Tripterygium wilfordii (Lei Gong Teng) [12] (Chinese cohort).

Another potentially useful therapeutic approach to slow down cyst growth might be the increase of intracellular calcium concentration, which may be achieved with calcimimetic agents or Saikosaponin-d. At least in an animal model this has been shown to lead to autophagy and subsequently decreased proliferation of ADPKD cells via the CaMKK β-AMPK-mTOR pathway [13]. Since allosteric activation of the calcium-sensing receptor (CaSR) by calcimimetics may be mimicked by gain-offunction single nucleotide polymorphisms (SNP) in the CaSR gene, the SNP rs1042636 is noteworthy in this regard, especially in East Asian patients. It causes a gain of function [14] and the allele frequencies are reversed between Whites/Blacks (arginine) on the one hand and East Asians (glycine) on the other hand. The glycine allele results in a more active receptor molecule, equivalent to about 30 mg of cinacalcet HCl o.d. As Jeong et al. [15] reported in a Korean dialysis patient cohort, rs1042636 is also associated with cinacalcet efficacy in these patients. Therefore, rs1042636 is a potential candidate to further improve the PROPKD score especially in East Asian patients.

Still at the experimental stage is another promising therapeutic approach which aims to utilize the extremely high expression of folate receptors in ADPKD cells: by coupling the mTor-inhibitor rapamycine with folate, much higher local concentrations of the drug within these cells might be achievable as compared with systemic administration of rapamycine alone [16].

For the sake of completeness, it should be mentioned, that Ganetespib [17] has been shown in ADPKD animal models to also slow down cyst growth.

Atypical genetic causes of polycystic kidney disease

Polycystic kidney disease with relatively slow progression to end-stage kidney failure may be due to rare mutations in genes other than PKD1 or PKD2. This was reported by Cornec-Le Gall et al. [18] who found mutations of the DNAJB11 gene in 23 members of wo families. The gene product is involved in the transport of membrane proteins from the endoplasmatic reticulum to the outer cell membrane. Seven patients of this cohort reached end-stage kidney failure at ages between 59 and 89 years. Finally, as anecdotal evidence from my own practice, the case of an 82 year old patient should be reported. She developed acute on chronic kidney failure in-the course of a urosepsis. Apparently, she had never seen a doctor in her entire life, but she reported that she could only sleep on her right side. In ultrasound a huge unilateral polycystic kidney was found which filled up the entire left side of her abdomen. Next generation sequencing of her leucocyte genome showed no abnormalities (un-published data) so that a somatic mutation of her left kidney anlage during embryogenesis needs to be assumed.


Statins, indicated for prophylaxis of coronary artery disease in any case of CKD, may possibly be of additional benefit in ADPKD by slowing down cyst growth. High fluid intake of about 3l per day should be aimed for in ADPKD and should decrease urine osmolality below 270 mOsmol/kg. Patients who can´t reach this threshold and whose PROPKD score is >6 should be considered for long-term tolvaptan therapy. In general, the more severe the polycystic kidney disease is the earlier tolvaptan should be administered, which has already been used successfully (offlabel) in a new-born infant with severe polycystic kidney disease ADPKD [19].

While therapeutic options for ADPKD have increased in recent years so has the need of nephrologists to get new prognostic tools in-order to optimize therapy for each individual patient. The PROPKD score may help for the decision when to start tolvaptan. The CaSR gene SNP rs1042636 could possibly be used to improve the PROPKD score especially in East Asian patients.


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