Introduction

Worldwide recent epidemiological data confirm that autosomal dominant polycystic kidney disease (ADPKD) is the fourth general and the first genetic cause of end-stage renal disease (ESRD), with 7–10 % of ESRD patients suffering from this inherited condition [1–4]. The two recognized causative genes of ADPKD are PKD1 and PKD2, which code for polycystin-1 (PC1) and polycystin-2 (PC2) respectively. Of the total number of pathogenic mutations found in ADPKD patients, PKD1 mutations make up about 85 % of the genetically defined cases, with the remaining 15 % due to mutations in PKD2, though in 5–15 % of patients no pathogenic mutation is found in either of the two genes [5, 6]. The phenotypic expression of the disease and the rate of disease progression are highly variable among subjects, depending largely on the genetic background (PKD1 being worse than PKD2, and truncating mutations worse than non-truncating), but also on other potential acquired conditions (life-style, drugs, additional comorbidities, etc.). In the last decade much effort has been made to reduce the progression of ADPKD [7–11]. However, none of the present therapeutic tools has been clearly demonstrated to substantially change the long-term outcome of the disease [12] and most of these patients continue to reach ESRD within their lifetime.

Since ESRD patients with ADPKD are generally younger and burdened by a relatively lower number of comorbidities in comparison to renal patients affected by other kidney diseases [13], and given the very good results of kidney transplantation (KTx) in ADPKD patients [14, 15], the number of these patients who are listed for or receive a KTx is continuously increasing over time [3].

Hence, nephrologists are more and more involved in facing some key problems related to the handling of ADPKD patients during the long course of the disease, and specifically at the time of programming and after performing a renal transplant in these patients. Most of these issues have been addressed by a comprehensive recent review [16]. However, given the growing interest and the increasing number of published studies on this topic, we think it is worthwhile updating our own knowledge, focusing mainly on the most recently published studies on the subject.

Evaluating the progression rate in the ADPKD patient

When planning renal replacement therapy (RRT) in patients with ADPKD, nephrologists need to know as precisely as possible the timing of disease progression, since some specific procedures need to be performed long before starting any replacement therapy and in particular before performing KTx (see below).

The reduction of glomerular filtration rate (GFR), evaluated in clinical practice using standardized formulas [17, 18], is considered the most reliable marker of the progression of any kidney disease. However, the reliability of estimated GFR (eGFR) has been questioned in ADPKD [19, 20]. Furthermore, it is common experience that the rate of eGFR changes is quite variable not only among ADPKD patients, but also in the same patient during the course of the disease. So the need to find more precise predictors of the time when ADPKD patients will achieve ESRD still remains unsatisfied.

A number of factors encompassing genetic, physical and clinical parameters, have been indicated as possible individual predictors of progression (Table 1) [2, 21–25].

Table 1 Proposed individual predictors of progression in ADPKD
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Recently, the group of CRISP investigators proposed a method for predicting progression in the typical forms of ADPKD, based on the measurement of the height-adjusted total kidney volume (ht-TKV) and the patient’s age. Assuming a starting ht-TKV of 150 ml, they measured its percentage annual increase and stratified patients into five subclasses based on the yearly percent increase: 1.5 % (subclass 1A), 1.5–3 % (1B), 3–4.5 % (1C), 4.5–6 % (1D), or.6 % (1E). The striking result was that the incidence of ESRD after 10 years was 2.4 and 66.9 % in the 1A and 1E subclasses, respectively [26]. More recently, a French group proposed a prognostic model derived from a multivariate analysis which identified four variables (genetic and clinical) which were highly related to the age of onset of ESRD. The authors built a scoring system (0 → 9) giving the following weight to the chosen variables: male gender (one point); hypertension before 35 years of age (two points); urologic events before 35 years of age (two points); PKD2 mutation (zero points); non truncating PKD1 mutation (two points); truncating PKD1 mutation (four points). Having a score ≤3 was associated with an incidence of ESRD before 60 years of age lower than 10 %, while a score >6 was associated with >80 % incidence of ESRD before 60 years in ADPKD patients [27].

Though the predictive power of the latter method seems to be higher than the former one, it has the disadvantage of needing genetic analysis which is as yet limited to only a few centers and still expensive. It is also worth mentioning that efforts directed to looking for reliable marker(s) of ADPKD progression also include proteomic analysis [28]; however, these proposals have not yet been proven superior to the clinical and radiological markers and, more importantly, are costly and as yet performable only in a few specialized laboratories.

From a practical point of view, for an indirect prediction of rapid progression one could also rely on the criteria recently proposed to define the group of ADPKD patients who could have access to new proposed therapies [29].

Clinical issues preceding renal transplant

KTx is by far the best therapy for any ESRD patient and in particular for patients with ADPKD, who are directed to the kidney transplant program more frequently than any other ESRD patients [3, 30]. This, despite the many problems that need to be confronted before listing an ADPKD patient for a KTx. In the following paragraphs, we address the most common problems that nephrologists have to deal with, in the light of the most recent literature and our own experience.

Programming the transplant from a living donor

The transplant community has long been aware that the KTx from a living donor (LD) has a graft outcome much better than that from a deceased donor (DD) [31, 32]. A further advantage of a KTX from a LD is the possibility to perform it before starting dialysis (pre-emptive KTx).

However, in the case of a living related donor exclusion of the presence of the disease in the potential donor is mandatory. The basic diagnostic criteria for ADPKD are based on the radiologic assessment (ultrasonography, US) of the number of renal cysts present in both kidneys, depending on the age of the subject and her/his family history (Table 2) [33, 34]. However, in many borderline cases, in particular in young subjects, the sensitivity of US is relatively limited. Though the diagnostic sensitivity could be improved by the use of computed tomography (CT) or magnetic resonance imaging (MRI) using different cut-offs for the number of cysts, in the case of dubious results it is recommended to perform a genetic diagnosis before proceeding to KTx in an ADPKD patient from a related living donor [25, 35–37]. It should, however, be borne in mind that also genetic analysis has some limitations. In addition to being a labor-intensive and costly procedure, the search for mutations in PKD1 and PKD2 can prove fruitless in up to 15 % of cases [5, 6, 25]. The reason for such a high number of undefined mutations is in great part due to the technical difficulties related to the presence of 6 pseudogenes homolog of the PKD1 gene, to the frequent presence of mosaicism and to the difficult interpretation of the meaning of inframe insertion/deletion mutations of unknown significance, etc. However, it cannot also be excluded that mutations in other not yet recognized genes may contribute to this percentage of genetically undefined cases. Anyway, more advanced tools of genetic analysis, such as next generation sequencing (NGS), could increase the diagnostic power of genetic analysis [38, 39].

Table 2 Radiological criteria for the diagnosis of ADPKD
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In our daily practice, in each proposed living donor genetically related to an ADPKD patient, we perform a precise preliminary radiological study, adding the genetic analysis when the donor age is lower than 40 or at any age if there is some interpretative diagnostic doubt regarding radiological diagnosis. In any case, even if both radiological and genetic tests are negative, in the case of ADPKD patients, we are usually unwilling to accept a living donation from a related donor younger than 25 years unless they have shown themselves to be very motivated and determined, even after in-depth information on the potential risks that the donor could develop a cystic disease later on during his/her life.

Combined liver-kidney transplant

Polycystic liver disease (PLD) is the most common extra-renal complication associated to ADPKD, occurring in over 80 % of patients [40, 41]. Though the number and volume of hepatic cysts usually grow progressively over time, particularly in women who undergo pregnancy or make use of estrogen [42–44], a clinically relevant impairment of liver function is observed only in a very limited number of cases, in contrast to the behavior of the renal function. So, the need for considering a combined liver and renal transplant due to the contemporary failure of both organs is very unusual and mostly limited to the presence of other genetic causes of liver disease (such as Caroli’s syndrome), which are more frequently associated with the recessive than the dominant form of PKD [45–47].

On the other hand, it can occasionally occur that the increase in the mass of liver cysts causes clinically relevant symptoms, due to the interference of the hugely increased liver volume with the function of other organs (Table 3). When the impact of the symptoms is so significant that it largely affects the well-being of the patient and his/her quality of life, it is worth considering a combined liver and kidney transplant, independently of the presence or not of a liver function impairment [48, 49]. As already mentioned, this circumstance is encountered more commonly in women than in men, due to the effects of estrogens in promoting liver cyst growth.

Table 3 Possible clinically relevant effects of increased liver cyst volume
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It is also worth mentioning that some transplant centers suggest a surgical intervention of partial hepatectomy and/or cyst fenestration as the alternative to the combined transplant [36, 50]. However, more knowledge and experience about this approach and on the long-term efficacy of such alternative surgical interventions are needed.

So, the final decision in these critical cases should be taken by a multidisciplinary team (liver and kidney transplant surgeons, nephrologists, hepatologists, anesthetists), taking into account the local expertise in the different surgical approaches.

Intracranial aneurisms (ICAs)

ICAs are a frequent and potentially life threatening complication in ADPKD. Their prevalence is reported to be at least seven times higher in ADPKD patients than the general population, though the reported values are quite different from one center to another (4–41 %), with this variability probably depending on the different indication criteria for screening ADPKD patients [51–53]. The potential rupture of an ICA in an ADPKD patient is often a catastrophic event and it usually occurs at a relatively younger age than in the general population [54]. The main risk factor for an ICA rupture is considered to be a positive family history of intracranial bleeding and the presence of persistent headaches, which are considered to be also the clearest indications to screen an ADPKD patient for an ICA. However, the presence of hypertension, a smoking habit, some occupational conditions (airplane pilots or subway drivers) might be an indication to perform a screening. There is no widespread agreement on the criteria for performing the screening for ICA when an ADPKD patient is put on the waiting list for a KTx, but all centers agree that angiographic nuclear MR (NMR) is the method of first choice to search for ICAs [25, 35, 36]. In our clinical practice, we perform screening for ICAs in all ADPKD patients waitlisted for KTx.

A second point is: which of the found ICAs need to be treated? Most guidelines agree that the need to treat ICAs is dependent on their rupture risk: there is agreement that, in addition to the above mentioned factors which are indications for the screening, the dimension of the lesion (>6–7 mm), the location (posterior at higher risk than anterior), and shape (saccular) can be considered factors to assist the decision-making for intervention or not [25, 36, 55].

Finally, the decision of which type of intervention should be preferred for unruptured ICAs is still not completely clear. In fact, although surgical clipping exposes the patient to a relatively higher operative risk, endovascular procedures (coil embolization) require the use of radiological contrast media, which sometimes can be critical for a patient still not on dialysis. However, taking into account that sometimes the number of ICAs to be closed are multiple, recent studies, though underlining an overall increased operative risk for all these procedures in ADPKD compared to the general population, underscore that coil embolization is the safest procedure [56, 57].

Again, each transplant center should decide the criteria for the screening, the indications and the type of intervention for ICA correction in the ADPKD patient on the KTx waiting-list, according to the local expertise in the field, possibly deciding to refer the patient to another transplant center when appropriate.

Programming nephrectomy

One of the most critical and debated issues in the ADPKD patient who has to be waitlisted for a KTx regards the indications, the timing and the type of a native kidney nephrectomy (Nx). There is general agreement that the removal of one or both polycystic kidneys in ADPKD patients is indicated and should be performed before KTx in the case of relapsing cyst infections, recurrent symptomatic hemorrhagic events, complicated nephrolithiasis and when there is the suspicion of a renal cancer: in all these conditions the choice of removing one or both kidneys will depend on the possibility to precisely define if the causative complication is monolateral or bilateral [25, 58–60]. Recent data suggest also that both unilateral and bilateral native Nx are associated with a better control of hypertension in ADPKD after KTx [61]. Much more complex and subjective is the decision to perform a pre-KTx Nx, when it is judged that there is not sufficient room for the allograft [62]. The decision is particularly critical in the case when a bilateral Nx is planned in a pre-emptive KTx, since this decision will make a temporary dialysis treatment necessary. Moreover, the decision of a Nx before KTx should also take into account the possibility of a regression of the native kidney volume after KTx as described [63, 64].

To maximize the use of native kidney renal function, many transplant centers prefer to perform Nx at the time of KTx, with the choice of removing one or both native kidneys, depending on the native kidney volume and the operative conditions evaluated at the time of the intervention. Though most of the studies sharing this surgical policy agree that the Nx performed simultaneously to KTx is characterized by longer intervention duration, increased need for transfusions and longer hospital stay, they also report at least equivalent long-term results related to the patient and graft outcomes, as compared with either mono or bilateral Nx performed before KTx [65–68].

Which technique is to be preferred for performing the Nx (laparoscopic vs. open surgery) is a further debated issue. A recent systematic review and meta-analysis identified seven studies which included 195 cases, of whom 118 were submitted to a laparoscopic Nx (LN) and 77 to open surgery Nx (ON). Though LN was associated with longer operative time, it was also characterized by a lower need of transfusions, less complications and a shorter hospital stay [69]. As an alternative to native kidney Nx, some centers propose the intravascular embolization of kidney(s) as a valid and effective method even in the long term [70].

In our opinion, the technique to be carried out should be the one which the local surgical team is more expert in and more used to performing.

Clinical issues after renal transplant

Patient and graft outcomes

As already discussed, KTx is considered to be by far the best therapeutic option for the treatment of ESRD in ADPKD patients, since it is associated with optimal outcomes for both the patient and the transplanted organ, which are even better than those observed in all the other cohorts of ESRD who receive a KTx [3, 4, 14, 30, 71–73].

The reasons for this particularly positive post-KTx outcome are not completely clear. A lower age at the time of ESRD and a reduced number of comorbidities could play a role [14]. However, it should also be borne in mind that these patients often benefit from nephrological care long before the achievement of ESRD. This implies a more strict control of the most common comorbidities and explains why ADPKD patients receive a pre-emptive KTx, peritoneal dialysis treatment and an arterial-venous fistula more often than other renal patients. All these factors might contribute to the better outcomes before and after KTx. Incidentally, this should make the medical community reflect on the beneficial effect of early referral to the nephrologist concerning the clinical outcomes of patients affected by any renal disease.

Immunosuppressive (IS) therapy

Though a potential beneficial role of the inhibitors of mammalian target of rapamycin (mTOR) in reducing the cyst growth after KTx has been suggested, there is no clear evidence that such hypothesized effects are relevant [16, 74]. Moreover, since these IS drugs are not free of side effects, their use should be based on strict immunological and clinical indications. In conclusion, the prescription of IS therapy in the transplanted ADPKD patient should follow the rationale used for any other KTx patient.

Renal complications after KTx

Although it has been reported that cyst volume could spontaneously regress after KTx [64], it is common experience that problems related to the increased cyst mass can sometimes heavily affect patient well-being. There is some anecdotal suggestion that somatostatin analogues can induce a regression or at least slow the growth of both kidney and liver cysts [75, 76]. However these drugs, in addition to the fact of not being as yet registered for that use, need to be administered by parenteral route and would be added to the already high burden of drugs which KTx patients take. So, at the present time, there is no strong evidence to support the use of such compounds in ADPKD patients after KTx.

Transplanted patients are more prone to infective complications due to the need of maintaining an immune-suppressed status, so there would be no wonder if cyst infections occur after KTx more frequently in ADPKD than in other groups of renal patients. However, in a survey on a relatively large group of KTx patients, the incidence of the overall number of urinary tract infections, including pyelonephritis, was not higher in ADPK than in the other patients [71]. Anyway, cyst infections when they happen after KTx are often a challenging diagnostic and therapeutic problem. It has been suggested that 18F-fluorodeoxyglucose positron emission tomography–CT (18-FDG PET–CT) can consistently improve the sensitivity and specificity in the diagnosis of cyst infections in ADPKD as compared to CT and MRI [77, 78].

Though some scanty data report on an increased risk for native kidney cancer in ADPKD after KTx [79], most of the available data suggest that the risk for kidney cancer is not different, if not lower, than that observed in all other KTx patients [69, 80]. This could be explained by a more strict diagnostic approach to the native kidneys and a more frequent use of Nx before KTx in ADPKD patients. However, it should be emphasized that the diagnosis of an asymptomatic and small renal cancer can be a challenging problem in a polycystic kidney with the US diagnostic approach, which is the tool most commonly utilized in the clinical practice.

Extra-renal complications after KTx

The main medical complications of KTx recipients fall into the following four categories: cardiovascular (CV) diseases, infections, cancer, and metabolic disease. So, it is worth knowing whether ADPKD patients have a comparable risk for each of these pathologies after KTx.

It is common knowledge, that ADPKD patients have a high number of CV risk factors, including a higher prevalence of hypertension, dyslipidemia, and post-transplant diabetes mellitus [21, 71]. However, CV events have not been found to be higher in ADPKD patients after KTx and their overall mortality has been reported to be even lower than that of other cohorts of KTx patients [14, 15, 71, 81, 82]. Nevertheless, it would be wise that ADPKD patients have a strict control of their blood pressure levels, be strongly encouraged to stop smoking, to increase their physical activity and to consume a low caloric diet.

As mentioned before, ADPKD patients have a number of clinical conditions which could be at risk of infections, such as renal and liver cyst, intestinal diverticulosis, heart valve diseases, etc. Though former reports indicated an increased occurrence of gastrointestinal infections [83], more recent data do not confirm such increased infection risks [71]. However, we should always be aware that some kinds of infection, such as liver cyst infections, when they happen, portray a serious complication in ADPKD. Checking for the changes in carbohydrate antigen 19-9 (CA 19-9), which is secreted by the biliary epithelium lining the cysts, may help in an early diagnosis of a liver cyst infection [84]. In the suspicion of an infectious complication in a transplanted ADPKD patient, a fast and complete diagnostic protocol should quickly be started to locate the origin of the process, starting antibiotic therapy as soon as possible.

We have already dealt with native kidney cancer risk in ADPKD. As far as the risk of other types of cancer is concerned, ADPKD patients not only seem not to have a higher, but an even reduced risk of cancer [71, 80], except for non-melanoma skin cancer which has been reported to be more frequent in ADPKD patients after KTx [85, 86]. So, a reduced and protected exposure to sunlight should be highly recommended to these patients.

Post-transplant diabetes mellitus (PTDM) is one of the most common metabolic complications after KTx and negatively impacts on patient and graft outcomes [87]. There is controversy about whether ADPKD is associated with an increased risk for PTDM or not, with some studies reporting a higher incidence of these metabolic complications [88] and others denying it [71, 89]. A recent meta-analysis [90] included 12 cohort studies, comprising 1379 ADPKD patients out of a total number of 9849 patients who received a KTx. The authors found a relative risk (RR) of PTDM higher in ADPKD than in the other KTx patients, and this result was confirmed also when the analysis was limited to studies where the results were adjusted for the confounders [RR 1.98; 95 % confidence interval (CI) 1.33–2.94]. On the other hand, the number of PTDM requiring insulin treatment was not significantly different between ADPKD and the other KTx patients. These results confirm that ADPKD patients are more prone to develop glucose metabolism derangements, but the clinical weight of these metabolic derangements is relatively mild.

Conclusive remarks

ADPKD is a complex disease characterized by both the involvement of the kidneys, which is the leading clinical problem, and the derangement of many other organs and tissues [91]. The progression of the renal disease is the most common event in these patients and many of them achieve ESRD during their life time. Despite the large number of potential complications, the outcome of KTx is optimal in these patients. So, it is mandatory to consider KTx every time we forecast the upcoming ESRD in these patients, possibly planning the transplant before starting dialysis. To obtain this result, it is important to program in a timely manner any operative decision and this can be done easily if these patients are referred to a nephrologist at an earlier stage during the course of their disease.