Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease.The estimated prevalence is highly controversial and ranges between 1 per 500 and 1 per 2000 people1–4.

Patients with ADPKD make up between 6% and 10%, approximately, of the population on dialysis or with a kidney transplant, being, therefore, a disease with a great social impact5,6. It is characterized by the progressive development of renal cysts that usually lead to end-stage CKD (ESRD), generally in adulthood. It is also associated with systemic manifestations, such as high blood pressure (HBP), intracranial aneurysms (ICA), polycystic liver disease, valve abnormalities and cysts in other organs. During the last 3 decades there have been great advances in the knowledge of the disease. In the mid-1990s, the genes that cause ADPKD were identified: PKD1 and PKD7,8. Other genes that cause autosomal dominant cystic nephropathy have been identified that clinically differ from ADPKD (GANAB, DNAJB11)9,10. PKD1 and PKD2 encode polycystins 1 and 2, which are located in the primary cilium11. Molecules that are overexpressed or deficient in polycystic cells are now potential therapeutic targets, so that there are currently several drugs under study as treatment for the disease. The therapeutic use of tolvaptan was approved In 2014, in Japan and in 2015 in Canada and Europe. It was approved for the treatment of patients over 18 years of age with ADPKD stages 1–3 and with signs of rapid progression. In June 2018, the European Medication Agency (EMA) extended the indications of tolvaptan to patients with ADPKD stages 1–4 at the initiation of treatment and withevidence of rapid progression (https://www.ema.europa.eu/en/documents/procedural-steps-after/jinarc-epar-procedural-steps-taken-scientific-information-after-authorisation_en.pdf) and in the same year it was approved in the United States for adults with rapidly progressing disease without defining the stage of CKD at the start of treatment12,13. There are a limited number of prospective randomized controlled trials, as well as clinical studies that incorporate an experimental design for the diagnosis and management of ADPKD. Such studies are difficult to perform due to the relatively low number of patients in each center, as well as the heterogeneity of the clinical presentation of the disease. The consensus recommendations in these clinical guidelines are based on a search of the literature and, to a large extent, on the experience and opinions of the authors. The Cochrane Library, MEDLINE, and the Systematic Reviews database (up to July 1, 2019) have been used to collect the ublications. We using the search terms ‘ADPKD’ or ‘polycystic kidney’ in combination with the terms ‘diagnosis’ or ‘imaging’ or ‘gene’ or ‘HTN’ or ‘CKD’ or ‘chronic kidney disease’ or ‘chronic renal failure’.” or “ESRD” or “end-stage kidney disease” or “dialysis” or “transplant” or “infection” or “pain” or “liver” or “aneurysm” or “cancer” or “pregnancy” or “children” or “tolvaptan”. To a large extent, we selected publications from the last 10 years, but relevant older publications were not excluded. The recent KDIGO (Kidney Disease Improved Global Outcomes) in ADPKD14 have been especially taken into account. The reference lists of the identified articles were also reviewed and those deemed relevant were selected. Review articles are cited to provide readers with more detail than that provided in these guidelines. The authors have tried to make this guide concise and very practical and, standardize, as much as possible, the care of patients with ADPKD.

The authors are members of the Hereditary Kidney Diseases Working Group of the Spanish Society of Nephrology. They sign the guides in alphabetical order, except the last author. The authors reached a consensus on the recommendations and considered that the benefits outweighed the potential risks. The document has been submitted to public review by the members of the Spanish Society of Nephrology. The levels of evidence are mostly low: levels C and D according to the Center for Evidence-Based Medicine (Oxford University) (http://www.cebm.net/?o=1025). These guidelines address the following aspects of the disease: diagnosis, hypertension, pain, assessment of kidney disease progression, end-stage kidney disease, polycystic liver disease, ICA, other extrarenal features, specific treatment of the disease, and ADPKD in children. The initial version of these guidelines was published in 2014 and updated in 201715.

Since ADPKD is an autosomal dominant disease, children of affected parents have a 50% chance of developing the disease. Due to its high penetrance, it is highly unlikely to skip a generation. Currently, ultrasound is used to detect and diagnose the disease in people with an affected family member. The diagnosis of sporadic cases, which represent ∼10% of patients, is based on the clinical characteristics of the disease, but sometimes a genetic study is necessary, especially in the early stages of the disease. ADPKD must be distinguished from other causes of renal cysts such as simple cysts, autosomal recessive polycystic kidney disease, nephropathy due to HNF1B mutations, and other cystic kidney diseases (Table 1). In an adult, the presence of enlarged cystic kidneys, a decreased estimated glomerular filtration rate (eGFR), hypertension, and liver cysts is highly indicative of ADPKD. But often, not all of these clinical features are present and diagnosis becomes more complicated. In these cases, the genetic study is very useful.

Early diagnosis in adults may improve cardiovascular (CV) risk factors and allows the consideration of a specific treatments to modify disease progression.

The advice or GC, according to the Biomedical Research Law (LIB 14/2007)39, is “the procedure intended to inform a person about the possible consequences for him or his offspring of the results of a genetic analysis or screening and its advantages and risks, and, where appropriate, to provide an advise in relation to the possible alternatives derived from the analysis”. Ideally, the GC should be provided by multidisciplinary team in which all the agents and specialists involved interact (including clinical and molecular geneticists, bioinformaticians and genetic counselors).

One of the objectives of GC is to prevent the patient or family regarding reproductive decision-making. During the GC process, the patient should be informed about the options available to him, but in no case should be advised about the decision to be made.

In terms of reproductive decisions, the possibilities for a patient with ADPKD in our country are the following: 1) assume a 50% chance of having an affected child; 2) selection of embryos by preimplantation genetic testing (PGT); 3) prenatal diagnosis; 4) gamete donation; 5) adoption, and 6) give up having offspring. Under no circumstances we may give directions to reach a decision and never judge the patient for the decision made.

The PGT is an assisted reproduction technique that includes a genetic diagnosis of the embryos and the selection of disease-free embryos to be transfer to the mother’s uterus. The PGT for ADPKD is approved by the National Commission for Assisted Reproduction. One of the advantages of PGT over prenatal diagnosis is that it avoids the termination of pregnancy. However, it has drawbacks such as the need to identify the causal sequence variant (not feasible in 10% of cases), an in vitro fertilization process (hormonal treatment not recommended in women with significant polycystic liver disease), the pregnancy rate it is approximately 40%, it has a high economic cost, it can be ethically questionable (especially in mild cases) and it is associated with a significant physical and psychological impact, especially for women.

Women with ADPKD who have kidney failure or hypertension may have an increased risk of developing preeclampsia and fetal loss during pregnancy due to their CKD, but it has not been specifically studied whether having ADPKD is an additional risk51. Pregnancy is not contraindicated in normotensive women with normal renal function. Special attention should be paid to those women who receive treatment with estrogens or progesterone, because polycystic liver could be aggravated14.

Urinary tract infections should also be monitored due to an increased predisposition during pregnancy80.

In ADPKD the renal carcinoma is not more frequent than in other populations with CKD, but it may be more difficult to make the diagnosis52,53.

The main causes of acute pain are pyelonephritis, cystic infection, cystic hemorrhage, and urolithiasis54,55. Both kidney and liver cysts may be symptomatic. Hemorrhage or rupture of cysts usually presents as acute pain that may be accompanied by macroscopic hematuria and/or anemia. Cystic infection presents with fever and lower back or abdominal pain. Imaging tests may help in the differential diagnosis of the causes of lower back or abdominal pain and in locating the infected cyst. The indications and limitations of the different imaging techniques in patients with ADPKD with pain, fever or bleeding are summarized in Table 556–58. When cystic infection is present, urine and blood culture may be negative, which make a confirmatory diagnosis difficult; in which case, it would require identification of the cyst, puncture, and a positive culture of the content. Given this difficulty, an operative definition of probable cyst infection has been proposed (recommendation 2B) and some authors add the absence of evidence of recent intracystic bleeding on CT without contrast56,58–61. However, the coexistence of infection and hemorrhage is possible. A recent international Delphi consensus endorsed this approach, suggesting that increased C-reactive protein (CRP) can be replaced by a leukocytosis greater than 11,000/μl and including a list of 18 items that increase diagnostic suspicion if routine tests failto identify another cause to explain the signs and symptoms. The diagnosis would be confirmed after image localization of the infected cyst62.

Treatment of cystic hemorrhage is generally symptomatic. Improvement has been reported with tranexamic acid, an antifibrinolytic agent, but there are no controlled studies available63.

Empirical treatment of cystic infection should cover the most frequent causative germs, enteric gram-negative bacteria, with antibiotics that penetrate well into cysts, such as quinolones64. Cystic penetration of meropenem is low, with intracystic levels 10 times lower than in plasma65. Increased levels of circulating CA19.9 have been described in patients with liver cyst infection66, but also in patients with ADPKD in general (mean values 3 times higher than in controls and higher in patients with large liver and higher values of gamma glutamyl transpeptidase [GGT])67. A 20–36% of ADPKD patients have urolithiasis, which can also cause acute pain. Uric acid stones are more common than calcium oxalate stones68. Predisposing factors include hypocitraturia, hyperoxaluria, hypercalciuria, hypomagnesuria, possible distal acidification defects, and, above all, urinary stasis due to compression of the collecting system by cysts. Potassium citrate is the treatment of choice for uric nephrolithiasis, calcium oxalate nephrolithiasis due to hypocitraturia, and distal acidification defects. The KHA-CARI guidelines recommend using CT without contrast to confirm the diagnosis of nephrolithiasis (1B) and, if identified, perform a metabolic study (1C), and correct the defects if possible (2D)69. Dual-energy CT differentiates uric acid stones from those containing calcium14.

Several clinical guidelines and documents have recently addressed the treatment of chronic pain14,70. The main causes of it are the increase in the size of the kidneys or the liver. Various invasive procedures have been reported in the literature for pain control if medical treatment fails, generally in case reports or small case series (reviewed in Chapman et al.14). These include celiac plexus block, radiofrequency ablation, spinal cord stimulation, and various forms of denervation (thoracoscopic sympathoplanknicectomy, laparoscopic renal denervation, and transluminal catheter denervation) and even nephrectomy, especially if the patient is already on renal replacement therapy. The KHA-CARI guidelines recommend evaluating chronic pain and involving the patient in the pain management, initially emphasizing non-pharmacological treatment (both 1D) and suggest surgical decortication of cysts if pain is severe and sustained (2C)70. A recently described denervation protocol improved chronic pain in 81% of a total of 44 patients. As a diagnostic maneuver, a temporary celiac plexus block is performed; If pain recurs after initial improvement, radiofrequency ablation of the celiac plexus is performed. If the pain does not improve, renal denervation is performed with a catheter71. In a preliminary study, renal catheter denervation reduced chronic pain in a mixed group of patients (n=11) that included patients with ADPKD72. A recent concept is the prevention of pain; the phase 3 randomized controlled trial TEMPO 3:4 study observed a 36% decrease in the incidence of pain episodes (secondary endpoint) in patients treated with tolvaptan, which was attributed to a lower incidence of urinary tract infections, stones and hematuria12. However, prevention of pain is not, by itself, an indication for tolvaptan at this time. Tolvaptan is discussed extensively in the ADPKD-specific treatment section.

The course of ADPKD is highly variable and not all patients progress to ESRD. Renal survival is affected by non-modifiable factors such as age, gender, the affected gene and the type of mutation, and by modifiable factors such as hypertension, proteinuria and others5,73.

The mean age at the start of renal replacement therapy (RRT) in patients with ADPKD is lower than in patients without ADPKD, and survival is longer.

Kidney complications can persist even after advanced or end-stage CKD but rarely lead to serious problems. In cases of uncontrollable frank hematuria, infection of a cyst or a large renal volume, nephrectomy would be considered.

CV disease is the main cause of death73.

Among the different dialysis modalities, it has been suggested that peritoneal dialysis is a reasonable option, offering a better prognosis and quality of life to patients with ADPKD than to those who do not carry this disease as a cause of CKD74,75. This modality should not be denied due to the mere existence of cystic nephromegaly76. However, in patients with very large kidneys or livers, the lack of space may restrict the area available for peritoneal exchange and increase the chances of hydrothorax and abdominal hernias. In these cases, hemodialysis should be considered as the best option. The same could be said for those patients with recurrent diverticulitis.

Kidney transplantation in ADPKD is the best RRT option. It has similar results to other non-diabetic patients5,73 and ADPKD is not a risk factor for the development of post-transplant diabetes77.

The main difference lies in the need to assess the existence of ICA and to decide whether to perform nephrectomy of a native kidney78 to leave the necessary space for a kidney transplant. There is not enough evidence about whether nephrectomy of the native kidney should be performed before transplantation or simultaneously in the act of transplantation79. Laparoscopic nephrectomy is a good option, as long as the center has experience in this type of surgery.

Preventive kidney transplantation from a living donor shows a better evolution.

Although the use of mTOR inhibitors has been suggested to reduce TRV after kidney transplantation, there is insufficient evidence to recommend their use as first-line treatment in patients with ADPKD.

Polycystic liver disease is the most common extrarenal manifestation. It occurs in up to 90% of patients older than 35 years81. It is defined as the presence of at least 20 simple cysts in the liver. Liver cysts usually appear later than renal cysts and are very variable in size.

The main risk factors for the development of liver cysts are age, female gender, multiple pregnancies, the use of estrogens, hormone replacement therapy or contraceptives83. Liver volume tends to decrease or not increase in women after 48 years of age, thus highlighting the importance of the hormonal role in the development of cysts81,82.

Most patients remain asymptomatic and only a small proportion (20%) develop massive liver disease. The main symptomatology derives from hepatomegaly, which can cause extrinsic compression of the thoracic and abdominal organs: abdominal distension, abdominal pain, gastroesophageal reflux, early satiety, nausea and vomiting, dyspnea, orthopnea, hernias, uterine prolapse, rib fractures, malnutrition, loss of muscle mass, back pain, venous obstruction (hepatic, inferior vena cava, portal), bile duct obstruction and others. Abdominal pain is usually the most frequent manifestation. The liver parenchyma is preserved despite the growth of liver cysts, so it is rare that they cause liver failure. Bile duct involvement is a serious complication that can occur in patients with ADPKD and must be taken into account in all patients with abdominal pain. It is more common in males. Bile duct dilation has been described in 17–40% of patients84.

The biochemical alterations that we can be observed are: elevation of alkaline phosphatase and GGT. Bilirubin levels are usually normal but can be elevated by compression of the bile duct by a cyst. CA19.9 levels are elevated in up to 45% of patients with polycystic liver disease and correlate with liver volume83 and has been proposed as a biomarker of hepatic cyst infection, since its levels tend to rise during this process and fall with its resolution66. It can also be elevated: CA125, CEA and AFP.

Early detection of polycystic liver disease does not provide advantages over a possible therapeutic intervention since only severe symptomatic cases are treated.

The indication for treatment is established when the patient presents severe symptoms, most of them derived from the compression of adjacent structures by hepatic growth. Therefore, the goal of treatment is to reduce liver volume.

Women should avoid taking oral contraceptives or hormonal therapy with estrogens to prevent the growth of cysts.

There are options of medical and surgical treatment. The interventional treatment options and the results are summarized in Table 6. Regarding medical treatment, somatostatin analogs (octeotride and lanreotide) are the only drugs that have been shown to modify the natural course of the disease. According to clinical trials somatostatin analogs may reduce liver volume by 6% reduction during 1–3 years85–87, but studies are needed to demonstrate long-term efficacy.

In animal models, a new somatostatin analog, pasireotide, is more powerful and effective than the current ones88. In general, they are well tolerated, but lose their efficacy after discontinuation. At the moment, they have not been approved by the EMA and can only be used in the context of a clinical trial or for compassionate use in highly symptomatic patients89.

The mTOR inhibitors have not been shown to be effective alone or in combination with somatostatin analogs. Ursodeoxycholic acid has been investigated as another possible therapeutic alternative, without definitive results so far. TGR5 antagonists are also being investigated84.

The efficacy of tolvaptan on liver cysts is not well characterized. It could act on the V2 receptors of the cholangiocytes, reducing the levels of AMPc and, therefore, the proliferation of the cysts. There are only 2 cases in the literature in which tolvaptan reduced liver size.

Polycystic liver disease can cause acute complications, such as cystic infection or bleeding. The infection is clinically characterized by abdominal pain in the right hypochondrium together with fever. Generally they are monomicrobial. The most common germs that cause infection are gram-negative bacilli (eg, Escherichia coli). Its route of entry is retrograde through the bile duct. Laboratory tests revealed leukocytosis, elevated erythrocyte sedimentation rate, CRP, elevated bilirubin, liver enzymes (GOT, GPT), GGT, and alkaline phosphatase.

The determination of CA19.9 has been proposed as a biomarker of hepatic cyst infection since its levels tend to rise during this process and fall with its resolution66.

Diagnosis is usually made by CT or MRI, but the most sensitive diagnostic tool for cystic infection is positron emission tomography after administration of 18-fluorodeoxyglucose (PET-FGD)58,90.

Intracystic bleeding is rare. Symptoms can be very similar to those of an infected cyst, although fever is rare. Abdominal pain is usually more intense. Diagnosis is made by CT or MRI. Treatment is based on the administration of analgesics.

Cyst rupture is rare and can cause acute abdominal pain and ascites. Treatment is symptomatic.

Another very rare complication is recurrent episodes of cholangitis91.

The prevalence of ICA in patients with ADPKD is around 8–12%, 5 times higher than that of the general population92–97. The mean age at rupture is 41 years; about 10 years earlier than in the population without ADPKD97. The most determining risk factor for having an ICA is a positive family history for ICA and/or subarachnoid hemorrhage (SAH), which is associated with a prevalence of 20–29% compared to 6–9% in those without a history94–97.

Clinically, ICA of ADPKD are generally asymptomatic, 85% are located in the anterior circulation and the measure is less than 7mm, and may be multiple in 20% of cases. The rupture of ICA causes SAH, the most serious complication of ADPKD. It is characterized by the appearance of sudden and intense headache, sometimes accompanied by loss of consciousness, it may cause death (30–60%) or severe disability (30%)98,99. The risk of rupture correlates with the size of the aneurysm and with the existence of a family history of ICA and/or HSA, but also with the location, the presence of an aneurysmal sac, tobacco consumption, the existence of hypertension, cocaine, the use of estrogens or anticoagulants92,96,98,100,101. Death due to neurological causes accounts for 11% (6% aneurysm rupture, 5 % cerebral hemorrhage) of the causes of death in ADPKD, behind cardiac causes (36%) and infections (24%). The risk of intracranial hemorrhage is 3 times higher in patients with ADPKD on RRT than in non-ADPKD, and the greatest difference is seen in patients on hemodialysis.

Gadolinium-free MRI is the technique of choice for diagnosing ICA as it avoids the iodinated contrast of CT angiography. There is agreement on the indication of preventive screening in patients with a family or personal history of ICA or SAH14,96,101. The rate of de novo aneurysm formation in patients with negative prior screening has been estimated at 0.32 (95% CI, 0 to 0.68) per 100 patient-year96. In patients with a positive family history and negative results, it is recommended to repeat the screening after 5 or 10 years96,101,102.

The treatment of ICA should be assessed by multidisciplinary teams with neurosurgeons and interventional radiologists from experienced centers. If cause symptoms they should be treated; asymptomatic patients always require follow-up and, depending on the case, intervention based on their characteristics (Table 7). The PHASES score is useful to assess the risk of rupture103,104.

Conservative treatment is desirable in polycystic patients with aneurysms <7mm of the anterior circulation. Although the risk of growth is low, initial radiological follow-up is recommended every 3–6 months, delaying it to annual and every 2–3 years once its stabilization is observed2,94,95,105. Treatment is not innocuous and iatrogenic events are more frequent in ADPKD than in the general population, both for neurosurgery (11.8% vs. 6.4%) and for interventional radiology (9.4% vs. 3%)106.

It is important not to forget the modifiable factors to reduce the risk of the appearance and growth of aneurysms in the general population and in ADPKD (smoking cessation, BP control and CV risk).

In general, universal screening for ICA is not recommended14,96,101,105 and it is indicated only in cases with a family or personal history, professions with risk, preparation for major elective surgery and patient anxiety despite adequate information (Table 7). Kidney transplantation is a major elective surgery, however there is no agreement on prior screening for ICA.

The indication, timing and frequency of screening for aneurysms is a matter of debate. Some authors propose universal screening based on the difficulty of obtaining a good family history, the non-negligible presence of aneurysms in cases with no history, and a higher rate of rupture in some series than the usually described108. The decision to perform universal screening depends on the accessibility of screening methods, the incidence of ICA and its rupture, the consequent morbidity and mortality, the possible therapeutic actions and their results. The selection of the groups studied is also decisive, and it is possible that in some subpopulations such as the Japanese and Finnish the risk is higher96,101.

Flahault et al.96 exhaustively review their experience at the Mayo Clinic and the information available, analyzing with particular attention the rate of aneurysm rupture per 100 patient-years in published series94,95,102,107 and in a group made up of 6,095 polycystic patients from clinical trials, without image screening, with clinical follow-up of 19,400 patient-years.The study confirms the importance of family history, highlighting the history of SAH as having more importance than the presence of ICA, although the majority (>60%) of patients with ICA did not have a family history. The rate of aneurysm rupture, in patients without prior screening, is 0.04 per 100 patient-years (95% CI, 0.01 to 0.06) and the indication for screening is reaffirmed, restricted to cases with family history according to Table 7. However, clinical trials usually recruit patients with more preserved kidney function and both the incidence of ICA and SAH increases with the progression of kidney disease, being higher in haemodialysis. Thus, in the REPRISE trial, which included patients with poorer renal function, the incidence of rupture was 0.19 per 100 patient-years (95% CI, 0 to 0.40).

Most of the clinical manifestations (renal and extrarenal) of ADPKD occur during adulthood. However, the disease is already present at birth and can be diagnosed in children, newborns and even fetuses109.

The KDIGO Guidelines14 and the international radiological consensus for cystic kidney diseases in children110 address the diagnosis of ADPKD in Pediatrics:

• –There are no specific radiological criteria for children. The Pei criteria were derived from patients older than 15 years and have low sensitivity in younger children.

• –In children under 15 years of age with a positive family history, the presence of a renal cyst, nephromegaly, or both should be considered highly indicative of ADPKD. Routine genetic testing is not recommended, since there is no specific treatment, directed at the pathogenesis of cysts, approved in children (see indications for genetic testing).

• –In the absence of a family history of ADPKD, and also in the absence of other data suggestive of a different cystic disease, the presence of large kidneys with cysts is indicative of ADPKD. An ultrasound should be performed on the parents and grandparents (especially if the parents are under 40 years old) and if they do not have the disease, a genetic study is recommended.

In ADPKD, large, hyperechoic, and even cystic kidneys may (although not necessarily) be seen prenatally. However, the main cause of prenatal bilateral renal hyperechogenicity is abnormalities in the HNF1B gene111.

In pediatric ADPKD we distinguish 2 presentations:

• 1

  Children with early symptoms (less than 2% of children): large, hyperechoic kidneys with multiple cysts are already evident in prenatal ultrasounds. Clinically, they present renal failure and hypertension in the first months-years of life and may be clinically indistinguishable from autosomal recessive polycystic kidney disease. This includes children with Potter sequence and significant perinatal/neonatal morbidity and mortality. Severe and early forms of ADPKD are usually caused by mutations in multiple genes causing cystic kidney disease, and hypomorphic PKD1 alleles 33 may occasionally be involved (seesection on genetic diagnosis). In general, children with enlarged kidneys on ultrasound tend to have more clinical manifestations than children with normal-sized kidneys109.

• 2

  Asymptomatic children with early diagnosis: here we would include children with a family history of ADPKD and who present a cyst in the prenatal ultrasound or in the first months of life. The vast majority of these children will be asymptomatic throughout their childhood years and will present with CKD in adulthood. However, it has been suggested that they have a worse prognosis than those diagnosed later in life109,112,113.

Most affected children have few or no symptoms during childhood, although some may develop renal cysts, hypertension, macroscopic hematuria, abdominal pain, abdominal mass and, less frequently renal failure112,114–116. Low birth weight per se may predispose to an earlier onset of ESRD in patients with ADPKD117.

Routine ultrasound screening of asymptomatic children with one parent affected by ADPKD remains controversial, given that there is no specific approved treatment in children under 18 years of age and, furthermore, a normal ultrasound result could be falsely reassuring. It is desirable not to carry out unnecessary examinations but since ADPKD begins in childhood, it is important to identify early risk factors for disease progression that can provide us with the greatest potential for effective early intervention. The main one is hypertension, which, although infrequent, may appear in childhood.

A prevalence of hypertension is estimated at around 20% in children and young adults (up to 21 years of age) with ADPKD118. The ABPM indicates a rate of HTN of 31, 42, and 35% during the day, night, or 24h, respectively. At the time of ABPM determination, 95% of the children had normal renal function119. These percentages are probably overestimated due to a severity bias in the pediatric cohorts. There is evidence that in children with ADPKD, borderline hypertension can increase left ventricular hypertrophy, reinforcing the need for optimal control120.

The ACE inhibitors offer a potential benefit for reduce CV function deterioration and the loss renal function over time in children with borderline hypertension (BP inthe 75th and 95th percentile)121.

Extrarenal manifestations are exceptional during the pediatric age.

The recommendations in the pediatric age are based on a fundamental fact: we do not have a specific treatment (aimed at the pathogenesis of the cysts) approved in children. The recommendations will be different when we have a specific treatment approved for children.

In 2015, the EMA approved the use of tolvaptan, a vasopressin V2 receptor antagonist, expressed mainly in the distal nephron and collecting duct, to slow down cystic development and the progression of kidney disease. This medication is indicated in adult patients with ADPKD in CKD stages 1–4 with evidence of rapid progression (see section Recommendations for assessment in ADPKD progression). Tolvaptan decreases cAMP levels in cystic cells and reduces fluid secretion into the cyst as well as cell proliferation. We cannot exclude the possibility that tolvaptan has other additional mechanisms of renoprotection, through effects on renal hemodynamics (glomerular hyperfiltration or anti-inflammatory effect). The goal of tolvaptan treatment is to maintain an inhibition the action of vasopressin on V2 receptors. Tolvaptan administration should always be associated with classic renoprotection measures such as changes in lifestyle, BP control, preferably with RAAS blockers.

Several randomized studies with more than 1,000 patients have shown that tolvaptan reduces the increase in total renal volume (TRV), improving symptoms caused by TRV, such as pain. In the TEMPO 3:4 study (1445 patients aged 18–55 years with Ccr≥60ml/min and TRV≥750ml with a duration of 3 years) the growth of TRV was reduced by 49% and the drop in eGFR measured by the inverse of plasma creatinine was also reduceby 26% as compared to placebo12. An extension of this study, TEMPO 4:4, showed persistence of these positive effects, especially on eGFR, in such a way that the earlier start of tolvaptan was associated with better conservation of GFR122. In patients with more advanced CKD, stages 2–4 and aged between 18–65 years, the REPRISE study showed a 35% reduction in the drop of GFR after one year of treatment with tolvaptan (2.34 vs 3.61ml/min /1.73m² in the group treated with tolvaptan vs. placebo)13. Other studies have reported a sustained and cumulative effect of tolvaptan up to 11 years later123. The impact of tolvaptan on eGFR loss is, in percentage terms, similar to that of RAS blockade in other kidney diseases.

A careful selection must be made of those patients who are candidates to start treatment with tolvaptan, assessing contraindications, adverse effects and the patient’s lifestyle, so the decision must be made jointly (Assessment of rapid progression in ADPKD section).

Among its adverse effects, 65%–95% of patients who start treatment with tolvaptan present water diuresis122, so patients must have easy access to water and maintain a consistent liquid intake. As a consequence, some patients may present hypernatremia, so it is important to insist on the need to drink water when thirsty, including at night if they get up to urinate, and monitor this parameter during treatment. A variable percentage of patients are unable to tolerate polyuria and abandon treatment.

There is a special control call for idiosyncratic hepatotoxicity, rare, but with the possibility of serious liver damage. In order to monitor this effect, transaminases and liver function tests should be monitored monthly during the first 18 months of treatment and every 3 months after 18 months (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002788/WC500187921.pdf).

There are clinical situations that must be taken into consideration when starting treatment with tolvaptan, such as the presence of a history of hyperuricaemia-gout, the use of diuretics, diabetes mellitus or urinary problems that prevent a high urinary flow. Such conditions can potentially be worsened by the use of tolvaptan. Tolvaptan (Jinarc®, Otsuka Pharmaceutical SA) should be given twice a day. The morning dose at least 30min before breakfast and the second dose 8h later with or without food. The dose regimen will be:

• –45mg+15mg

• –60mg+30mg

• –90mg+30mg.

After the initial dose, the dose will be escalated until reaching the maximum of 120mg/day. This dose escalation and at the discretion of the nephrologist can be done between 1 and 4 weeks. Patients should be maintained on the highest tolerated dose of tolvaptan.

It is recommended to evaluate urinary osmolarity, in the first urine of the morning (before the morning intake) to confirm tolvaptan intake and the achievement of its objective in those patients at the beginning and follow-up of treatment with tolvaptan. A reduction below 275–295mOsm/kg is considered ideal in most cases, although in those patients in an early phase of ADPKD, it could be considered a reduction of up to 200 mOsm/kg, more sensitive to aquaretic effects of tolvaptan. There is controversy about titrating the dose of tolvaptan based on urine osmolarity. According to American recommendations124, the goal of treatment would be to achieve a urinary osmolarity of less than 280mOsm/l in the first morning urine, before the morning dose. Therefore, if this is achieved with the minimum dose of tolvaptan, it would not be necessary to continue escalating the dose, facilitating tolerance. However, although it seems reasonable to look for ways to individualize the dose, several considerations must be made and in fact Chebib et al.124 suggest that more studies are needed in this regard:

• a

  Urine osmolarity was not used to guide tolvaptan dosing in clinical trials, therefore, dose adjustment based on urine osmolarity has not been tested in a clinical trial and should be considered experimental.

• b

  The goal of tolvaptan treatment is to maintain a continuous inhibition of the action of vasopressin on V2 receptors. If increasing the dose leads to a greater increase in urine osmolarity, this implies that the V2 receptors were not sufficiently blocked with the previous dose.

• c

  In ADPKD there is a progressive defect in the ability to concentrate urine (partial resistance to ADH, partial nephrogenic diabetes insipidus), a phenomenon common to all advanced CKD but magnified in ADPKD by the presence of cysts that distort renal architecture and limit the ability to form an adequate corticomedullary osmolar concentration gradient. As a consequence, these patients may have high ADH levels despite, and precisely because, they have polyuria with low urine osmolarity. That is, in a given patient it may be difficult to distinguish low but not very low urine osmolarity because a reasonable degree of V2 receptor blockade has been achieved or because the patient has an inability to concentrate urine due to ADPKD and, as consequence, they have estimulation of ADH, with persistent activation of V2 receptors.

• d

  The main argument in favor of adjusting the dose according to urinary osmolarity would be to facilitate clinical tolerance by limiting the aquaretic effect; the tolerance to aquaretic effects is usually lower when the eGFR is more conserved, since patients usually start with a smaller volume of diuresis (having not yet developed the inability to concentrate urine) and have a greater diuretic response, given their higher eGFR. In this sense, the discussion of the magnitude of the symptoms with the patient could guide the dose adjustment to improve tolerance.

Tolvaptan is the only ADPKD medication that modifies progression of the disease and it approved by the EMA for ADPKD. Based on the aforementioned clinical variability and the inclusion criteria of clinical trials, the current indication for tolvaptan according to the EMA is “The treatment of adults with ADPKD G1-G4 with evidence of rapid progression of the disease” (https://www.ema.europa.eu/en/documents/product-information/jinarc-epar-product-information_en.pdf; accessed 21 Aug 2019). The EMA does not specify what it considers rapid progression. The EMA indication does not clarify what is considered as rapid progression.

To adequately define rapid progression, it is necessary to understand the clinical history of the disease, which, on average, is 6 decades. Thus, in ADPKD patients the renal function remains normal during the first decades of life despite the growth of the TRV. So at this stage it is especially useful to assess the TRV to determine the prognosis125. The clinical spectrum of polycystic disease is broad; there are patients who only develop a limited number of bilateral cysts, which are unlikely to lead to loss of renal function and require renal replacement therapy, while at the other extreme there are severe neonatal forms of the disease.

Therefore we recognize 2 situations:

• a

  The patient who is already losing eGFR rapidly.

• b

  The patient who is still in the initial stage of apparent stability of renal function during the first decades of life but with data that predict a rapid progression of CKD. These data may be a prediction of rapid progression based on genetic and clinical data or a finding that rapid progression is already occurring subclinically in the form of a rapid increase in TRV. The identification of risk factors for the rapid progression of CKD will make it possible to start early treatment in high-risk patients and start it before the stage of rapid loss of eGFR is achieved.

An additional problem is what is considered a rapid progression from the point of view of eGFR. There is a KDIGO consensus definition: loss of more than 5ml/min/1.73m²/year of eGFR. But this definition seems too strict for patients with ADPKD, which has a long natural history of disease (60 years). In fact, the mean GFR loss in the placebo group in the tolvaptan clinical trials was 3.6–3.8ml/min/year. To be practical, all those patients who need RRT before the average age of starting RRT in Spain, that is, around 65 years, can be considered that progresses rapidly.

The main risk factors for progression of CKD in ADPKD are genetic, VRT and hypertension. Genetic factors depend on the mutated gene (a pathogenic variant in PKD1 has a worse prognosis) and the type of sequence variant (the truncating type being more serious)126. VRT is the best predictor of CKD progression125,127. As renal volume increases, the rate of decrease in eGFR is greater125, although there are discordant results from clinical trials, where an improvement in TRV is not accompanied by an improvement in the evolution of eGFR128. HTN is associated with a higher TRV41.

The Working Group of Inherited Kidney Diseases (WGIKD) of the European Dialysis and Transplant Association (EDTA) together with the European Renal Best Practice Guidelines (ERBP) group proposed a definition of rapid progression in ADPKD that has now become obsolete as mentioned in their website (http://www.european-renal-best-practice.org/content/erbp-documents-topic; accessed 20 Aug 2019).

• 1

  We suggest to stop using the EDTA/ERBP algorithm.

• 2

  We suggest including patients up to 60 years of age in the assessment of rapid progression. The average age of ESRD in Spain is 65 years. We consider rapid progressors those patients with ADPKD who require RRT before the mean age of RRT in Spain (D).

• 3

  We suggest to include, for assessment of rapid progression, patients with eGFR>30ml/min. At the individual level, treatment can be considered with eGFR>15ml/min (D).

• 4

  We suggest that patients between 55 and 60 years should have a GFR<60ml/min at the start of treatment. If at this age the GFR is >60ml/min, it would be very unlikely for them to need RRT before the age of 65 (D).

• 5

  We suggest that to assess the start of treatment with tolvaptan all patients should have a measurement of TRV by MRI or CT (or in cases with symptoms before the age of 35, although a genetic study showing a truncating mutation in PKD1 may be sufficient).

• 6

  We suggest that a patient who meets one of the following criteria be considered a rapid progresser (Figs. 1 and 2), simplified algorithm:

  • i

    VRT adjusted for height, in patients with bilateral symmetric involvement, belonging to the Mayo classification 1D or 1E (C) or

  • ii

    PRO-PKD score>6 (C) or

  • iii

    Height-adjusted VRT in patients with bilateral symmetric involvement belonging to the Mayo 1C classification:

    • a

      If the retrospective decline in eGFR over the past 3 years is ≥3.5ml/year (corresponding to the average decline in eGFR in patients in Mayo Clinic class 1D) or

    • b

      If most of the relatives reached ESRD before 58 years (the mean age of RRT in Europe for ADPKD) (D).

  
  

  Fig. 1.

  Algorithm for the evaluation of rapid progression in ADPKD.

  (0.37MB).
  
  

  Fig. 2.

  Simplified algorithm for the evaluation of rapid progression in ADPKD.

  (0.24MB).
• 7

  When defining eGFR decline, we must take into account the following considerations (D).

  • i

    There are medications that modify the eGFR, including NSAIDs, ACE inhibitors, ARBs, and fenofibrate that must be taken into account (B).

  • ii

    Other causes besides ADPKD that justify a drop in eGFR (C) must be ruled out.

• 8

  When defining the eGFR, it must be taken into account the following considerations (D):

  • i

    In routine clinical practice, eGFR is used based on serum creatinine (CKD-EPI equation or MDRD4 in case of GFR<60). However, this is just an estimate that only applies to people who have an expected muscle mass for their gender or age.

  • ii

    The equation is wrong and its use is not recommended for people who have more muscle mass than expected (eg athletes) or less (eg malnutrition).

  • iii

    If it is suspected that the eGFR formulas cannot be applied to a particular patient, there are alternatives:

    • -

      24-h urine creatinine clearance.

    • -

      Measure eGFR with iohexol clearance.

    • -

      Cystatin C measurement.

• 9

  We suggest that the VRT be evaluated by MRI (C).

  • i

    Currently, gadolinium-free MRI is the gold standard for measuring TRV when both kidneys are enlarged. The use of the ellipsoid formula is acceptable to measure the VRT. The distinction between “typical” and “atypical” is recommended with respect to renal morphology (B).

  • ii

    In patients with kidneys >13cm in diameter by ultrasound, we suggest to assess: based on age (slightly enlarged kidneys in young adults may indicate rapid progression while this is not the case in older ages) and renal appearance (eg, a large renal cyst is not significant but multiple cysts that increase renal size are). Perform a baseline MRI and repeat every 3–5 years if the patient is not receiving treatment with tolvaptan (D).

  • iii

    Serial TRV measurements are not recommended in routine clinical practice if renal diameter is normal or, during treatment with tolvaptan. Although they may be of interest in specific clinical situations (D). Centers that do not have access to MR can:

    • a

      Refer the patient to a center with an ADPKD unit.

    • b

      Use the PRO-PKD if the patient has presented urological symptoms or HTN before the age of 35.

    • c

      Perform a CT once and evaluate according to the Mayo classification.

The authors do not declare any conflict of interest. Otsuka Pharmaceutical has not been involved in the development of the guidelines. Their participation has consisted exclusively of financing their layout.