n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 Revista de la Sociedad Española de Nefrología www.revistanefrologia.com Special article Consensus document on autosomal dominant polycystic kindey disease from the Spanish Working Group on Inherited Kindey Diseases. Review 2020 Elisabet Ars a , Carmen Bernis b , Gloria Fraga c , Mónica Furlano d , Víctor Martínez e , Judith Martins f , Alberto Ortiz g , Maria Vanessa Pérez-Gómez g , José Carlos Rodríguez-Pérez h , Laia Sans i , Roser Torra d,∗ , en nombre del grupo de trabajo de Enfermedades Renales Hereditarias de la Sociedad Española de Nefrología a Laboratorio de Biología Molecular, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain b Servicio de Nefrología, Hospital de la Princesa, REDinREN, Instituto de Investigación Carlos III, Madrid, Spain c Sección de Nefrología Pediátrica, Hospital de la Santa Creu i Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain d Enfermedades Renales Hereditarias, Servicio de Nefrología, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universidad Autónoma de Barcelona (Departamento de Medicina), REDinREN, Barcelona, Spain e Servicio de Nefrología, Hospital Virgen de la Arrixaca, Murcia, Spain f Servicio de Nefrología, Hospital Universitario de Getafe, Universidad Europea de Madrid, Getafe, Madrid, Spain g Servicio de Nefrología, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, IRSIN, REDinREN, Madrid, Spain h Servicio de Nefrología, Hospital Universitario de Gran Canaria Dr. Negrín, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Las Palmas, Spain i Servicio de Nefrología, REDinREN, Instituto de Investigación Carlos III, Hospital del Mar, Barcelona, Spain a r t i c l e i n f o a b s t r a c t Article history: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of Received 17 June 2020 genetic renal disease and accounts for 6–10% of patients on kidney replacement therapy Accepted 2 May 2021 (KRT). Very few prospective, randomized trials or clinical studies address the diagnosis and man- agement of this relatively frequent disorder. No clinical guidelines are available to date. This Keywords: is a revised consensus statement from the previous 2014 version, presenting the recommen- ADPKD dations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to Autosomal dominant polycystic following a literature search and discussions. Levels of evidence mostly are C and D accord- kidney disease ing to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations Recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of Management hypertension, pain, cyst infections and bleeding, extra-renal involvement including poly- Progression cystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) Consensus DOI of original article: https://doi.org/10.1016/j.nefro.2021.05.009. ∗ Corresponding author. E-mail address: rtorra@fundacio-puigvert.es (R. Torra). 2013-2514/© 2021 Sociedad Española de Nefrologı́a. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 368 n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 and KRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are provided as well as the recommendation to assess rapid progression. © 2021 Sociedad Española de Nefrologı́a. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/). Documento de consenso de poliquistosis renal autosómica dominante del grupo de trabajo de enfermedades hereditarias de la Sociedad Española de Nefrología. Revisión 2020 r e s u m e n Palabras clave: La poliquístosis renal autosómica dominante (PQRAD) es la causa más frecuente de PQRAD nefropatía genética y representa entre 6 a 10% de los pacientes en terapia de reemplazo Poliquistosis renal autosómica renal (TRR). dominante Muy pocos ensayos prospectivos, aleatorizados o estudios clínicos abordan el diagnóstico y Recomendaciones el tratamiento de este trastorno relativamente frecuente. No hay guías clínicas disponibles Manejo hasta la fecha. Esta es un docuemento de consenso revisada de la versión anterior de 2014, Progresión que presenta las recomendaciones del Grupo de Trabajo Español de Enfermedades Renales Consenso Hereditarias, acordadas tras la búsqueda bibliográfica y discusiones. Los niveles de eviden- cia en su mayoría son C y D según el Centro de Medicina Basada en Evidencia (Universidad de Oxford). Las recomendaciones se relacionan, entre otros temas, con el uso de diagnós- tico por imágenes y genético, el manejo de la hipertensión, el dolor, las infecciones y el sangrado quístico, la afectación extrarrenal, incluida la enfermedad poliquística hepática y los aneurismas craneales, el manejo de la enfermedad renal crónica (ERC) y el TRR asi como el seguimiento de niños con PQRAD. Se proporcionan recomendaciones sobre terapias específicas para la PQRAD, así como la recomendación para evaluar la rápida progresión. © 2021 Sociedad Española de Nefrologı́a. Publicado por Elsevier España, S.L.U. Este es un artı́culo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/ by-nc-nd/4.0/). for the treatment of patients over 18 years of age with ADPKD Introduction stages 1–3 and with signs of rapid progression. In June 2018, the European Medication Agency (EMA) extended the indica- Autosomal dominant polycystic kidney disease (ADPKD) is tions of tolvaptan to patients with ADPKD stages 1–4 at the the most common hereditary kidney disease.The estimated initiation of treatment and withevidence of rapid progres- prevalence is highly controversial and ranges between 1 per sion (https://www.ema.europa.eu/en/documents/procedural- 500 and 1 per 2000 people1–4 . steps-after/jinarc-epar-procedural-steps-taken-scientific- Patients with ADPKD make up between 6% and 10%, information-after-authorisation en.pdf) and in the same year approximately, of the population on dialysis or with a kidney it was approved in the United States for adults with rapidly transplant, being, therefore, a disease with a great social progressing disease without defining the stage of CKD at the impact5,6 . It is characterized by the progressive development start of treatment12,13 . There are a limited number of prospec- of renal cysts that usually lead to end-stage CKD (ESRD), tive randomized controlled trials, as well as clinical studies generally in adulthood. It is also associated with systemic that incorporate an experimental design for the diagnosis and manifestations, such as high blood pressure (HBP), intracranial management of ADPKD. Such studies are difficult to perform aneurysms (ICA), polycystic liver disease, valve abnormalities due to the relatively low number of patients in each center, as and cysts in other organs. During the last 3 decades there well as the heterogeneity of the clinical presentation of the have been great advances in the knowledge of the disease. In disease. The consensus recommendations in these clinical the mid-1990s, the genes that cause ADPKD were identified: guidelines are based on a search of the literature and, to a PKD1 and PKD7,8 . Other genes that cause autosomal dominant large extent, on the experience and opinions of the authors. cystic nephropathy have been identified that clinically differ The Cochrane Library, MEDLINE, and the Systematic Reviews from ADPKD (GANAB, DNAJB11)9,10 . PKD1 and PKD2 encode database (up to July 1, 2019) have been used to collect the polycystins 1 and 2, which are located in the primary cilium11 . ublications. We using the search terms ‘ADPKD’ or ‘polycystic Molecules that are overexpressed or deficient in polycystic kidney’ in combination with the terms ‘diagnosis’ or ‘imag- cells are now potential therapeutic targets, so that there are ing’ or ‘gene’ or ‘HTN’ or ‘CKD’ or ‘chronic kidney disease’ currently several drugs under study as treatment for the dis- or ‘chronic renal failure’.” or “ESRD” or “end-stage kidney ease. The therapeutic use of tolvaptan was approved In 2014, disease” or “dialysis” or “transplant” or “infection” or “pain” or in Japan and in 2015 in Canada and Europe. It was approved “liver” or “aneurysm” or “cancer” or “pregnancy” or “children” n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 369 or “tolvaptan”. To a large extent, we selected publications Imaging diagnosis of ADPKD from the last 10 years, but relevant older publications were Ultrasound is the most widely used imaging technique for the not excluded. The recent KDIGO (Kidney Disease Improved diagnosis and follow-up of ADPKD. This technique is widely Global Outcomes) in ADPKD14 have been especially taken into available, inexpensive, and does not require radiation or con- account. The reference lists of the identified articles were also trast. The new generation of ultrasound scanners provides a reviewed and those deemed relevant were selected. Review resolution of up to 2–3 mm, although this depends on the body articles are cited to provide readers with more detail than characteristics of the patient and the experience of the sono- that provided in these guidelines. The authors have tried to grapher. Ultrasonography is also useful to explore abdominal make this guide concise and very practical and, standardize, extrarenal involvement of ADPKD, such as liver or pancreatic as much as possible, the care of patients with ADPKD. cysts, which support the diagnosis of ADPKD. However, it is The authors are members of the Hereditary Kidney Dis- not a good method of measuring total renal volume (TRV), eases Working Group of the Spanish Society of Nephrology. especially if the renal diameter is greater than 17 cm. They sign the guides in alphabetical order, except the last Diagnostic criteria by ultrasound have been defined for author. The authors reached a consensus on the recommen- relatives of patients with mutations in the PKD1 gene16 or dations and considered that the benefits outweighed the unknown genotype17 (Table 2). The sensitivity of classical potential risks. The document has been submitted to public ultrasound for PKD1 patients is significantly higher than in PKD2 review by the members of the Spanish Society of Nephrology. patients. The levels of evidence are mostly low: levels C and D according Computed tomography (CT) is more sensitive than classical to the Center for Evidence-Based Medicine (Oxford University) ultrasound and can detect cysts as small as 1–2 mm18 , as well (http://www.cebm.net/?o=1025). These guidelines address the as stones. Aditionally, it is better than ultrasound in identify- following aspects of the disease: diagnosis, hypertension, ing kidney tumors. However, CT exposes patients to radiation pain, assessment of kidney disease progression, end-stage and is more expensive, so while it can determine TRV, it is not kidney disease, polycystic liver disease, ICA, other extrarenal routinely used for follow-up. features, specific treatment of the disease, and ADPKD in chil- Magnetic resonance imaging (MRI) is more sensitive than dren. The initial version of these guidelines was published in ultrasound or CT. It may be even more helpful in distinguish- 2014 and updated in 201715 . ing renal cell carcinoma from simple cysts. It turns out to be the best imaging technique to define TRV, especially repeat- edly, as it does not expose the patient to radiation. However, in many centers it is not easily accessible. There are different Diagnosis approaches to determine the TRV, but currently it is considered that the approximation using the ellipsoid formula is the most Since ADPKD is an autosomal dominant disease, children of cost-effective, although planimetry and semi-automatic stud- affected parents have a 50% chance of developing the dis- ies are gaining ground19–22 . Recently, it has been suggested ease. Due to its high penetrance, it is highly unlikely to skip a diagnostic criteria for ADPKD using MRI23 (Table 3). generation. Currently, ultrasound is used to detect and diag- nose the disease in people with an affected family member. The diagnosis of sporadic cases, which represent ∼10% of Recommendations patients, is based on the clinical characteristics of the dis- ease, but sometimes a genetic study is necessary, especially in 1 Ultrasound is the recommended diagnostic screening tool for rel- the early stages of the disease. ADPKD must be distinguished atives of an index case. The criteria defined in Table 2 (C) should from other causes of renal cysts such as simple cysts, autoso- be used. mal recessive polycystic kidney disease, nephropathy due to 2 CT or MRI should be used in doubtful cases or in those with sus- HNF1B mutations, and other cystic kidney diseases (Table 1). In picion of another associated renal pathology such as stones or an adult, the presence of enlarged cystic kidneys, a decreased tumors (D) or to define which patients are rapid progressors by estimated glomerular filtration rate (eGFR), hypertension, and measuring the TRV. liver cysts is highly indicative of ADPKD. But often, not all 3 The use of CT or MRI will depend on the availability of the tech- of these clinical features are present and diagnosis becomes nique. They would be the best choice: more complicated. In these cases, the genetic study is very a Use CT when stones should be evaluated (D). useful. b Use MRI if regular VRT monitoring is planned, such as in the Early diagnosis in adults may improve cardiovascular (CV) context of clinical trials (D). risk factors and allows the consideration of a specific treat- 4 In the event of inconclusive results from the imaging tests, ments to modify disease progression. a genetic study is recommended (D). Recommendations Genetic diagnosis of ADPKD 1 Patients diagnosed with ADPKD should be advised to inform their At present, the genetic diagnosis of ADPKD is affordable, but first-degree relatives about the diagnosis, and the relatives should still has a non-negligible cost, which is why it is indicated in be offered ADPKD screening (D). certain circumstances. 2 Genetic counseling (GC) should always be offered (C). The indications for the genetic study of ADPKD are: 370 n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 Table 1 – Differential diagnosis of ADPKD. Illness Differentiating signs or symptoms differentiating tests Acquired cystic disease •Medical history • Kidney size is usually small, • Pre-existing CKD unlike the cystic nephromegaly of ADPKD; rarely there may have some nephromegaly • Frequent hemorrhagic cysts simple cysts • Common in adults. Its incidence • Diagnosis based on increases with age. Uncommon in ultrasound: absence of internal those under 40 years of age echoes, well-defined wall, No family history and does not meet acoustic enhancement, Pei’s criteria spherical or ovoid shape • They are rarely complicated • It is used the Bosniak classification tuberous sclerosis • Facial angiofibromas, hypomelanic • Mutational analysis of TSC1 spots, nail fibromas, rough plaques, and TSC2 genes cortical tubers, subependymal • More frequent nodules, giant astrocytomas, angiomyolipomas than cysts. pulmonary More frequent in TSC2 than in lymphangioleiomyomatosis, cardiac TSC1 rhabdomyomas, renal • TSC2/PKD1 contiguous gene angiomyolipomas syndrome: early-onset ADPKD and deletion tuberous sclerosis involving both genes V on Hippel-Lindau • Renal carcinoma, retinal or central VHL gene mutational analysis syndrome nervous system hemangioblastoma, pheochromocytomas, pancreatic cysts, and epididymal cystadenomas Disease due to mutations in • Type 2 DM, renal cysts, renal • HNF1-B gene mutational the HNF1B gene hypoplasia, renal agenesia, analysis hyperechoic kidneys, genital abnormalities, hypomagnesemia Autosomal dominant • Tubulointerstitial nephropathy, • MRI sometimes shows cysts tubulointerstitial frequent gout or hyperuricemia, at the corticomedullary nephropathy due to sometimes cysts at the junction mutations in the corticomedullary junction • Mutational analysis of the UMOD/MUC1 genes UMOD gene and the MUC1 gene Autosomal dominant • CKD, hypotension, cysts, • Mutational analysis of the tubulointerstitial hyperuricemia, hyperkalemia REN gene nephropathy due to mutations in the REN gene Orofaciodigital syndrome • Only affects women. Lethal in males • Mutational analysis of the type 1 Radiological pattern similar to ADPKD, OFD1 gene but less increase inrenal volume in 70% of adult female patients. Renal spongiosis or • Absence of family history or • IVU precaliciliary renal ectasia autosomal dominant or Cacchi-Ricci disease • Radiated image for urography • Frequent stones • Dilation of collecting ducts at the level of the pyramids Autosomal recessive • Neonatal-childhood diagnosis • PKHD1 gene mutational polycystic kidney disease usually analysis Always liver fibrosis more or less symptomatic. In adults renal insufficiency with cystic kidneys of normal size or minimally enlarged. HANAC syndrome • Cysts, hematuria, CKD, muscle • Mutational analysis in the cramps, intracranial aneurysms, COL4A1 gene cataracts, retinal tortuosities. Autosomal dominant ADPKD ESRD PQH • Mutational analysis of polycystic liver disease: PRKCSH, SEC63, LRP5 • ADPLD-PRKCSH Absent or Mild No Moderate to severe ADPLD-GANAB, ALG8 and • ADPLD-SEC63 Absent or Mild No Moderate to severe SEC61B • ADPLD-LRP5 Absent or Mild No Moderate to severe • ADPLD-GANAB Absent or Mild No Moderate to severe • ADPLD-ALG8 Absent or Mild No Moderate to severe • ADPLD-S EC61B Absent or Mild No Moderate to severe MRI: magnetic resonance; IVU: intravenous urography. n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 371 Table 2 – Diagnostic criteria for ADPKD by ultrasound. Ravine criteria (1994) for patients at risk of PKD1 mutation: • At least 2 cysts in the kidneys or 1 cyst in each kidney in patients younger than 30 years • At least 2 cysts in each kidney in patients aged 30-59 years • At least 4 cysts in each kidney in patients 60 years of age or older Pei cirteria (2009) for ADPKD patients with unknown genotype and positive family history (=modified Ravine criteria): • Three or more renal cysts (unilateral or bilateral) in patients aged 15 to 39 years • Two or more cysts in each kidney in patients aged 40 to 59 years The presence of less than 2 renal cysts offers a negative predictive value of 100% and can be considered sufficient to rule out the disease in individuals at risk older than 40 years. Table 3 – Diagnostic criteria for ADPKD by magnetic resonance imaging. Subjects between 16 and 40 years of age at risk of presenting ADPKD: • > 10 cysts between the two kidneys: ADPKD • < 10 cysts between the 2 kidneys: no ADPKD Subjects between 16 and 40 years old at risk of presenting ADPKD and who wish to be kidney donors • < 5 cysts between the two kidneys: acceptable as a donor 1 Young subjects who need to confirm/rule out the diagnosis tioned whether they should be called ADPKD24 . Mutations in of ADPKD, such as relatives of patients with ADPKD who are the GANAB gene have been described in very few families and candidates for living donors with inconclusive ultrasound. represent approximately 0.3% of all cases of polycystic kid- 2 Patients with no family history of ADPKD, due to phenotypic ney disease. They cause a fairly mild renal phenotype, without overlap with other cystic kidney diseases (Table 1). renal failure, and a polycystic liver disease phenotype of vari- 3 Patients with equivocal or atypical imaging (eg, markedly able severity ranging from no liver cysts to severe polycystic asymmetric polycystic kidney disease, renal failure without liver disease. The DNAJB11 gene has been described only in significant nephromegaly); highly discordant disease sever- 5 families as the cause of a combination of polycystic kid- ity among members of the same family; ADPKD very mild or ney disease and autosomal dominant tubulointerstitial kidney very early onset or very severe or with syndromic features. disease (ADTKD) with normal-sized cystic kidneys and pro- 4 Patients who want GA, especially couples who want preim- gressive interstitial fibrosis with late-onset kidney failure. plantation genetic diagnosis (PGD). Routine genetic diagnosis to identify the gene causing the 5 Patients with hypertension or urological symptoms of the disease (PKD1 78% of cases; PKD2 15%; GANAB 0.3%; DNAJB11 disease before the age of 35, in whom the presence of 0.1%) is currently questionable since there is considerable a mutation in PKD1 would allow the application of the clinical variability associated with each gene and the type of PROPKD score for the risk of rapid progression and, there- mutation and, in general, the result does not usually signifi- fore, indicate a specific treatment. cantly modify the therapeutic approach. However, it should be noted that an important genotype-phenotype correlation has Recently, 2 new genes have been described that infre- been described with a possible influence on the decision to quently cause atypical forms of polycystic kidney disease: start treatment25 : truncating PKD1 pathogenic variants (those GANAB and DNAJB119,10 . The disease caused by mutations in that generate a protein with a smaller size than the normal these genes differs from classic ADPKD and it has been ques- protein or there is no of protein) have a worse prognosis than Table 4 – Indication of genetic diagnosis of ADPKD. a) Individual characteristics Potential living donor: each case must be assessed individually, taking into account age, severity of the disease in the family and imaging tests Patients with no family history of ADPKD. Especially indicated: - When radiological findings are atypical (eg, marked renal asymmetry, multiple small cysts, renal failure in the presence of cystic kidneys of normal size) - In patients with very mild involvement. - In patients with atypical extrarenal manifestations of ADPKD. - When a relative prognostic information is required, since truncating PKD1 mutations are associated with a worse prognosis than non-truncating PKD1 mutations and PKD2 mutations are associated with a better prognosis than PKD1 mutations. Patients with a very early onset of the disease - In families with a typical presentation of ADPKD, but with a relative with a very early presentation, genetic testing may identify a hypomorphic allele in addition to the allele with the pathogenic mutation or a hypomorphic allele in both copies of PKD1 - In patients with no family history of ADPKD and in whom no mutations have been identified in the PKHD1 gene (causing autosomal recessive polycystic kidney disease) or with radiological features of ADPKD Patients with or without a family history who desire future preimplantation or prenatal genetic diagnosis b) Family characteristics Families with multiple relatives with renal cysts with an atypical radiological pattern of ADPKD, candidates for a differential diagnosis of other cystic renal diseases 372 n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 non-truncating PKD1 pathogenic variants (those that generate probably pathogenic, of uncertain clinical significance (VUS), a protein with an amino acid change or an insertion/deletion probably benign, benign or hypomorphic, and 4) the existence of a number of amino acids less than 5) and this information is of mosaicism. For all these reasons, it is important that the part of some risk scores for rapid progression that allows a spe- genetic diagnosis is carried out by laboratories with the appro- cific treatment to be indicated (see the Progression section)26 . priate experience. Genetic diagnosis based on family linkage analysis is cur- Recommendations rently obsolete, since it requires the participation of at least 3 family members diagnosed with ADPKD with absolute 1 Routine genetic diagnosis of ADPKD is not recommended if the certainty. Linkage analysis would only be recommended in clinical and imaging diagnosis is clear (no grade of recommenda- familial cases with 100% positive symptoms of ADPKD, in tion). which sequencing of the genes that cause ADPKD has not 2 The specific situations in which the genetic diagnosis of ADPKD is identified any pathogenic variant. It cannot be used in patients indicated are: potential living donor from a family with ADPKD, who do not have a family history or in cases with doubtful young patients without a family history of ADPKD or with an symptoms of ADPKD. Furthermore, it is not applicable, or may uncertain clinical diagnosis, very early onset of the disease, PGD, lead to false results, if there are de novo mutations, hypomorphic urological symptoms or hypertension before 35 years of age to alleles31,32 , recombinations, or mosaicism37,38 . define the risk of rapid progression and indication of specific treat- ment (Table 4) (D). Recommendations Currently, the most widely used methodology for the 1 Mutational analysis of PKD1, PKD2, GANAB and DNAJB11 is genetic diagnosis of ADPKD is the sequencing of the caus- currently the genetic diagnostic method of choice in ADPKD ing genes by massive sequencing (also called next-generation (D). sequencing) or classic Sanger sequencing. 2 Mass sequencing of PKD1, PKD2, GANAB, and DNAJB11 is Mass sequencing allows simultaneous sequencing of PKD1, highly recommended, along with a broad panel of other genes PKD2, GANAB and DNAJB11, along with a large number of other also associated with cystic kidney disease in patients with genes also associated with cystic kidney disease; it reduces atypical phenotypes (D). the time and cost of mutational analysis and provides addi- tional information in patients with atypical phenotypes27–30 . More than 100 genes associated with renal cysts are currently Genetic counseling in ADPKD known. Patients with an earlier and more severe presentation of the disease than their relatives, in addition to the family The advice or GC, according to the Biomedical Research Law mutation, may also have an altered copy of the PKD1 gene with (LIB 14/2007)39 , is “the procedure intended to inform a per- a hypomorphic allele (sequence variant that generates a par- son about the possible consequences for him or his offspring tially functioning protein)31,32 or with a mutation in another of the results of a genetic analysis or screening and its advan- ADPKD-causing gene such as HNF1B or PKHD133,34 . tages and risks, and, where appropriate, to provide an advise in Classical Sanger sequencing involves sequential (not relation to the possible alternatives derived from the analysis”. simultaneous) analysis of the 46 exons and intronic flanking Ideally, the GC should be provided by multidisciplinary team in regions of PKD1 and the 15 of PKD2. Generally, is initiated the which all the agents and specialists involved interact (includ- analysis of PKD1, since it is the most frequently mutated in ing clinical and molecular geneticists, bioinformaticians and ADPKD35 . However, if a relative has reached ESRD after the genetic counselors). age of 70, the analysis begins with PKD2 sequencing. One of the objectives of GC is to prevent the patient or If sequencing does not identify any clearly pathogenic family regarding reproductive decision-making. During the GC (truncating) variant or a variant with an amino acid change process, the patient should be informed about the options widely described in the literature as pathogenic, the MLPA available to him, but in no case should be advised about the (Multiplex Ligation-dependent Probe Amplification) technique decision to be made. should also be performed, which detects large deletions and In terms of reproductive decisions, the possibilities for duplications in approximately 4% of cases36 . a patient with ADPKD in our country are the following: 1) The main limitation of mutational analysis is that the sen- assume a 50% chance of having an affected child; 2) selection sitivity of the technique is always less than 100%, so not of embryos by preimplantation genetic testing (PGT); 3) prena- identifying a mutation does not allow either ruling out or tal diagnosis; 4) gamete donation; 5) adoption, and 6) give up confirming the suspected diagnosis. However, studies in large having offspring. Under no circumstances we may give direc- cohorts have reported a high sensitivity of between 88% and tions to reach a decision and never judge the patient for the 94%26 . decision made. The difficulties in mutational analysis of the genes that The PGT is an assisted reproduction technique that cause ADPKD lie mainly in: 1) the high allelic heterogene- includes a genetic diagnosis of the embryos and the selec- ity of these genes, such that the same pathogenic variant tion of disease-free embryos to be transfer to the mother’s is not found in more than 2% of families; 2) the complexity uterus. The PGT for ADPKD is approved by the National Com- of PKD1, due to the existence of 6 pseudogenes with a 98% mission for Assisted Reproduction. One of the advantages of identical sequence in exons 1–33 of this gene; 3) the diffi- PGT over prenatal diagnosis is that it avoids the termination culty of classifying non-truncating variants into pathogenic, of pregnancy. However, it has drawbacks such as the need to n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 373 identify the causal sequence variant (not feasible in 10% of development of HTN in polycystic disease are high concen- cases), an in vitro fertilization process (hormonal treatment trations of erythropoietin, alterations in tubular handling of not recommended in women with significant polycystic liver sodium, increased tone of the sympathetic nervous system disease), the pregnancy rate it is approximately 40%, it has a and increased levels of vasopressin42,46 . high economic cost, it can be ethically questionable (especially in mild cases) and it is associated with a significant physical Treatment and psychological impact, especially for women. Changes in lifestyle are a fundamental part in the treatment of Recommendations essential hypertension. Although the efficacy of these recom- mendations has not been specificaly studied in hypertensive Every patient with ADPKD should have access to GC (A). patients with ADPKD, it is advisable to maintain an adequate The patient of reproductive age should be informed of the weight, perform aerobic physical exercise on a regular basis, options available to avoid the transmission of the disease (A). quit smoking and limit salt intake to 5–6 g/day. The patient should not be directed to make a specific deci- Given that the main etiological mechanism in the gene- sion; however, the professional should inform so that the sis of hypertension seems to be the activation of the RAAS, couple can make an autonomous decision with exhaustive ACE inhibitors (ACEIs) and angiotensin II receptor antagonists knowledge of the possibilities (A). (ARBs) should be the first-line antihypertensive drugs. The The TGP is available for patients with ADPKD in Spain. combined use of ACE inhibitors and ARBs was tested in the When offering the PGT option to patients, its advantages, HALT study47,48 and did not show additional benefits over the disadvantages, and average rate of pregnancy (A) should be use of one of them, neither in ADPKD progression nor in the explained. CV profile, so their joint use is not recommended. Calcium Psychological support is advisable for patients with ADPKD channel blockers (due to their theoretical deleterious effect in at critical moments in their lives, such as: the process of diag- worsening the disease) and diuretics (because they activate nosis, reproductive decision-making, management of pain the RAAS) should be reserved for cases of resistant HTN and and the need for RRT (B). for those patients with renal failure and fluid overload and beta-blockers would probably be second-line antihypertensive drugs. Despite these theoretical considerations about diuret- Management of arterial hypertension and ics, in the PKD-HALT trials, the second line of treatment after cardiovascular risk RAAS blockade was a diuretic, also in line with the recent Euro- pean guidelines on HTN in CKD49 and the third, metoprolol. Introduction Blood pressure goal The HTN is a very common manifestation in patients with ADPKD. A 60% of patients develop HTN before presenting The best evidence available regarding the target BP to be alterations in renal function40 . Ambulatory blood pressure achieved in patients with ADPKD comes from the results of (BP) measurement techniques such as self-measurement of the HALT-PKD studies47,48 . In general, and as in the rest of the BP (SMBP) or ambulatory BP monitoring (ABPM) facilitate the population with kidney disease, a goal of BP < 140/90 mmHg is early diagnosis of HTN and masked HTN, which prevalence is recommended (ideally, and in case of good tolerance to treat- higher than in the general population of HTN patients41 . The ment, aiming for a goal around 130/80 mmHg)49 . However, onset of hypertension is earlier in patients with mutations in in young patients (<50 years) with normal renal function, PKD1 than in PKD2 and in polycystic patients with hyperten- the HALT A study has shown that very strict BP control with sive parents, affected or not by the disease42 . Hypertension is an ambulatory BP target of around 95–110/60–75 mmHg has associated with a faster progression to ESRD and contributes advantages versus standard control (<130/80 mmHg) in terms to increased CV morbidity and mortality. of disease progression and improvement of the CV profile. Therefore, in this group of patients, it seems reasonable to Pathogenesis seek this stricter BP target, taking into account individual tolerance. Several mechanisms have been implicated in the pathogen- esis of hypertension in ADPKD, but the main one seems to Global cardiovascular risk be the activation of the renin-angiotensin system (RAS) sec- ondary to intrarenal ischemia caused by compression of the Part of the increased CV risk presented by patients with ADPKD intrarenal vasculature by expanding cysts43 . Although the is linked to the presence of hypertension as a risk factor, but evidence of a systemic activation of the renin-angiotensin- also to the appearance and early progression of subclinical aldosterone system (RAAS) is contradictory, hyperactivation organ damage. Even normotensive polycystic patients present of the intrarenal RAAS could itself promote hypertension44 . greater subclinical organ damage than healthy normotensive Endothelial dysfunction from early stages of the disease controls50 . Early detection and correct treatment of hyperten- could also contribute to the genesis of hypertension45 . Dys- sion and other CV risk factors should allow to act on reducing function of the polycystin 1-polycystin 2 complex of the the progression of CV disease and prevent subclinical organ primary cilia of endothelial cells worsens the response to damage and the appearance of CV events. shear stress, reducing the release of nitric oxide, which con- For the evaluation and treatment of the rest of the CV risk tributes to hypertension. Other mechanisms involved in the factors, there is no specific evidence for ADPKD, so will be 374 n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 applicable strategies of the renal population in general (http:// Recommendations kdigo.org/home/guidelines) and that of the general hyperten- sive population. 1 If macroscopic hematuria lasts more than a week or if the initial episode occurs after the age of 50 years, an imaging test should Recommendations be performed to rule out renal carcinoma (D). 2 A solid mass on ultrasound, speckled calcifications on CT, con- 1 Lifestyle changes should be implemented: maintain a healthy trast enhancement, the presence of a tumor thrombus, or regional weight, engage in regular aerobic exercise, and limit salt intake to adenopathy on CT or MRI should raise suspicion of renal carci- a maximum of 5–6 g/day (C). noma (C). 2 Performing SMBP or ABPM is recommended to achieve an early diagnosis of AHT (D). 3 A very strict ambulatory BP target (BP < 110/75 mmHg) in young Acute or chronic pain, cystic infection and patients (<50 years) with normal renal function would be feasible. bleeding In the rest of the patients, the BP goal should be similar to that of the other patients with CKD (B). The main causes of acute pain are pyelonephritis, cystic infec- 4 Antihypertensive pharmacological treatment should include an tion, cystic hemorrhage, and urolithiasis54,55 . Both kidney and RAAS inhibitor as the first option; this is based on its theoretical liver cysts may be symptomatic. Hemorrhage or rupture of advantages (C). cysts usually presents as acute pain that may be accompanied 5 CV risk should be assessed and all modifiable CV risk factors by macroscopic hematuria and/or anemia. Cystic infection should be treated according to the CKD guidelines (no grade of presents with fever and lower back or abdominal pain. Imag- recommendation). ing 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 tech- Pregnancy in ADPKD niques in patients with ADPKD with pain, fever or bleeding are summarized in Table 556–58 . When cystic infection is present, Women with ADPKD who have kidney failure or hyperten- urine and blood culture may be negative, which make a con- sion may have an increased risk of developing preeclampsia firmatory diagnosis difficult; in which case, it would require and fetal loss during pregnancy due to their CKD, but it identification of the cyst, puncture, and a positive culture has not been specifically studied whether having ADPKD of the content. Given this difficulty, an operative definition is an additional risk51 . Pregnancy is not contraindicated in of probable cyst infection has been proposed (recommen- normotensive women with normal renal function. Special dation 2B) and some authors add the absence of evidence attention should be paid to those women who receive treat- of recent intracystic bleeding on CT without contrast56,58–61 . ment with estrogens or progesterone, because polycystic liver However, the coexistence of infection and hemorrhage is pos- could be aggravated14 . sible. A recent international Delphi consensus endorsed this Urinary tract infections should also be monitored due to an approach, suggesting that increased C-reactive protein (CRP) increased predisposition during pregnancy80 . can be replaced by a leukocytosis greater than 11,000/␮l and including a list of 18 items that increase diagnostic suspicion if routine tests failto identify another cause to explain the signs Recommendations and symptoms. The diagnosis would be confirmed after image localization of the infected cyst62 . 1 Pregnancy is not recommended in women with ADPKD with CKD Treatment of cystic hemorrhage is generally symptomatic. stages 3–5 and excluding transplant patients (D). Improvement has been reported with tranexamic acid, an 2 Pregnant ADPKD with Hypertension should be controlled as a antifibrinolytic agent, but there are no controlled studies high-risk pregnancy (C). available63 . 3 Pregnant women with ADPKD who are normotensive and have Empirical treatment of cystic infection should cover the normal renal function do not require special follow-up, although most frequent causative germs, enteric gram-negative bac- special attention should be paid to BP control (no degree of evi- teria, with antibiotics that penetrate well into cysts, such as dence). quinolones64 . Cystic penetration of meropenem is low, with 4 It is recommended to suspend ACEI/ARA-II due to the risks of ter- intracystic levels 10 times lower than in plasma65 . Increased atogenicity (C). Likewise, it is recommended to suspend tolvaptan levels of circulating CA19.9 have been described in patients during pregnancy (B) and use contraception during its use (B). with liver cyst infection66 , but also in patients with ADPKD 5 In vitro fertilization process is not recommended, due to its inher- in general (mean values 3 times higher than in controls and ent hormonal treatment, in women with significant polycystic liver higher in patients with large liver and higher values of gamma disease. (no degree of evidence). glutamyl transpeptidase [GGT])67 . A 20–36% of ADPKD patients have urolithiasis, which can also cause acute pain. Uric acid Renal carcinoma stones are more common than calcium oxalate stones68 . Predisposing factors include hypocitraturia, hyperoxaluria, In ADPKD the renal carcinoma is not more frequent than in hypercalciuria, hypomagnesuria, possible distal acidification other populations with CKD, but it may be more difficult to defects, and, above all, urinary stasis due to compression make the diagnosis52,53 . of the collecting system by cysts. Potassium citrate is the n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 375 Table 5 – Radiological tests in patients with ADPKD and pain, fever or bleeding. Test Advantage Additional benefits Disadvantages Indication Plain abdominal X-ray Affordable, accessible Radiation, does not Initial evaluation of evaluate cysts abdominal pain Abdominal/renal Can identify obstruction of Diagnosis of ADPKD, it Does not differentiate Initial assessment of ultrasound the urinary tract, lithiasis informs on kidney size between cyst with infection abdominal pain/fever and complicated cyst or hemorrhage CT Sensitive to distinguish Estimation of renal Radiation, often identifies Initial assessment of lithiasis, images suggestive volume; estimation of multiple images of abdominal pain/fever of recent intracystic interstitial fibrosis. complicated cysts, does not hemorrhage can be differentiate well between observed, and sometimes infection or old cystic suggestive of infection (gas, hemorrhage, often contrast intracystic level, increased cannot be used due to renal density of nearby fat) insufficiency, contrast may elucidate normal pericyst parenchyma Lithiasis a MR T1 and T2 sequences Less available, no difference Evaluation of fever if CT similar to CT. DWI MRI between infection or does not resolve shows changes in infected hemorrhage on T1/T2, cysts often contrast cannot be used due to renal insufficiency, contrast can elucidate normal pericyst parenchyma 18F -FDG PET/CT Test of choice to locate with Radiation, expensive, little Decision-making in precision an infected availability, no defined patients with poor kidney or liver cyst, it can criteria for diagnosis and evolution when locate other foci of infection follow-up of infected cysts, traditional imaging has also detects tumors and failed, especially if hematomas, possible persistent fever interference of renal failure in the elimination of the marker Scintigraphy with Location the inflammation Little availability, Consider if PET/CT is leukocytes labeled with preparation takes 48 h, not available when radioactive gallium or requires external traditional imaging has indium manipulation of leukocytes, failed poor precision, only positive in 50% of cases Arteriography Diagnosis and possible Radiation, invasive, Severe bleeding treatment of severe active possibility of l contrast cystic hemorrhage nephrotoxicity DWI: diffusion-weighted imaging; MRI: magnetic resonance; CT: computed tomography; 18 F-FDG-PET/CT: positron emission tomography with fluorodeoxyglucose labeled with fluorine-18. a Dual-energy CT allows to distinguish between uric acid and calcium stones. treatment of choice for uric nephrolithiasis, calcium oxalate vation (thoracoscopic sympathoplanknicectomy, laparoscopic nephrolithiasis due to hypocitraturia, and distal acidification renal denervation, and transluminal catheter denervation) defects. The KHA-CARI guidelines recommend using CT with- and even nephrectomy, especially if the patient is already out contrast to confirm the diagnosis of nephrolithiasis (1B) on renal replacement therapy. The KHA-CARI guidelines and, if identified, perform a metabolic study (1C), and correct recommend evaluating chronic pain and involving the the defects if possible (2D)69 . Dual-energy CT differentiates patient in the pain management, initially emphasizing non- uric acid stones from those containing calcium14 . pharmacological treatment (both 1D) and suggest surgical Several clinical guidelines and documents have recently decortication of cysts if pain is severe and sustained (2C)70 . addressed the treatment of chronic pain14,70 . The main causes A recently described denervation protocol improved chronic of it are the increase in the size of the kidneys or the liver. pain in 81% of a total of 44 patients. As a diagnostic maneu- Various invasive procedures have been reported in the lit- ver, a temporary celiac plexus block is performed; If pain erature for pain control if medical treatment fails, generally recurs after initial improvement, radiofrequency ablation of in case reports or small case series (reviewed in Chapman the celiac plexus is performed. If the pain does not improve, et al.14 ). These include celiac plexus block, radiofrequency renal denervation is performed with a catheter71 . In a prelimi- ablation, spinal cord stimulation, and various forms of dener- nary study, renal catheter denervation reduced chronic pain in 376 n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 a mixed group of patients (n = 11) that included patients with sive procedures. It is suggested to perform PET/CT if the ADPKD72 . A recent concept is the prevention of pain; the phase infected cyst has not been located using other techniques 3 randomized controlled trial TEMPO 3:4 study observed a 36% (D). decrease in the incidence of pain episodes (secondary end- i It is suggested to consider invasive procedures if the point) in patients treated with tolvaptan, which was attributed infected cyst has been identified through imaging tests to a lower incidence of urinary tract infections, stones and and there is no response to antibiotics. Invasive proce- hematuria12 . However, prevention of pain is not, by itself, an dures may include percutaneous or surgical drainage if the indication for tolvaptan at this time. Tolvaptan is discussed cyst diameter is >3–5 cm, and nephrectomy for emphyse- extensively in the ADPKD-specific treatment section. matous cysts, recurrent infections, transplant candidates with recent refractory cystic infection, or staghorn calculus Recommendations causing recurrent urinary tract infections in the presence of poor or absent kidney function (C). 1. Bleeding: j Complications such as urinary tract obstruction, perirenal abscess, or urolithiasis should be ruled out if fever recurs a For symptomatic treatment of cystic hemorrhage it is after discontinuation of antibiotics. If these complications suggested bed rest, analgesics, and in case of significant are not identified, it is suggested to prolong antibiotic hematuria, sufficient hydration to increase diuresis to treatment, even several months, in order to eradicate the 2–3 L per day (D). infection (D). b It is suggested to advise home self-treatment of macro- scopic hematuria, following pre-established instructions 3. Lithiasis: in patients with previous episodes of similar character- istics. If the bleeding is severe or persistent, the patient a Noncontrast CT is recommended to confirm the diagnosis should go to the Emergency Room (no degree of evidence). of nephrolithiasis (B). c It is suggested that the following therapeutic options b In case of nephrolithiasis, it is recommended a metabolic be considered depending on the magnitude and persis- study (C). It is suggested to consider oral potassium citrate tence of the hemorrhage: intravenous fluids, red blood cell in patients with urolithiasis and hypocitraturia (C). transfusion in case of anemia, desmopressin if the eGFR c It is suggested to consider urine alkalinization in uric acid is <15 ml/min/1.73 m2 , bladder catheterization if there lithiasis (C). are clots with the hematuria to prevent obstruction of d The indication for percutaneous nephrolithotomy and the urethra and, in severe active bleeding, percutaneous extracorporeal shock wave lithotripsy must be individu- embolization of the bleeding artery or nephrectomy (D). alized (D). d A risk-benefit assessment should be performed when starting anticoagulants or antiplatelets in patients with 4. Chronic pain: a history of macroscopic hematuria (D). a It is suggested to evaluate the presence of chronic pain 2. Infection: and identify and treat, if possible, the cause (D). b It is suggested symptomatic treatment of mechanical a It is recommended to hospitalize the patient with symp- musculoskeletal pain or secondary to increased kidney toms of infection of renal or hepatic cyst (D). size is (D). b The diagnosis of a probable cystic infection can be based c Opioid analgesics are suggested to be reserved for on the following criteria: a) fever >38 ◦ C; b) localized flank episodes of acute pain (D). pain, and c) CRP > 5 mg/dl (D). d It is suggested that invasive procedures be considered, c Elevation of alkaline phosphatase and CA19.9 compared to such as a celiac plexus block or others, if the pain sec- baseline values suggest hepatic cyst infection (C). ondary to increased kidney or liver size is not controlled d It is recommended to perform urine and blood cultures if with medical treatment (D). urinary or cystic infection is suspected (D). e In case of suspected cystic infection, is recommended empirical antibiotic therapy with lipid-soluble drugs with good penetration into cysts and activity against gram- Renal replacement therapy negative enterobacteriaceae, such as quinolones. It is suggested to adjust the antibiotic treatment according to The course of ADPKD is highly variable and not all patients the evolution and sensitivity tests (D). progress to ESRD. Renal survival is affected by non-modifiable f The duration of antibiotic treatment should be 4–6 weeks factors such as age, gender, the affected gene and the type (D). of mutation, and by modifiable factors such as hypertension, g It is suggested to add a second antibiotic (cephalosporins proteinuria and others5,73 . or carbapenems) and perform imaging tests to reassess the The mean age at the start of renal replacement therapy presence of possible complications if no improvement is (RRT) in patients with ADPKD is lower than in patients without observed within the first 72 h (D). ADPKD, and survival is longer. h Imaging tests are recommended to locate the infected cyst Kidney complications can persist even after advanced or in case of poor evolution and the need to perform inva- end-stage CKD but rarely lead to serious problems. In cases of n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 377 uncontrollable frank hematuria, infection of a cyst or a large in the liver. Liver cysts usually appear later than renal cysts renal volume, nephrectomy would be considered. and are very variable in size. CV disease is the main cause of death73 . The main risk factors for the development of liver cysts are Among the different dialysis modalities, it has been sug- age, female gender, multiple pregnancies, the use of estrogens, gested that peritoneal dialysis is a reasonable option, offering hormone replacement therapy or contraceptives83 . Liver vol- a better prognosis and quality of life to patients with ADPKD ume tends to decrease or not increase in women after 48 years than to those who do not carry this disease as a cause of of age, thus highlighting the importance of the hormonal role CKD74,75 . This modality should not be denied due to the mere in the development of cysts81,82 . existence of cystic nephromegaly76 . However, in patients with Most patients remain asymptomatic and only a small very large kidneys or livers, the lack of space may restrict proportion (20%) develop massive liver disease. The main the area available for peritoneal exchange and increase the symptomatology derives from hepatomegaly, which can cause chances of hydrothorax and abdominal hernias. In these extrinsic compression of the thoracic and abdominal organs: cases, hemodialysis should be considered as the best option. abdominal distension, abdominal pain, gastroesophageal The same could be said for those patients with recurrent diver- reflux, early satiety, nausea and vomiting, dyspnea, orthop- ticulitis. nea, hernias, uterine prolapse, rib fractures, malnutrition, Kidney transplantation in ADPKD is the best RRT option. loss of muscle mass, back pain, venous obstruction (hepatic, It has similar results to other non-diabetic patients5,73 and inferior vena cava, portal), bile duct obstruction and others. ADPKD is not a risk factor for the development of post- Abdominal pain is usually the most frequent manifestation. transplant diabetes77 . The liver parenchyma is preserved despite the growth of liver The main difference lies in the need to assess the cysts, so it is rare that they cause liver failure. Bile duct involve- existence of ICA and to decide whether to perform nephrec- ment is a serious complication that can occur in patients with tomy of a native kidney78 to leave the necessary space for ADPKD and must be taken into account in all patients with a kidney transplant. There is not enough evidence about abdominal pain. It is more common in males. Bile duct dilation whether nephrectomy of the native kidney should be per- has been described in 17–40% of patients84 . formed before transplantation or simultaneously in the act The biochemical alterations that we can be observed are: of transplantation79 . Laparoscopic nephrectomy is a good elevation of alkaline phosphatase and GGT. Bilirubin levels option, as long as the center has experience in this type of are usually normal but can be elevated by compression of the surgery. bile duct by a cyst. CA19.9 levels are elevated in up to 45% of Preventive kidney transplantation from a living donor patients with polycystic liver disease and correlate with liver shows a better evolution. volume83 and has been proposed as a biomarker of hepatic Although the use of mTOR inhibitors has been suggested to cyst infection, since its levels tend to rise during this process reduce TRV after kidney transplantation, there is insufficient and fall with its resolution66 . It can also be elevated: CA125, evidence to recommend their use as first-line treatment in CEA and AFP. patients with ADPKD. Early detection of polycystic liver disease does not provide advantages over a possible therapeutic intervention since only Recommendations severe symptomatic cases are treated. The indication for treatment is established when the 1 Peritoneal dialysis and hemodialysis are valid RRT modal- patient presents severe symptoms, most of them derived from ities for patients with end-stage CKD secondary to ADPKD the compression of adjacent structures by hepatic growth. (C). Therefore, the goal of treatment is to reduce liver volume. 2 Heparin should be avoided during hemodialysis in patients Women should avoid taking oral contraceptives or hor- with frank and recurrent hematuria (C). monal therapy with estrogens to prevent the growth of 3 Kidney transplant is the recommended form of RRT. Living cysts. donor transplantation is a valid option to consider due to There are options of medical and surgical treatment. The its better evolution (D). interventional treatment options and the results are summa- 4 Elective native nephrectomy should be considered before rized in Table 6. Regarding medical treatment, somatostatin renal transplantation when kidney size precludes adequate analogs (octeotride and lanreotide) are the only drugs that graft placement and in symptomatic patients. Whether it have been shown to modify the natural course of the disease. is done before or during the transplant will depend on the According to clinical trials somatostatin analogs may reduce experience of each center. (D) liver volume by 6% reduction during 1–3 years85–87 , but studies 5 Nephrectomy of a native kidney should also be considered are needed to demonstrate long-term efficacy. in the event of complications such as neoplasia, hemor- In animal models, a new somatostatin analog, pasireotide, rhage, or persistent infection (D). is more powerful and effective than the current ones88 . In general, they are well tolerated, but lose their efficacy after dis- continuation. At the moment, they have not been approved by Polycystic liver disease the EMA and can only be used in the context of a clinical trial or for compassionate use in highly symptomatic patients89 . Polycystic liver disease is the most common extrarenal man- The mTOR inhibitors have not been shown to be effec- ifestation. It occurs in up to 90% of patients older than 35 tive alone or in combination with somatostatin analogs. years81 . It is defined as the presence of at least 20 simple cysts Ursodeoxycholic acid has been investigated as another pos- 378 Table 6 – Interventional treatment of complications derived from polycystic liver disease. Method Indication Result Aspiration- Cyst aspiration and subsequent Dominant cyst (greater In 70% improves or makes symptoms sclerotherapy administration of a sclerosing agent than 5 cm) responsible of disappear (ethanol the most frequent) the symptoms Other agents used: minocycline or Cyst regression: 22% total/19% partial tetracycline Causes destruction of the epithelial lining Recurrences up to 21% of the cyst Few side effects. The most frequent: abdominal pain due to peritoneal irritation during the instillation of ethanol n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 Fenestration Combines aspiration with resection of the Patients that do not Reduces the severity of symptoms in 92% superficial walls of the cysts respond to cases, aspiration-sclerotherapy Two types: 1) laparoscopic: preferred due to Recurs in 24% and less associated complications; 2) open 23% present complications: ascites, pleural effusion, arterial or venous bleeding Predictive factors for poor outcome: previous surgery, diffuse cystic disease, deep cysts liver resection Resect the most affected liver fragment Severely affected with at Effective in 86% least some unaffected liver segment It is usually combined with fenestration Complication rate rises up to 50%: ascites, in the area that is not resected hemorrhage, bleeding Mortality rate: 3% May complicate a future liver transplant Liver transplant Liver transplant Very severe involvement The only curative treatment and complications difficult-to-treat Sometimes conbined liver-renal Five year survival: 92% transplant Other options Embolization of branches of hepatic Little experience artery n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 379 sible therapeutic alternative, without definitive results so far. TGR5 antagonists are also being investigated84 . Intracranial aneurysms The efficacy of tolvaptan on liver cysts is not well charac- terized. It could act on the V2 receptors of the cholangiocytes, The prevalence of ICA in patients with ADPKD is around 8–12%, reducing the levels of AMPc and, therefore, the proliferation 5 times higher than that of the general population92–97 . The of the cysts. There are only 2 cases in the literature in which mean age at rupture is 41 years; about 10 years earlier than tolvaptan reduced liver size. in the population without ADPKD97 . The most determining Polycystic liver disease can cause acute complications, risk factor for having an ICA is a positive family history for such as cystic infection or bleeding. The infection is clinically ICA and/or subarachnoid hemorrhage (SAH), which is associ- characterized by abdominal pain in the right hypochondrium ated with a prevalence of 20–29% compared to 6–9% in those together with fever. Generally they are monomicrobial. The without a history94–97 . most common germs that cause infection are gram-negative Clinically, ICA of ADPKD are generally asymptomatic, 85% bacilli (eg, Escherichia coli). Its route of entry is retrograde are located in the anterior circulation and the measure is less through the bile duct. Laboratory tests revealed leukocytosis, than 7 mm, and may be multiple in 20% of cases. The rupture elevated erythrocyte sedimentation rate, CRP, elevated biliru- of ICA causes SAH, the most serious complication of ADPKD. bin, liver enzymes (GOT, GPT), GGT, and alkaline phosphatase. It is characterized by the appearance of sudden and intense The determination of CA19.9 has been proposed as a headache, sometimes accompanied by loss of consciousness, biomarker of hepatic cyst infection since its levels tend to rise it may cause death (30–60%) or severe disability (30%)98,99 . The during this process and fall with its resolution66 . risk of rupture correlates with the size of the aneurysm and Diagnosis is usually made by CT or MRI, but the most sen- with the existence of a family history of ICA and/or HSA, but sitive diagnostic tool for cystic infection is positron emission also with the location, the presence of an aneurysmal sac, tomography after administration of 18-fluorodeoxyglucose tobacco consumption, the existence of hypertension, cocaine, (PET-FGD)58,90 . the use of estrogens or anticoagulants92,96,98,100,101 . Death due Intracystic bleeding is rare. Symptoms can be very similar to neurological causes accounts for 11% (6% aneurysm rup- to those of an infected cyst, although fever is rare. Abdominal ture, 5 % cerebral hemorrhage) of the causes of death in pain is usually more intense. Diagnosis is made by CT or MRI. ADPKD, behind cardiac causes (36%) and infections (24%). The Treatment is based on the administration of analgesics. risk of intracranial hemorrhage is 3 times higher in patients Cyst rupture is rare and can cause acute abdominal pain with ADPKD on RRT than in non-ADPKD, and the greatest dif- and ascites. Treatment is symptomatic. ference is seen in patients on hemodialysis. Another very rare complication is recurrent episodes of Gadolinium-free MRI is the technique of choice for diagnos- cholangitis91 . ing ICA as it avoids the iodinated contrast of CT angiography. There is agreement on the indication of preventive screen- ing 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 Recommendations 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 rec- 1 Patients with moderate-severe polycystic liver disease should ommended to repeat the screening after 5 or 10 years96,101,102 . avoid taking estrogens and drugs that stimulate cAMP accumu- The treatment of ICA should be assessed by multi- lation (eg, caffeine) (D). disciplinary teams with neurosurgeons and interventional 2 In patients with mild polycystic liver disease with hormone radiologists from experienced centers. If cause symptoms replacement therapy, the minimum effective dose should be they should be treated; asymptomatic patients always require administered and, if possible, by transdermal route (D). follow-up and, depending on the case, intervention based on 3 If hepatic cystic infection is suspected, a CT should be per- their characteristics (Table 7). The PHASES score is useful to formed. The treatment of choice is the administration of antibiotics assess the risk of rupture103,104 . (quinolones) for at least 6 weeks. If fever persists 72 h after start- Conservative treatment is desirable in polycystic patients ing antibiotic treatment, a 3rd generation cephalosporin should with aneurysms <7 mm of the anterior circulation. Although be associated. When signs of infection persist after 3–5 days of the risk of growth is low, initial radiological follow-up is rec- starting treatment, a PET-FGD is recommended to try to locate ommended every 3–6 months, delaying it to annual and every the infected cyst, if it was not located with CT or MRI. Percu- 2–3 years once its stabilization is observed2,94,95,105 . Treatment taneous drainage of the cyst under radiological control is only is not innocuous and iatrogenic events are more frequent recommended if signs of infection persist, to identify the causative in ADPKD than in the general population, both for neuro- agent (D). surgery (11.8% vs. 6.4%) and for interventional radiology (9.4% 4 Intracystic hemorrhage should be diagnosed with MRI and should vs. 3%)106 . be treated with analgesics (D). It is important not to forget the modifiable factors to reduce 5 Treatment of polycystic liver disease is only indicated in highly the risk of the appearance and growth of aneurysms in the symptomatic patients. The goal is to reduce liver volume. Polycys- general population and in ADPKD (smoking cessation, BP con- tic liver surgery requires an expert surgeon, given the abnormal trol and CV risk). liver anatomy and the high morbidity of surgical procedures in In general, universal screening for ICA is not these cases (C). recommended14,96,101,105 and it is indicated only in cases 380 n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 Table 7 – Management of ntracranial aneurysms (ICA) in ADPKD. Indications for preventive detection, screening, of ICA in patients with ADPKD - Family or personal history of subarachnoid hemorrhage and/or aneurysm - Symptoms suggestive of aneurysm - Work or activity in which loss of consciousness can be lethal - Preparation for major elective surgery - Extreme anxiety of the patient in relation to the risk of having an aneurysm Management of asymptomatic ICA without rupture (modified from Williams and Brown RD, Neurol Clin Pract. 2013) A) Treatment is recommended: - ICA ≥ 12 mm in diameter - Symptomatic ICA - ICA that changes and increases the size B) Treatment may be considered: 1) AIC 7–12 mm in diameter that meet any of the following characteristics: - Young patient - High-risk location (posterior circulation or posterior communicating artery) - Saccular aneurysm -Family history of subarachnoid hemorrhage 2) ICA < 7 mm in diameter in young patients who meet any of the following characteristics: - High-risk location (posterior circulation or posterior communicating artery) - Saccular aneurysm - Family history of subarachnoid hemorrhage C) Treatment is not recommended: - ICA < 7 mm in diameter in the anterior circulation without a family history of subarachnoid hemorrhage and non-saccular characteristic - Cavernous aneurysm of the internal carotid artery The type of intervention must be personalized, it may consist of surgical clamping or the use of an intravascular coil. ICA: intracranial aneurysm. with a family or personal history, professions with risk, of kidney disease, being higher in haemodialysis. Thus, in the preparation for major elective surgery and patient anxiety REPRISE trial, which included patients with poorer renal func- despite adequate information (Table 7). Kidney transplanta- tion, the incidence of rupture was 0.19 per 100 patient-years tion is a major elective surgery, however there is no agreement (95% CI, 0 to 0.40). on prior screening for ICA. The indication, timing and frequency of screening for Recommendations aneurysms is a matter of debate. Some authors propose uni- versal screening based on the difficulty of obtaining a good 1 The most suitable examination to detect ICA is MR angiography family history, the non-negligible presence of aneurysms in without gadolinium. If this is not possible, CT angiography is an cases with no history, and a higher rate of rupture in some acceptable alternative (C). series than the usually described108 . The decision to perform 2 Preventive detection of ICA should be performed only in the situ- universal screening depends on the accessibility of screening ations indicated in Table 7 (D). methods, the incidence of ICA and its rupture, the consequent 3 Asymptomatic ICA should be evaluated in collaboration with neu- morbidity and mortality, the possible therapeutic actions and rosurgery and interventional radiology according to the guidelines their results. The selection of the groups studied is also deci- shown in Table 7 (C). sive, and it is possible that in some subpopulations such as 4 Urgent brain CT is indicated if a patient with ADPKD develops the Japanese and Finnish the risk is higher96,101 . severe acute headache with or without loss of consciousness (C). Flahault et al.96 exhaustively review their experience at 5 All symptomatic aneurysms should be treated (C). the Mayo Clinic and the information available, analyzing with 6 The type of ICA treatment should be decided in a personalized particular attention the rate of aneurysm rupture per 100 multidisciplinary session and may include surgical clamping of patient-years in published series94,95,102,107 and in a group the aneurysm neck or endovascular treatment with a platinum made up of 6,095 polycystic patients from clinical trials, coil(C). without image screening, with clinical follow-up of 19,400 patient-years.The study confirms the importance of family Autosomal dominant polycystic kidney disease history, highlighting the history of SAH as having more impor- in childhood tance than the presence of ICA, although the majority (>60%) of patients with ICA did not have a family history. The rate Most of the clinical manifestations (renal and extrarenal) of aneurysm rupture, in patients without prior screening, is of ADPKD occur during adulthood. However, the disease is 0.04 per 100 patient-years (95% CI, 0.01 to 0.06) and the indica- already present at birth and can be diagnosed in children, tion for screening is reaffirmed, restricted to cases with family newborns and even fetuses109 . history according to Table 7. However, clinical trials usually The KDIGO Guidelines14 and the international radiological recruit patients with more preserved kidney function and both consensus for cystic kidney diseases in children110 address the the incidence of ICA and SAH increases with the progression diagnosis of ADPKD in Pediatrics: n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 381 –There are no specific radiological criteria for children. The for effective early intervention. The main one is hypertension, Pei criteria were derived from patients older than 15 years which, although infrequent, may appear in childhood. and have low sensitivity in younger children. A prevalence of hypertension is estimated at around 20% –In children under 15 years of age with a positive family in children and young adults (up to 21 years of age) with history, the presence of a renal cyst, nephromegaly, or both ADPKD118 . The ABPM indicates a rate of HTN of 31, 42, and should be considered highly indicative of ADPKD. Routine 35% during the day, night, or 24 h, respectively. At the time of genetic testing is not recommended, since there is no specific ABPM determination, 95% of the children had normal renal treatment, directed at the pathogenesis of cysts, approved in function119 . These percentages are probably overestimated children (see indications for genetic testing). due to a severity bias in the pediatric cohorts. There is evi- –In the absence of a family history of ADPKD, and also in dence that in children with ADPKD, borderline hypertension the absence of other data suggestive of a different cystic dis- can increase left ventricular hypertrophy, reinforcing the need ease, the presence of large kidneys with cysts is indicative for optimal control120 . of ADPKD. An ultrasound should be performed on the par- The ACE inhibitors offer a potential benefit for reduce CV ents and grandparents (especially if the parents are under 40 function deterioration and the loss renal function over time in years old) and if they do not have the disease, a genetic study children with borderline hypertension (BP inthe 75th and 95th is recommended. percentile)121 . Extrarenal manifestations are exceptional during the pedi- In ADPKD, large, hyperechoic, and even cystic kidneys may atric age. (although not necessarily) be seen prenatally. However, the The recommendations in the pediatric age are based on a main cause of prenatal bilateral renal hyperechogenicity is fundamental fact: we do not have a specific treatment (aimed abnormalities in the HNF1B gene111 . at the pathogenesis of the cysts) approved in children. The In pediatric ADPKD we distinguish 2 presentations: recommendations will be different when we have a specific treatment approved for children. 1 Children with early symptoms (less than 2% of children): large, hyperechoic kidneys with multiple cysts are already Recommendations evident in prenatal ultrasounds. Clinically, they present renal failure and hypertension in the first months-years of 1 Screening for ADPKD in children of polycystic parents is question- life and may be clinically indistinguishable from autosomal able from an ethical point of view since there is no absence of a recessive polycystic kidney disease. This includes children specific treatment (no degree of evidence). with Potter sequence and significant perinatal/neonatal 2 An imaging study should be performed in children of polycys- morbidity and mortality. Severe and early forms of ADPKD tic parents who present hypertension or hematuria (no degree of are usually caused by mutations in multiple genes causing evidence). cystic kidney disease, and hypomorphic PKD1 alleles 33 may 3 A genetic study should be carried out in children with very early occasionally be involved (see section on genetic diagnosis). In and severe manifestations; this is to assess the contribution to the general, children with enlarged kidneys on ultrasound tend phenotype of other genes involved in renal cystic diseases (D). to have more clinical manifestations than children with 4 All children with ADPKD with symptomatic disease should be normal-sized kidneys109 . followed by a pediatric nephrologist (D). 2 Asymptomatic children with early diagnosis: here we would 5 Every child of a patient with polycystic disease should have their include children with a family history of ADPKD and who BP checked at each routine visit with their pediatrician (D). present a cyst in the prenatal ultrasound or in the first 6 If hypertension is detected, treatment with ACE inhibitors should months of life. The vast majority of these children will be started (no degree of evidence). be asymptomatic throughout their childhood years and 7 Routine evaluation of extrarenal manifestations in childhood is not will present with CKD in adulthood. However, it has been advised (no grade of evidence). suggested that they have a worse prognosis than those diag- nosed later in life109,112,113 . Specific treatment of autosomal dominant Most affected children have few or no symptoms during polycystic kidney disease childhood, although some may develop renal cysts, hyper- tension, macroscopic hematuria, abdominal pain, abdominal In 2015, the EMA approved the use of tolvaptan, a vaso- mass and, less frequently renal failure112,114–116 . Low birth pressin V2 receptor antagonist, expressed mainly in the distal weight per se may predispose to an earlier onset of ESRD in nephron and collecting duct, to slow down cystic development patients with ADPKD117 . and the progression of kidney disease. This medication is indi- Routine ultrasound screening of asymptomatic children cated in adult patients with ADPKD in CKD stages 1–4 with with one parent affected by ADPKD remains controversial, evidence of rapid progression (see section Recommendations given that there is no specific approved treatment in children for assessment in ADPKD progression). Tolvaptan decreases under 18 years of age and, furthermore, a normal ultrasound cAMP levels in cystic cells and reduces fluid secretion into result could be falsely reassuring. It is desirable not to carry out the cyst as well as cell proliferation. We cannot exclude the unnecessary examinations but since ADPKD begins in child- possibility that tolvaptan has other additional mechanisms hood, it is important to identify early risk factors for disease of renoprotection, through effects on renal hemodynamics progression that can provide us with the greatest potential (glomerular hyperfiltration or anti-inflammatory effect). The 382 n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 goal of tolvaptan treatment is to maintain an inhibition the After the initial dose, the dose will be escalated until reach- action of vasopressin on V2 receptors. Tolvaptan administra- ing the maximum of 120 mg/day. This dose escalation and at tion should always be associated with classic renoprotection the discretion of the nephrologist can be done between 1 and 4 measures such as changes in lifestyle, BP control, preferably weeks. Patients should be maintained on the highest tolerated with RAAS blockers. dose of tolvaptan. Several randomized studies with more than 1,000 patients It is recommended to evaluate urinary osmolarity, in the have shown that tolvaptan reduces the increase in total renal first urine of the morning (before the morning intake) to con- volume (TRV), improving symptoms caused by TRV, such as firm tolvaptan intake and the achievement of its objective in pain. In the TEMPO 3:4 study (1445 patients aged 18–55 years those patients at the beginning and follow-up of treatment with Ccr ≥ 60 ml/min and TRV ≥ 750 ml with a duration of 3 with tolvaptan. A reduction below 275–295 mOsm/kg is con- years) the growth of TRV was reduced by 49% and the drop sidered ideal in most cases, although in those patients in in eGFR measured by the inverse of plasma creatinine was an early phase of ADPKD, it could be considered a reduction also reduceby 26% as compared to placebo12 . An extension of up to 200 mOsm/kg, more sensitive to aquaretic effects of this study, TEMPO 4:4, showed persistence of these posi- of tolvaptan. There is controversy about titrating the dose tive effects, especially on eGFR, in such a way that the earlier of tolvaptan based on urine osmolarity. According to Amer- start of tolvaptan was associated with better conservation of ican recommendations124 , the goal of treatment would be to GFR122 . In patients with more advanced CKD, stages 2–4 and achieve a urinary osmolarity of less than 280 mOsm/l in the aged between 18–65 years, the REPRISE study showed a 35% first morning urine, before the morning dose. Therefore, if reduction in the drop of GFR after one year of treatment with this is achieved with the minimum dose of tolvaptan, it would tolvaptan (2.34 vs 3.61 ml/min /1.73 m2 in the group treated not be necessary to continue escalating the dose, facilitating with tolvaptan vs. placebo)13 . Other studies have reported a tolerance. However, although it seems reasonable to look for sustained and cumulative effect of tolvaptan up to 11 years ways to individualize the dose, several considerations must be later123 . The impact of tolvaptan on eGFR loss is, in percentage made and in fact Chebib et al.124 suggest that more studies are terms, similar to that of RAS blockade in other kidney diseases. needed in this regard: A careful selection must be made of those patients who are candidates to start treatment with tolvaptan, assessing a Urine osmolarity was not used to guide tolvaptan dosing contraindications, adverse effects and the patient’s lifestyle, in clinical trials, therefore, dose adjustment based on urine so the decision must be made jointly (Assessment of rapid osmolarity has not been tested in a clinical trial and should progression in ADPKD section). be considered experimental. Among its adverse effects, 65%–95% of patients who b The goal of tolvaptan treatment is to maintain a continu- start treatment with tolvaptan present water diuresis122 , so ous inhibition of the action of vasopressin on V2 receptors. patients must have easy access to water and maintain a con- If increasing the dose leads to a greater increase in urine sistent liquid intake. As a consequence, some patients may osmolarity, this implies that the V2 receptors were not suf- present hypernatremia, so it is important to insist on the need ficiently blocked with the previous dose. to drink water when thirsty, including at night if they get up c In ADPKD there is a progressive defect in the ability to urinate, and monitor this parameter during treatment. A to concentrate urine (partial resistance to ADH, partial variable percentage of patients are unable to tolerate polyuria nephrogenic diabetes insipidus), a phenomenon common and abandon treatment. to all advanced CKD but magnified in ADPKD by the pres- There is a special control call for idiosyncratic hepatotox- ence of cysts that distort renal architecture and limit the icity, rare, but with the possibility of serious liver damage. ability to form an adequate corticomedullary osmolar con- In order to monitor this effect, transaminases and liver centration gradient. As a consequence, these patients may function tests should be monitored monthly during the first have high ADH levels despite, and precisely because, they 18 months of treatment and every 3 months after 18 months have polyuria with low urine osmolarity. That is, in a given (http://www.ema.europa.eu/docs/en GB/document library/ patient it may be difficult to distinguish low but not very low EPAR - Product Information/human/002788/WC500187921. urine osmolarity because a reasonable degree of V2 recep- pdf). tor blockade has been achieved or because the patient has There are clinical situations that must be taken into con- an inability to concentrate urine due to ADPKD and, as con- sideration when starting treatment with tolvaptan, such as sequence, they have estimulation of ADH, with persistent the presence of a history of hyperuricaemia-gout, the use activation of V2 receptors. of diuretics, diabetes mellitus or urinary problems that pre- d The main argument in favor of adjusting the dose according vent a high urinary flow. Such conditions can potentially be to urinary osmolarity would be to facilitate clinical tol- worsened by the use of tolvaptan. Tolvaptan (Jinarc® , Otsuka erance by limiting the aquaretic effect; the tolerance to Pharmaceutical SA) should be given twice a day. The morning aquaretic effects is usually lower when the eGFR is more dose at least 30 min before breakfast and the second dose 8 h conserved, since patients usually start with a smaller vol- later with or without food. The dose regimen will be: ume of diuresis (having not yet developed the inability to concentrate urine) and have a greater diuretic response, –45 mg + 15 mg given their higher eGFR. In this sense, the discussion of the –60 mg + 30 mg magnitude of the symptoms with the patient could guide –90 mg + 30 mg. the dose adjustment to improve tolerance. n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 383 Recommendations (see section Recommendations for consensus definition: loss of more than 5 ml/min/1.73 m2 /year Assessment in ADPKD Progression) of eGFR. But this definition seems too strict for patients with ADPKD, which has a long natural history of disease (60 years). 1 Treatment with tolvaptan can be considered in patients with In fact, the mean GFR loss in the placebo group in the tolvap- ADPKD up to 60 years of age and criteria of rapid progression tan clinical trials was 3.6–3.8 ml/min/year. To be practical, all in CKD stages 1–3b and exceptionally stage 4 (D). those patients who need RRT before the average age of start- 2 It is recommended that the indication of the treatment be shared ing RRT in Spain, that is, around 65 years, can be considered between the patient and the nephrologist once the patient’s clinical that progresses rapidly. characteristics and lifestyle have been assessed (D). The main risk factors for progression of CKD in ADPKD 3 It is recommended to take into account and assess adverse effects, are genetic, VRT and hypertension. Genetic factors depend especially hepatotoxicity during treatment with tolvaptan (D). on the mutated gene (a pathogenic variant in PKD1 has a 4 It is recommended to start treatment with tolvaptan with 45 mg in worse prognosis) and the type of sequence variant (the trun- the morning and 15 mg after 8 h of the morning dose and increase cating type being more serious)126 . VRT is the best predictor the dose until reaching 90/30 mg as the highest tolerable dose (D). of CKD progression125,127 . As renal volume increases, the rate 5 It is recommended to evaluate the osmolarity urine in the first of decrease in eGFR is greater125 , although there are discor- urine in the morning, at the beginning and follow-up of treatment dant results from clinical trials, where an improvement in TRV with tolvaptan to confirm therapeutic compliance and its efficacy. is not accompanied by an improvement in the evolution of (D) eGFR128 . HTN is associated with a higher TRV41 . The Working Group of Inherited Kidney Diseases (WGIKD) of the European Dialysis and Transplant Association (EDTA) Assessment of rapid progression in ADPKD together with the European Renal Best Practice Guidelines (ERBP) group proposed a definition of rapid progression Tolvaptan is the only ADPKD medication that modifies in ADPKD that has now become obsolete as mentioned progression of the disease and it approved by the EMA for in their website (http://www.european-renal-best-practice. ADPKD. Based on the aforementioned clinical variability and org/content/erbp-documents-topic; accessed 20 Aug 2019). 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 Based on the evidence provided by the of the disease” (https://www.ema.europa.eu/en/documents/ TEMPO3/4, TEMPO 4/4 and REPRISE studies, we product-information/jinarc-epar-product-information en.pdf; propose the following criteria to define rapid accessed 21 Aug 2019). The EMA does not specify what it progression considers rapid progression. The EMA indication does not clarify what is considered as rapid progression. To adequately define rapid progression, it is necessary to 1 We suggest to stop using the EDTA/ERBP algorithm. understand the clinical history of the disease, which, on aver- 2 We suggest including patients up to 60 years of age in the age, is 6 decades. Thus, in ADPKD patients the renal function assessment of rapid progression. The average age of ESRD remains normal during the first decades of life despite the in Spain is 65 years. We consider rapid progressors those growth of the TRV. So at this stage it is especially useful to patients with ADPKD who require RRT before the mean age assess the TRV to determine the prognosis125 . The clinical of RRT in Spain (D). spectrum of polycystic disease is broad; there are patients who 3 We suggest to include, for assessment of rapid progres- only develop a limited number of bilateral cysts, which are sion, patients with eGFR > 30 ml/min. At the individual level, unlikely to lead to loss of renal function and require renal treatment can be considered with eGFR > 15 ml/min (D). replacement therapy, while at the other extreme there are 4 We suggest that patients between 55 and 60 years should severe neonatal forms of the disease. have a GFR < 60 ml/min at the start of treatment. If at this Therefore we recognize 2 situations: age the GFR is >60 ml/min, it would be very unlikely for them to need RRT before the age of 65 (D). a The patient who is already losing eGFR rapidly. 5 We suggest that to assess the start of treatment with tolvap- b The patient who is still in the initial stage of apparent sta- tan all patients should have a measurement of TRV by MRI bility of renal function during the first decades of life but or CT (or in cases with symptoms before the age of 35, with data that predict a rapid progression of CKD. These although a genetic study showing a truncating mutation in data may be a prediction of rapid progression based on PKD1 may be sufficient). genetic and clinical data or a finding that rapid progres- 6 We suggest that a patient who meets one of the follow- sion is already occurring subclinically in the form of a rapid ing criteria be considered a rapid progresser (Figs. 1 and 2), increase in TRV. The identification of risk factors for the simplified algorithm: rapid progression of CKD will make it possible to start early i VRT adjusted for height, in patients with bilateral sym- treatment in high-risk patients and start it before the stage metric involvement, belonging to the Mayo classification of rapid loss of eGFR is achieved. 1D or 1E (C) or ii PRO-PKD score > 6 (C) or An additional problem is what is considered a rapid pro- iii Height-adjusted VRT in patients with bilateral symmet- gression from the point of view of eGFR. There is a KDIGO ric involvement belonging to the Mayo 1C classification: 384 n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 Age Age 55 a 60 years Age >60years Age 18 a 55 years GFRe≤ 60 no*,** It is suggested to no*,** GFRe≥ 30 y ≥ 30 exclude evaluation yes yes Rapid progression criteria Image test PRO-PKD Score Renal ultrasound Abdominal MR or CT no >6 yes no Kidneys Mayo Class Mayo Class Mayo Class >13cm 1A o 1B 1C 1D o 1E yes*** Reduction GFRe yes Start Perform abdominal FGe ≥3.5 ml/in Tolvaptan MR or CT 3 years no *Assess individually if GFR 15-30 ml/min At this moment it is not Most family yes ** Consider the use of Cystatin clearace, creatinine considered a fast progressor members terminal clearance, Iohexol in special circumstances CKD no<58 *** Consider to take into acount the age and the morphology no of the kidneys Fig. 1 – Algorithm for the evaluation of rapid progression in ADPKD. Age Age > 60 years Age 55 a 60 years Age 18 a 55 years FG 30 -60 ml/min FG > 30 ml/min Do not treat * individualize 15 - 30 ml/min * individualize 15 - 30 ml/min + + * Criteria RP * Criteria RP * Criteria RP: criteria of rapid progression • TRV (Mayo clinic Model) • Class 1D/1E • Class 1 C + decrease GFR 3,5 ml/min/year During 3 years or family Hx of RRT<58 years • PROADPKD > 6 Fig. 2 – Simplified algorithm for the evaluation of rapid progression in ADPKD. a If the retrospective decline in eGFR over the past 3 i In routine clinical practice, eGFR is used based on years is ≥3.5 ml/year (corresponding to the average serum creatinine (CKD-EPI equation or MDRD4 in case decline in eGFR in patients in Mayo Clinic class 1D) of GFR < 60). However, this is just an estimate that only or applies to people who have an expected muscle mass for b If most of the relatives reached ESRD before 58 years their gender or age. (the mean age of RRT in Europe for ADPKD) (D). ii The equation is wrong and its use is not recommended 7 When defining eGFR decline, we must take into account the for people who have more muscle mass than expected following considerations (D). (eg athletes) or less (eg malnutrition). i There are medications that modify the eGFR, including iii If it is suspected that the eGFR formulas cannot be NSAIDs, ACE inhibitors, ARBs, and fenofibrate that must applied to a particular patient, there are alternatives: be taken into account (B). - 24-h urine creatinine clearance. ii Other causes besides ADPKD that justify a drop in eGFR - Measure eGFR with iohexol clearance. (C) must be ruled out. - Cystatin C measurement. 8 When defining the eGFR, it must be taken into account the 9 We suggest that the VRT be evaluated by MRI (C). following considerations (D): i Currently, gadolinium-free MRI is the gold standard for measuring TRV when both kidneys are enlarged. The n e f r o l o g i a. 2 0 2 2;4 2(4):367–389 385 use of the ellipsoid formula is acceptable to measure the Transplant. 2013;28:1472–87, VRT. The distinction between “typical” and “atypical” is http://dx.doi.org/10.1093/ndt/gfs551. recommended with respect to renal morphology (B). 4. Morales Garcia AI, Martinez Atienza M, Garcia Valverde M, et al. Overview of autosomal dominant polycystic kidney ii In patients with kidneys >13 cm in diameter by ultra- disease in the south of Spain. Nefrologia. 2018;38:190–6, sound, we suggest to assess: based on age (slightly http://dx.doi.org/10.1016/j.nefro.2017.07.002. enlarged kidneys in young adults may indicate rapid pro- 5. Martínez V, Comas J, Arcos E, et al. Renal replacement gression while this is not the case in older ages) and renal therapy in ADPKD patients: a 25-year survey based on the appearance (eg, a large renal cyst is not significant but Catalan registry. BMC Nephrol. 2013;14:186, multiple cysts that increase renal size are). Perform a http://dx.doi.org/10.1186/1471-2369-14-186. baseline MRI and repeat every 3–5 years if the patient is 6. Collins AJ, Foley RN, Herzog C, et al. US renal data system 2012 annual data report. Am J Kidney Dis. 2013;61, not receiving treatment with tolvaptan (D). http://dx.doi.org/10.1053/j.ajkd.2012.11.031. A7, e1-476. iii Serial TRV measurements are not recommended in rou- 7. Mochizuki T, Wu G, Hayashi T, et al. PKD2, a gene for tine clinical practice if renal diameter is normal or, polycystic kidney disease that encodes an integral during treatment with tolvaptan. Although they may be membrane protein. Science (80-). 1996;272:1339–42, of interest in specific clinical situations (D). Centers that http://dx.doi.org/10.1126/science.272.5266.1339. do not have access to MR can: 8. The European Polycystic Kidney Disease Consortium. The polycystic kidney disease 1 gene encodes a 14 kb transcript a Refer the patient to a center with an ADPKD unit. and lies within a duplicated region on chromosome 16. The b Use the PRO-PKD if the patient has presented urolog- European Polycystic Kidney Disease Consortium. Cell. ical symptoms or HTN before the age of 35. 1994;77:881–94, c Perform a CT once and evaluate according to the Mayo http://dx.doi.org/10.1016/0092-8674(94)90137-6. classification. 9. Porath B, Gainullin VG, Cornec-Le Gall E, et al. Mutations in GANAB, encoding the glucosidase iialpha subunit, cause autosomal-dominant polycystic kidney and liver disease. Am J Hum Genet. 2016;98:1193–207, Conflict of interests http://dx.doi.org/10.1016/j.ajhg.2016.05.004. 10. Cornec-Le Gall E, Olson RJ, Besse W, et al. Monoallelic The authors do not declare any conflict of interest. Otsuka mutations to DNAJB11 cause atypical autosomal-dominant Pharmaceutical has not been involved in the development of polycystic kidney disease. Am J Hum Genet. 2018;102:832–44, the guidelines. Their participation has consisted exclusively http://dx.doi.org/10.1016/j.ajhg.2018.03.013. of financing their layout. 11. Carney EF. Polycystic kidney disease: cyst growth and cilia in ADPKD. Nat Rev Nephrol. 2013;9:555, http://dx.doi.org/10.1038/nrneph.2013.160. 12. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in Thanks patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367:2407–18, The Spanish clinical guidelines for ADPKD are endorsed by http://dx.doi.org/10.1056/NEJMoa1205511. the Spanish Society of Nephrology (SEN), the Spanish Net- 13. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in work for Renal Research (REDinREN RD016/0006)) and the later-stage autosomal dominant polycystic kidney disease. patient association: Association for Research and Information N Engl J Med. 2017;377:1930–42, on Hereditary Renal Diseases (AIRG -AND). http://dx.doi.org/10.1056/NEJMoa1710030. 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