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American Journal of Kidney Diseases

Preimplantation Genetic Diagnosis Counseling in Autosomal Dominant Polycystic Kidney Disease

Published:March 30, 2018DOI:https://doi.org/10.1053/j.ajkd.2018.01.048
      Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary forms of chronic kidney disease. Mutations within PKD1 or PKD2 lead to innumerable fluid-filled cysts in the kidneys and in some instances, end-stage renal disease (ESRD). Affected individuals have a 50% chance of passing the mutation to each of their offspring. Assisted reproductive technology using preimplantation genetic diagnosis (PGD) allows these individuals to reduce this risk to 1% to 2%. We assess the disease burden of 8 individuals with ADPKD who have undergone genetic testing in preparation for PGD. Clinical features that predict high risk for progression to ESRD in patients with ADPKD include genotype, early onset of hypertension, a urologic event before age 35 years, and a large height-adjusted total kidney volume. Patients may have a family history of intracranial aneurysms or complications involving hepatic cysts, which may further influence the decision to pursue PGD. We also explore the cost, risks, and benefits of using PGD. All patients with ADPKD of childbearing potential, regardless of risk for progression to ESRD or risk for a significant disease burden, will likely benefit from genetic counseling.

      Index Words

      Introduction

      Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disease characterized by the development and growth of numerous fluid-filled cysts within the kidneys and other organs. It is a genetically heterogeneous disorder caused primarily by mutations in either the PKD1 or the PKD2 gene.
      • Torres V.E.
      • Harris P.C.
      • Pirson Y.
      Autosomal dominant polycystic kidney disease.
      Approximately 78% and 15% of ADPKD cases are due to mutations in PKD1and PKD2, respectively; 0.3% are due to mutations in GANAB, with no mutation detected in the remaining cases.
      • Heyer C.M.
      • Sundsbak J.L.
      • Abebe K.Z.
      • et al.
      Predicted mutation strength of nontruncating PKD1 mutations aids genotype-phenotype correlations in autosomal dominant polycystic kidney disease.
      • Cornec-Le Gall E.
      • Torres V.
      • Harris P.C.
      Genetic complexity of autosomal dominant polycystic kidney and liver diseases.
      No case of end-stage renal disease (ESRD) due to a GANAB mutation has been described.
      • Cornec-Le Gall E.
      • Torres V.
      • Harris P.C.
      Genetic complexity of autosomal dominant polycystic kidney and liver diseases.
      PKD1 mutations are more severe; the median ages of ESRD from PKD1 and PKD2 mutations are 58.1 and 79.7 years, respectively.
      • Cornec-Le Gall E.
      • Audrezet M.P.
      • Chen J.M.
      • et al.
      Type of PKD1 mutation influences renal outcome in ADPKD.
      The type of mutation within PKD1 strongly influences the severity and progression of ADPKD, with truncating PKD1 mutations associated with more aggressive disease and earlier ESRD onset.
      • Cornec-Le Gall E.
      • Audrezet M.P.
      • Chen J.M.
      • et al.
      Type of PKD1 mutation influences renal outcome in ADPKD.
      Nontruncating PKD1 mutations differ in pathogenicity because of chemical differences in the amino acid side chain at the site of the substitution.
      • Heyer C.M.
      • Sundsbak J.L.
      • Abebe K.Z.
      • et al.
      Predicted mutation strength of nontruncating PKD1 mutations aids genotype-phenotype correlations in autosomal dominant polycystic kidney disease.
      Conversely, patients with no mutation detected and no family history may have a more benign clinical course.
      • Braun W.E.
      • AK
      • Brosnahan G.
      • Patterson C.G.
      • Chapman A.B.
      • Harris P.C.
      ADPKD progression in patients with no apparent family history and no mutation detected by sanger sequencing.
      Abnormalities such as necrospermia, ultrastructural flagellar defects, immotile sperm, and seminal vesicle and ejaculatory duct cysts, which can cause infertility or subfertility in men with ADPKD, have been noted.
      • Vora N.
      • Perrone R.
      • Bianchi D.W.
      Reproductive issues for adults with autosomal dominant polycystic kidney disease.
      Men with abnormal sperm parameters that decrease or eliminate the probability of natural conception may wish to seek in vitro fertilization (IVF) with or without preimplantation genetic diagnosis (PGD) with their partner.
      • Vora N.
      • Perrone R.
      • Bianchi D.W.
      Reproductive issues for adults with autosomal dominant polycystic kidney disease.
      Pregnant women with ADPKD and decreased kidney function should be closely monitored for the development of hypertension and preeclampsia.
      • Vora N.
      • Perrone R.
      • Bianchi D.W.
      Reproductive issues for adults with autosomal dominant polycystic kidney disease.
      A detailed fetal ultrasonographic examination at 18 to 20 weeks of gestation is also indicated because ADPKD has occasionally been associated with early-onset severe in utero disease.
      Because of the high probability of disease transmission, IVF with PGD may be an attractive option for patients with ADPKD who wish to have unaffected children. For single-gene disorders, PGD involves extraction, amplification, and analysis of DNA removed from the blastomere or trophectoderm of embryos created using IVF. The accuracy of PGD is highest when DNA analysis includes both direct mutation testing and linkage analysis of polymorphic markers closely linked to the gene of interest to ensure that there is no allelic drop out.
      Identification of the pathogenic mutation is a prerequisite for PGD. If direct mutation analysis fails to identify a single pathogenic mutation, either because multiple potential pathogenic variants are identified or no mutation is detected, the use of family-based linkage analysis may be required to determine the locus of the pathogenic PKD mutation.
      • Harris P.C.
      • Rossetti S.
      Molecular diagnostics for autosomal dominant polycystic kidney disease.
      • Bogdanova N.
      • Markoff A.
      • Gerke V.
      • McCluskey M.
      • Horst J.
      • Dworniczak B.
      Homologues to the first gene for autosomal dominant polycystic kidney disease are pseudogenes.
      The patient must have a large enough family to support linkage to PKD1 or PKD2. Thus, failure to identify a causative gene mutation in a patient with ADPKD may preclude the use of PGD in cases in which small family size may not permit robust conclusions from a linkage-based study.
      When a genetic variant of uncertain pathologic significance is identified in a person with ADPKD, testing of other family members is necessary to demonstrate segregation of the variant with affected family members (and its absence in unaffected family members), thereby providing more evidence for or excluding the pathogenicity of the variant.
      With PGD, embryos may also be screened for aneuploidy; only euploid embryos predicted to be without the familial ADPKD mutation are transferred into the womb or frozen for future use.
      • Swift O.
      • Vilar E.
      • Rahman B.
      • Side L.
      • Gale D.P.
      Attitudes in patients with autosomal dominant polycystic kidney disease toward prenatal diagnosis and preimplantation genetic diagnosis.
      Diagnostic error rates associated with PGD for single-gene disorders are 1% to 2% and are attributable to various technical complications and biological phenomena. For this reason, invasive prenatal diagnosis by chorionic villus sampling at 10 weeks’ gestation or amniocentesis at 15 weeks’ gestation is recommended to confirm the results of PGD if pregnancy termination would be considered if the fetus were affected. Regardless of whether PGD has been performed, the risk for birth defects associated with IVF adds about a 1% risk to the 3% background risk faced by the general population. Whether this small increased risk is attributable to abnormalities caused by manipulation of the gametes outside the womb or parental characteristics that lead them to seek treatment for infertility (the most common reason for IVF) has not been established. Before IVF with PGD, patients are thoroughly counseled and asked to sign a consent that acknowledges all known risks and diagnostic limitations associated with these procedures and includes the recommendation for confirmatory prenatal diagnosis by invasive testing.
      IVF with PGD has been reported to successfully prevent transmission of ADPKD to a child.
      • De Rycke M.
      • Georgiou I.
      • Sermon K.
      • et al.
      PGD for autosomal dominant polycystic kidney disease type 1.
      In this Perspective, we describe a case of a woman with ADPKD who used IVF with PGD to increase the likelihood of achieving an unaffected pregnancy. We use this case to illustrate why PGD, a costly procedure, is a reasonable option for some individuals with ADPKD, particularly in the setting of severe disease in a parent or other relatives. We also provide some suggestions for counseling patients with ADPKD.

      Case Presentation

      A 31-year-old white woman with renal and hepatic cysts who has a family history of ADPKD has decided to pursue IVF with PGD because of her mother’s experience with ADPKD. At age 29 years, the patient’s kidney volumes were 165 mL bilaterally and her height-adjusted total kidney volume (htTKV) was 217 mL/m (imaging class 1A).
      • Irazabal M.V.
      • Rangel L.J.
      • Bergstralh E.J.
      • et al.
      Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials.
      Within 1 year, her total kidney volume (TKV) increased by 45%, with the right and left kidneys measuring 217 and 261 mL, respectively, with htTKV of 304 mL/m (imaging class 1B). Magnetic resonance imaging showed innumerable renal cysts; some contained proteinaceous material and hemorrhage (Fig 1A). The patient developed hypertension at age 29 years and experienced preeclampsia during her first pregnancy, described later.
      Figure thumbnail gr1
      Figure 1Magnetic resonance imaging and preimplantation genetic diagnosis (PGD) data for a patient with a truncating PKD1 mutation. (A) Coronal T2-weighted magnetic resonance image in the 30-year-old case patient performed before genetic testing. (B) Pedigree depiction of the family linkage analysis performed using short tandem repeat (STR) analysis. Samples were collected from the case patient (IIIi), her husband, and her mother (IIiii). Microsatellite markers (STRs) linked to the mutant allele are depicted in red. (C) Linked STRs from (B) were used to determine autosomal dominant polycystic kidney disease (ADPKD) status of embryos from both in vitro fertilization cycles. All viable embryos, regardless of ADPKD status, were tested for aneuploidies. Only embryos predicted to be negative for aneuploidy without the familial mutation were considered for embryo transfer. Abbreviations: ADO, allele drop out; FA, failed amplification due to the absence or severe degradation of DNA; NGS, next-generation sequencing.
      The patient’s maternal grandfather died of a cerebral hemorrhage at age 48 years and likely had ADPKD (Fig 1B, number Ii). Her mother had ADPKD diagnosed in her mid-20s and currently has stage 4 chronic kidney disease (Fig 1B, number IIiii). Though this patient (Fig 1B, number IIIi) had small kidneys, she is at high risk for progression to ESRD because of early-onset hypertension, a truncating PKD1 mutation, and a very large increase in TKV during 1 year.
      The patient underwent complete ADPKD gene analysis through Athena Diagnostics,

      Athena Diagnostics. Complete PKDx Evaluation. http://www.athenadiagnostics.com/view-full-catalog/c/complete-pkdx-evaluation. Accessed May 8, 2017.

      which detects mutations and deletions in PKD1 and PKD2 through Sanger sequencing and multiplex ligation-dependent probe amplification. Several other laboratories also provide complete PKD1 and PKD2 analysis. We favor those that have a demonstrated track record with PKD1 sequencing, which is technically difficult because of the presence of 6 pseudogenes. Analysis showed a heterozygous transition mutation (c.8978C>T [a cytosine to thymine substitution at nucleotide 8978 of the coding sequence]) resulting in a truncating and known disease-associated mutation of PKD1. Family linkage analysis of the PKD1 locus using short tandem repeats (STRs; ie, microsatellite markers) was performed on DNA samples from the patient, her partner, and her mother (Fig 1C). Figure 1B depicts the ADPKD pedigree and lists the microsatellite markers associated with her PKD1 mutation.
      The patient underwent 2 cycles of IVF with PGD for ADPKD and for aneuploidy screening (Fig 1C). PGD was performed by linkage analysis only because the testing laboratory cited concern over the presence of PKD1 pseudogenes that could complicate direct mutation detection. The unique STRs associated with the disease-causing mutation are D16S-525, D16S-3024, KG8, and Intron 1 (Fig 1B and C). The ADPKD-associated STR in this family are 161, 123, 92, and 218, respectively, highlighted in red. STR 181, 135, 98, and 225 are associated with the patient’s non–mutation-bearing copy of PKD1, while 173, 127, 98, and 225 are from her unaffected partner.
      The first IVF cycle produced 2 embryos; 1 was predicted to be both unaffected by ADPKD and euploid. It was transferred into the womb but did not result in pregnancy. The second cycle produced 9 embryos; 4 were predicted to be unaffected by ADPKD. Of those, 1 embryo predicted to be euploid was transferred and resulted in a viable pregnancy. No fetal abnormalities were noted on ultrasound at 18 weeks’ gestation. At 37 weeks’ gestation, the patient delivered a healthy baby girl weighing 2.5 kg (Fig 1B, number IVi). Neither prenatal nor postnatal PKD1 testing of the baby was performed.

      Chart Review of Other Cases of ADPKD Patients Seeking IVF With PGD

      In addition to the case patient (patient 1), 7 other patients with ADPKD under our care recently sought IVF with PGD to conceive (Table 1). Individual and family medical histories pertaining to ADPKD were collected to predict disease severity and prognosis. Molecular testing through Athena Diagnostics identified the genetic mutations, and the Mayo Clinic ADPKD Mutation Database

      PKD Foundation. Autosomal Dominant Polycystic Kidney Disease Mutation Database: PKDB. http://pkdb.mayo.edu. Accessed April 1, 2017.

      was used to determine whether a mutation was novel. Seven patients had novel mutations, 4 patients had truncating mutations, and 4 patients required additional testing of family members to determine whether the variant (of uncertain pathologic significance) detected was associated with disease. Cases 4, 5, and 6 are likely to have truncating PKD1 mutations based on the location of the mutation.
      Table 1Medical History, Family History, and Genotype of ADPKD Patients Seeking IVF With PGD
      PtFactors Affecting ProgressionAdditional HistoryPKD Mutation
      A novel mutation is one not listed in the Mayo ADPKD Mutation Database.13
      Risk of Progression to ESRD
      Risk of progression to ESRD was determined by PROPKD score14 (0-9 points; risk classified as low [0-3 points], intermediate [4-6 points], or high [7-9 points]) or by genetics score, which was used for patients aged <35 years and calculated based on sex and mutation type (1-4 points; risk classified as low [1 point] or high [≥2 points]), and by Mayo imaging classification11 of ADPKD (risk classified as low [1A and 1B] or high [1C, 1D, and 1E].
      1
      • 31 y; F
      • TKV: 478 mL
      • htTKV: 304.5 mL/m
      • HTN
      • No urologic events
      • Innumerable hepatic cysts
      • Possibly affected maternal grandfather died due to a cerebral hemorrhage at age 48
      • Affected mother reached CKD4 in mid-50s
      PKD1: c.8978C>T (p.Q2923X) (truncating; not novel)Genetics score: 3 (high risk); imaging class: 1B (low risk)
      2
      • 30 y; F
      • Kidney size on US: 16 cm (R), 17 cm (L)
      • HTN
      • No urologic events
      • Multiple scattered hepatic cysts
      • Affected father reached ESRD in mid-40s
      • Affected paternal aunt died due to a ruptured cerebral aneurysm (late 40s)
      PKD1: deletion of exons 27-29 (truncating; novel)Genetics score: 3 (high risk); imaging class: NA
      3
      • 39 y; F
      • TKV: 1,110 mL
      • htTKV: 730.3 mL/m
      • HTN
      • No urologic events
      • Innumerable hepatic cysts
      • Affected father reached ESRD at age 60; received kidney and liver transplant
      • Affected paternal uncle
      • Affected brother
      PKD1: c.2540C>T (p.Q777X) (truncating; novel)PROPKD score: 6 (intermediate risk); imaging class: 1C (high risk)
      4
      • 27 y; F
      • Kidney size on US: 13.8 cm (R), 14.9 cm (L)
      • HTN
      • Persistent flank pain (L)
      • No hepatic cysts
      • Affected mother reached ESRD at age 56
      PKD1: c.8537_8532dup11 (p.T2775fs) (frameshift; may be truncating; novel)PROPKD score: 8 (high risk); imaging class: NA
      5
      • 32 y; M
      • Kidney size on US: 11.3 cm (R), 13.2 cm (L)
      • HTN
      • No urologic events
      • Hepatic cysts
      • Affected mother has CKD4 (age 59)
      • Affected maternal grandfather died age 54
      • Affected maternal great-grandmother died age 40
      PKD1: c.9779G>A (p.G3190R) (likely truncating [near splice site]; novel)

      PKD1: c.8387C>T (p.S2726S) (silent; likely benign; not novel)
      Genetics score: 4 (high risk); imaging class: NA
      6
      • 32 y; F
      • Diagnosed at age 6 mo
      • Imaging NA
      • HTN
      • No urologic events
      • Affected mother reached ESRD at age 52
      • Affected maternal uncle received transplant
      • Affected maternal grandmother reached ESRD at age 65
      PKD1: IVS42-3C>G (likely truncating; novel) PKD1: c.7489T>C (p.S2426S) (silent; likely benign; not novel)Genetics score: 3 (high risk); imaging class: NA
      7
      • 37 y; M
      • TKV: 5,079 mL
      • htTKV: 2,565.2 mL/m
      • HTN
      • No urologic events
      • Multiple hepatic cysts
      • Affected father reached ESRD at age 40; died due to CVA at age 44
      • Possibly affected paternal grandfather, died due to CVA, age 45
      PKD1: c.7008G>C (p.R2266P) (nontruncating; novel); PKD1: c.355C>G (p.R48R) (silent; likely benign; novel); 18 other PKD1 variants and 1 PKD2 variant (all likely benign; novel)PROPKD score: 5 (intermediate risk); imaging class: 1E, (high risk)
      8
      • 44 y; M
      • TKV: 3,336 mL
      • htTKV: 1,774.5 mL/m
      • HTN
      • Upper UTI (kidney/bladder)
      • No hepatic cysts
      • Affected mother
      PKD2: deletion of exons 5-15 (truncating; novel)PROPKD score: 5 (intermediate risk); imaging class: 1D (high risk)
      Note: Retrospective chart review was approved by the Yale Human Investigation Committee (HIC Protocol ID 2000020101); informed consent was not deemed applicable for this chart review.
      Abbreviations and definitions: ADPKD, autosomal dominant polycystic kidney disease; C, cytosine; CKD4, chronic kidney disease stage 4; CVA, cerebrovascular accident; dup, duplication; ESRD, end-stage renal disease; fs, frameshift; G, glycine (protein level) or guanine (DNA level); HTN, hypertension; htTKV, height-adjusted total kidney volume; IVF, in vitro fertilization; NA, not available; PGD, preimplantation genetic diagnosis; PROPKD, Predicting Renal Outcomes in PKD; Pt, patient; Q, glutamine; R, arginine; S, serine; TKV, total kidney volume; US, ultrasound; UTI, urinary tract infection; X, termination codon.
      a A novel mutation is one not listed in the Mayo ADPKD Mutation Database.

      PKD Foundation. Autosomal Dominant Polycystic Kidney Disease Mutation Database: PKDB. http://pkdb.mayo.edu. Accessed April 1, 2017.

      b Risk of progression to ESRD was determined by PROPKD score
      • Cornec-Le Gall E.
      • Audrezet M.P.
      • Rousseau A.
      • et al.
      The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease.
      (0-9 points; risk classified as low [0-3 points], intermediate [4-6 points], or high [7-9 points]) or by genetics score, which was used for patients aged <35 years and calculated based on sex and mutation type (1-4 points; risk classified as low [1 point] or high [≥2 points]), and by Mayo imaging classification
      • Irazabal M.V.
      • Rangel L.J.
      • Bergstralh E.J.
      • et al.
      Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials.
      of ADPKD (risk classified as low [1A and 1B] or high [1C, 1D, and 1E].
      Genotype and clinical characteristics were used to determine a PROPKD or genetics score
      • Cornec-Le Gall E.
      • Audrezet M.P.
      • Rousseau A.
      • et al.
      The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease.
      and Mayo imaging classification.
      • Irazabal M.V.
      • Rangel L.J.
      • Bergstralh E.J.
      • et al.
      Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials.
      These assessments were then used to determine each patient’s risk for progression to ESRD. A summary of clinical risk factors, additional medical histories, mutation information including the predicted effects on protein structure, risk scores, and imaging classification are shown in Table 1. In general, there is good correlation between severity by imaging classification and that by genetic score or PROPKD score; however, patients 1 and 8 show strikingly different risk categorization. This may be due to the patient’s young age in case 1 and unknown genetic modifiers in case 8.

      Discussion

      ADPKD and its complications adversely affect quality of life. Significantly worse kidney function is seen in patients who experience their first urologic events at an early age (≤35 years old), and although hypertension is common with ADPKD, an early diagnosis (≤35 years old) is associated with greater risk for progression.
      • Cornec-Le Gall E.
      • Audrezet M.P.
      • Rousseau A.
      • et al.
      The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease.
      An increase in TKV can be attributed to an increase in cyst burden and is a commonly used method to determine progression.
      • Tangri N.
      • Hougen I.
      • Alam A.
      • Perrone R.
      • McFarlane P.
      • Pei Y.
      Total kidney volume as a biomarker of disease progression in autosomal dominant polycystic kidney disease.
      On average, TKV increases by 5.27% ± 3.92% per year and a baseline TKV > 1,500 mL is associated with a declining glomerular filtration rate by an average of 4.33 ± 8.07 mL/min per year.
      • Grantham J.J.
      • Torres V.
      • Chapman A.B.
      • Guay-Woodford L.M.
      • et al.
      Volume progression in polycystic kidney disease.
      htTKV is a prognostic biomarker for ADPKD progression because a large baseline htTKV of 600 mL/m predicts an increased risk for developing decreased kidney function within 8 years.
      • Chapman A.B.
      • Bost J.E.
      • Torres V.E.
      • et al.
      Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease.
      Average TKV measurements in healthy men and women are 202 ± 36 mL and 154 ± 33 mL, respectively.
      • Cheong B.
      • Muthupillai R.
      • Rubin M.F.
      • Flamm S.D.
      Normal values for renal length and volume as measured by magnetic resonance imaging.
      ADPKD is a systemic disease. Patients may consider IVF with PGD because of a family history of early death or disability from a ruptured cerebral aneurysm or from pain and discomfort because of liver cysts. More than 20% of patients with ADPKD have a family history of intracranial aneurysms or subarachnoid hemorrhage, although a link to disease progression and severity is not well established.
      • Huston 3rd, J.
      • Torres V.E.
      • Sulivan P.P.
      • Offord K.P.
      • Wiebers D.O.
      Value of magnetic resonance angiography for the detection of intracranial aneurysms in autosomal dominant polycystic kidney disease.
      A family history of liver cysts may also influence choosing PGD because quality of life is greatly diminished in patients with large liver volumes.
      • Neijenhuis M.K.
      • Kievit W.
      • Perrone R.D.
      • et al.
      The effect of disease severity markers on quality of life in autosomal dominant polycystic kidney disease: a systematic review, meta-analysis and meta-regression.
      As shown in Table 1, genetic and phenotypic findings can aide in determining which patients with ADPKD might be at high risk for loss of kidney function and therefore may be more likely to elect IVF with PGD. The ADPKD (PROPKD) score
      • Cornec-Le Gall E.
      • Audrezet M.P.
      • Rousseau A.
      • et al.
      The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease.
      or the Mayo imaging classification
      • Irazabal M.V.
      • Rangel L.J.
      • Bergstralh E.J.
      • et al.
      Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials.
      may further guide a dialogue regarding risk for ESRD. The risk calculators define risk for the patient but do not provide prognostic information for the patient’s offspring. Although men and women with severe disease might self-select for IVF with PGD, clinicians should consider discussing reproductive options and available genetic services to all patients with ADPKD except those who decline.
      Four of the 8 individuals in Table 1 subsequently underwent IVF with PGD, resulting in live births. Direct mutation detection was used to validate the PKD status of the embryos from 2 cases, whereas linkage analysis was used for the third. There were no data pertaining to the testing methods used for the fourth case. The preferred testing method is specific to the laboratory providing the analysis. Accuracy is highest when both direct mutation testing and linkage analysis are used.
      PGD is performed before embryo transfer into the womb, thereby minimizing the difficult decision of early-term abortions of affected pregnancies diagnosed prenatally. Though abortion laws vary within the United States, in the state of Connecticut, for example, pregnancy termination is an option for any woman regardless of fetal health status until 23 weeks 6 days’ gestation. PGD with IVF may be ethically preferable for some couples at risk for a child with ADPKD for whom pregnancy termination is not an option. Confirmation of the results of PGD using a prenatal diagnosis procedure or testing of the newborn is always recommended and is the standard of care for severe childhood-onset disorders. However, in our experience, this confirmatory testing has not been done routinely for ADPKD.
      All nephrologists should feel comfortable discussing the reproductive options currently available to patients (Box 1). If a patient remains interested, clinicians should order necessary genetic testing and consider referral to fertility and genetics specialists to provide a more in-depth discussion regarding the diagnostic capabilities, limitations, and risks associated with various reproductive testing approaches. In addition, reproductive counseling should be ongoing, occurring initially with every patient and approached again as patients or partners feel ready to discuss family planning. Counseling will be more nuanced in patients without a family history of ADPKD (ie, patients who are adopted or who have de novo mutations) or without a detectable genetic mutation compared with patients who have a family history and/or a known pathogenic mutation.
      Initiating a Dialogue Regarding PGD
      • All patients with ADPKD who might consider having children in the future should be counseled about family planning and reproductive options, including PGD and available genetic services.
      • The decision to pursue or decline assisted reproductive technology or prenatal diagnosis of ADPKD is a personal choice based on patient beliefs, experience, and preferences; either decision should be fully supported.
      • Genotype, early-onset hypertension, and large htTKV predict high risk for clinical progression to ESRD.
      • Other factors that may lead to patient interest in PGD include family history of aggressive disease manifestations such as intracranial aneurysm rupture or complications of hepatic cysts.
      • Initial genetic testing consists of identifying the disease-causing mutation. In a minority of patients, no mutation may be identified.
      • DNA from additional affected family members may be required to determine the pathogenicity of a PKD gene variant and to increase the accuracy of PGD.
      Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; ESRD, end-stage renal disease; htTKV, height-adjusted total kidney volume; PGD, preimplantation genetic diagnosis.
      The attitudes of patients with ADPKD toward PGD have largely been in favor. In a study involving 96 patients with ADPKD from the United Kingdom, 18% of patients with ESRD would consider prenatal diagnosis and termination of an affected pregnancy and 63% would have undergone PGD or would consider it if it were available and funded by the UK National Health Service.
      • Swift O.
      • Vilar E.
      • Rahman B.
      • Side L.
      • Gale D.P.
      Attitudes in patients with autosomal dominant polycystic kidney disease toward prenatal diagnosis and preimplantation genetic diagnosis.
      Participants shared that they would not want their child to experience the symptoms and burden of the disease.
      • Swift O.
      • Vilar E.
      • Rahman B.
      • Side L.
      • Gale D.P.
      Attitudes in patients with autosomal dominant polycystic kidney disease toward prenatal diagnosis and preimplantation genetic diagnosis.
      IVF and PGD are subject to varying country-specific regulations and professional standards. For example, PGD is currently banned in some European countries, which has led to increased transborder travel of PGD-seeking patients to the United States, Belgium, Israel, and the United Kingdom, which allow PGD procedures to be used for the prevention of transmitting serious genetic disorders.
      • Corveleyn A.
      • Morris M.A.
      • Dequeker E.
      • et al.
      Provision and quality assurance of preimplantation genetic diagnosis in Europe.
      • Robertson J.A.
      Reproductive technology in Germany and the United States: an essay in comparative law and bioethics.
      In some countries, such as Canada and the United States, there are no limitations to which conditions can be screened, which may engender discriminatory attitudes toward individuals living with such conditions and those who choose to have offspring with genetically linked disabilities.
      • Corveleyn A.
      • Morris M.A.
      • Dequeker E.
      • et al.
      Provision and quality assurance of preimplantation genetic diagnosis in Europe.
      Other ethical dilemmas surrounding PGD (and other assisted reproductive technologies) include the procedure usually being restricted to those who can afford it and theoretically being used for eugenic purposes.
      Many European health care centers reimburse for the cost of genetic testing and/or IVF, whereas coverage and reimbursement in the United States vary.
      • Barua M.
      • Cil O.
      • Paterson A.D.
      • et al.
      Family history of renal disease severity predicts the mutated gene in ADPKD.
      In the United States, the cost for IVF is approximately $9,000 to $12,500 per cycle, with an additional $2,500 to $6,000 for PGD. Often more than 1 cycle is necessary to achieve pregnancy.
      • Drazba K.T.
      • Kelley M.A.
      • Hershberger P.E.
      A qualitative inquiry of the financial concerns of couples opting to use preimplantation genetic diagnosis to prevent the transmission of known genetic disorders.
      Although costly, the expense of IVF with PGD is significantly less than paying for a lifetime of treatment for ADPKD. Even patients with ADPKD with stage 1 CKD have higher direct medical costs than healthy controls.
      • Knight T.
      • Schaefer C.
      • Krasa H.
      • Oberdhan D.
      • Chapman A.
      • Perrone R.D.
      Medical resource utilization and costs associated with autosomal dominant polycystic kidney disease in the USA: a retrospective matched cohort analysis of private insurer data.
      Currently, only 15 US states have laws mandating health insurance companies to cover or offer infertility-related treatments. Eight states require coverage of IVF with specific regulations regarding who qualifies for coverage.
      • Drazba K.T.
      • Kelley M.A.
      • Hershberger P.E.
      A qualitative inquiry of the financial concerns of couples opting to use preimplantation genetic diagnosis to prevent the transmission of known genetic disorders.
      Insurance companies may also have eligibility requirements (eg, infertility) and some may only cover PGD or IVF, but not both procedures. This can create an economic barrier for some prospective parents, which can sometimes be reduced through provider advocacy, which emphasizes the need for IVF with PGD for prospective high-risk parents.
      The use of PGD has successfully resulted in children unaffected by the single-gene disorder present in their family.
      • De Rycke M.
      • Georgiou I.
      • Sermon K.
      • et al.
      PGD for autosomal dominant polycystic kidney disease type 1.
      Each child of an individual with ADPKD has a 50% chance of disease inheritance, while PGD reduces this risk to 1% to 2%.

      Appold K. Preimplantation genetic diagnosis: how should labs grapple with ethics? Clin Lab News. Online: American Association for Clinical Chemisty 2014.

      However, IVF with PGD poses small health risks to both the fetus and the mother, including increased risk for multiple gestations, a small increased risk of birth defects, ovarian hyperstimulation syndrome, and ectopic pregnancy, and egg-retrieval procedure complications (bleeding, infection, or damage to the bowel, bladder, or blood vessels); and stress and anxiety.

      The Mayo Clinic. In vitro fertilization (IVF). https://www.mayoclinic.org/tests-procedures/in-vitro-fertilization/details/risks/cmc-20207080. Accessed December 1, 2017.

      It also does not guarantee that pregnancy will be achieved or a normal pregnancy outcome.
      • Swift O.
      • Vilar E.
      • Rahman B.
      • Side L.
      • Gale D.P.
      Attitudes in patients with autosomal dominant polycystic kidney disease toward prenatal diagnosis and preimplantation genetic diagnosis.
      It is important to note that the entire testing process, which includes mutation identification, potential family linkage-based studies, IVF, PGD, and successfully achieving a pregnancy, could take many months or even years (Table 2). In addition, multiple IVF cycles may be required to identify unaffected euploid embryos for autosomal dominant disorders because the a priori risk that each embryo will be affected is 50%, eliminating many embryos for transfer. This can become even more challenging as maternal age advances because there is a substantial decline in the number and quality of ova available. All patients should be made aware of these limitations so that they may appropriately plan for IVF with PGD.
      Table 2Procedures and Potential Pitfalls of IVF With PGD
      ProcedureDescriptionPotential Pitfall
      1Mutation identification for ADPKD using direct mutation analysis (common) or linkage analysis (rare)Failure to identify a pathogenic mutation
      2Family linkage analysis may be needed to determine variant pathogenicityPatient may have a de novo mutation or may not have enough affected family members to perform a linkage-based study
      3Egg harvest and sperm collection with subsequent IVFSmall risks to mother associated with IVF-related hormonal stimulation and egg harvesting; small increased risk for birth defects
      4DNA removal by biopsy from blastomere or trophectodermDamage to the embryo rendering it unusable
      5Genetic analysis of embryonic tissue by direct mutation analysis and/or linkage-based analysisDNA degradation; low risk for misdiagnosis due to biological phenomenon or technical problems
      6Transfer to womb or freezing of embryos predicted to be without the pathogenic mutationPregnancy may not be achieved
      7Confirmatory prenatal or postnatal diagnosisLow risks for miscarriage associated with confirmatory prenatal diagnosis procedure; risk that the fetus may have been misdiagnosed as unaffected
      Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; IVF, in vitro fertilization; PGD, preimplantation genetic diagnosis.
      Although mutations can be detected in most affected individuals, approximately 10% of families with ADPKD do not have detectable mutations. This may be attributed to PKD1 or PKD2 mutations that cannot be detected by current testing methods
      • Pei Y.
      • Watnick T.
      Diagnosis and screening of autosomal dominant polycystic kidney disease.
      or to mutations in other genes associated with kidney or liver cysts leading to a similar phenotype, especially for de novo cases.
      • Cornec-Le Gall E.
      • Torres V.
      • Harris P.C.
      Genetic complexity of autosomal dominant polycystic kidney and liver diseases.
      Additionally, while heterozygous mutant ADPKD alleles are generally 100% penetrant, there are rare cases of hypomorphic PKD alleles that demonstrate reduced gene expression and may cause symptoms only when present in a trans configuration with another PKD variant.
      • Rossetti S.
      • Kubly V.J.
      • Consugar M.B.
      • et al.
      Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease.
      These situations can complicate genetic counseling of patients with ADPKD and limit assisted reproductive technology options. However, as advancing technology provides more information about the molecular basis of ADPKD and other cystogenic or ciliopathy genes that may produce a similar phenotype or modify the ADPKD course, strategies for genetic counseling and developing robust protocols for PGD will continue to improve.
      The decision to pursue or decline assisted reproductive technology or prenatal diagnosis of ADPKD is a personal choice based on patient beliefs, experience, and preferences. Either decision should be fully supported.

      Acknowledgements

      We thank Maurice Mahoney, MD, JD, Ashima Gulati, MD, and Whitney Besse, MD, for thoughtful commentary.
      Peer Review: Received October 2, 2017. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form January 19, 2018.

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