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Review
. 2016 May;67(5):792-810.
doi: 10.1053/j.ajkd.2015.07.037. Epub 2015 Oct 31.

Autosomal Dominant Polycystic Kidney Disease: Core Curriculum 2016

Fouad T Chebib  1 , Vicente E Torres  2
Affiliations
Review

Autosomal Dominant Polycystic Kidney Disease: Core Curriculum 2016

Fouad T Chebib et al. Am J Kidney Dis. 2016 May.
No abstract available

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Figures

Figure 1
Figure 1
A) PKD1 and PKD2 genes and transcripts. Numbered boxes indicate exons; in total there are 46 for PKD1 (top) and 15 for PKD2 (bottom). The coding regions are shaded; 5’ and 3’ untranslated regions are not shaded. Reproduced from Torres et al (“Autosomal dominant polycystic kidney disease.” Lancet. 2007;369(9569):1287-301) with permission of Elsevier. B) Predicted structures of polycystin 1 (PC1) and polycystin 2 (PC2): PC1 is a receptor-like protein with a large ectodomain, 11 transmembrane domains, and a cytoplasmic tail consisting of ~200 amino acids. The last six transmembrane domains of PC1 are homologous to the transmembrane region of PC2. PC2 is a transient receptor potential–like calcium channel that has an EF-hand motif and an endoplasmic reticulum retention signal in the carboxy (C) terminus and a proposed cilia targeting sequence in the amino (N) terminus. PC1 and PC2 physically interact through coiled-coil domains in the cytoplasmic tail of PC1 and in the carboxy-terminal tail of PC2. Reproduced from Chebib et al (“Vasopressin and disruption of calcium signaling in polycystic kidney disease.” [published online ahead of print April 14, 2015] Nat Rev Nephrol. doi: 10.1038/nrneph.2015.39) with permission of Nature Publishing Group. Abbreviations: GPCR, G protein–coupled receptor; ER, endoplasmic reticulum; LLR, leucine rich repeat;
Figure 1
Figure 1
A) PKD1 and PKD2 genes and transcripts. Numbered boxes indicate exons; in total there are 46 for PKD1 (top) and 15 for PKD2 (bottom). The coding regions are shaded; 5’ and 3’ untranslated regions are not shaded. Reproduced from Torres et al (“Autosomal dominant polycystic kidney disease.” Lancet. 2007;369(9569):1287-301) with permission of Elsevier. B) Predicted structures of polycystin 1 (PC1) and polycystin 2 (PC2): PC1 is a receptor-like protein with a large ectodomain, 11 transmembrane domains, and a cytoplasmic tail consisting of ~200 amino acids. The last six transmembrane domains of PC1 are homologous to the transmembrane region of PC2. PC2 is a transient receptor potential–like calcium channel that has an EF-hand motif and an endoplasmic reticulum retention signal in the carboxy (C) terminus and a proposed cilia targeting sequence in the amino (N) terminus. PC1 and PC2 physically interact through coiled-coil domains in the cytoplasmic tail of PC1 and in the carboxy-terminal tail of PC2. Reproduced from Chebib et al (“Vasopressin and disruption of calcium signaling in polycystic kidney disease.” [published online ahead of print April 14, 2015] Nat Rev Nephrol. doi: 10.1038/nrneph.2015.39) with permission of Nature Publishing Group. Abbreviations: GPCR, G protein–coupled receptor; ER, endoplasmic reticulum; LLR, leucine rich repeat;
Figure 2
Figure 2
Putative up- or down-regulated pathways in polycystic kidney disease. Dysregulation of intracellular Ca2+ and increased concentrations of cAMP play a central role. Increased accumulation of cAMP in polycystic kidneys may be explained by the following hypotheses. (1) Reduced Ca2+ activates Ca2+-inhibitable AC6, inhibits Ca2+/calmodulin-dependent PDE1 directly, and cGMP-inhibitable PDE3 indirectly. (2) Disruption of a ciliary protein complex (comprising AKAP150, AC5/6, PC2, PDE4C, and PKA), which normally restrains cAMP signaling through inhibition of AC5/6 activity by PC2–mediated Ca2+ entry and degradation of cAMP by PDE4C transcriptionally controlled by HNF1β. (3) Depletion of the ER Ca2+ stores that triggers oligomerization and translocation of STIM1 to the plasma membrane, where it recruits and activates AC6. (4) Other contributory factors include disruption of PC1 binding to heterotrimeric G proteins, upregulation of the V2R, and increased levels of circulating vasopressin or accumulation of forskolin, lisophosphatidic acid, ATP, or other AC agonists in the cyst fluid. Increased cAMP levels disrupt tubulogenesis, stimulate chloride and fluid secretion, and activate proproliferative signaling pathways, including MAPK/ERK (in a Src- and Ras-dependent manner), mTOR, and β-catenin signaling. Activated mTOR transcriptionally stimulates aerobic glycolysis, increasing ATP synthesis and lowering AMP levels, which together with B-Raf–dependent activation of LKB1, inhibits AMPK, further enhancing mTOR activity and CFTR-driven chloride and fluid secretion. PKA signaling also activates a number of transcription factors, including STAT3. Activated STAT3 induces the transcription of cytokines, chemokines, and growth factors that, in turn, activate STAT3 signaling in interstitial alternatively activated M2 macrophages and result in a feedforward loop between cyst-lining cells and M2 macrophages. Aberrant integrin–extracellular membrane interaction and cAMP signaling within focal adhesion complexes may contribute to the increased adhesion of cyst-derived cells to laminin-322 and collagen. Abbreviations: AKAP, A-kinase anchoring protein; AC, adenylyl cyclase; AMPK, AMP kinase; AMP, adenosine monophosphate; ATP, adenosine triphosphate; B-Raf, B rapidly accelerated fibrosarcoma kinase; cAMP, cyclic AMP; cGMP, cyclic guanosine monophosphate; ER, endoplasmic reticulum; ERK, extracellularly-regulated kinase; LKB1, liver kinase B1; MAPK, mitogen-activated protein kinase; PC, polycystin; PDE, phosphodiesterase; PKA, protein kinase A; STAT3, signal transducer and activator of transcription 3; STIM1, stromal interaction molecule 1; V2R, vassopressin 2 receptor; HNF1β, hepatocyte nuclear factor 1β; mTOR, mechanistic target of rapamycin; CFTR, cystic fibrosis transmembrane conductance regulator. Reproduced from Torres and Harris “Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease.” J Am Soc Nephrol. 2014 Jan;25(1):18-32) with permission of American Society of Nephrology.
Figure 3
Figure 3
Right (R; 1,830 g) and left (L; 1,040 g) nephrectomy specimens resected from a 51 year-old woman with autosomal polycystic kidney disease four months after kidney transplantation.
Figure 4
Figure 4
A) Axial contrast enhanced computed tomography (CT) image and B) coronal T2-weighted single shot fast spin echo magnetic resonance imaging (MRI) in a 39 year old woman with autosomal polycystic kidney disease. Contrast administration is necessary to differentiate the cystic tissue from preserved parenchyma and to detect small cysts using CT, but it is not necessary using MRI.
Figure 5
Figure 5
Practical algorithm for diagnostic evaluation of patients 18 years or older with kidney cysts. * At least one affected member with ESRD ≤ 50 years old strongly suggests PKD1 mutation; at least one affected family member without ESRD ≥ 70 years old suggests PKD2 mutation. † Polycystic kidneys with multiple angiomyolipomas (contiguous PKD1-TSC2 syndrome) ADTKD-MUC1, Autosomal dominant tubulointerstitial kidney disease – tumor-associated mucin (preivously known as medullary cystic kidney disease type 1); ADTKD-UMOD, Autosomal dominant tubulointerstitial kidney disease – Uromodulin (previously known as medullary cystic kidney disease type 2); ADPKD, autosomal polycystic kidney disease; PKD1, polycystic kidney disease 1; PKD2, polycystic kidney disease 2; US, ultrasound; MRI, magnetic resonance imaging; ADPLD, autosomal dominant polycystic liver disease; ARPKD, autosomal recessive polycystic kidney disease; RCC, renal cell carcinoma; CKD, chronic kidney disease; OFD1, oral-facial-digital syndrome type 1; ESRD, end-stage renal disease.
Figure 6
Figure 6
An imaging classification of autosomal polycystic kidney disease predicts the change in estimated glomerular filtration rate (eGFR) over time in patients with typical, bilateral, and diffuse distribution of cysts. (A) The A through E classification is based on height-adjusted total kidney volume (htTKV) and age at the time of imaging, assuming kidney growth rates of <1.5%, 1.5%–3%, 3%–4.5%, 4.5%–6%, or >6% per year and a theoretic, initial htTKV of 150 ml/m; the dots correspond to the patients in panel B. (B) Magnetic resonance imaging studies corresponding to three 41 year-old patients in classes A (bottom), C (middle) and E (top), respectively. (C) Estimated glomerular filtration rate (eGFR) slopes in a cohort of 376 patients stratified by imaging class (−0.23, −1.33, −2.63, −3.48, and −4.78 ml/min/1.73 m2 per year for classes A through E, respectively); the average eGFR at baseline (75 ml/min/1.73 m2) and the average age at baseline (44 years) for all patients were used for the model; values for normal slope were obtained from a population of healthy kidney donors; eGFR slopes were significantly different among the classes, and all but class A were significantly different from the control population of healthy kidney donors. Panels A and B courtesy of MV Irazabal; panel C reproduced from Irazabal MV et al (“Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials.” J Am Soc Nephrol. 2015;26(1):160-72) with permission of American Society of Nephrology.
Figure 7
Figure 7
Axial unenhanced computed tomography (CT) scans showing (A, B) hyperdense lesions in the left kidney due to cyst and parenchymal hemorrhage and (C) a small staghorn calculus in a right polycystic kidney (D) containing uric acid on a dual-energy CT. (E) Coronal T1-weighted and (F) axial T2-weighted images showing an irregular mass (red arrows) in the lower pole of a left polycystic kidney proven to be a renal cell carcinoma.
Figure 8
Figure 8
Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography scan in a 45-year-old woman with a one-month history of malaise and low grade fever. The scan shows a 6-7 cm cyst within the most inferior aspect of the right polycystic kidney with (A, B) an intense focus of hypermetabolism along its anterior margin and (A, C) more moderate hypermetabolism about the periphery of the remainder of the cyst. Other activity seen within both kidneys represents activity within remnant functioning renal parenchyma and excreted activity within the collecting systems.
Figure 9
Figure 9
(A) Deep-seated large cyst in the right hepatic lobe best treated by cyst aspiration and alcohol sclerosis. (B) Superficial large cyst arising from the right lobe of the liver suited for laparoscopic fenestration. (C) Polycystic liver disease involving both lobes, more severely segments VII and VIII; this patient is not a good candidate for combined liver resection and cyst fenestration because of the distribution of the cysts and involvement of the less severely affected segments by many small cysts with further potential for growth. This patient might benefit from embolization of hepatic artery branches supplying segments VII and VIII that have no recognizable hepatic parenchyma. (D and E) Polycystic liver (D) before and (E) after combined right lobectomy and cyst fenestration (note compensatory hypertrophy of the left lobe after surgery). (F) Massive polycystic liver without relative preservation of any liver segment; the only feasible treatment in this patient is liver transplantation. Reproduced from Torres (“Treatment of polycystic liver disease: one size does not fit all.” Am J Kidney Dis. 2007;49(6):725-8) with permission of Elsevier.
Figure 10
Figure 10
MR follow-up illustrating the stability of small intracranial aneurysms detected by pre-symptomatic screening in ADPKD patients. (A) A 59-year-old woman was found to have a 4.0-mm right carotid siphon aneurysm in 1991 that remained unchanged during 17 years of follow-up. (B) A 45-year-old woman was found to have a 2.0-mm basilar tip aneurysm that remained unchanged between 1991 and 2008. (C) A 49-year-old woman was found to have a 6.0-mm right carotid siphon aneurysm in 1992 that also remained unchanged over 17 years of follow-up. Reproduced from Irazabal et al (“Extended follow-up of unruptured intracranial aneurysms detected by presymptomatic screening in patients with autosomal dominant polycystic kidney disease.” Clin J Am Soc Nephrol. 20116(6):1274-85) with permission of American Society of Nephrology.
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