Polycystic kidney disease explained

Polycystic kidney disease
Synonyms:Kidney - polycystic
Field:Nephrology
Symptoms:Abdominal pain
Types:ADPKD[1] and ARPKD[2]
Diagnosis:MRI, CT scan, Ultrasound
Treatment:Antihypertensives, Life style management[3]

Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a genetic disorder[4] [5] in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cysts may begin to develop in utero, in infancy, in childhood, or in adulthood.[6] Cysts are non-functioning tubules filled with fluid pumped into them, which range in size from microscopic to enormous, crushing adjacent normal tubules and eventually rendering them non-functional as well.

PKD is caused by abnormal genes that produce a specific abnormal protein; this protein has an adverse effect on tubule development. PKD is a general term for two types, each having their own pathology and genetic cause: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). The abnormal gene exists in all cells in the body; as a result, cysts may occur in the liver, seminal vesicles, and pancreas. This genetic defect can also cause aortic root aneurysms, and aneurysms in the circle of Willis cerebral arteries, which if they rupture, can cause a subarachnoid hemorrhage.

Diagnosis may be suspected from one, some, or all of the following: new onset flank pain or red urine; a positive family history; palpation of enlarged kidneys on physical exam; an incidental finding on abdominal sonogram; or an incidental finding of abnormal kidney function on routine lab work (BUN, serum creatinine, or eGFR). Definitive diagnosis is made by abdominal CT exam.

Complications include hypertension due to the activation of the renin–angiotensin–aldosterone system (RAAS), frequent cyst infections, urinary bleeding, and declining renal function. Hypertension is treated with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). Infections are treated with antibiotics. Declining renal function is treated with renal replacement therapy (RRT): dialysis and/or transplantation. Management from the time of the suspected or definitive diagnosis is by an appropriately trained doctor.

Signs and symptoms

Signs and symptoms include high blood pressure, headaches, abdominal pain, blood in the urine, and excessive urination.[7] Other symptoms include pain in the back, and cyst formation (renal and other organs).[8]

Cause

PKD is caused by abnormal genes which produce a specific abnormal protein which has an adverse effect on tubule development. PKD is a general term for two types, each having their own pathology and genetic cause: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).[9] [10]

Autosomal dominant

See main article: article and Autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of all the inherited cystic kidney diseases[11] [12] with an incidence of 1:500 live births. Studies show that 10% of end-stage kidney disease (ESKD) patients being treated with dialysis in Europe and the U.S. were initially diagnosed and treated for ADPKD.[10]

Genetic mutations in any of the three genes PKD1, PKD2, and PKD3 have similar phenotypical presentations.[13]

Autosomal recessive

Autosomal recessive polycystic kidney disease (ARPKD) (OMIM #263200) is the less common of the two types of PKD, with an incidence of 1:20,000 live births and is typically identified in the first few weeks after birth. Unfortunately, the kidneys are often underdeveloped, resulting in a 30% death rate in newborns with ARPKD. PKHD1 is involved.[10]

Mechanism

Both autosomal dominant and autosomal recessive polycystic kidney disease cyst formation are tied to abnormal cilia-mediated signaling. The polycystin-1 and polycystin-2 proteins appear to be involved in both autosomal dominant and recessive polycystic kidney disease due to defects in both proteins.[19] Both proteins have communication with calcium channel proteins, and causes reduction in resting (intracellular) calcium and endoplasmic reticulum storage of calcium.[20]

The disease is characterized by a ‘second hit’ phenomenon, in which a mutated dominant allele is inherited from a parent, with cyst formation occurring only after the normal, wild-type gene sustains a subsequent second genetic ‘hit’, resulting in renal tubular cyst formation and disease progression.

PKD results from defects in the primary cilium, an immotile, hair-like cellular organelle present on the surface of most cells in the body, anchored in the cell body by the basal body.[19] In the kidney, primary cilia have been found to be present on most cells of the nephron, projecting from the apical surface of the renal epithelium into the tubule lumen. The cilia were believed to bend in the urine flow, leading to changes in signalling, however this has since been shown to be an experimental error (the bending of cilia was an artifact of focal plane compensation, and also the actual effect on micturition by severe hypertension and cardiac arrest) and that bending of cilia does not contribute to alterations in Ca flux. While it is not known how defects in the primary cilium lead to cyst development, it is thought to possibly be related to disruption of one of the many signaling pathways regulated by the primary cilium, including intracellular calcium, Wnt/β-catenin, cyclic adenosine monophosphate (cAMP), or planar cell polarity (PCP). Function of the primary cilium is impaired, resulting in disruption of a number of intracellular signaling cascades which produce differentiation of cystic epithelium, increased cell division, increased apoptosis, and loss of resorptive capacity.[10] [19]

Diagnosis

Polycystic kidney disease can be ascertained via a CT scan of abdomen, as well as an MRI and ultrasound of the same area.[21] A physical exam/test can reveal enlarged liver, heart murmurs and elevated blood pressure.[7]

Natural history

Most cases progress to bilateral disease in adulthood.[22]

Treatment

In 2018, Jynarque (Tolvaptan) was introduced [23] as the first FDA-approved treatment for PKD. In a recent long-term study, patients using Tolvaptan had a 6.4% higher kidney function after 5 years compared to standard of care.[24] In 2019, a team of researchers at UCSB found that a ketogenic diet might be able to halt, or even reverse progression in mice,[25] and the results of a first human case series study are showing potential benefit.[26] The results of a 3-month randomized, prospective dietary intervention clinical trial are pending.[27] In addition, recent research indicates that mild to moderate calorie restriction or time-restricted feeding [28] slow the progression of autosomal dominant polycystic kidney disease (ADPKD) in mice[29] [30] Patient communities have been combining both ketogenic diets [31] and time-restricted feeding with a low-oxalate diet to prevent the formation of stones [32] and early reports show an average of 17% increase in kidney function after approximately one year on a ketogenic, time-restricted dietary regimen.[33] If and when the disease progresses enough in a given case, the nephrologist or other practitioner and the patient will have to decide what form of renal replacement therapy will be used to treat end-stage kidney disease (kidney failure, typically stage 4 or 5 of chronic kidney disease).

That will either be some form of dialysis, which can be done at least two different ways at varying frequencies and durations (whether it is done at home or in the clinic depends on the method used and the patient's stability and training) and eventually, if they are eligible because of the nature and severity of their condition and if a suitable match can be found, unilateral or bilateral kidney transplantation.

A Cochrane Review study of autosomal dominant polycystic kidney disease made note of the fact that it is important at all times, while avoiding antibiotic resistance, to control infections of the cysts in the kidneys, and if affected, the liver, when needed for a certain duration to combat infection, by using, "bacteriostatic and bacteriocidal drugs".[10] [34]

Prognosis

ADPKD individuals might have a normal life; conversely, ARPKD can cause kidney dysfunction and can lead to kidney failure by the age of 40–60. ADPKD1 and ADPKD2 are very different, in that ADPKD2 is much milder.[35]

Currently, there are no therapies proven effective to prevent the progression of ADPKD.[36]

Epidemiology

PKD is one of the most common hereditary diseases in the United States, affecting more than 600,000 people. It is the cause of nearly 10% of all end-stage renal disease. It equally affects men, women, and all races.[37] PKD occurs in some animals as well as humans.[38] [39]

See also

Further reading

Notes and References

  1. Web site: Autosomal Dominant Polycystic Kidney Disease . National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) . 3 January 2018.
  2. Web site: Autosomal Recessive Polycystic Kidney Disease . National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) . 3 January 2018.
  3. Web site: What Is Polycystic Kidney Disease? . National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) . 3 January 2018.
  4. Hildebrandt F . Genetic kidney diseases . Lancet . 375 . 9722 . 1287–1295 . April 2010 . 20382325 . 2898711 . 10.1016/S0140-6736(10)60236-X .
  5. Kimberling WJ, Pieke-Dahl SA, Kumar S . The genetics of cystic diseases of the kidney . Seminars in Nephrology . 11 . 6 . 596–606 . November 1991 . 1767134 .
  6. Cramer MT, Guay-Woodford LM . Cystic kidney disease: a primer . Advances in Chronic Kidney Disease . 22 . 4 . 297–305 . July 2015 . 26088074 . 10.1053/j.ackd.2015.04.001 . free .
  7. Encyclopedia: Polycystic kidney disease. MedlinePlus Medical Encyclopedia. 2015-07-30.
  8. Web site: Polycystic Kidney Disease. www.niddk.nih.gov. 2015-07-31. 2017-01-04. https://web.archive.org/web/20170104194545/https://www.niddk.nih.gov/health-information/health-topics/kidney-disease/polycystic-kidney-disease-pkd/Pages/facts.aspx. dead.
  9. Book: Essentials of Pathophysiology: Concepts of Altered Health States. Lippincott Williams & Wilkins. 2011-01-01. 9781582557243. Porth C .
  10. Phua YL, Ho J . MicroRNAs in the pathogenesis of cystic kidney disease . Current Opinion in Pediatrics . 27 . 2 . 219–226 . April 2015 . 25490692 . 4409326 . 10.1097/mop.0000000000000168 .
  11. Torres VE, Harris PC, Pirson Y . Autosomal dominant polycystic kidney disease . Lancet . 369 . 9569 . 1287–1301 . April 2007 . 17434405 . 10.1016/S0140-6736(07)60601-1 . 1700992 .
  12. Simons M, Walz G . Polycystic kidney disease: cell division without a c(l)ue? . Kidney International . 70 . 5 . 854–864 . September 2006 . 16816842 . 10.1038/sj.ki.5001534 . free .
  13. Porath B, Gainullin VG, Cornec-Le Gall E, Dillinger EK, Heyer CM, Hopp K, Edwards ME, Madsen CD, Mauritz SR, Banks CJ, Baheti S, Reddy B, Herrero JI, Bañales JM, Hogan MC, Tasic V, Watnick TJ, Chapman AB, Vigneau C, Lavainne F, Audrézet MP, Ferec C, Le Meur Y, Torres VE, Harris PC . 6 . Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease . American Journal of Human Genetics . 98 . 6 . 1193–1207 . June 2016 . 27259053 . 4908191 . 10.1016/j.ajhg.2016.05.004 .
  14. Thivierge C, Kurbegovic A, Couillard M, Guillaume R, Coté O, Trudel M . Overexpression of PKD1 causes polycystic kidney disease . Molecular and Cellular Biology . 26 . 4 . 1538–1548 . February 2006 . 16449663 . 1367205 . 10.1128/MCB.26.4.1538-1548.2006 .
  15. Kumar S, Kimberling WJ, Gabow PA, Kenyon JB . Genetic linkage studies of autosomal dominant polycystic kidney disease: search for the second gene in a large Sicilian family . Human Genetics . 87 . 2 . 129–133 . June 1991 . 1676697 . 10.1007/BF00204167 . 22331271 .
  16. Kumar S, Kimberling WJ, Gabow PA, Shugart YY, Pieke-Dahl S . Exclusion of autosomal dominant polycystic kidney disease type II (ADPKD2) from 160 cM of chromosome 1 . Journal of Medical Genetics . 27 . 11 . 697–700 . November 1990 . 1980516 . 10.1136/jmg.27.11.697 . 1017261 .
  17. Kimberling WJ, Kumar S, Gabow PA, Kenyon JB, Connolly CJ, Somlo S . Autosomal dominant polycystic kidney disease: localization of the second gene to chromosome 4q13-q23 . Genomics . 18 . 3 . 467–472 . December 1993 . 8307555 . 10.1016/S0888-7543(11)80001-7 .
  18. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S . 6 . PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein . Science . 272 . 5266 . 1339–1342 . May 1996 . 8650545 . 10.1126/science.272.5266.1339 . 1996Sci...272.1339M . 28192819 .
  19. Halvorson CR, Bremmer MS, Jacobs SC . Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment . International Journal of Nephrology and Renovascular Disease . 3 . 69–83 . 2010-06-24 . 21694932 . 3108786 . 10.2147/ijnrd.s6939 . free .
  20. Book: Comprehensive Clinical Nephrology: Expert Consult - Online. Elsevier Health Sciences. 2014-09-05. 9780323242875. Johnson RJ, Feehally J, Floege J .
  21. Web site: 2016-01-07 . Polycystic Kidney Disease . 2022-11-17 . National Kidney Foundation . en-US.
  22. Bisceglia M, Galliani CA, Senger C, Stallone C, Sessa A . Renal cystic diseases: a review . Advances in Anatomic Pathology . 13 . 1 . 26–56 . January 2006 . 16462154 . 10.1097/01.pap.0000201831.77472.d3 . 12417947 .
  23. 2018-06-01 . FDA Approves Tolvaptan for ADPKD . Kidney News . EN . 10 . 6 . 1555-905X.
  24. Zhou X, Davenport E, Ouyang J, Hoke ME, Garbinsky D, Agarwal I, Krasa HB, Oberdhan D . 6 . Pooled Data Analysis of the Long-Term Treatment Effects of Tolvaptan in ADPKD . English . Kidney International Reports . 7 . 5 . 1037–1048 . May 2022 . 35570988 . 9091612 . 10.1016/j.ekir.2022.02.009 .
  25. Torres JA, Kruger SL, Broderick C, Amarlkhagva T, Agrawal S, Dodam JR, Mrug M, Lyons LA, Weimbs T . 6 . Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease . Cell Metabolism . 30 . 6 . 1007–1023.e5 . December 2019 . 31631001 . 6904245 . 10.1016/j.cmet.2019.09.012 .
  26. Strubl S, Oehm S, Torres JA, Grundmann F, Haratani J, Decker M, Vuong S, Kaur Bhandal A, Methot N, Haynie-Cion R, Meyer F, Siedek F, Korst U, Müller RU, Weimbs T . 6 . Ketogenic dietary interventions in autosomal dominant polycystic kidney disease-a retrospective case series study: first insights into feasibility, safety and effects . Clinical Kidney Journal . 15 . 6 . 1079–1092 . June 2022 . 35664270 . 9155228 . 10.1093/ckj/sfab162 .
  27. Web site: Müller R . 2022-08-23 . University of Cologne . Ketogenic Dietary Interventions in Autosomal Dominant Polycystic Kidney Disease (ADPKD) .
  28. Nowak KL, Hopp K . Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease: Evidence and Therapeutic Potential . Clinical Journal of the American Society of Nephrology . 15 . 4 . 577–584 . April 2020 . 32086281 . 7133124 . 10.2215/CJN.13291019 .
  29. Warner G, Hein KZ, Nin V, Edwards M, Chini CC, Hopp K, Harris PC, Torres VE, Chini EN . 6 . Food Restriction Ameliorates the Development of Polycystic Kidney Disease . Journal of the American Society of Nephrology . 27 . 5 . 1437–1447 . May 2016 . 26538633 . 4849816 . 10.1681/ASN.2015020132 .
  30. Kipp KR, Rezaei M, Lin L, Dewey EC, Weimbs T . A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease . American Journal of Physiology. Renal Physiology . 310 . 8 . F726–F731 . April 2016 . 26764208 . 4835927 . 10.1152/ajprenal.00551.2015 .
  31. Web site: Spencer S . 2021-12-25 . 6 Ways People with PKD Can Lower Their Blood Pressure . 2022-10-24 . Medium . en.
  32. Torres JA, Rezaei M, Broderick C, Lin L, Wang X, Hoppe B, Cowley BD, Savica V, Torres VE, Khan S, Holmes RP, Mrug M, Weimbs T . 6 . Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease . The Journal of Clinical Investigation . 129 . 10 . 4506–4522 . July 2019 . 31361604 . 6763267 . 10.1172/JCI128503 .
  33. Web site: 2022-10-20 . Breakthrough Results After 7 Years of Reversing Pkd . 2022-10-24 . en-US.
  34. Montero N, Sans L, Webster AC, Pascual J . Interventions for infected cysts in people with autosomal dominant polycystic kidney disease. Cochrane Database of Systematic Reviews. 29 January 2014. 10.1002/14651858.cd010946. 70649130 . free.
  35. Torra R . Talavera F, Aronoff GR . Medscape . Polycystic Kidney Disease: Practice Essentials, Background, Pathophysiology. 2018-07-20.
  36. Bolignano D, Palmer SC, Ruospo M, Zoccali C, Craig JC, Strippoli GF . Interventions for preventing the progression of autosomal dominant polycystic kidney disease . The Cochrane Database of Systematic Reviews . 2015 . 7 . CD010294 . July 2015 . 26171904 . 8406618 . 10.1002/14651858.CD010294.pub2 .
  37. Book: Fifth Edition: Diseases of the Human Body. Tamparo C . F.A. Davis Company. 2011. 978-0-8036-2505-1. Philadelphia, PA. 443.
  38. Web site: Polycystic kidney disease (PKD): Gene test and negative register. International Cat Care. 2 November 2014. https://web.archive.org/web/20161117065146/http://www.icatcare.org:8080/advice/cat-health/polycystic-kidney-disease-pkd-gene-test-and-negative-register-0. 17 November 2016. dead.
  39. Web site: PKD - Polycystic Kidney Disease - British Shorthair. Antagene. 2 November 2014. 17 August 2018. https://web.archive.org/web/20180817055953/http://www.antagene.com/en/pkd-polycystic-kidney-diseasebritish-shorthair. dead.

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