Polycystic kidney disease

Signs and symptoms include high blood pressure, headaches, abdominal pain, blood in the urine, and excessive urination.[1] Other symptoms include pain in the back, and cyst formation (renal and other organs).[7]

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).[8][9]

Autosomal dominant

Main article: Autosomal dominant polycystic kidney disease

CT scan showing autosomal dominant polycystic kidney disease

Cartoon of autosomal dominant polycystic kidney disease with normal kidney inset to right of diagram

Cartoon of autosomal recessive polycystic kidney disease with normal kidney inset to right of diagram

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of all the inherited cystic kidney diseases[10][11][12] with an incidence of 1:500 live births.[10][12] 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][9]

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

• Gene PKD1 is located on chromosome 16 and codes for a protein involved in regulation of cell cycle and intracellular calcium transport in epithelial cells, and is responsible for 85% of the cases of ADPKD.[13]
• A group of voltage-linked cation channels, with inward selectivity for K>Na>>Ca and outward selectivity for Ca2+ ≈ Ba2+ > Na+ ≈ K+, are coded for by PKD2 on chromosome 4
• PKD3 recently appeared in research papers as a postulated third gene.[10][11] Fewer than 10% of cases of ADPKD appear in non-ADPKD families. Cyst formation begins in utero from any point along the nephron, although fewer than 5% of nephrons are thought to be involved. As the cysts accumulate fluid, they enlarge, separate entirely from the nephron, compress the neighboring kidney parenchyma, and progressively compromise kidney function.[9]

PKD1 and PKD2

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.[14] Both proteins have communication with calcium channel proteins, and causes reduction in resting (intracellular) calcium and endoplasmic reticulum storage of calcium.[15]

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.[16]

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.[16] 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.[9][16]

Polycystic kidney disease can be ascertained via a CT scan of abdomen, as well as, an MRI and ultrasound of the same area. A physical exam/test can reveal enlarged liver, heart murmurs and elevated blood pressure[1]

Chr 11 FISH-mapped BACs from CGAP

In 2018, Jynarque (Tolvaptan) was introduced [17] 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. [18] In 2019, a team of researchers at UCSB found that a ketogenic diet might be able to halt, or even reverse progression in mice,[19] and the results of a first human case series study are showing potential benefit. [20] The results of a 3-month randomized, prospective dietary intervention clinical trial are pending. [21] In addition, recent research indicates that mild to moderate calorie restriction or time-restricted feeding [22] slow the progression of autosomal dominant polycystic kidney disease (ADPKD) in mice[23] [24] Patient communities have been combining both ketogenic diets [25] and time-restricted feeding with a low-oxalate diet to prevent the formation of stones [26] and early reports show an average of 17% increase in kidney function after approximately one year on a ketogenic, time-restricted dietary regimen. [27] 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).[28]

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.[28]

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".[9][28]

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.[31] PKD occurs in some animals as well as humans.[32][33]

• Autosomal recessive polycystic kidney disease

• Chapin, Hannah C.; Caplan, Michael J. (2010-11-15). "The cell biology of polycystic kidney disease". The Journal of Cell Biology. 191 (4): 701–710. doi:10.1083/jcb.201006173. ISSN 0021-9525. PMC 2983067. PMID 21079243.
• Harris, Peter C.; Torres, Vicente E. (2009-01-01). "Polycystic Kidney Disease". Annual Review of Medicine. 60: 321–337. doi:10.1146/annurev.med.60.101707.125712. ISSN 0066-4219. PMC 2834200. PMID 18947299.
• Press, Dove (2010). "Polycystic kidney disease: inheritance, pathophysiology, prognosis, an | IJNRD". International Journal of Nephrology and Renovascular Disease. 3: 69–83. doi:10.2147/IJNRD.S6939. PMC 3108786. PMID 21694932.