1. Molecular advances in autosomal dominant polycystic kidney disease.
Second-hit mutations inactivate the normal copy of the PKD gene resulting in cyst formation that deforms the kidney and eventually impairs kidney functioning.

2. Mutations in ADPKD2 cysts suggest a pathogenic effect of transheterozygous mutations.
Support for two hit phenomenon: Results suggest that somatic mutation of PKD1 may be a modifier of disease severity in ADPKD2.
3. Molecular basis of focal cyst formation ADPKD type 1
Support for two hit phenomenon
4. A critical developmental switch defines the kinetics of kidney cyst formation after loss of pkd1
Support for two hit phenomenon
5. Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease.1998.
The data extends the "two-hit" model of cyst formation to include a second focal manifestation of PKD.
6. Loss of Polycystin-1 in Human Cyst-Lining Epithelia Leads to Ciliary Dysfunction 2006
The data supports a two hit hypotheses is as a mechanism of cystogenesis (cyst formation)
7. Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2). 2004
8. Autosomal dominant PKD: clues to pathogenesis 1999 Peter Harris
Why do cysts develop? It is a two hit process. Support for this theory has come from DNA analysis of cystic epithelia isolated from single cysts.
9. Inheritance of a stable mutation in a family with early-onset disease. 2001
The occurrence of very early-onset cases of ADPKD (sometimes in utero) in a few PKD1 families or the increased severity of the disease in successive generations . . .may include segregation of modifying genes or unidentified factors and the two-hit mechanism.
10. Greg Germino MD first established the two - hit model for PKD Polycystic Kidney Disease. This is the lecture that started this all.
     Genetics ADPKD part 1
     Genetics ADPKD part 2
     Genetics ADPKD part 3
11. Polycystic Liver Disease - page 2   

“Inactivating somatic mutations have been found in liver cyst epithelia, like in renal cysts, supporting the “two-hit” model as a unifying mechanism of cystogenesis"

Dr. Greg Germino named Deputy Director of NIH’s National Institute of Diabetes and Digestive and Kidney Diseases.
Dr. Greg Germino has been named Deputy Director of NIH’s National Institute of Diabetes and Digestive and Kidney Diseases. Ever since I heard his lecture at a PKD conference many many years ago, I have taken special care to avoid anything in the environment which might impact my DNA negatively. I have purposefully eaten things that are known to help build DNA as well as foods that increase estrogen metabolism of estrogen through the liver. I took off from the two hit PKD model. At this same lecture amongst the audience was the Italian geneticist responsible for the discovery of a single town in Italy where no one had heart disease. This was attributed to a genetic mutation. This Italian researcher asked if Dr. Germino would allow him to take a photograph of the two of them. Dr. Germino kindly obliged, and felt honored that this particular researcher would wish to have a picture taken.

In his explanation of the two hit model for PKD way back some 13 years ago, I was sprinted forward to learn more about what it is that causes more cysts to form in some individuals and less in others. According to Dr. Germino's lecture way back then, the inheritance of PKD loads the genetic gun but it is exposure to things in the environment that pulls the trigger to start the process of more and more cyst formation. I hung around at the end of his lecture to listen to the questions and answers asked by fellow PKD'rs.
Dr. Germino was asked what begins this second hit with ADPKD? He reluctantly provided information that it was anything that is known to alter the DNA in anyway, any carcinogens. From this point onward I have taken special care with choosing foods, asking how they are grown; avoiding foods with additives, chemicals and grown with round up, dropped in bleach baths and herbicides, pesticides and other chemicals.

Dr. Germino is indeed a wonderful PKD researcher, a fine human being, and a helpful for person for us with PKD. I have devoted a page to him on my website. His wife practices medicine at Johns Hopkins University and many on this support group have seen her. Dr. Germino continues to teach fellow physicians and continues his PKD research. Now his two hit PKD model is no longer a theory but a bonafide reality as an explanation of how some individuals develop more cysts than others.

I remember that PKD conference well. It was when I met for the first time Dr. V Torres. As Dr. Germino began speaking, Dr. Torres hushed me, as he really wanted to hear what Dr. Germino had to say.

I had liver resection surgery within the next few months at the Mayo in Rochester MN.

Dr. Nagorney, my surgeon, has released a paper about liver resections and the Mayo Experience. As a result of my surgery and the two hit PKD model lecture – at 62 years old, I am proud to announce that my kidney functioning has improved. It has improved as I age. My creatinine is 0.8. My iothalmate clearance is 69. I take no blood pressure medications. I take no medications, none at all. I am PKD1 though both of my parents died from ADPKD. All in my family who have PKD are dead. I fully hope to live to be at least 120, thanks to a fine lecture on the two-hit model for PKD that I listened to many many years ago.