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The article we will be discussing today is:

Renal plasticity revealed through reversal of polycystic kidney disease in mice

Ke Dong, Chao Zhang, Xin Tian, Daniel Colman, Fahmeed Hyder, Ming Ma and Stefan Somlo (2021).

Nature Genetics Volume 53 Issue 12

https://doi.org/10.1038/s41588-021-00946-4

Journal Club Discussion

Do you have polycystic kidney disease (PKD)?

Have you been told by your doctor that PKD is relentlessly progressive and only gets worse but never better?

Have you been told that there is nothing you can do to stop this disease, and that you should prepare yourself for the inevitable: dialysis or kidney transplantation?

Of course you have been told all this. That’s the current dogma.

Sidebar: What is PKD?

PKD is a common, genetically inherited disease caused by mutations in either the PKD1 or PKD2 gene. The disease leads to the growth of cysts in both kidneys that slowly cause tissue damage and scarring (fibrosis) in the kidneys until they eventually fail to function altogether. When this happens, an individual with PKD needs to go on dialysis. If a kidney donor can be found, the individual can also get a transplanted kidney. Besides the loss of kidney function, PKD causes numerous other symptoms and complications such as hypertension, pain, liver cysts, and brain aneurisms that can increase the risk of stroke.

Indeed, there is only one pharmacological treatment currently available that slows the progression of PKD, but it does not stop progression, let alone reverse it. So, the bar for PKD treatments is relatively low right now.

Everyone thinks that the deterioration of the kidneys in PKD is irreversible. And that’s, unfortunately, what is seen in clinical practice. Nobody ever gets better.

But is it POSSIBLE that PKD kidneys could get better with the right treatment? Has anyone ever tried this at least in the laboratory using animals with PKD?

It turns out that the answer is “yes”. Read on.

A recent paper in Nature Genetics (1) by Dr. Stefan Somlo’s group at Yale University used genetically engineered mice in which the PKD1 or PKD2 genes could be turned off first, and then turned on again. This genetic “flip-flop” had never been tried before.

What did they find? As one would expect, when the researchers turned off the PKD genes, the mice developed polycystic kidneys. Nothing new here. This has been done many times in many labs. But when the researchers turned the PKD genes back on – after the mice already had polycystic kidneys – the kidneys got better again. A lot better. The cysts shrank, fibrosis improved, and the kidneys functioned better. So, it is possible to reverse PKD, at least in mice and with some genetic trickery that “fixes” the “broken” PKD genes in all the kidney cells.

This is great news.

The researchers, however, also found that the disease reversal works best if the broken PKD genes are “fixed” relatively soon after kidneys became polycystic. If they waited too long, then the scarring in the kidneys became permanent.

Can the “genetic treatment” that was used in mice be applied to humans with PKD to reverse their disease?

Unfortunately, the answer is “no”. At least not for a very long time, perhaps never. Replacing the broken PKD genes with intact genes would be a form of gene therapy. Gene therapy is very promising for certain genetic diseases but not for PKD. There is really no method on the horizon that can achieve the gene replacement for every single kidney cell in a patient.

Have other treatments been shown to reverse PKD in rodents?

Here, the answer is “yes”. Reversal of PKD has already been shown by other groups previously. The group of Thomas Weimbs at the University of California in Santa Barbara already showed in 2010 that treatment of PKD mice with the drug rapamycin caused reversal of renal cysts and greatly improved kidney function (2). Unfortunately, rapamycin is a drug that has too many side effects to be useful in a chronic disease like PKD (3).

More recently, however, the same group at UCSB also showed that a ketogenic diet was able to reverse the disease in rats with PKD (4). Wait, a diet? Really? Yes, really. No drugs were needed in this dietary study (4, 5).

So, an exciting picture emerges: the new study (1) confirms that PKD is reversible with the right kind of treatment, at least in rodents.

How about humans? Could PKD be reversible in patients?

A clinical retrospective case series study was recently published – again by the Weimbs lab at UCSB (6). These researchers showed that PKD symptoms, including pain, hypertension and kidney function improved in a large fraction of the 131 individuals with PKD who had switched to ketogenic diets (6). While this study is preliminary and needs to be repeated, it is the first human study that showed that individuals with PKD can experience improvement of their disease.

Improvement? In humans with PKD? Yes, improvement in Homo Sapiens. This goes against long-standing dogma and against everything that patients have always been told.

With the new paper in Nature Genetics (1), now we have another mouse study that shows that improving PKD may not be such a crazy idea.

Importantly, this paper strongly suggests that interventions in PKD should start as early as possible before the scarring in the affected kidneys becomes so widespread that it cannot be reversed.

Bottom line: If you have PKD and your doctor tells you that there is nothing you can do about it, let them know about these studies.

The bar has been raised.

References:

  1. Dong, K., Zhang, C., Tian, X., Coman, D., Hyder, F., Ma, M., and Somlo, S. (2021). Renal plasticity revealed through reversal of polycystic kidney disease in mice. Nature Genetics 1–15. https://doi.org/10.1038/s41588-021-00946-4; PMID: 34635846
  2. Shillingford, J.M., Piontek, K.B., Germino, G.G., and Weimbs, T. (2010). Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. Journal of the American Society of Nephrology: JASN 21, 489–497. https://doi.org/10.1681/ASN.2009040421; PMID: 20075061
  3. Weimbs T, Shillingford JM, Torres J, Kruger SL, Bourgeois BC. Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease. Clinical Kidney Journal. 2018 ;11(suppl_1):i27–i38. https://doi.org/10.1093/ckj/sfy089; PMID: 30581563
  4. Torres, J.A., Kruger, S.L., Broderick, C., Amarlkhagva, T., Agrawal, S., Dodam, J.R., Mrug, M., Lyons, L.A., and Weimbs, T. (2019). Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease. Cell Metabolism 30, 1007-1023.e5. https://doi.org/10.1016/j.cmet.2019.09.012; PMID: 31631001
  5. Carney, E.F. (2020). Ketosis slows the progression of PKD. Nature Reviews Nephrology 16, 1–1. https://doi.org/10.1038/s41581-019-0226-4; PMID: 31654043
  6. Strubl, S., Oehm, S., Torres, J.A., Grundmann, F., Haratani, J., Decker, M., Vuong, S., Kaur Bhandal, A., Methot, N., Haynie-Cion, R., Meyer, F., Siedek, F., Korst, U., Müller, R-U., Weimbs, T.  (2021). Ketogenic Dietary Interventions in Autosomal-Dominant Polycystic Kidney Disease (ADPKD)– A Retrospective Case Series Study: First insights into Feasibility, Safety and Effects. Clinical Kidney Journal (in press). https://doi.org/10.1093/ckj/sfab162

3 Replies to “Renal Plasticity Revealed Through Reversal of PKD in Mice”

  1. This is so exciting! Congratulations and keep up this amazing work🙏🏼

  2. That kidneys are phenotypically plastic, at least prior to fibrosis, is super cool! Did the authors measure kidney function? My thought: If kidney function decline is associated with compression of healthy tissue that can “bounce back” then improved function might be expected. But if healthy tissue doesn’t recover from being compromised then perhaps a change in morphology would not be associated with functional gains. Is function expected to return?

  3. Hello Erika, good question. Yes, they see functional improvement, too. However, less so if the intervention is done late (despite morphological improvement). Here is what they say in the paper: “The late-stage reactivation studies show that kidney volume and structure, and specifically the presence of cysts, remain highly responsive to polycystin protein expression despite advanced disease. Kidney functional recovery is more variable and less complete, probably because underlying scarring and fibrosis and nephron dropout are not reversible.”

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