Wednesday, February 24, 2016

What can high nephron abundance teach us about CKD?

If you are fortunate, you’ll start life with somewhere in the neighborhood of two million nephrons at birth, and for most, that’s enough to journey through life without a hint of uremia. Even those who maintain good health experience a gradual loss of renal function through life.

But what about those who have and maintain really fantastic renal function? 

Do possessors of “elite kidneys” have something to teach us for the benefit of those with failing kidneys? 

The concept that low nephron endowment is associated with the development of renal disease, has been around since at least 1988, with the work of Brenner and colleagues. Despite the technical difficulties in estimating glomerular number from biopsies and autopsy samples, low nephron number has been reproducibly associated with hypertension and chronic kidney disease in human populations and experimental models. This is particularly true of disadvantaged populations such as Aboriginal Australians. And an association between low nephron number and hypertension has been demonstrated at autopsy after accidental death in patients and matched controls.

It’s fair to say the converse - high nephron endowment - is little studied. 

Interestingly, when studies from a variety of populations (totalling 182 subjects) are taken together, the number of glomeruli per kidney averages ≈850,000 with an enormous 8.6 fold range (≈230,000 - ≈1,960,000).

So, what of these well endowed people with nearly 2 million glomeruli per kidney? Do they resist an age associated decline in renal function? Do they weather pathologic insults better? Do they develop hypertension less readily? Would they be amongst the best transplant donors?

  • Experimental models of high nephron endowment have examined murine models with altered TGF-β family signalling. Mice expressing a dominant negative truncated type II activin receptor (tActRII) have a 1.8x increase in glomerular number compared to wild type mice. Despite this, creatinine clearance and blood urea nitrogen did not significantly differ.
  • Another experimental study from 2012 examined tgfb2+/- heterozygous mice, which constitutionally bear 30% greater nephron number [6]. Compared to their wild type counterparts, there was no difference in terms of blood pressure or creatinine clearance. However when challenged with a chronic high salt diet, moving from 0.9%, to 4%, then 8% saline, tgfb2+/- mice proved resistant to the hypertensive effects. 
In terms of translating this to humans, the weight of evidence supports a model in which a wide range of nephron number is determined principally by birth weight, and higher nephron number might prove protective against the development of hypertension and CKD. It is certainly tempting to speculate that a very high filtration area would provide robust renal reserve in the face of aging, or overt renal insults. Further studies of the effects of nephron number are hampered by the lack of non-invasive measures. Use of MRI in the measurement of glomerular number and size in perfused kidney has been described, but this is not yet ready for use in vivo.

Nephron endowment is a purely structural measure. In looking for “elite kidneys”, functional measures may be much more valuable. The concept of renal functional reserve (RFR) reflects the idea that stressing a physiological system reveals its dynamic range to a greater extent than a static measure (e.g GFR). Renal function reserve is therefore the capacity of the kidney to increase glomerular filtration rate in response to a physiological stimulus (e.g. amino acid load, pregnancy, increased renal perfusion pressure), or a pathological stimulus. In the diseased state the maximal GFR that can be achieved by residual nephrons should be a better measure of renal function than average GFR, which may be near normal early on. It appears that renal functional reserve (measured by assessing the rise in GFR after vasodilator stimuli) does decline even with healthy aging. But this only tells us young kidneys are functionally better than old ones. We knew that anyway. Amongst healthy children there is a surprising range of RFR. In a study of 89 children challenged with a protein meal, 46% were able to raise their GFR to ≥20% baseline, with a quarter struggling to increase beyond 10% [10]. Unfortunately, we don’t know what happened to the owners of these high performance kidneys in adulthood.

Overall, this is a very open question. The best route to answering it likely lies in identifying young subjects with normal GFR, but a high renal functional reserve, perhaps with an associated high (non-invasively measured) nephron number. The key questions would be: what are the factors associated with supranormal function, and are there any modifiable factors which might be translatable to those with pathologically subnormal function?

Post by Benjamin Stewart, NSMC Intern

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