Nephron number, not glomerular filtration rate

Nephrologists for many years have been able to accurately measure kidney function, a measure termed the glomerular filtration rate or GFR. To this end we have been the envy of many other specialties. However the GFR can be a very misleading test when dealing with kidney pathology both acutely and chronically. The GFR is not the equivalent of Troponin-I for the heart, a factor released from injured cells of the heart. The reason for this is that as nephrons cease to function, the other nephrons have spare capacity and can take over the function of lost nephrons. Thus the GFR can and does remain normal even as nephrons are being lost. This compensation can be best seen following a nephrectomy. Rarely does GFR fall acutely by 50% as would be expected and within a few weeks GFR is often at or greater than 80% of the pre-nephrectomy GFR. Unfortunately, because the kidney cannot generate new nephrons, the existing nephrons hyperfilter, and as was so elegantly demonstrated by Brenner, Rennke and colleagues in the 70's to 80's, hyperfiltering nephrons eventually succumb to glomerular injury, proteinuria and sclerosis.

The point of this discussion may be clearly brought home by comparing the renal function of a female patient, age 36 with SLE (Creatinine 0.5mg/dL, eGFR >80ml/min) yet all three cores of a renal biopsy show the pathology in the figure above. The primary histological finding is of widespread glomerulosclerosis with tubular atrophy. While obviously not all nephrons can be obsolescent, the normal GFR obscure the fact that this patient may have fewer than 50% of nephrons intact.

I encourage my fellows strongly to intervene in active kidney pathology before there is a detectable decline in GFR. In my opinion, frequently, once the GFR declines, overwhelming kidney damage has already been done and even if the disease can be controlled, the recovery may at best be partial. Even the most minor of declines in GFR in patients with active kidney pathology may be an ominous sign and should be attended to urgently.
What we really need is a non-invasive measure of nephron number, or possibly GFR reserve. This was discussed at the Renal Grand Rounds recently and the eminent Dr. Barry Brenner suggested a large protein meal with GFR assessed before and after. This kind of test may not be practicable, but any ideas on this pressing question would be greatly welcomed.