Correspondence

Nephron Number and Primary Hypertension

N Engl J Med 2003; 348:1717-1719April 24, 2003

Article

To the Editor:

Keller et al. (Jan. 9 issue)1 report that patients with hypertension have fewer nephrons than do age-matched normotensive controls. Is hypertension therefore predetermined by a low nephron number, and, if so, how does this occur? Reduction of the surface area of glomerular capillaries, resulting in a limitation of sodium filtration, does not explain the findings, since kidney donation is not associated with hypertension, even many years later.2

We propose that most primary hypertension results from subtle, acquired renal injury,3 mediated by transient renal vasoconstriction (such as that resulting from catecholamines, diets low in potassium, or hyperuricemia), or from transient increases in blood pressure (caused by a hyperactive sympathetic nervous system) that induce microvascular and tubulointerstitial injury. Consequent renal ischemia and an interstitial infiltration of leukocytes generate oxidants and perpetuate the vasoconstriction. The preglomerular vessels also thicken, giving rise to arteriolosclerosis that impairs renal autoregulation, transmitting systemic pressure to the glomerular and postglomerular circulation, where it mediates capillary injury,4 and causing ischemia.3 Intrarenal vasoconstriction, decreased blood flow, and capillary injury lead to decreased sodium filtration, increased sodium reabsorption, and the development of hypertension.3

Persons with fewer nephrons may be prone to the development of hypertension because their vasodilated, hyperfiltering glomeruli are more vulnerable to any transient increase in systemic pressure.5 Blocking interstitial inflammation, stimulating vascular remodeling, or blocking glomerular hypertension may prevent engagement of this pathway. Thus, even for persons with fewer nephrons, hypertension may be preventable and potentially curable.

Richard J. Johnson, M.D.
Baylor College of Medicine, Houston, TX 77030
rjohnson@bcm.tmc.edu

Bernardo Rodríguez-Iturbe, M.D.
University of Zulia, Maracaibo 4001-A, Venezuela

Jaime Herrera-Acosta, M.D.
Instituto Nacional Cardiologia I Chavez, 14080 Mexico City, Mexico

5 References

1
Keller G, Zimmer G, Mall G, Ritz E, Amann K. Nephron number in patients with primary hypertension. N Engl J Med 2003;348:101-108
Full Text | Web of Science | Medline

2
Goldfarb DA, Matin SF, Braun WE, et al. Renal outcome 25 years after donor nephrectomy. J Urol 2001;166:2043-2047
CrossRef | Web of Science | Medline

3
Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B. Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med 2002;346:913-923
Full Text | Web of Science | Medline

4
Sanchez-Lozada LG, Tapia E, Avila-Casado C, et al. Mild hyperuricemia induces glomerular hypertension in normal rats. Am J Physiol Renal Physiol 2002;283:F1105-F1110
Web of Science | Medline

5
Kang D-H, Nakagawa T, Feng L, Johnson RJ. Nitric oxide modulates vascular disease in the remnant kidney model. Am J Pathol 2002;161:239-248
CrossRef | Web of Science | Medline

To the Editor:

The reduction in glomeruli in the kidneys of patients with hypertension reported by Keller et al. is striking. But kidney weight and cortical weight were actually slightly greater in the kidneys of patients with hypertension, despite a 50 percent reduction in the number of nephrons. Since tubules, not glomeruli, form the bulk of the renal parenchyma, the normal size of the kidneys in patients with hypertension implies the presence of a substantial degree of tubular hypertrophy. This hypertrophy is certainly not unexpected, but it should have been apparent on histologic analysis. An alternative explanation would be an expansion of the interstitium, most likely with fibrosis. In this regard, it would be informative to have more histologic data on these kidneys.

W. Charles O'Neill, M.D.
Emory University School of Medicine, Atlanta, GA 30322
woneill@emory.edu

To the Editor:

If a reduced number of glomeruli and an increase in glomerular volume lead to systemic hypertension, as suggested by Keller et al., then oligomeganephronia would appear to be nature's experiment to prove that these factors are causal. Children with this rare congenital disease are born with bilateral hypoplastic kidneys with a severely reduced number of nephrons (20 to 25 percent of the normal number), a highly enlarged glomerular volume (diameter, 250 to 325 μm, as compared with the normal range of 100 to 150 μm), and hypertrophic and elongated tubules. In both original1 and recent2 descriptions of oligomeganephronia, however, arterial hypertension has rarely been encountered. In children with oligomeganephronia, polyuria typically develops in early childhood, along with a failure to thrive, metabolic acidosis, and proteinuria, and end-stage renal disease develops during late childhood, in the absence of systemic hypertension. This course is consistent with the hyperfiltration theory but does not support the view that a reduced number of glomeruli and an increase in glomerular volume themselves cause hypertension. Instead, mutations in genes affecting the development of nephrons3,4 could either be associated with arterial hypertension or, apparently, protect persons from hypertension, as in oligomeganephronia.

Uwe Querfeld, M.D.
Charité University Hospital, 10117 Berlin, Germany
uwe.querfeld@charite.de

Patrick Niaudet, M.D.
Hôpital Necker–Enfants Malades, 75743 Paris CEDEX 15, France

4 References

1
Royer P, Habib R, Mathieu H, Courtecuisse V. L'hypoplasie rénale bilatérale congénitale avec réduction du nombre et hypertrophie des néphrons chez l'enfant. Ann Pediatr (Paris) 1962;38:133-146

2
Broyer M, Niaudet P. Oligomeganephronia. In: Rose BD, ed. UpToDate. Wellesley, Mass.: UpToDate, 2002.

3
Salomon R, Tellier AL, Attie-Bitach T, et al. PAX2 mutations in oligomeganephronia. Kidney Int 2001;59:457-462
CrossRef | Web of Science | Medline

4
Ingelfinger JR. Is microanatomy destiny? N Engl J Med 2003;348:99-100
Full Text | Web of Science | Medline

Author/Editor Response

Dr. Johnson and colleagues raise the issue that kidney transplantation from living donors — which is, so to speak, a human model of nephron “underdosing” — is not associated with hypertension. This statement is not entirely correct: a number of long-term observations indicate that hypertension is somewhat more frequent, though by no means universal, after kidney donation.1-5 It is also conceivable that the presence of a reduced number of nephrons at birth has implications that differ from those of the postnatal loss of nephrons.

We carefully refrained from any speculation concerning the mechanism of the relation between a reduced number of nephrons and hypertension. It would certainly be naive to believe that all patients with essential hypertension are the same; we and others believe that essential hypertension is a heterogeneous entity. Some support for this notion comes from genetic studies suggesting that genes as diverse as those involved in the renin–angiotensin system and those involved in the sympathetic nervous system are related to essential hypertension. We also acknowledge that, for logistic reasons, our sample was relatively small, so that it would be quite inappropriate to claim that all patients with essential hypertension have a reduced number of nephrons. One plausible hypothesis, however, would be that a lower number of nephrons exposes a person to a greater risk of the development of hypertension when additional injury occurs, as Johnson et al. suggest.

Dr. O'Neill comments that there is a discrepancy between the reduced numbers of nephrons and the absence of a change in the weights of the kidneys. This discrepancy may be the result of some compensatory growth, which is also illustrated, for instance, by glomerulomegaly. We did not quantitate the percentage of the total volume that consisted of tubular epithelial cells or interstitial cells, but on qualitative inspection, there was no major tubulointerstitial fibrosis to account for this observation.

Drs. Querfeld and Niaudet comment on the known entity of oligomeganephronia, a condition involving low numbers of nephrons and no hypertension. To the best of our knowledge, the pathogenesis of this rare condition is unknown. There are, however, a few reports in the literature that mention hypertension in the context of oligomeganephronia and associated syndromes. In the absence of definite information on this point, however, it is difficult to comment. One possibility to consider is that the failure to thrive may have a role, since weight loss alone may reduce blood pressure. Given the multifactorial and complex genesis of essential hypertension, it would be inappropriate to conclude that all essential hypertension is due to the presence of reduced numbers of nephrons or, conversely, that all such reductions must necessarily cause hypertension.

Kerstin Amann, M.D.
University of Erlangen-Nürnberg, 91054 Erlangen, Germany
kerstin.amann@patho.imed.uni-erlangen.de

Eberhard Ritz, M.D.
University of Heidelberg, 69115 Heidelberg, Germany

5 References

1
Gossmann J, Wilhelm A, Kachel H-G, Geiger H, Scheuermann E-H. Near complete follow up of living kidney donors at a single center. J Am Soc Nephrol 2002;13:11A-11A abstract.
Web of Science

2
Saran R, Marshall SM, Madsen R, Keavey P, Tapson JS. Long-term follow-up of kidney donors: a longitudinal study. Nephrol Dial Transplant 1997;12:1615-1621
CrossRef | Web of Science | Medline

3
Eberhard OK, Kliem V, Offner G, et al. Assessment of long-term risks for living related kidney donors by 24-h blood pressure monitoring and testing for microalbuminuria. Clin Transplant 1997;11:415-419
Web of Science | Medline

4
Fehrman-Ekholm I, Elinder CG, Stenbeck M, Tyden G, Groth CG. Kidney donors live longer. Transplantation 1997;64:976-978
CrossRef | Web of Science | Medline

5
Watnick TJ, Jenkins RR, Rackoff P, Baumgarten A, Bia MJ. Microalbuminuria and hypertension in long-term renal donors. Transplantation 1988;45:59-65
CrossRef | Web of Science | Medline

Citing Articles (1)