Kidney International, Vol. 55 (1999), pp. 2526–2527

EDITORIAL

Why do we have to invoke genetic susceptibilityfor diabetic nephropathy?

Kidney disease is one of the most serious and costly years ago we and other workers showed that the functioncomplications of diabetes. However, the kidney does not of a red-cell membrane transport system, the sodium-fail in all people with diabetes. Sometimes this is because lithium countertransport, which had been associatedother competing causes, such as cardiovascular disease, with essential hypertension, was abnormally high in dia-lead to death before end-stage renal failure intervenes, betic patients with diabetic nephropathy [3, 4]. Mostbut in many cases, in spite of long-standing diabetes, the of the interindividual variability of the activity of thisfunction of the kidney is preserved. The incidence of transport system was believed to be explained by geneticdiabetic nephropathy increases up to 17 years from the influence, a view recently confirmed by the finding of ainitial diagnosis of diabetes and then sharply declines. close concordance of sodium-lithium countertransportHyperglycemia, though critically necessary for kidney activity in identical twins discordant for type 1 diabetesdisease development, is insufficient to totally account [5]. However, the sodium-lithium countertransport is anfor it. in vitro artifactual system that does not operate in vivo

Why then are some diabetic people susceptible to and and its relevance to the pathogenesis of diabetic renalothers protected from renal disease? Familial factors are disease remains uncertain. The sodium-hydrogen anti-important. A diabetic sibling of a person with type 1 port is an integral plasma membrane protein that cata-diabetes and nephropathy has a 72% cumulative risk of lyzes the electroneutral exchange of extracellular sodiumdeveloping renal disease, while a diabetic sibling of a for intracellular hydrogen and regulates major cellularperson with type 1 diabetes but without nephropathy events such as intracellular pH, cell volume and stimulus-only has a 25% risk, a staggering 47% difference [1]. response coupling and cell proliferation. Of the five iso-Diabetic patients who develop nephropathy have a forms described the NHE1 is the most widely studied.higher incidence of arterial hypertension and cardiovas- Increased sodium-hydrogen antiport activity was first re-cular disease. Indeed, a predisposition to hypertension ported in leukocytes and in red blood cells of type 1and coronary heart disease may be an important determi- diabetic patients with microalbuminuria or proteinurianant of susceptibility to renal disease, since raised blood as well as in subjects with arterial hypertension [6]. How-pressure, frequency of cardiovascular disease and insulin ever, because the activity and the expression level ofresistance are significantly more prevalent in first degree this antiporter is modulated by a large variety of stimulirelatives of diabetic patients with nephropathy [2]. including growth factors, tumor promoters, hormones,

All these observations are consistent with a genetic changes in cell volume and extracellular pH, these earlypredisposition to diabetic nephropathy and are by and studies could not exclude the possibility that the phe-large true for both type 1 and type 2 diabetes. Clinical nomenon observed was a consequence of the disturbedmanifestations (such as renal disease, arterial hyperten- metabolic milieu of the diabetes state. More recently wesion, etc.), however, are complex multifactorial pheno- were able to show that this abnormal phenotype wastypes that are affected by an interaction of environmen- preserved in vitro in cultured skin fibroblasts after sev-tal, familial and genetic influences and are far removed eral passages [7], and Ng et al [8] confirmed this findingfrom a direct gene effect. To get closer to the genetic in immortalized lymphoblasts of type 1 diabetic patientsbasis and pathogenic mechanisms of diabetic nephropa- with nephropathy. The elevated maximal velocity ofthy, researchers have attempted to move down from the Na1/H1 exchanger was due to an increased turnover rateheight of complexity, at the whole organism level, to per site. The speculation was that because the anomalythe simple DNA sequence alteration by dissecting the persisted in culture in vitro, the activity of the Na1/H1

disease phenotype into several intermediate phenotypes antiporter was intrinsically determined. The article byat the different levels of biological organization. Some Trevisan and his colleagues in this issue [9] showing a

very close concordance for sodium-hydrogen antiportactivity in cultured skin fibroblasts of type 1 diabeticKey words: diabetes, genetic predisposition, sodium-hydrogen anti-

port, extracellular matrix, phenotype. siblings, makes a compelling case in favor of the view thatthese in vitro cell phenotypic characteristics are under 1999 by the International Society of Nephrology

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Editorial 2527

genetic control. Trevisan et al also provide supportive to diabetes. Genetic dissection of a complex trait suchas diabetic nephropathy, which is likely to involve anevidence that the degree of proteinuria and metabolic

control do not explain the concordance in Na1/H1 ex- interaction between more than one gene, environmentalfactors and compensatory factors, may prove arduous.changer activity between diabetic sibling pairs. A possi-

bility exists that the genetic alteration that explains the In the meantime, the use of reliable intermediate pheno-types in our quest for early diagnosis, risk assessmentoveractivity of the Na1/H1 antiporter is not located in

the Na1/H1 exchanger gene(s), but resides in some other and targeting of preventive and intensive therapiesshould not be discounted.process that carries as an obligate step an increase in

antiporter activity.Giancarlo VibertiIs the overactivity of this membrane transport system

London, England, United Kingdoma mechanism of diabetic kidney disease? Abnormalitiesof Na1/H1 antiporter activity in diabetic nephropathy Correspondence to Prof. G.C. Viberti, Unit for Metabolic Medi-

cine, 5th Floor, Thomas Guy House, KCL Guy’s Hospital, Londonhave been described in a variety of cell types, and thusSE1 9RT, England, United Kingdomfar there is remarkably absolute concordance in this ob- E-mail: giancarlo.viberti@kcl.ac.uk

servation from different research groups [6]. Moreover,both for type 1 and type 2 diabetes, the activity of the REFERENCESred cell Na1/H1 exchanger has been found to be pre-

1. Quinn M, Angelico MC, Warram JH, Krolewski AS: Familialdictive, in prospective studies, of the development of factors determine the development of diabetic nephropathy inproteinuria [10, 11]. One has to assume that the abnor- patients with IDDM. Diabetologia 39:940–945, 1996

2. De Cosmo S, Bacci S, Piras GP, Cignarelli M, Placentino G,mality of the Na1/H1 exchanger is a generalized phe-Margaglione M, Colaizzo D, Di Minno G, Giorgino R, Liuzzinomenon that is also present in renal cells and that the A, Viberti GC: High prevalence of risk factors for cardiovascular

isoform type, whose abnormal function has been re- disease in parents of IDDM patients with albuminuria. Diabeto-logia 40:191–196, 1997ported, is relevant in the context of the kidney. This

3. Mangili R, Bending JJ, Scott G, Li LK, Gupta A, Viberti GC:remains to be proven. There is plenty of circumstantial Increased sodium-lithium countertransport activity in red cells ofevidence that cellular features associated with increased patients with insulin-dependent diabetes and nephropathy. N Engl

J Med 318:146–150, 1988Na1/H1 antiport activity may be implicated in the patho-4. Krolewski AS, Canessa M, Warram JH, Laffel LM, Christliebgenesis of diabetic nephropathy. These include abnor- AR, Knowler WC, Rand LI: Predisposition to hypertension and

malities in DNA synthesis, cell cycle, cell life span, colla- susceptibility to renal disease in insulin-dependent diabetes melli-tus. N Engl J Med 318:140–145, 1988gen production, PKC activity and perhaps in the degree

5. Hardman TC, Dubrey SW, Leslie DG, Hafiz M, Noble MI,of Na1/H1 protein phosphorylation [6]. A most intri- Lant AF: Erythrocyte sodium-lithium countertransport and bloodguing observation comes from this same group of investi- pressure in identical twin pairs discordant for insulin dependent

diabetes. BMJ 305:215–219, 1992gators who have shown that there is concordance in6. Trevisan R, Viberti GC: Sodium-hydrogen antiporter: Its possiblethe glomerular structural lesions in these same type 1 role in the genesis of diabetic nephropathy. Nephrol Dial Trans-

diabetic sib-pairs [12]. Since the Na1/H1 antiporter can plant 12:643–645, 19977. Trevisan R, Li LK, Messent J, Tariq T, Earle K, Walker JD,be activated by extracellular matrix molecules, an in-

Viberti GC: Na1/H1 antiport activity and cell growth in culturedteraction between excess matrix production and the skin fibroblasts of IDDM patients with nephropathy. DiabetesNa1/H1 antiporter appears of particular importance in 41:1239–1246, 1992

8. Ng LL, Davies JE, Siczkowski M, Sweeney FP, Quinn PA, Kro-the process leading to diabetic glomerulopathy [6]. Thelewski B, Krolewski AS: Abnormal sodium-lithium antiporter

assumption here would be that diabetic patients who phenotype and turnover of immortalized lymphoblasts from type1 diabetic patients with nephropathy. J Clin Invest 93:2750–2757,develop nephropathy have a genetic predisposition to1994lay down more matrix, and this has as an obligate accom-

9. Trevisan R, Fioretto P, Barbosa J, Mauer M: Insulin-dependentpaniment a higher Na1/H1 exchanger rate. Studies of diabetic sibling pairs are concordant for sodium-hydrogen antiport

activity. Kidney Int 55:2383–2389, 1999candidate genes for diabetic nephropathy have so far,10. Koren W, Koldanov R, Pronin VS, Postnov IY, Peleg E, Rosen-however, been largely inconclusive and have excluded

thal T, Berezin M, Postnov YV: Enhanced erythrocyte Na1/H1

modifications in the sodium-hydrogen antiporter gene(s) exchange predicts diabetic nephropathy in patients with IDDM.Diabetologia 41:201–205, 1998and in genes regulating matrix synthesis.

11. Koren W, Koldanov R, Pronin VS, Postnov IY, Peleg E, Rosen-Has the study of Na1/H1 antiporter advanced our thal T, Berezin M, Postnov YV: Amiloride-sensitive Na1/H1

understanding of the genetic susceptibility to diabetic exchange in erythrocytes of patients with NIDDM: A prospectivestudy. Diabetologia 40:302–306, 1997nephropathy? I believe it has established the fundamen-

12. Fioretto P, Steffes MW, Barbosa J, Rich SS, Miller ME, Mauertal concept that the increased susceptibility to nephropa- M: Is diabetic nephropathy inherited? Studies on glomerular struc-thy resides in a genetically determined host-cell response ture in type 1 diabetic sibling pairs. Diabetes 48:865–869, 1999