Blood pressure salt sensitivity: a biomeasure of kidney disease susceptibility in diabetics?

Matthew R. Weir

Division of Nephrology, Department of Medicine, University of Maryland, School of Medicine, Baltimore, MD 21201, USA

Correspondence and offprint requests to: Matthew R. Weir, University of Maryland Hospital, Renal Division, Baltimore, MD 21201, USA. Email: mweir{at}medicine.umaryland.edu



   Introduction
 Top
 Introduction
 The Strojek study
 Is a salt-induced change...
 Conclusions
 References
 
Is it this simple? Could it be that simply defining blood pressure responses to variations in dietary salt will identify those patients genetically, or possibly environmentally, predisposed to developing kidney disease? Is salt-sensitive blood pressure an intermediate phenotype linked to the genesis of diabetic kidney disease?



   The Strojek study
 Top
 Introduction
 The Strojek study
 Is a salt-induced change...
 Conclusions
 References
 
The interesting study of Strojek et al. [1] does not answer the question. What this study does suggest is that in a highly selected, small population of offspring of diabetics with chronic kidney disease (CKD), there are intriguing relationships of salt-induced changes in blood pressure and a higher mean urinary (THF + 5{alpha}THF)/THE ratio. Thus, there is biological plausibility to explain the blood pressure change in response to change in dietary salt. However, does this explain a proclivity for developing diabetic kidney disease?

Give the authors credit for a creative pilot study to test the hypothesis that maybe the offspring of diabetics with CKD may have a kidney sodium-handling problem which could explain salt-induced changes in blood pressure. However, they did exclude offspring with hypertension, fasting hyperglycaemia, smokers and oral contraceptive users. This induces informative censoring bias, as these measures may impact salt-induced changes in blood pressure, the primary outcome measure of the study! Also important were the definitions employed to define ‘nephropathy’ in the diabetic patients. End-stage renal disease (ESRD), or 24 h urine protein of 500 mg/day or more seems quite narrow. No estimate of glomerular filtration rate (GFR) or measurements of microalbuminuria was performed which may have captured more diabetic patients with CKD.

Perhaps the biggest flawed assumption of the authors is that salt-induced higher blood pressure or ‘hypertension’ before the development of glucose intolerance predisposes to nephropathy. There still remains great debate as to whether elevated blood pressure, or ‘hypertension’, depending on the terminology, initiates kidney disease or instead propagates it, once an insult has occurred.

What are the risk factors for diabetic nephropathy? Is there a relationship between salt ingestion and kidney disease?

Rather than criticize this study, what may be more important to consider are the potential factors that could increase the risk for the development of kidney and cardiovascular disease in the offspring of diabetic parents. The critical need for identifying genes which code for this risk is essential. Multiple genetic projects are underway to evaluate heredity and phenotype interactions which could assist in the identification of patients at risk who may derive advantage from earlier risk reduction measures. Some of these studies do include salt sensitivity profiling, cold pressor testing, vascular reactivity, etc. However, the salt relationship may be one of the most interesting!

The fascination with blood pressure salt sensitivity was born out of numerous epidemiological and clinical trials which demonstrated that higher levels of blood pressure are associated with increased risk for progression of kidney disease [2–4], and that populations who are more commonly salt sensitive such as diabetics and African Americans more commonly have kidney disease [5]. Moreover, increased salt consumption in patients with salt sensitivity has been shown to result in increased glomerular filtration fraction and intraglomerular capillary pressure as well as increased proteinuria [6,7]. These are subclinical measures which have been associated with adverse renal outcomes [8].

Yet, which comes first? Is there a genetic or environmental interaction which sets the kidney up for future injury? Some have theorized that a vascular toxin, perhaps uric acid [9] or even salt [10], in susceptible patients, could lead to afferent glomerular arteriolar injury which could limit autoregulatory responses to increases in blood pressure. The kidney could become more vulnerable to the effects of even subtle elevations of systemic blood pressure. Subsequent glomerular capillary hypertension over time could lead to peritubular capillary rarefaction and injury which could limit kidney sodium excretory capability with the subsequent development of salt-sensitive hypertension [11]. Other theories have linked diminished nephron mass, and an overall reduction in glomerular filtration or altered filtration capacity with increased sodium reabsorption [12], with subsequent changes in the blood pressure–natriuresis response. However, these are all theoretical possibilities which have not been tested in clinical trials. Thus, the link between salt, blood pressure salt sensitivity and proclivity for kidney disease progression remains a hypothesis which needs to be tested.



   Is a salt-induced change in microalbuminuria a better target for study?
 Top
 Introduction
 The Strojek study
 Is a salt-induced change...
 Conclusions
 References
 
Perhaps microalbuminuria is a more important biomeasure to predict risk for nephropathy and response to therapy in type 2 diabetes. In patients with type 1 diabetes, where the onset of the disease process is known with relative certainty, screening for microalbuminuria is a valuable asset in heralding the onset of kidney disease. On the other hand, in the patient with type 2 diabetes, where the onset of the disease is insidious and variably progressive, the diagnosis may be delayed for years. Consequently, there is no consistency in the literature on the relationship of albuminuria and clinical outcome. Moreover, in the microalbuminuria type 2 diabetic population, there is the competing hazard of cardiovascular events which limits the numbers of patients who are likely to progress to develop CKD. There is important and consistent clinical evidence from numerous post hoc analyses of clinical trials in patients with hypertension, with or without diabetes or kidney disease, indicating that time-varying albuminuria during follow-up correlates with both cardiovascular and kidney outcomes [8,13–15]. Perhaps one needs to see a salt-induced change in both blood pressure and albuminuria in order to predict nephropathy. Or maybe albuminuria alone, independent of blood pressure, is good enough to predict adverse outcomes.

In the Strojek paper, albuminuria was not different between controls and the offspring of patients with or without diabetic nephropathy. Given the strong relationship between albuminuria and cardiovascular and kidney outcomes, I was surprised at this lack of difference, given their hypothesis. Without a salt-induced change in albuminuria, risk for kidney injury may be less likely. If so, then the blood pressure changes with salt, albeit provocative and of limited validity for the previously mentioned reasons, may be nothing more than a play of chance.



   Conclusions
 Top
 Introduction
 The Strojek study
 Is a salt-induced change...
 Conclusions
 References
 
More studies like the Strojek trial [1] need to be conducted to explore possible biomeasures of kidney disease susceptibility carefully in the offspring of diabetics. I think using salt-induced changes in microalbuminuria might prove to be a better tool. It may miss people at risk in the ‘pre-microalbuminuria’ range but, given our inexact ability to identify patients at risk with specific candidate genes, it may be the best we can do to narrow the field.

Conflict of interest statement. None declared.

[See related Original Article by Strojek et al., p. 2113]



   References
 Top
 Introduction
 The Strojek study
 Is a salt-induced change...
 Conclusions
 References
 

  1. Strojek K, Nicod J, Ferrari P et al. Salt-sensitive blood pressure predisposing to nephropathy. Nephrol Dial Transplant doi:10.1093/ndt/gfh873
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Related articles in NDT:

Salt-sensitive blood pressure—an intermediate phenotype predisposing to diabetic nephropathy?
Krzysztof Strojek, Jerome Nicod, Paolo Ferrari, Wladyslaw Grzeszczak, Juta Gorska, Bernard Dick, Felix Frey, and Eberhard Ritz
NDT 2005 20: 2113-2119. [Abstract] [FREE Full Text]  




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