The Intellectual Gambit

That hypertension causes end-stage-renal-disease (ESRD) is a shibboleth trademarked to nephrology. So ingrained is this bedrock belief that the United States Renal Data System, in its 1999 report, lists hypertension as the cause for 20,066 of 79,102 (25.4%) incident ESRD cases in 1997.(1) Support for this view is provided by multiple affirmations from many nations, as indicated by the results of a PubMed (Library of Congress) search for articles on hypertensive nephropathy that yielded 5,398 reports (04/30/99). If we limit the scope of the search to "controlled studies," we can prune the number of articles to 102. There are fewer than ten long-term controlled studies of defined populations in which the consequences to the kidney of hypertension are addressed.

Does the Emperor Lack Clothes?

Epstein, in an insightful analysis of hypertension as a risk factor for progression of chronic renal disease over the preceding decade, contrasts the "declining mortality due to coronary artery disease and stroke," attributed to improved effectiveness and application of antihypertensive therapy, with the "striking contrast" of continuing increase in ESRD due to hypertension.(2) Similarly, Mehta, Wilcox and Shulman, who surveyed physicians to determine their treatment for hypertension, point to the reduction in stroke mortality as reason to follow Joint National Committee guidelines on hypertension to lower the risk of death from kidney disease.(3) The question is asked as to why the rate of ESRD attributed to hypertension is rising, while deaths from myocardial infarction and stroke are declining? Jaimes, Galceran and Raij suggest that "variation in the mechanisms at work in hypertensive patients of different races and variation in the degree to which antihypertensive agents affect systemic blood pressure and glomerular capillary pressure" may be responsible.(4)

For Rahn, it is a "given" that hypertension causes ESRD: "There is now increasing evidence that essential hypertension is a serious risk factor for renal insufficiency. This can be prevented by treatment with anti-hypertensive drugs."(5) But maybe the reason that billions of dollars expended for antihypertensive drugs has not reduced the incidence of ESRD due to hypertension is that hypertension - per se - does not cause ESRD? After all, as admitted by Epstein, "No data are readily available on repeated measurement of glomerular filtration rate during prolonged treatment of mild hypertension in patients with normal or near-normal renal function."(2) To raise this issue in no way detracts from the brilliant successes of reducing hypertensive blood pressure, thereby preserving renal function, in diabetic nephropathy and other kidney disorders.

Consider the Numbers

If 10% of America's 50 million hypertensive individuals progress to ESRD each year, the incidence would be five million. Lower the rate of progression to 1% and the incidence of new ESRD cases is 500,000. Decrease the estimate to 0.1% and the prediction would be for 50,000 new ESRD cases attributed to hypertension per year. Now return to the USRDS 1999 report, which lists 20,066 incident ESRD cases as due to hypertension,(1) and the actual proportion of hypertensive people progressing to ESRD is 0.04%. Furthermore, within the group labeled primary hypertensives are a substantial, though undefined, number of misdiagnosed people with other kidney diseases.

As concluded by Schlessinger, Tankersley and Curtis, "the number of patients reaching dialysis and transplantation with renal failure attributed to hypertensive ESRD may be overestimated."(6) This is especially true among African-American hypertensives, in whom: "Nephrologists are twice as likely to label as having hypertensive nephrosclerosis compared with a white patient, when presented with identical clinical histories."(7)

Malignant Hypertension

Without question, malignant hypertension (untreated) causes ESRD.(8) Ample evidence sustains the direct progression from abrupt onset to renal failure of a syndrome encompassing grade IV hypertensive retinopathy, proteinuria, fibrinoid necrosis and hyalinization of small arteries and arterioles. Until recently, malignant hypertension has had a grim prognosis that is improved by normalizing hypertensive blood pressures.(9) With aggressive regulation of blood pressure, however, a disease with a mortality of approximately 50% in three years a decade ago(10) may now afford survival of as high as 100% for a decade or longer.(11) Industrialized nations having access to (i.e., affording) powerful (i.e., expensive) antihypertensive drugs now find malignant hypertension a rarity. A precise relationship between essential and malignant hypertension or primary or secondary malignant hypertension is difficult circumscribe. In the present context, primary malignant hypertension is excluded from the discourse as the disorder constitutes only a minute component of the population of hypertensive people potentially at risk for ESRD.

Clues From the Other Side

Of the few careful prospective studies of populations to discern the ESRD risk imposed by hypertension, it is not possible to extract a convincing case for concern. Weisstuch and Dworkin reviewed published studies to date in 1992 and remarked: "Although an increase in serum creatinine or decline in clearance has been reported, progression to end-stage renal disease has not been documented. Therefore, additional studies are necessary to determine the frequency with which essential hypertension leads to end-stage renal disease."(12) Tomson, Petersen, and Heagerty, in order to address the question of how frequently essential hypertension results in renal impairment, conducted a follow-up study of 176 patients for 12-14 years. They noted that 15 (8%) had died (11 cardiovascular deaths) but that: "no significant change in serum creatinine was detected in the group as a whole."(13)

Perhaps the most impressive long-term, prospective, observational study of essential hypertension was performed in Goteborg, Sweden, in which a random third of the male population, aged 47-55 years, yielded 7,495 study participants for 20 years.(14) There were 686 hypertensives identified, of whom 61 (8.9%) had an initial elevation of serum creatinine level above 130 micromol during the 20 years of follow-up. An underlying renal disorder was discovered in 49 of these subjects. After 20 years, none of the subjects developed either ESRD or a "clinically important reduction in renal function." In fairness, there were no black participants, nor were women or other entry age groups included. Despite these strictures, the Goteborg study suggests that ESRD, if it is a consequence of essential hypertension, is not a common outcome.

Marching Orders

So, where does the interested sideliner come out on this issue (Table 1)?

First, hypertension should be treated in every individual with special attention to those with diabetes. Second, huge observational trials in progress, such as the Antihypertensive and Lipid Lowering Treatment to Prevent heart Attack Trial (ALLHAT) study,(15) are appropriate and should illuminate an arena now filled with much heat and minimal factual conclusions. If learning something new is its own reward, then the recognition that ESRD incidence has not declined (at the same time that strokes and heart attacks have fallen) does not represent a failure in hypertensive regulation. Rather, we can view the trend as the natural history of renal disease as our population ages, becomes increasingly obese and the prevalence of diabetes swells to a pandemic.(16)