‘Hypertensive nephrosclerosis’ is moving up the charts to number 2 in terms of diagnostic frequency cited as causing end‐stage renal disease (ESRD) in chronic dialysis patients; the entity was recognized as early as 1873 . Type 2 diabetes mellitus holds first place and glomerulonephritis (all types) has fallen to third place in the ranking. The diagnostic criteria for type 2 diabetes and glomerulonephritis are relatively secure. Malignant hypertension with fibrinoid necrosis and relatively acute renal failure is a well understood pathological entity. However, hypertensive nephrosclerosis resulting from essential hypertension per se is far less clear.
Frequency of end‐stage renal disease in hypertensive patients
There is no doubt that elevations of blood pressure are a strong independent risk factor for ESRD. The 332 544 men participating in the MRFIT study showed that a strong, graded relationship between systolic and diastolic blood pressure and the subsequent development of ESRD exists, independent of associations between ESRD and age, race, income, diabetes mellitus, history of myocardial infarction, serum cholesterol, and cigarette smoking . Also well recognized is the fact that African‐Americans have a higher risk than white Americans. The same MRFIT cohort indicated that higher blood pressure and lower income are associated with increased ESRD in both whites and African‐Americans. Furthermore, disparities in blood pressure and socioeconomic status largely explain the excess of ESRD in African‐Americans . In a large cohort of hypertensive American veterans followed longitudinally, ESRD attributed to hypertension was more common in African‐Americans than white Americans . However, the risk of ESRD was greatly increased by the presence of myocardial infarction or heart failure. This study also showed the now well recognized fact that lowering blood pressure decreases the risk of ESRD; a 20 mmHg decrease in systolic blood pressure reduced risk by two‐thirds. On the basis of epidemiological data from various sources, projections have been made to predict the amount of hypertension‐related ESRD the United States might expect . From these predictions, the authors concluded that 5300 Americans come to dialysis with ESRD from hypertension yearly. Nevertheless, progression to ESRD is rare in persons with hypertension‐related renal disease, and factors other than blood pressure probably play an important role. This observation is important because it suggests that other interventions in addition to blood pressure reduction may be effective.
The renal histology of hypertension‐related renal failure
Few biopsy data are available in patients labelled as having hypertension‐related ESRD. Since the problem is particularly acute in African‐Americans, the African‐American Study of Kidney Disease (AASK) trial has been organized by the National Institutes of Health. A renal biopsy study was performed on patients entering this study to better document the diagnosis of hypertensive nephrosclerosis. Eighty‐eight AASK patients were asked to submit to renal biopsy . Forty‐six patients agreed and 39 biopsies were performed. The mean blood pressure of these patients was 109±15 mmHg and their mean GFR was 52±13 ml/min. The main findings were arteriosclerosis and/or arteriolosclerosis, interstitial fibrosis, basement membrane thickening, and global glomerulosclerosis. One patient with focal segmental glomerulosclerosis and another with diabetic changes were identified. The authors concluded that non‐diabetic hypertensive African‐Americans without marked proteinuria, but with decreased renal function, are very likely to show renal vascular lesions consistent with the clinical diagnosis of hypertensive nephrosclerosis. The AASK study, which includes two treatment arms in terms of target blood pressure levels, will be completed in 2001. Suffice it to say that with great probability, the AASK study will show that intensive blood pressure reduction is better than casual blood pressure reduction. But is that the end of hypertensive nephrosclerosis?
Interaction between blood pressure and genetic background
There are good reasons to believe that hypertensive nephrosclerosis is as heterogeneous as hypertension itself . Furthermore, numerous confounders exist in patients with elevated blood pressure. The AASK study and a host of animal studies document the strong genetic component exerted on hypertension‐induced vascular injury. Spontaneously hypertensive rats (SHR), unless uninephrectomized, develop very little renal damage, while Dahl salt‐sensitive rats exhibit proteinuria before blood pressure increases and before a high salt diet is given. Moreover, elegant transplantation experiments involving SHR and Brown Norway rats indicate that certain kidneys have a propensity to damage while others do not . A gene for hypertensive nephrosclerosis in the rat has been mapped .
A diagnostic mixed bag
Intrinsic renal diseases may mimic hypertensive nephrosclerosis, since virtually all renal diseases are characterized by high blood pressure. For instance, in renal biopsy specimens from 27 patients with hypertension and proteinuria suspected to have hypertensive nephrosclerosis, six had glomerulonephritis . Eight others had enlarged glomeruli with segmental glomerulonephropathy. In nine of the remaining 13 patients, glomerular abnormalities of one sort or another were identified. Who knows what these patients had? How about obesity as a confounding factor or as a cause of focal segmental or generalized nephrosclerosis? All are aware of the frightening epidemic of obesity in the United States . The righteous indignation of a certain Frenchman in attacking American fast‐food restaurants is clear indication of a growing European problem. However, traditionally slim cultures are not immune. A recent study in Hong Kong Chinese demonstrated that hypertension, carbohydrate intolerance, dyslipidaemia and albuminuria can be predicted by means of a nomogram relying on simple anthropometric indices . Other confounders influencing renal disease progression are lipid disturbances and particularly smoking .
Generalized atherosclerosis is common in older hypertensive patients and large vessel disease may go unrecognized. Hypertensive nephrosclerosis may in fact frequently indicate the presence of atherosclerotic nephropathy . Cholesterol emboli may go unrecognized. Such emboli were identified in the AASK study biopsies. A recently described animal model showed heterogeneous changes similar to human chronic renal failure, particularly in terms of tubular atrophy and interstitial fibrosis . With the popularity of angiography and invasive intravascular therapies, a new dimension of hypertension and chronic renal disease with minimal proteinuria is developing. The treatment of cholesterol emboli is for the most part supportive . Experts advise the discontinuance of anticoagulation. No information is available, whether or not aggressive HMG Co‐A reductase therapy might be helpful in terms of plaque stabilization; however, such a strategy is probably indicated in these patients for other reasons and would appear worth pursuing.
Fixing big vessels may not help
Individual renal function in atherosclerotic nephropathy does not appear to be related to the presence of renal artery stenosis, unless the vessel is totally occluded . In 79 patients, renal function was not better in the nonstenosed kidney, compared to the kidney residing behind a stenosis. Single kidney glomerular filtration rate was measured using a novel method of synchronous (51)Chromium ethylenediamine tetraacetic acid glomerular filtration rate and (99 m)Technetium dimercaptosuccinic acid scintigraphy. The authors suggests that there is a process causing renal dysfunction in patients with atherosclerotic disease independent of renal artery narrowing. The results predict the findings in the DRASTIC study which suggests that opening stenotic vessels is of little value in patients with atherosclerotic renal artery stenosis. The idea seems like such a good one. The cardiologists swear by the ‘open vessel’ philosophy. The DRASTIC investigators randomized 106 patients with renal artery stenosis to medical treatment or angioplasty. After 3 months, those in medical therapy could be offered angioplasty if the physicians thought it wise to do so. Patency of the renal artery was assessed at 12 months. Blood pressure control and renal function was not favourably influenced by angioplasty.
Finally, neither the prevalence nor the severity of non‐malignant essential hypertension is a reliable predictor of individuals at risk for subsequent nephropathy. In the Hypertension Detection and Follow‐up Program, renal function was found to decline in some patients despite optimal antihypertensive treatment . The nature of hypertensive nephrosclerosis is so heterogeneous and hampered by the lack of rigorous disease criteria that no one seems to know exactly what the term may mean. Perhaps the identification of renal disease susceptibility genes will be of some assistance . However, the clear knowledge that obesity, smoking, carbohydrate intolerance, hyperlipidaemia, and nephrotoxin exposure all contribute to what we call hypertensive nephrosclerosis is a very good reason for us to deal with these additional treatable factors while we lower blood pressure to optimal levels.
Correspondence and offprint requests to: Friedrich C. Luft, MD, Charité Campus‐Buch, Franz Volhard Clinic, Wiltberg Strasse 50, D‐13125 Berlin, Germany.