Systemic and Glomerular Hypertension and Progression of Chronic Renal Disease: the Dilemma of Nephrosclerosis

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Kidney International, Vol. 68, Supplement 99 (2005), pp. S52–S56

Systemic and glomerular hypertension and progression of chronic renal disease: The dilemma of nephrosclerosis

RAFAEL MARı´N,MANUEL GOROSTIDI,FRANCISCO FERNANDEZ´ -VEGA, and RAFAEL A´ LVAREZ-NAVASCUES´

Nephrology Service, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain; and Nephrology Service, Hospital San Agust´ın, Aviles,´ Asturias, Spain

Systemic and glomerular hypertension and progression of ered the basis of therapy for slowing renal deterioration chronic renal disease: The dilemma of nephrosclerosis. The [2–4]. Nevertheless, the risk of renal failure due to less link between the kidney and hypertension has been consid- severe hypertension has been a matter of debate [5]. ered a villain-victim relationship. High blood pressure levels are a well-recognized feature in chronic renal disease, but Nephrosclerosis, benign nephrosclerosis, hypertensive the ability of mild-to-moderate hypertension to produce re- kidney disease, or nephroangiosclerosis are terms that nal insufficiency has been questioned. Nephrosclerosis, benign clinicians use to identify renal damage associated with nephrosclerosis, and hypertensive kidney disease are terms that essential hypertension. Two clinicopathologic patterns clinicians use when renal damage is thought to be secondary have been described. One is malignant nephrosclerosis, to essential hypertension. Many cases of end-stage renal disease are ascribed to so-called benign nephrosclerosis. This en- which is associated with accelerated or malignant hy- tity could actually be a primary renal disease affecting the pertension and characterized by fibrinoid necrosis and preglomerular microvasculature, perhaps genetically mediated myointimal hyperplasia. If left untreated, progressive re- and ethnically influenced, and showing a heterogeneous clin- nal insufficiency occurs. Malignant nephrosclerosis is a ical expression. African Americans suffer from nephrosclero- rare entity today because of improvements in antihy- sis more frequently than Caucasians. Nephrosclerosis affecting Caucasians seems to show a less aggressive pattern and could pertensive management [6]. The other form is the so- represent early age-related renal sclerosis. The risk of end-stage called benign nephrosclerosis or simply nephrosclerosis, renal disease is increased when atherosclerotic lesions in large in which histopathologic features include microvascular renal arteries coexist. Age, systolic blood pressure, protein- changes with hyalinosis of the preglomerular vessel walls uria, and concomitant cardiovascular disease are well-known and thickening of the intima and reduplication of the promoters of renal failure. A multifactorial strategy, including antihypertensive and antiproteinuric drugs, and lipid-lowering internal elastic lamina of the arcuate and interlobar ar- and anti-platelet agents, could improve cardiovascular and re- teries. These changes may lead to glomerular damage, nal outcomes in patients with nephrosclerosis. glomerulosclerosis, patchy tubular atrophy, and interstitial fibrosis. Nephrosclerosis has actually been seen as a form of intrarrenal renovascular disease [7, 8]. Neverthe- The link between the kidney and hypertension has less, a specific linkage between mild-to-moderate essen- been considered a villain-victim relationship because of tial hypertension and nephrosclerosis has been debatable, the potential two-way causality between high blood pres- because these histologic abnormalities have also been de- sure (BP) and renal disease. Guyton et al stated more than scribed in the aging process, in diabetic nephropathy, and 30 years ago that the kidneys play a key role in the con- in advanced stages of various nephropathies [9–11]. Fur- trol of sodium homeostasis and through this mechanism thermore, the diagnosis of hypertensive nephrosclerosis on blood pressure regulation [1]. Primary renal diseases is usually presumptive because few patients with essen- cause secondary hypertension, and malignant hyperten- tial hypertension undergo renal biopsy, which leads to a sion has been associated with the development of renal lack of accuracy if strict clinical diagnostic criteria are not dysfunction. Furthermore, high BP is a marker of estab- fulfilled [5, 12]. lished renal disease, and strict BP control has been consid- Although these controversies exist, in the past two decades nephrosclerosis has been recognized as a pro- gressively increasing cause of end-stage renal disease (ESRD). Registries from the United States and Europe Keywords: hypertension, nephrosclerosis, hypertensive nephropathy. indicate that diabetic nephropathy and nephrosclerosis C 2005 by the International Society of Nephrology are the leading causes of ESRD.

S-52 Mar´ın et al: The dilemma of nephrosclerosis S-53

Table 1. Studies analyzing the incidence of renal disease in relation to blood pressure Study Patients/Subjects N Main results Shulman et al, 1989 [13] Participants in the HDFP study 10,940 Baseline BP predicted increase in serum creatinine Perneger et al, 1993 [14] General population 1399 Baseline BP predicted serum creatinine 12 years later Perry et al, 1995 [15] Hypertensive patients of the VA 11,912 Baseline BP predicted ESRD 15 years later Klag et al, 1996 [16] Participants in the MRFIT study 332,544 Continuous relation between BP and risk of ESRD 16 years later Siewert-Delle et al, 1998 [17] Participants in the G ¨oteborgstudy 686 Treated patients with hypertension did not develop ESRD after 20 years of follow-up Young et al, 2002 [18] Participants in the SHEP study 2181 Systolic BP was an independent predictor for kidney function decline Tozawa et al, 2003 [19] Participants in the Okinawa study 98,759 Continuous relationship between BP and risk of ESRD 17 years later Vupputuri et al, 2003 [20] Treated male patients with hypertension 722 Uncontrolled BP predicted early renal function decline Segura et al, 2004 [21] Treated patients with hypertension 281 14.6% developed renal disease in a 13-year follow-up Hsu et al, 2005 [22] General population with baseline 316,675 Continuous relationship between BP and remote normal renal function risk of ESRD

Abbreviations are: HDFP,Hypertension Detection and Follow-up Program; BP,blood pressure; VA, Veterans Administration Hypertension Screening and Treatment Program; ESRD, end-stage renal disease; MRFIT, Multiple Risk Factor Intervention Trial; SHEP, Systolic Hypertension in the Elderly Program.

DOES MILD-TO-MODERATE ESSENTIAL Treated essential Untreated HYPERTENSION LEAD TO RENAL FAILURE? hypertension essential The risk of ESRD associated with nonmalignant hy- hypertension pertension has been investigated only recently. The majority of studies assessing this issue have been short-term Atherosclerotic renal vascular evaluations of small sample size and post hoc analyses of ESRD attributed disease epidemiologic observations. Although these studies have No to essential Yes been criticized because of various limitations, an increas- hypertension Malignant or ing amount of evidence links mild-to-moderate essential accelerated hypertension with the development of ESRD (Table 1) hypertension [13–22]. Three large cohort studies have reported that elevated BP predicts remote risk of renal failure. Klag Occult et al [16] analyzed data from 332,544 men who were primary renal screened for the Multiple Risk Factor Intervention Trial, disease and Tozawa et al [19] evaluated data from 98,759 men Fig. 1. Essential hypertension and ESRD. When essential hyperten- and women who were screened in Okinawa, Japan. Both sion is associated with ESRD, many other conditions (right side) could studies showed an increasing relationship between base- be present. Reproduced from Ljungman [25], with permission. line BP,from the high-normal stage, and the risk of ESRD 16 to 17 years later. Because renal function was not care- fully evaluated at baseline in the Multiple Risk Factor Intervention Trial and Okinawa studies, it is conceivable [17, 23, 24]. Siewert-Delle et al [17] analyzed the develop- that renal disease was already present in those patients ment of renal disease in 686 white men with treated hyper- who later developed ESRD. Nevertheless, Hsu et al [22] tension during a 20-year follow-up. Incidence of a serum have recently published a similar analysis of 316,675 indi- creatinine level above 1.5 mg/dL was observed in 8.9% of viduals with baseline-estimated glomerular ﬁltration rate patients, but an underlying renal abnormality was found ≥60 mL/min/1.73 m2 and negative proteinuria or hema- in the majority of such cases. Only 1.7% of the whole sam- turia by dipstick urinalysis. They observed that even rel- ple showed an unexplained increase in serum creatinine, atively modest elevations in BP from optimal levels were but none of these cases developed ESRD. The authors independently related to the incidence of ESRD. concluded that controlled nonmalignant essential hypertension did not lead to ESRD or clinically signiﬁcant renal dysfunction. It has been stated that a myriad of other con- DOES TREATED MILD-TO-MODERATE ditions could actually be the cause of ESRD attributed to ESSENTIAL HYPERTENSION CAUSE RENAL essential hypertension in Caucasians (Fig. 1) [25]. Never- FAILURE? theless, in African American patients, who show a special Few studies have evaluated the incidence of renal fail- susceptibility to nephrosclerosis, it has been documented ure from treated nonmalignant essential hypertension progression to ESRD [26]. S-54 Mar´ın et al: The dilemma of nephrosclerosis

A meta-analysis including data from classical random- was renovascular disease, which shows the close relation- ized clinical trials of antihypertensive therapy that eval- ship between the clinical diagnosis of nephrosclerosis, in- uated renal dysfunction among the outcomes has been trarenal vascular damage, and large renal artery disease. published. There was no difference in the relative risk of developing renal dysfunction between actively treated cases and control patients [27]. It can be argued that non- PROGNOSIS OF NEPHROSCLEROSIS malignant hypertension is not a cause of ESRD, because Progression of renal insufficiency, secondary to no beneficial effect of correcting high BP was observed nephrosclerosis, used to be relatively slow when com- as compared with leaving hypertension untreated. pared with that of primary glomerulopathies or diabetic Some authors suggest that nephrosclerosis is actually nephropathy [26, 31]. Renal function often remains sta- an intrinsic dysfunction of the preglomerular microvas- ble during prolonged periods of time provided that BP is culature primarily causing afferent arteriole vasocon- adequately controlled, although some patients progress striction. This abnormality could lead to high BP and to ESRD. Factors promoting this ominous prognosis are glomerular injury, and subsequently renal scarring [7]. not fully identified, although known markers for unfavor- Renal function deterioration would be slow and almost able renal outcomes are age, African descent, systolic BP indistinguishable from that related with normal aging, levels, proteinuria, and concomitant cardiovascular dis- but some circumstances such as atherosclerotic renal eases. Vikse et al [32] have reported that 32% of patients artery disease or diabetes could precipitate renal failure. with biopsy-proven benign nephrosclerosis developed Nephrosclerosis could be the renal expression of a sys- ESRD during a 13-year follow-up. Forty-seven percent of temic disorder causing other vascular alterations such as these patients died during the same period. Marcantoni coronary heart disease or cerebrovascular disease. Tracy et al [33] performed a retrospective analysis of biopsies et al [28] showed, in an autopsy study of patients aged with a diagnosis of hypertensive nephrosclerosis and de- 25 to 54 years with deaths unrelated to atherosclerosis, scribed two different phenotypes of glomerulosclerosis that there was an association between incipient intrarenal related to race. African Americans were younger and vascular damage and coronary artery or aorta diseases. showed higher levels of serum creatinine at the time of Keller et al [29] have recently reported that the number biopsy when compared with Caucasians. Glomeruloscle- of glomeruli was lower in the kidneys of hypertensive pa- rosis and interstitial fibrosis were more pronounced in tients when comparing with that of controls with normal African Americans. Morphologic abnormalities in Cau- BP.Individuals with a nephron number at the lowest per- casians mimic those related to aging. centiles could be at the highest risk of developing renal Nephrosclerosis is being increasingly diagnosed in insufficiency. older patients with cardiovascular diseases. Nephroscle- rosis in patients older than 65 years could actually represent an added expression of diffuse atherosclero- PROBLEMS IN DIAGNOSING sis. Coexistence of intrarenal microvascular lesions with NEPHROSCLEROSIS atherosclerotic changes in large arteries is a common find- As stated before, the diagnosis of nephrosclerosis is ing. Nephrosclerosis can thus be seen as a component of usually a presumption because histopathologic confirma- renal vascular disease comprising renal artery disease, is- tion is often lacking. Findings should suggest nephroscle- chemic nephropathy, or even cholesterol atheroembolic rosis as the cause of renal dysfunction when the patient disease. Other alterations such as diabetes, metabolic syn- has long-standing hypertension, is of male sex, is aged drome, and/or dyslipidemia could act as aggravating con- >55 years, has a family history of hypertension, has signs ditions. Renal function at diagnosis and histologic status of hypertensive damage in other territories such as left of renal tissue are key factors in prognosis, because ag- ventricular hypertrophy or retinopathy, extrarenal mani- gressive intervention to correct lesions in large vessels festations of atherosclerosis, relatively slow deterioration does not often improve outcomes [34]. Factors influenc- of renal function, and has no data pointing to another pri- ing the development of nephrosclerosis are illustrated in mary nephropathy such as significant proteinuria and/or Figure 2. hematuria. However, the clinical diagnosis of nephroscle- Some authors have recently reported that concomitant rosis can be inaccurate despite fulfilling these criteria as cardiovascular disease was associated with a poor prog- shown by Zucchelli and Zuccalà[30] in 56 patients dia- nosis [35, 36]. Levin et al [35] showed a 1.58 relative risk gnosed as having nephrosclerosis. When kidney biopsy of ESRD in patients with renal insufficiency and cardio- or renal angiography was performed, only 46% of pa- vascular disease versus patients with renal insufficiency tients retained the original diagnosis. Similarly, Zarif et al but free of cardiovascular disease. A decrease in the cir- [12] found in a retrospective analysis that the presump- culatory status due to cardiovascular events would lead tive diagnosis of nephrosclerosis was correct in only 50% to deterioration of renal function, which starts a vicious of cases. Nevertheless, the primary cause of misdiagnosis circle in which the deleterious milieu of chronic kidney Mar´ın et al: The dilemma of nephrosclerosis S-55

Intrinsic microvascular disease Genetic factors Aging Black race Concomitant Congenital oligonephronia Cardiovascular disease

Preglomerular Large renal microvascular arteries lesions lesion

Hypertension Hypertension Dyslipidemia Dyslipidemia Fig. 2. Factors inﬂuencing in the develop- Glomerular ischemia Smoking Smoking ment of nephrosclerosis. Initiators could be Glomerular hypertension Proteinuria Proteinuria genetic, an intrinsic abnormality of pre- Insulin resistance Insulin resistance glomerular microvasculature, and/or a congenital reduction in nephron number. In the elderly, the aging process could be accelerated by concomitant cardiovascular disease and/or atherosclerotic aortorenal changes. Nephrosclerosis Other conditions (gray shadowed) could act as aggravating factors.

Table 2. Integrated approach for renoprotection and cardiovascular Disease and Hypertension [37] recruited 1094 African prevention in patients with chronic kidney disease Americans with hypertensive renal disease that were ran- Goals domly assigned to one of two mean BP goals (102 or BP control <130/80 mm Hg 107 mm Hg) and to treatment based on a beta-blocker, Many patients will need two or more antihypertensive drugs an angiotensin-converting enzyme (ACE) inhibitor, or a < Reduction of proteinuria 0.5 g/day or ratio of protein to creatinine calcium-channel blocker. The outcome was no different on spot urine collection <200 mg/g Considered a BP-independent goal between the two BP groups. Patients receiving the ACE Dual blockade with ACE inhibitors and ARBs may exert an inhibitor-based therapy showed a 22% reduction in risk of additional benefit < the composite end point that included unfavorable renal HbA1c 7% in diabetics Smoking cessation outcomes and death. Segura et al [38] performed a retro- Lipid-lowering therapy spective analysis of Spanish patients diagnosed as hav- < < Total cholesterol 175 mg/dL and LDL cholesterol 100 mg/dL ing nephrosclerosis. Patients receiving ACE inhibitors Anti-platelet therapy Control of calcium-phosphorus product <55 mg2/dL2 showed a marked reduction in the risk of a 50% reduction Control of anemia >12 g/dL in creatinine clearance during a 7-year follow-up. Antihypertensive therapy Renal and cardiovascular risk is highly increased in pa- First step, ACE inhibitor or ARB tients with nephrosclerosis. A multifactorial therapeutic Trytoup-titrate to high doses, because the antiproteinuric effect is probably dose-dependent approach for chronic kidney disease has been recently Monitor serum creatinine and potassium 1 to 2 weeks after proposed to minimize both renal and cardiovascular initiation events (Table 2). This strategy might prevent patients Second step, diuretic In stages 3 and 4, loop diuretic with nephrosclerosis from progressing to ESRD and car- Third step, calcium-channel blocker or beta-blocker diovascular disease. Beta-blocker preferred if coronary heart disease or heart failure Fourth step, beta-blocker or calcium-channel blocker if not used Reprint requests to Rafael Mar´ın, Servicio de Nefrolog´ıa, Hospital before. Universitario Central de Asturias, C/Celestino Villamil s/n, 33006 Oviedo Consider other alternatives such as alpha-blockers or centrally (Spain). E-mail [email protected] acting drugs Abbreviations are: BP, blood pressure; ACE, angiotensin-converting REFERENCES enzyme; ARB, angiotensin II receptor blocker; HbA1c, hemoglobin A1c; LDL, low-density lipoprotein. 1. GUYTON AC, COLEMAN TG, COWLEY AV Jr, et al: Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension. AmJMed52:584–594, 1972 2. SARNAK JA, GREENE T, WANG X, et al:The effect of a lower target disease, and the so-called therapeutic nihilism that renal blood pressure on the progression of kidney disease: Long-term follow-up of the modification of diet in renal disease study. Ann patients suffer from, accelerates cardiovascular disease. Intern Med 142:342–351, 2005 3. MASCHIO G, ALBERTI D, JANIN G, et al: Effect of the angiotensin- converting-enzyme inhibitor on the progression of chronic renal THERAPEUTIC OPTIONS insufficiency. N Engl J Med 334:939–945, 1996 4. NATIONAL KIDNEY FOUNDATION: K/DOQI clinical practice guidelines There are few studies dealing with treatment for on hypertension and antihypertensive agents in chronic kidney dis- nephrosclerosis. The African American Study of Kidney ease. Am J Kidney Dis 43(Suppl 1):S1–S290, 2004 S-56 Mar´ın et al: The dilemma of nephrosclerosis

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