Kidney International, Vol. 61, Supplement 80 (2002), pp. S62–S67

Kidney and hypertension

MARCIN ADAMCZAK, MARTIN ZEIER, RALF DIKOW, and EBERHARD RITZ

Department Internal Medicine Ruperto Carola University Heidelberg, Germany; and Department of Nephrology,Endocrinology and Metabolic Diseases, Silesian University School of Medicine, Katowice, Poland

Kidney and hypertension. There is a unique relationship be- the ultimate determinant of BP must be renal handlingtween the kidney and blood pressure (BP): on the one hand, of sodium according to this concept. This does not implyrenal dysfunction and particularly renal disease cause an in- that hypertension (HT) is a renal disease, but indicatescrease in BP, while on the other hand, high BP accelerates loss

that a renal functional abnormality, i.e. disturbed BP/of function of the diseased kidney. Transplantation studies,natriuresis relationship, is a sine-qua-non condition forboth in experimental animals and humans, documented that

“blood pressure goes with the kidney,” a normotensive recipi- the development of any type of HT.ent of a kidney genetically programmed for hypertension (HT) Early studies of Bianchi et al [2] and more definitewill develop HT, while conversely hypertensive patients with

well controlled experimental studies of Rettig et al [3, 4]renal failure receiving the kidney of a normotensive donorshowed that “blood pressure goes with the kidney.”may develop normotension. Family studies showed higher BP

values and more frequent HT in first degree relatives of patients Transplantation of the kidney from a genetically hyper-with primary glomerulonephritis or diabetic nephropathy, both tension-prone donor rat, even when it had been kepttype 1 and type 2. The notion that HT accelerates the loss of normotensive from weaning by antihypertensive medica-renal function has been proposed at the turn of the century,

tion, caused progressive increase of BP in a recipientbut definite evidence by observational and interventional stud-animal which was immunologically manipulated to pre-ies has only been provided in the last two decades. The issue has

been much confounded by the mistaken believe that damaged vent a rejection reaction. In contrast, and quantitativelykidneys require higher BP values in order to function properly. less impressive, transplantation of a kidney graft from aThe mechanisms of BP increase in renal disease comprise:

donor genetically programmed for normotension pro-salt retention, inappropriate activity of the renin-angiotensinvoked normotension in the recipient.system (RAS) and of the sympathetic nerve system as well

as impaired endothelial cell-mediated vasodilatation. There is There is also some analogous evidence in humans. Re-ample evidence both in primary renal disease (AIPRI and cipients of grafts of genetically hypertension-prone do-REIN trials) and in nephropathy of type 1 and type 2 di- nors required more antihypertensive medication [5] andabetes (IDNT, RENAAL) that pharmacological blockade of

recipients of kidneys from donors dying from cerebralthe RAS by angiotensin-converting enzyme inhibitors or angio-hemorrhage, presumably because of hypertension, hadtensin II type 1 receptor blockers has BP-independent renopro-

tective effects. More recently, it has also been shown that a higher risk to develop hypertension [6]. Conversely,blockade of the sympathetic nerve system has BP-independent patients who had become dialysis-dependent because ofeffects on albuminuria and on glomerulosclerosis.

hypertension-induced renal injury turned normotensiveafter the kidney of a normotensive donor had been suc-cessfully grafted [7].

ROLE OF THE KIDNEY IN THE GENESIS RELATION BETWEEN RENAL DISEASE ANDOF HYPERTENSION BLOOD PRESSURE

Guyton [1] proposed the hypothesis, supported by ex- A classical concept had been that renal disease causesperimental evidence, that the disturbance of the blood

hypertension. Individuals with renal disease develop hy-pressure (BP)/natriuresis relationship (“renal function

pertension, as had indirectly been concluded very ele-curve”) is responsible for the BP elevation when renal

gantly by Richard Bright [8]. As early as 1923 Franzfunction is impaired. Because the gain of the BP-natri-Volhard postulated: “I doubt very much whether hyper-uresis relationship overrides all other regulatory systems,tension has any useful purpose. We are confronted witha vicious circle which is responsible for progression ofhypertensive renal disease and the final outcome of renalKey words: hypertension, kidney, renal disease, sodium retention, re-

nin angiotensin system, sympathetic nerve system. insufficiency” [9].It has recently emerged that the relation is more com- 2002 by the International Society of Nephrology

S-62

Adamczak et al: Kidney and hypertension S-63

Table 2. Blood pressure and urinary albumin excretion in offspringTable 1. Blood pressure status of parents with biopsy-confirmedglomerulonephritis and controls (after [10]) of parents with type 2 diabetes according to absence or presence

of diabetic nephropathy in the parents (after [12])Glomerulonephritis Control

(N�39) (N�87) Parents type 2 diabetes

Without WithHypertensive 36 (57%) 45 (33%)15/28 fathers 17/54 fathers nephropathy nephropathy

Offspring (N�30) Offspring (N�26)21/35 mothers 28/84 mothersBorderline hypertensive 7 (11%) 11 (8%)

Ambulatory blood pressure6/28 fathers 2/54 fathersmm Hg systolic 117 �12.9 125�16.91/35 mothers 9/84 mothers

Albumin excretion rateNormotensive 20 (32%) 82 (59%)lg · mL�1 4.8 (0.36–17.5) 7.8 (1.04–19.0)7/28 fathers 35/54 fathers

Increase in urinary albumin13/35 mothers 47/84 mothersafter ergonometry 6.3-fold (1.5–231) 16-fold (1.2–236)

Significant difference (by �2 test) between hypertensives versus others withglomerulonephritis and controls. Definitions are: hypertensive, blood pressure�160/95 mm Hg or on antihypertensive medication; borderline hypertensive,blood pressure 140–159/90–94 mm Hg; normotensive, blood pressure �140/90

sion, renal failure may develop, although this presumablymm Hg.

is a slow process requiring decades to develop. Perera[17] noted that during long-term follow-up, renal failuredeveloped in 92 of 500 patients with essential hyperten-

plex. While undoubtedly renal disease causes hyperten- sion. More recently, Klag et al [18] and Perry et al [19]sion, there is increasing evidence that a genetic predispo- showed a relation between baseline BP and ESRD insition to hypertension increases the risk to develop renal patients without a priori evidence of renal disease. Thedisease. This has been shown in patients with glomerulo- evidence that such progressive slow renal damage is pre-nephritis (Table 1) [10]. Blood pressure values were ventable with antihypertensive agents is not perfectlyhigher in the parents of patients with glomerulonephritis convincing [20]. It may be argued, however, that in thesethan in the parents of matched controls. The same is studies target blood pressure had not been sufficientlytrue for diabetic nephropathy. Higher blood pressure low [21].values were found in parents of type 1 diabetic patientsas compared to parents of patients without diabetic ne-

RELATIONSHIP OF BLOOD PRESSURE ANDphropathy [11]. In offspring of type 2 diabetic patientsPROGRESSION OF RENAL FAILUREwith as compared to offspring of type 2 diabetic parents

without diabetic nephropathy, Strojek et al [12] found Despite the above postulate of Volhard [8] it took dec-higher blood pressure values by ambulatory blood pres- ades until the deleterious effect of high BP values onsure measurement (Table 2). In the offspring of diabetic progression could be proven first by observational stud-parents with nephropathy, blood pressure was also so- ies in diabetic [22, 23] and later non-diabetic renal diseasedium-dependent compared with offspring of diabetic [24]. In patients with non-diabetic renal disease evenparents without hypertension. more time was required before definite evidence was

Another misconception had been that in order for provided by interventional trials that lowering of bloodBP to rise, an impairment of glomerular filtration rate pressure effectively attenuated the rate of progression(GFR) was necessary. This is definitely not the case. In in patients with proteinuria exceeding 1 g/day [25].children with a nephrotic syndrome, Kuster et al [13]found that blood pressure values, although remaining

WHAT IS THE APPROPRIATE TARGETwithin the range of normotension, were systematicallyBLOOD PRESSURE?higher during the nephrotic episode than after remission

There is good evidence that there is a continuous in-of the disease. That a reduction of total kidney GFR iscrease of renal risk with increasing blood pressure with-not a pre-condition for the increase in BP was also shownout a definite threshold. One piece of observation comesby Stefanski et al (Table 3) [14]. In patients with biopsy-from the study of Opelz et al [26] that in renal graftconfirmed IgA glomerulonephritis and normal inulinrecipients (as one model of renal damage) 6 year graftclearance, he observed higher 24 h BP values, and thissurvival is progressively worse with increasing levels ofwas accompanied by greater septal thickness and evi-systolic blood pressure (Fig. 1). This concept has recentlydence of impaired compliance of the left ventricle.been confirmed by a meta-analysis of controlled inter-In the distant past it was well known that hypertensionvention trials in patients with non-diabetic renal diseasemay cause renal failure in the absence of primary renalwhere the best renal prognosis was found in individualsdisease. The most frequent cause for this was malignantwith systolic BP �110 mm Hg (abstract: Jafar TH J Amhypertension, i.e. a phase of accelerated hypertensionSoc Nephrol 11:63A, 2000).with arteriolar necrosis [15, 16]. There is also evidence,

however, that even in the absence of malignant hyperten- It is likely, but currently not definitely proven that

Adamczak et al: Kidney and hypertensionS-64

Table 3. Blood pressure status in patients with IgA glomerulonephritis and normal inulin clearence (after [14])

Casual BP mm Hg 24-hour BP Day-time BP Night-time BP

Systolic Diastolic Systolic Diastolic Systolic Diastolic Systolic Diastolic

Glomerulonephritis 125 80 124.5 76.5 129 82 111 64.8(N�20) (110–140) (70–90) (107–135) (69–84) (107–141) (73–88) (97–129) (56.5–72)

Matched controls 120 72.5 114.5 70.5 119 75 103 58(N�20) (105–130) (60–85) (106–135) (62–79) (108–144) (66–87) (91–117) (48–70)

P 0.04 0.04 0.007 0.0006 0.012 0.003 0.003 0.001

Fig. 1. Association of systolic blood pressureat 1 year after transplantation with subsequentgraft survival in recipients of cadaver kidneytransplants. Data taken from Opelz et al [26],reprinted with permission.

Fig. 3. Relationship between irbesartan dose and peak renal blood flow(RBF) response in healthy subjects and patients with type 2 diabetesmellitus. Despite the fact that type 2 diabetic patients with nephropathy

Fig. 2. Rate of glomerular filtration rate (GFR) decline, dependent on is a low-renin state and that the plasma renin activity (PRA) was lower,blood pressure and proteinuria. Symbols are: (dashed line) proteinuria the renal vascular response to irbesartan was significantly higher in�1 g/day; (solid line) �1 g/day. Data are taken from Peterson et al diabetic patients (P � 0.01). Symbols are: (�) diabetics; (�) normals.[25], reprinted with permission. Data are taken from Price et al [38], reprinted with permission.

ambulatory blood pressure (ABPM) is more predictive with attenuated night-time decrease of BP (non-dippers)than office BP, particularly an attenuation of the night- had a greater rate of loss of endogenous creatinine clear-time decrease of BP [27]. In patients with IgA glomerulo- ance than dippers. In type 2 diabetic patients, Nakanonephritis [28], as well as in patients with more advanced et al found that patients with an obliterated night-time

decrease of BP had a 20-fold higher rate of death (unad-diabetic [29] and non-diabetic renal disease [30], patients

Adamczak et al: Kidney and hypertension S-65

Table 4. Selected studies showing renoprotection properties of angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptortype 1 antagonists (AT-1-RB)

Study [Reference] AIPRI [41] REIN [42] Lewis et al [43] IDNT [44] RENAAL [45]Various Non-diabetic Nephropathy Nephropathy Nephropathy

Study group nephropathiesa nephropathy type 1 diabetes type 2 diabetes type 2 diabetes

Sample size 583 323 409 1715 1513Planned duration of follow-up years 3.0 2.2 3.0 2.6 4.5Study medication (ACEI or AT-1-RB) Benazepril Ramipril Captopril Irbesartan LosartanDosage of study medication mg/day 10 1.25–5.0 75 75–300 50–100Baseline serum creatinine concentration

lmol/L 186 194 115 148 168Relative risk (95% CI) of ESRD in the 0.89 0.51 0.50 0.83 0.75

treated group (0.06–14.2) (0.30–0.87) (0.18–0.70)b (0.62–1.11)Relative risk (95% CI) of doubling serum 0.44 0.47 0.48 0.71 0.72

creatinine in the treated group (0.27–0.70) (0.29–0.77) (0.16–0.69) (0.54–0.92)a Mainly non-diabetic nephropathy; diabetic nephropathy was a cause of renal insufficiency only in 21 of 583 patientsb Combined end points (death, dialysis or kidney transplantation) relative risk

justed for variables) [31] and also a 9-time higher risk tion, Wagner et al [40] found that the expression ofangiotensin II type 1-receptor mRNA in biopsies of pa-to end up on dialysis [32].tients with glomerulonephritis or diabetic nephropathyFigure 2 shows the post hoc analysis of the MDRD trialwas low, consistent with the notion of homeostatic downby Peterson et al [25]. It shows that in patients with pro-regulation of the receptor in response to high intrarenalteinuric renal disease with progressively lower achievedangiotensin II concentrations.mean arterial pressure (MAP) values, the rate of loss of

Today there is no more doubt that pharmacologicalGFR was progressively lower. A minimum rate of loss ofblockade of the RAS by administration of angiotensin-GFR was seen when a MAP of 85–90 mm Hg was reached.converting enzyme inhibitors (ACEI) or angiotensin IIToday there is widespread consensus that in patientsreceptor type 1 blockers (AT-1-RB) provides blood pres-with proteinuric renal disease, blood pressure should besure-independent renoprotection. The major studies, i.e.,lowered to values below the currently accepted upperAIPRI [41] and REIN [42], Lewis et al trial in type 1value of normotension, i.e., 130/85 mm Hg [33, 34]. Most[43] and IDNT [44] and RENAAL [45], respectively, inauthorities propose a target blood pressure of 120/75type 2 diabetes are summarized in Table 4.mm Hg [34, 35].

What is currently uncertain is whether ACEI or AT-1-RB should be titrated according to blood pressure or

DOES SELECTION OF ANTIHYPERTENSIVE whether, despite no further lowering of blood pressure,AGENTS MATTER? the dose should be increased to optimize the decrease

There is overwhelming evidence for a role of angioten- in proteinuria. According to recent concepts, proteinuriasin II in progression, both by hemodynamic and by non- is a “nephrotoxin” [46] and exposure of tubular epithelialhemodynamic factors [36]. It is of interest, however, that cells to protein induces an activated inflammatory phe-pharmacological blockade of the renin-angiotensin sys- notype [47]. In line with the idea that a further increasetem (RAS) is renoprotective even in states where pre- in the dose of ACEI or AT-1-RB is sensible was providedsumably the RAS is suppressed, as indicated by circulat- by the experimental study of Peters et al [48]. It is plausi-ing plasma renin activity. This paradox can be explained ble that the same principle applies to humans accordingby recent observations that within the kidney, the RAS to some preliminary experience [49, 50, 51]. In patientsis activated not only in the juxtaglomerular apparatus, with IgA glomerulonephritis, Palla et al [51] showed thatbut also in tubular epithelial cells [37]. This has been increasing doses of lisinopril (5, 10, 15, 20 mg/day) causedshown in the ablation model, but is also true in diabetes progressive decrease in proteinuria (39, 44, 61, and 67%,and in ageing. Price et al [38] showed that the increment respectively), although blood pressure was lowered max-in renal plasma flow upon administration of an angioten- imally (mean 22%) by the lowest dose of lisinopril.sin receptor blocker, i.e., an index of the angiotensin II- Recently, a role of sympathetic nervous system in pro-dependency of renal vascular tone, was higher in type 2 gression of renal diseases has been postulated as well.diabetic patients despite low plasma renin activity (Fig. 3). In experimental animals [52, 53] as well in humans withIt has recently been shown that such suprasensitivity to renal diseases [54], increased efferent sympathetic nerveangiotensin II type 1-receptor blockade was present only traffic have been shown. There is both experimental andunder conditions of the hyperglycemic clamp, not under clinical evidence that sympathetic overactivity contrib-

utes to progression independently of any effect on bloodconditions of euglycemia [39]. In line with this observa-

Adamczak et al: Kidney and hypertensionS-66

type II diabetes: Evidence for hereditary factors? Kidney Intpressure. Non-hypotensive doses of the central sympath-51:1602–1607, 1997

icoplegic agent moxonidine reduced the development of 13. Kuster S, Mehls O, Seidel C, Ritz E: Blood pressure in minimalglomerulosclosis and of albuminuria in subtotally ne- change and other types of nephrotic syndrome. Am J Nephrol 10

(Suppl 1):76–80, 1990phrectomized rats [55]. That this effect is not unique to14. Stefanski A, Schmidt KG, Waldherr R, Ritz E: Early increase inthe centrally acting drug moxonidine is shown by fur- blood pressure and diastolic left ventricular malfunction in patients

ther experiments: metoprolol at doses which failed to with glomerulonephritis. Kidney Int 50:1321–1326, 199615. Kincaid-Smith P, McMicheal J, Murphy EA: The clinical courseaffect systemic blood pressure [56], or surgical denerva-

and pathology of hypertension with papilloedema (malignant hy-tion of the kidney (abstract; Odoni G, J Am Soc Nephrol pertension). Q J Med 27:117–153, 195811:626A, 2000) had a similar renoprotective effect. The 16. Byrom FB: The evolution of acute hypertensive arterial disease.

Prog Cardiovasc Dis 17:31–37, 1974in vivo relevance of these observations in humans is17. Perera GA: Hypertensive vascular disease description and naturaldocumented by the observation of Strojek et al, who history. J Chron Dis 1:33–42, 1955

showed that moxonidine at doses that did not affect 18. Klag MJ, Whelton PK, Randall BL, et al: Blood pressure andend-stage renal disease in men. N Engl J Med 334:13–18, 1996blood pressure caused significant lowering of albumin

19. Perry HM, Miller JP, Fornoff JR, et al: Early predictor of 15-excretion in the morning urine in normotensive, non-year end-stage renal disease in hypertensive patients. Hypertens

smoking microalbuminuric type I diabetic patients [57]. 25:587–594, 199520. Rostand SG, Brown G, Kirk KA, et al: Renal insufficiency inIt emerges from the above that many details concern-

treated essential hypertension. N Engl J Med 320:684–688, 1994ing blood pressure in the kidney are currently unre-21. Jacobson HR, Striker GE: Report on a workshop to develop

solved. It is also certain, however, that antihypertensive management recommendations for the prevention of progressionin chronic renal disease. Am J Kidney 25:103–106, 1995treatment has become the most effective therapeutic in-

22. Mogensen CE: Long-term antihypertensive treatment inhibitingtervention available today to retard progressive loss ofprogression of diabetic nephropathy. BMJ 285:685–688, 1982

renal function. 23. Parving HH, Andersen AR, Smidt UM, Svendsen PA: Earlyaggressive antihypertensive treatment reduces rate of decline inkidney function in diabetic nephropathy. Lancet 28:1175–1179, 1983ACKNOWLEDGMENT

24. Brazy PC, Stead WW, Fitzwilliam JF: Progression of renal insuf-ficiency: role of blood pressure. Kidney Int 35:670–674, 1989Marcin Adamczak is supported by the International Society of Ne-

25. Peterson JC, Adler S, Burkart JM, et al: Blood pressure control,phrology Fellowship Programme.proteinuria and the progression of renal disease. The Modificationof Diet in Renal Disease Study. Ann Int Med 123:754–762, 1995Reprint requests to Prof. E. Ritz, Department Internal Medicine,

26. Opelz G, Wujciak T: Ritz E for the Collaborative TransplantUniversity of Heidelberg, Bergheimer Str. 56a, D-69115 Heidelberg.E-mail: prof.e.ritz@t-online.de Study: Association of chronic kidney graft failure with recipient

blood pressure. Kidney Int 53:217–222, 199827. Ritz E, Schwenger V, Zeier M, Rychlik I: Ambulatory blood

REFERENCES pressure monitoring: fancy gadgetry or clinical useful exercise?Nephrol Dial Transplant 16:1550–1554, 20011. Guyton AC: Renal function curve: A key to understanding the

28. Csiky B, Kovacs T, Wagner L, et al: Ambulatory blood pressurepathogenesis of hypertension. Hypertens 10:1–6, 1987monitoring and progression in patients with IgA nephropathy.2. Bianchi G, Fox U, DiFrancesco GF, et al: Blood pressure changesNephrol Dial Transpl 14:86–90, 1999produced by kidney cross-transplantation between spontaneously

29. Farmer CKT, Goldsmith DJA, Quin JD, et al: Progression ofhypertensive and normotensive rats. Clin Sci Mol Med 47:435–diabetic nephropathy—Is diurnal pressure rhythm as important as438, 1974absolute blood pressure level. Nephrol Dial Transplant 13:635–3. Rettig R, Folberth C, Stauss H, et al: Role of the kidney in639, 1998primary hypertension: a renal transplantation study in rats. Am J

30. Timio M, Venanzi S, Lolli S, et al: Non-dipper“ hypertensivePhysiol 258:F606–F611, 1990patients and progressive renal insufficiency: A 3-year longitudinal4. Patschan O, Kuttler B, Heeman U, et al: Kidneys from normoten-study. Clin Nephrol 43:382–387, 1995sive donors lower blood pressure in young transplanted spontane-

31. Nakano S, Fukuda M, Hotta F, et al: Reversed circadian bloodously hypertensive rats. Am J Physiol 273:R175–R180, 1997pressure rhythm is associated with occurrences of both fatal and5. Guidi E, Bianchi G, Rivolta E, et al: Hypertension in man withnonfatal vascular events in NIDDM subjects. Diabetes 47:1501–a kidney transplant: Role of familial versus other factors. Nephron1506, 199841:14–21, 1985

32. Nakano S, Ogihara M, Tamura C, et al: Reversed circadian blood6. Strandgaard S, Hansen U: Hypertension in renal allograft recipi-pressure rhythm independently predicts endstage renal failure inents may be conveyed by cadaveric kidneys from donors withnon-insulin-dependent diabetes mellitus subjects. J Diabetes Compsubarachnoidal haemorrhage. Br J Med 292:1041–1044, 198613:224–231, 19997. Curtis JJ, Luke RG, Dustan HP, et al: Remission of essential

33. American Diabetes Association: Standards of Medical care forhypertension after renal transplantation. N Engl J Med 309:1009–patients with diabetes mellitus. Diabetes Care 21(Suppl):S23–1014, 1983S31, 19988. Bright R: Tabular view of the morbid appearance in 100 cases

34. Guidelines Subcommittee: 1999 World Health Organization—connected with albominous urine with observation. Guy’s HospInternational society of hypertension guidelines for the manage-Rep 1:380–400, 1846ment of hypertension. J Hypertens 17:151–183, 19999. Volhard F, Der arterielle Blutdruck: Verh Dtsch Ges Inn Med

35. The sixth report of the Joint National Committee on Preven-35:134–184, 1923tion: Detection, evaluation, and treatment of high blood pressure10. Schmid M, Meyer S, Wegner R, Ritz E: Increased genetic risk of(JNC VI). Arch Intern Med 157:2413–2446, 1997hypertension in glomerulonephritis? J Hypertens 8:573–577, 1990

36. Wolf G: Angiotensin II: A pivotal factor in the progression of11. Fagerudd JA, Tarnow L, Jacobsen P, et al: Predisposition torenal diseases. Nephrol Dial Transplant 14(Suppl 1):42–44, 1999essential hypertension and development of diabetic nephropathy

37. Gilbert RE, Wu LL, Kelly DJ, et al: Pathological expression ofin IDDM patients. Diabetes 47:439–444, 199812. Strojek K, Grzeszczak W, Morawin E, et al: Nephropathy of renin and angiotensin II in the renal tubule after subtotal nephrec-

Adamczak et al: Kidney and hypertension S-67

tomy. Implications for the pathogenesis of tubulo-interstinal fibro- 48. Peters H, Border WA, Noble NA: Angiotensin II blockade andlow-protein diet produce additive therapeutic effects in experimen-sis. Am J Pathol 155:429–440, 1999tal glomerulonephritis. Kidney Int 57:1493–1501, 200038. Price DA, Porter LE, Gordon M, et al: The paradox of the low-

49. Peters H, Ritz E: Dosing angiotensin II blockers—beyond bloodrenin state in diabetic nephropathy. J Am Soc Nephrol 10:2382–pressure. Nephrol Dial Transplant 14:2568–2570, 19992391, 1999

50. Lewington AJP, Arici M, Harris KPG, et al: Modulation of the39. Miller JA: Impact of hyperglycemia on the renin angiotensinrenin-angiotensin system in proteinuric renal disease: Are theresystem in early human type 1 diabetes mellitus. J Am Soc Nephroladded benefits? Nephrol Dial Transplant 16:885–888, 200110:1778–1785, 1999

51. Palla R, Panichi V, Finato V, et al: Effect of increasing doses40. Wagner J, Gehlen F, Ciechanowicz A, Ritz E: Angiotensin IIof lisinopril on proteinuria of normotensive patients with IgAreceptor type 1 gene expression in human glomerulonephritis andnephropathy and normal renal function. Int J Clin Pharmacol Resdiabetes mellitus. J Am Soc Nephrol 10:545–551, 199912:234–235, 199741. Maschio G, Alberti D, Janin G, et al: Effect of angiotensin-

52. Campese VM, Kogosov E: Renal afferent denervation preventsconverting enzyme inhibitor benazepril on the progression ofhypertension in rats with chronic renal failure. Hypertens 25:878–chronic renal insufficiency. N Engl J Med 334:939–945, 1996882, 199542. The GISEN Group (Gruppo Italiano di Studi Epidemiologici

53. Campese VM, Kogosov E, Koss M: Renal afferent denervationin Nefrologia). Randomized placebo-controlled trial of effect ofprevents the progression of renal disease in the renal ablationramipril on decline in glomerular filtration rate and risk of terminalmodel of chronic renal failure in the rat. Am J Kidney Dis 26:861–renal failure in proteinuric: Non-diabetic nephropathy. Lancet865, 1995349:1857–1863, 1997

54. Converse RL, Jacobsen TN, Toto RD, et al: Sympathetic overacti-43. Lewis EJ, Hunsicker LG, Bain RP, et al: The effect of angiotensin-vity in patients with chronic renal failure. N Engl J Med 327:1912–converting-enzyme inhibition on diabetic nephropathy. N Engl J 1918, 1992

Med 329:1456–1462, 1993 55. Amann K, Rump LC, Simonaviciene A, et al: Effects of low dose44. Lewis EJ, Hunsicker LG, Clarke WR, et al: Renoprotective effect sympathetic inhibition on glomerulosclerosis and albuminuria

of the angiotensin-receptor antagonist irbesartan in patients with in subtotally nephrectomized rats. J Am Soc Nephrol 11:1469–nephropathy due to type 2 diabetes. N Engl J Med 345:851–860, 2001 1478, 2000

45. Brenner BM, Cooper MK, de Zeeuw D, et al: Effects of losartan 56. Amann K, Koch A, Hofstetter J, et al: Glomerulosclerosis andon renal and cardiovascular outcomes in patients with type 2 diabe- progression: Effect of subantihypertensive doses of � and � block-tes and nephropathy. N Engl J Med 345:861–869, 2001 ers. Kidney Int 60:1309–1323, 2001

46. Remuzzi G, Bertani T: Pathophysiology of progressive nephropa- 57. Strojek K, Grzeszczak W, Gorska J, et al: Lowering of microalbu-thies. N Engl J Med 339:1448–1456, 1998 minuria in diabetic patients by a symphatoplegic agent: A novel

47. Brunskill NJ: Albumin and proximal tubular cells—beyond endo- approach to prevent progression of diabetic nephropathy? J AmSoc Nephrol 12:602–605, 2001cytosis. Nephrol Dial Transplant 15:1732–1734, 2000