Use of angiotensin-converting enzyme inhibitors and angiotensin II antagonists in renal transplantation: Delaying the progression of chronic allograft nephropathy?

Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Antagonists in Renal Transplantation: Delaying the Progression of Chronic Allograft Nephropathy? Alan Wilkinson

Advances in immunosuppressive therapy have improved the survival of both cadaveric and living donor renal transplants. The improved long-term survival is probably a consequence of these advances and concurrent improvements in the general medical management of the transplant recipients. One area of care that remains controversial in renal transplantation is the use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB). ACEI and ARB are now commonly used in patients with chronic renal insufficiency, proteinuria and hypertension caused by the disease of their own native kidneys. This article reviews the potential benefits of interrupting the production of angiotensin II (All) or blockade of the AT1 receptor for All in renal transplant recipients. The current hypotheses for the pathophysiology and the cytokine abnormalities in the progression of renal dysfunction include a facilitative role for All. In addition, calcineurin inhibitor nephrotoxicity, with the increased generation of transforming growth factor-I~, is also affected by the actions of All. It is suggested that ACEI and ARB be used more widely in transplantation patients. Copyright© 2000 by W.B. Saunders Company

F rom 1988 to 1996, there has been a marked improvement in short-term kidney allograft sur-

vival. Even more gratifying, the half-life of these allografts has increased. The half-life for grafts from living donors increased from 12.7 to 21.6 years and that for cadaveric grafts from 7.9 to 13.8 years. When death with a functioning graft is not included as a cause of graft loss, the half-life for grafts from living donors increased from 16.9 to 35.9 years and that for cadaveric grafts from 11.0 to 19.5 years. Acute rejection remains one of the most significant causes for the reduction of graft survival, and there remains a marked difference in the outcomes of living and cadaveric organs. I Most of this difference relates to events that affect the cadaveric organ before its removal from the donor, such as hypotension and brain injury. These data support the hypothesis that long-term graft survival is affected by both immuno-

From the University of California at Los Angeles School of Medicine, Los Angeles, CA.

Address reprint requests to Alan H~lkinson, M_D, FRCP, Professor of Medicine, Director, Kidney and Pancreas Transplantation, UCLA School of Medicine, Los Angeles, CA 90095-1693.

Col?yright © 2000 by H~B. Saunders Company 0955-470X/00/1403-0003510. 00/0 doi: 10.1053/trre.2000. 7445

logic and nonimmunologic factors. Despite these dramatic improvements in the survival of renal allografts, the loss of renal allografts to chronic allograft nephropathy (CAIN) is second only to death with a functioning graft as a cause of graft failure. The most important cause of CAN is an acute rejection episode. 2,3

Interventions that increase the time that kidney allografts survive will be of enormous benefit to patients and significantly reduce the cost of treatment for end-stage renal disease. In addition to new immunosuppressive strategies to reduce the incidence and impact of acute rejection, other interventions that slow the progression of CAN by reducing the impact ofnonimmunologic factors would prolong the half-life of compromised organs. Coronary artery disease remains the leading cause of death in patients with allografts that survive for longer periods, and recent studies emphasize the benefits of therapies that reduce this morbidity and mortality. These therapies include the use of angiotensin-converting enzyme inbibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) for the prevention of hypertension and vascular disease.

The use of agents that either inhibit the production of angiotensin II (AII), the ACEIs, or block the

138 Transplantation Reviews, Vo114, No 3 (Ju~v), 2000.'pp 138-144

ACEIs andARBs in CAN 139

receptor to which AII binds, the ARBs, has gained widespread acceptance for the treatment of hypertension, proteinuria, progressive renal insufficiency, and congestive heart failure. 4-8 More recent evidence suggests these agents will also reduce the morbidity from a variety of vascular diseases. For the purposes of this article, it is presumed that most of the benefits of ACEIs will also be achieved by using ARBs, and the two classes will be grouped as ACEI/ARB.

When ACEIs were first introduced for the treatment of hypertension, it was considered too dangerous to use them in patients with chronic renal insufficiency (CRI). This was in large part because of two known and potentially dangerous side effects. Hyperkalemia was a common complication of their use, and renal function was reported to decline quite rapidly in some patients treated with these agents, particularly those known to have a single kidney or renal artery stenosis. The first drug in this class, captopril, was also shown to cause a proteinuric membranous glomerulonephritis in some patients. This complication was linked to the presence of a sulflaydryl group and to treatment with greater doses of the drug than currently recommended. For these reasons, it was some time before the use of ACEIs was studied in CRI.

The potential benefits of ACEI treatment in patients with diabetic nephropathy was suggested by studies in animal models of diabetic nephropathy. 9'j° These studies ascribed the preservation of renal function in an animal model of diabetic nephropathy to a decrease in glomerular capillary pressure, which resulted from an ACEI-induced reduction in the resistance of the efferent glomerular arteriole. Subse- quent studies of small numbers of patients with CRI or diabetic renal disease suggested that the use of ACEIs decreased proteinuria and slowed the decline in renal function. The report by Lewis et al4 on the use of captopril, an ACEI, in patients with diabetes with more than 500 mg/d of urinary protein and a serum creatinine concentration of 2.5 mg/dL or less showed a significant benefit in a large number of patients. As a consequence of that study and others, the use of ACEIs in patients with type 1 diabetic nephropathy is now included in the recommenda- tions of the 6th Report of the Joint National Commit- tee on Prevention, Detection, Evaluation and Treat- ment of High Blood Pressure and those of the American Diabetes Association.

Subsequent studies of patients with types 1 and 2 diabetes and patients without diabetes with proteinuric nephropathies have shown that a reduction in

the activity of AII is beneficial for nearly all patients with CRI. t 1-,4 There are a number ofpossible reasons that ACEI therapy may benefit these patients, including the reduction in glomerular capillary pressure, inhibition of A/I-enhanced or All-induced elaboration of cytokines and fibrosing growth factors, and prevention of the infiltration of mononuclear cells. Inhibition of AII also seems to reduce the increase in extracapillary matrix proteins that occurs in many of these conditions. There are a number of studies that show a benefit of ACEI/ARB therapy in animal models of immunologically mediated glomerulonephritis) 5-]9 These models also showed the remark- able extent to which inhibition of AII reduced the expression of gene products of inflammatory and fibrosing cytokines, such as transforming growth factor-J3 (TGF-[3). The beneficial effect of a reduction in TGF-I3 activity is in keeping with the evidence that it has a major role in the progression of various nephropathies. 2°,2]

Current Use of ACEI/ARB Therapy in Renal Transplantation

Although there are good theoretical reasons to consider the use of ACEIs in renal transplant recipients, many renal transplant programs continue to advise against their use or use them with considerable hesitation, and debate still exists about the benefit of their use in this setting. 22 This hesitation stems from the same concerns that general nephrologists had with regard to using them in patients with CRI. The renal allograft is a single kidney, and some narrowing of the renal artery is not uncommon. In addition, both cyclosporine and tacrolimus cause hyperkalemia, which may be aggravated by ACEIs.

Conversely, there are programs that routinely use ACEIs both for the treatment of hypertension and their known benefits in patients with CRI and proteinuria. Posttransplantation erythrocytosis is effectively treated with ACEIs, and programs that would other- wise not consider these agents use ACEIs for this indication. 2s In our transplant program at the Univer- sity of California at Los Angeles (UCLA), we intro- duce ACEI therapy in the majority of patients as soon as the serum creatinine level has reached a normal concentration and hyperkalemia is no longer present. Whereas we previously always performed a Doppler ultrasound to assess for renal artery stenosis before starting ACEI/ARB therapy, the infrequency of com- plications has changed our practice, and we now only evaluate for renal artery narrowing if the serum

140 Alan Wilkinson

creatinine level increases after the introduction of ACEI/ARB therapy. We have seen only a few patients in whom the serum creatinine level increased significantly after the introduction of ACEI/ARB therapy.

The report by Stigant et al24 confirms the validity of this approach, provided that patients are moni- tored for an unacceptable decline in glomerular filtration rate, hyperkalemia, and anemia. This study showed no detrimental effect of the use of ACEI/ ARB therapy on renal function over 36 months and that they are safe and effective for the treatment of hypertension, the primary reason for which they were prescribed. These findings confirm those of other smaller studies. 25"27 Only 2% of the patients showed a decline in renal function, and anemia occurred in only 3 patients. Our experience at UCLA is that the incidence of anemia related to ACEI/ARB use is greater than that reported by Stigant et al.2~

Renal transplant recipients should be regarded as a subset of all patients with CRI and should not be denied the known benefits of treatment with these agents. Table 1 lists the possible indications for the use of ACEI/ARB therapy. The recent report from the Heart Outcomes Prevention Evaluation study has shown that at least for ramipril, an ACEI, there was a dramatic reduction in vascular morbidity and mortality in patients administered ACEI therapy. 2899 This study showed that in patients with and without diabetes at high risk for vascular morbidity, the use of ACEIs significantly reduced mortality and morbid events. One of every 6 patients in the study arm benefitted from this treatment.

Few transplanted kidneys survive the transfer from donor to recipient without injury during the period immediately before the organ is removed, during preservation, and after reperfusion. Many kidneys are now obtained from older donors who already have histological evidence of prior glomerular and interstitial fibrosis. The significantly improved outcome of transplants from unrelated living

Table 1. Indications for the Use ofACE Inhibitors and Angiotensin Receptor Antagonists

Hypertension Proteinuria Congestive heart failure Coronary vascular disease Cercbrovascular disease Peripheral vascular disease Chronic allograft nephropathy (?)

Table 2. Risk Factors for the Progression of Kidney Disease

Persistent activity of the underlying disease Amplifiers of risk

Uncontrolled hypertension Obstruction/reflux Infection Analgesic or other nephrotoxins Calcium or urate deposits

Marked reduction in nephron number Other factors promoting increase in glomerular pres-

sures/flows High-protein diet Diabetes mellitus Chronic renal vasodilator therapy Pregnancy Diastolic blood pressure >90 mm Hg

Hyperlipidemia Persistent proteinuria Cigarette smoking Black race Obesity

Adapted and reprinted with permission? 4

donors highlights the consequences of the effects of brain injury in the donor, donor hemodynamic instability, longer cold ischemia time, and increase in reperfusion injury that result in early injury to the cadaveric organ, resulting in a shorter half-life for these organs. Added to these early insults is the further harm done to all kidneys during episodes of rejection and by the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus. Finally, CAN results in further inflammation and fibrosis.

Factors That Accelerate the Progression of Renal Disease

Arterial hypertension and proteinuria are 2 of the most important factors in the progression of renal disease. 3°-34 Almost without exception, renal transplant recipients with CAN have elevated blood pressure and proteinuria. Mackenzie and Brenner 3~ re° viewed the most important risk factors for the progression of kidney disease. They emphasized a number of factors in addition to hypertension and proteinuria, listed in Table 2. It can readily be seen that many of these persist in renal transplant recipients even when they have relatively normal kidney function. All transplant recipients have a marked reduction in nephron number, and hyperlipidemia and diabetes mellitus are common.

ACEIs and ARBs in CAN 141

Hypertension and Proteinuria

Renal transplant recipients with hypertension are at high risk for the progression of vascular disease and renal failure. The presence of even small amounts of proteinuria increases this risk significantly, and both hypertension and proteinuria must be treated aggres- sively. The target blood pressure reduction should be to 135/85 mm Hg or less. Studies have shown that even if there are particular benefits to the use of ACEI/ARB therapy, the most important factor in delaying renal failure is an adequate reduction in mean arterial blood pressure. All antihypertensive drugs will reduce the progression of renal disease provided the blood pressure is reduced adequately.

The pathophysiological mechanisms by which proteinuria and hypertension impact on the progression of renal failure include increased intraglomerular pressure and increased production of fibrosing cytokines, such as TGF-[3, platelet-derived growth factor, and endothelin, which cause mesangial and interstitial fibrosis. 3s,36 Hypertension leads additionally to endothelial damage and myointimal proliferation. This process is characterized by similar disturbances in the secretion of fibrosing cytokines and growth factors. This progressive arteriosclerosis leads to renal ischemia. Proteinuria, previously considered only as a marker of glomerular damage, is now known to have harmful effects on renal tubular cells) 2 These cells, when subjected to an increased luminal protein concentration, secrete such chemoat- tractants as monocyte chemoattractant protein-1 and endothelin-1. These lead to recruitment of and infiltration by macrophages that, in turn, increase the local concentration of platelet-derived growth factor, TGF-I3, and other cytokines, with activation of fibroblasts in the renal interstitium leading to progressive fibrosis. It is also possible that renal tubular cells may transform directly into fibroblasts. In these conditions, AII enhances the activity of many of the genes responsible for' the production of these cytokines) 7 It is probable that ACEI/ARB therapy, which reduces the effects of AII and proteinuria, also slows the progression of renal interstitial fibrosis by interrupting this inflammatory process? 8,39

When treating hypertension in the period after transplantation when renal function is returning to normal and the levels of the CNIs are being adjusted, it is reasonable to withhold treatment with ACEIs and/or ARBs. This is also the time that hyperkalemia, a side effect ofboth these classes of drug, is most

common. Most patients are administered a dihydropyridine antagonist as first-line treatment for hypertension. However, once patients are stable, serious consideration should be given to adding treatment with an ACEI/ARB, particularly in patients with proteinuria or an elevated serum creatinine concentration in addition to hypertension. Even normotensive patients with proteinuria should be considered candidates for such intervention.

Studies of chronic renal failure have shown some dissociation between the protective effects of ACEI/ ARB therapy, which reduces both mean arterial blood pressure and proteinuria, and those antihypertensive agents that only reduce blood pressure, such as the majority of the dihydropyridine calcium antagonists. Those that reduce proteinuria, have a more profound impact. The difference may in part relate to the decreased afferent arteriolar tone in patients administered these calcium antagonists, with a less significant decrease in the glomerular capillary pressure. The afferent arteriolar vasoconstriction caused by the CNIs makes this potential difference between these classes of less concern.

Studies of patients with diabetes mellitus have also shown the beneficial effect of treating patients with ACEIs and ARBs. The use of a combination of an ACEI or ARB and a calcium antagonist is usually at least as effective as the use of an ACEI alone. In transplant recipients, the use of a calcium antagonist has the added benefit of counteracting some of the afferent arteriolar vasoconstriction induced by the CNIs, improving the effective renal blood flow and glomerular Filtration. The mechanism by which calcium antagonists protect against this vasoconstriction is probably that by preventing thromboxane Az- and endothelin-induced increases in afferent vascular tone. 2

Hyperlipidemia The use of AGEJ/ARB therapy has no direct benefit for patients with hyperlipidemia. However, some of the other antihypertensive agents may increase cho- lesterol levels and reduce insulin sensitivity. There is a reported correlation between hyperlipidemia and the incidence of acute rejection 4° and treatment with pravastatin, a 3-hydroxy-3-methyl coenzyme A reductase inhibitor shown to reduce acute rejection in heart and renal transplant recipients. 41,42 A study showing that lovastatin inhibits TGF-[3 expression in diabetic rat glomeruli is further evidence that the

142 Alan Wilkinson

endothelial protection provided by drugs of this class is a consequence of other factors in addition to their lipid-reducing properties. 43

Calcineurin Inhibitors

The kidney of the renal transplant recipient is ex- posed to a different hemodynamic balance from that ofpretransplantation patients not administered CNIs. In transplant recipients, the afferent glomerular arteriole is constricted by the CNI in the same way as if they were administered a nonsteroidal anti- inflammatory prostaglandin inhibitor. This constric- tion reduces the impact ofelevations in mean arterial pressure on the glomerular capillaries but may be so profound as to impair blood flow through the kidney and reduce renal function, and perhaps promote renal fibrosis as a consequence of ischemia. Calcium antagonists, which reduce afferent resistance, have been shown to improve the glomerular filtration rate of renal transplant recipients compared with similar controls not administered calcium antagonists.

The pathophysiological state of calcineurin nephrotoxicity is believed to include an increase in the production of TGF-I3 and other cytokines. ~ Because the production of TGF-[3 is affected by inhibition of the effects of AII on gene transcription, the use of ACE/ARB therapy would reduce the toxicity of these immunosuppressive agents. There are a few experimental studies that suggest this benefit but no long-term studies of renal transplant recipients that address this issue.

Chronic Allograft Nephropathy

Our understanding of the factors responsible for the condition previously known as chronic rejection or chronic allograft vasculopathy has increased significantly, and the condition is now best called chronic allograft nephropathy. 3,45"47 The factors that lead to allograft damage have been reviewed by Halloran et al 3 and are fisted in Table 3. The pathological changes that occur are nonspecific and include tubular atrophy, interstitial fibrosis, and fibrous intimal thickening in the arteries, with variable glomerular lesions. Some of these changes are similar to those occurring in patients with hypertensive and proteinuric renal diseases.

A number of studies including small numbers of patients of the effectiveness of the use of ACEI/ARB therapy in renal transplant recipients 48 suggest that the same benefits should be obtained as in the

Table 3. Risk Factors for Chronic Allograft Nephropathy

Donor Age Hypertension Vascular disease Brain death Hemodynamic instability Preservation/reperfusion injury

Recipient Preformed antibodies HI_,A match Immunosuppression Acute rejection Size mismatch Hypertension Drug toxicity Proteinuria Hyperlipidemia CMV status of donor Recurrent or de novo disease

Abbrex4ation: C/vlV, cytomegalovirus. Adapted and reprinted xOth permission?

treatment of patients with chronic renal failure. To maximize the benefits, mean arterial pressure must be adequately reduced by reducing blood pressure to less than 135/85 mm Hg. The dose of the ACEI or ARB should be increased further, even when blood pressure is adequ~/tely controlled, if there is still significant proteinuria.

Summary

Although the half-life of renal allografts has improved over the past decade, a significant number of patients lose their grafts as a consequence of the progression of renal insufficiency. The most important cause of late graft loss is CAN, and the rate of loss of renal transplant function is accelerated by the general factors known to increase the rate of progression of renal disease. In particular, hypertension, proteinuria, and hyperlipidemia are present in the majority of transplant recipients. There are similari- ties in the pathophysiological characteristics of these conditions; in particular, the role of elevated levels of TGF-[3 appears in the descriptions of the pathophysiological characteristics of all these disease states. Similarly, an excess of TGF-[3 characterizes CNI nephrotoxicity. Inhibition of the production or action of AII by the use of ACEI/ARB therapy is 1 factor believed to be responsible for the beneficial effects of these agents in proteinuric nephropathies. Part of this benefit is a result of hemodynamic changes, but probably more important are the effects on the elaboration of harmful cytokines. There is sufficient

ACEIs and ARBs in CAN 143

evidence that they are likely to be o f benefi t in renal

t ransplant recipients to r e c o m m e n d thei r more wide-

spread use.

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144 Alan Wilkinson

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Use of angiotensin-converting enzyme inhibitors and angiotensin II antagonists in renal transplantation: Delaying the progression of chronic allograft nephropathy?