Antihypertensive agents and renal transplantation

Abstract

Advances in the field of kidney transplantation have led to a significant increase in the life of renal allograft with 1 - year graft survival rates of 93% to 99%.This increase in early graft survival has made it possible to observe the long-term morbidities that accompany renal transplantation.

Studies correlating the reduction of arterial blood pressure with patient and graft survival as well as the risk of cardiovascular disease do not exist. The recommendations come from the general population and from comparative studies of hypertensive and normotensive kidney graft recipients. It is known that in the general population hypertension is a risk factor for chronic kidney disease but at the same time a risk factor for death, ischaemic heart disease, chronic heart failure and left ventricular hypertrophy. We must always have in mind that there are many similarities between a kidney graft recipient and a patient with chronic kidney disease. Renal transplant recipients represent a patient population with a very high risk for development of cardiovascular disease which has been identified as the leading cause of death in these patients¹. Of 18,482 deaths among renal allograft recipients, 38% had functioning renal allografts ^{2, 3}. Successful renal transplantation (Rt) can result in partial regression of left ventricular hypertrophy (LVH) if it is associated with hypertension (HTN) remission or if HTN is controlled by medications. Frequently post transplant HTN is associated with failure of LVH to regress. Transplant clinicians must choose antihypertensive agents that will provide their patients with maximum benefit from renal allograft and cardiovascular perspective. The target must always be long term patient and graft survival and acceptable quality of life. The antihypertensive drugs usually used after kidney transplantation are diuretics, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and β – blockers. Most emphasis is given lately to ACEIs/ARBs and β – blockers because of their cardioprotecive effect.

Posttransplant hypertension, perhaps the comorbidity with the greatest concern, occurs in about 70% to 90% of renal transplant recipients (Figure 1) in the cyclosporine era^4–6. Systolic blood pressure⁷ (Figure 2) as well as the pulse pressure (unpublished data) of recipients with graft function longer than 10 years is significantly lower compared with those of patients with graft survival >1 and < 10 years. Posttransplant hypertension has been recognized as an independent risk factor for chronic allograft dysfunction-nephropathy and graft loss^{8, 9} (Figure 3). Finally hypertension causes cardiac hypertrophy and is associated with increased cardiac morbidity and patient mortality in both the general and transplant populations^{2, 8, 10–12} (Table 1).

Figure 1. Five year follow up of systolic and diastolic blood pressure after kidney transplantation• 272 patients, period 1987-1995 (normal blood pressure considered to be systolic > 140 mmHg and diastolic > 90 mmHg) • Frequency on 7th pt day: 72.7%, on 5th year:67.6%.

Figure 2. Five year systolic blood pressure of patients with graft survival > 10 years and patients with graft survival <1 and > 10 years graft survival (p: 0.01).

Figure 3. Graft survival in patients with normal blood pressure (red line) and hypertension (green line)⁹.

Table 1. Cardiovascular disease as leading cause of death², ³.

Etiology and mechanisms causing hypertension after renal transplantation

Many factors have been incriminated for the development of hypertension after renal transplantation (Table 2). Donor hypertension and death due to subarachnoid hemorrhage have been connected with higher blood pressure of the recipient. Recurrence of primary renal disease has been considered responsible for hypertension after a renal transplant. Hypertension is common among patients with acute or hyperacute rejection and this is due to impairment of graft excretory function. Renal artery stenosis may cause hypertension not responding to antihypertensive drugs.

Table 2. Etiology of hypertension after renal transplantation¹³.

Uncontrolled renin secretion from the native kidneys can be responsible for hypertension in the renal transplant recipient.

Treatment of hypertension after renal transplantation

Treatment of elevated blood pressure in renal transplant recipients significantly reduces morbidity and mortality^{14, 15}. Aggressine treatment of hypertemsion must be voidel the first few days after transplantation. A systolic blood pressure of 140 – 160 mmHg and a diastolic < 90 mmHg is preferred in order to achieve a sufficient blood perfusion of the transplanted kidney. When the systolic blood pressure is > 200 mm Hg and diastolic blood pressure is > 120 mm Hg, hypertension may precipitate a medical emergency requiring rapid reduction of blood pressure to prevent vital organ damage.

The final regulation of blood pressure should be managed on an outpatient basis (Table 3) in a stable transplant recipient. Multiple factors may play important role in the fluctuation of blood pressure. It is important to take into account life style, the associated risk factors and the immunosuppressive regimen. So, the treatment of hypertension is individualized (Table 3, 4).

Table 3. Therapeutic approach of hypertension in renal transplant recipients.

Table 4. Adjustment of immunosuppressive medications.

Immunosuppression manipulation and arterial hypertension

Corticosteroids

During the initial high dose corticosteroid therapy, sodium retention occurs and plasma volume increases substantially (mineralocorticoid action) and leads to an increase of blood pressure and cardiac output16. Other postulated mechanisms of corticosteroids causing hypertension include increased sensitivity to endothelin-1 and angiotensin II leading to increased vascular resistance, increased density of glucocorticoid receptors in the vascular muscle and decreased production of vasodilatory prostaglandins^{5, 17, 18}. The daily dose and cumulative dose of prednisone are related to blood pressure^{19, 20}. High long term maintenance dose may cause or aggravate hypertension. The estimated incidence of arterial hypertension induced by corticosteroids is 15% ²¹. The conversion from every day to alternate day corticosteroid therapy may cause a reduction in arterial blood pressure. Steroid withdrawal is associated with fall of arterial blood pressure²². The lowest possible corticosteroid dose coupled with low salt diet and judicious use of diuretics is an interesting option.

Calcineurin inhibitors: Cyclosporine - tacrolimus

Both CsA and tacrolimus cause hypertension¹⁷. The mechanism is multifactorial, causes reduction in GFR and renal blood flow, and includes increase in sympathetic nervous tone, increase of intra-renal vascular resistance and increased sodium retention, a rise in peripheral vascular resistance and vasoconstriction of the afferent arterioles which produces vessel wall damage and impaired autoregulatory function^{17, 23, 24}. These may be the result of imbalance between vasoconstrictive (endothelin and thromboxane) and vasodilator factors (NO and prostacyclin) in CsA and tacrolimus treated patients^{25, 26}. Endothelin may play an important role in the development of hypertension in these patients²⁷. Calcinurin is present in several tissues including the kidney, vascular smooth muscle and nervous system, all of which are targets for hypertension. Possibly, calcinurin inhibition in these tissues is the cause of the increased sodium and water retention, vasoconstriction and sympathetic activity²⁸. Hypertension in patients taking cyclosporine in combination with corticosteroids has been described in 50% to 80% of cases²⁶. CsA induced hypertension is characterized by nocturnal hypertension²⁵.

Tacrolimus has been associated with less systemic vasoconstriction and less arterial hypertension than CsA in liver transplant patients²⁹. The most recent European multicentre study comparing tacrolimus with CsA microemulsion in kidney transplantation showed that the incidence of new onset or worsening hypertension was less common in the tacrolimus group³⁰. In general, the existing data today suggest that renal transplant patients under tacrolimus based therapy show less arterial hypertension compared with patients under CsA immunosuppression³¹.

Mycophenolate Mofetil

All the available literature support that MMF is not nephrotoxic and does not have any hypertensive effect, does not cause diabetes or hyperlipidaemia^{22, 32–34}.

Sirolimus

In Phase III studies using sirolimus in combination with CsA, there was a higher frequency of hypertension than control groups. It is possible that sirolimus potentiates the nephrotoxic effect of cyclosporine, which would explain the increase of blood pressure³⁵.

Immunosuppressive protocols

Immunosuppression protocols using MMF or azathioprine with CsA and steroids did not show difference in the incidence of hypertension³⁶. Protocols with steroid low dose and discontinuation present lower incidence of hypertension compared to triple scheme³⁷. These protocols have the drawback of high acute rejection rate³⁸.

The dose reduction or discontinuation of cyclosporine, in protocols with MMF and steroids, results in lower systolic and diastolic blood pressure³⁹.

Protocols based on sirolimus (plus steroid and azathioprine/MMF) show lower systolic and diastolic blood pressure but renal function at two years was lower in sirolimus treated compared to cyclosporine treated patients⁴⁰.

Use of antihypertensive drugs

The selection of antihypertensive therapy in the kidney transplant recipient should be guided, in part, on prior history of success of antihypertensive medications in facilitating blood pressure control before the transplant. In spite the use of new antihypertensive agents, the best treatment of arterial blood pressure after transplantation is not known yet. No single antihypertensive agent (Table 5) has been found to be more efficacious and better tolerated than the others used in the treatment of posttransplant hypertension and the initial antihypertensive therapy must aim at the patient’s risk factors. We diagnose hypertension when the blood pressure is > 130 / 85 mmHg in Rt recipients without proteinuria, or it is > 125 / 75 mmHg in Rt with proteinuria^41–43.

Table 5. Pharmacological therapy.

Diuretics (Table 6,7)

Table 6. Diuretics⁵⁰.

Table 7. Dose, renal effects, dosage adjustment in renal failure of the more commonly used diuretics in renal transplantation.

A careful assessment of blood volume is important in all kidney transplant recipients because they frequently receive corticosteroids and calcinurin inhibitors which may interfere with sodium and water excretion. Depending on the level of the kidney function a thiazide or a loop diuretic may be appropriate.

The mechanism by which diuretics reduce blood pressure is not known. The first period after starting diuretic therapy, the control of blood pressure is by volume depletion. Later possibly there is a vascular hyporesponsiveness to the sympathetic nervous system⁴⁴. The use of diuretics is mandatory in the immediate post-transplant period in case of hypertension and fluid overload. Loop diuretics are the drugs of choice, alone or in combination with CCBs, especially in cases with urine output less than 50 ml/h and gross haematuria. Sodium load, food-drug interactions and drug-drug interactions may lessen or ablate the effectiveness of diuretic therapy^45–47. Loop diuretics can cause prerenal azotemia, hypokalemia, hyperuricemia, hypocalcaemia and exacerbate hyperparathyroidism. A potential problem associated with hypokalemia is interference with insulin release and subsequent impairment of glycemic control. The extended use of diuretics and calcineurin inhibitors may require close electrolyte monitoring to avoid gout and cardiac mortality associated with low magnesium levels⁴⁸. On the contrary thiazide diuretics may induce hypercalcaemia and potassium sparing agents hyperkalemia. The use of cyclosporine, FK506, ACE inhibitors, b-blockers and cotrimoxazole has been connected with hyperkalemia. Hyperuricaemia and hypomagnessaemia are complications of cyclosporine and tacrolimus therapy⁴⁹.

Calcium channel blockers (CCBs)

CCBs are usually well tolerated and it has been proved that reduce mean arterial pressure and total renal vascular resistance, provide selective afferent glomerular arterioral dilatation, increase renal blood flow and GFR, reduce cyclosporine toxicity and combat the vasoconstrictive effect of CNIs, cause natriuresis, decrease perfusion injury and the rate of acute tubular necrosis immediately after transplantation because they offer protection to tubular epithelium and may reduce CsA induced hyperuricaemia^51–56. The main action of these drugs is the inhibition of entrance of calcium into the smooth muscles of vasoconstricted arterioles through voltage potential-dependent channels (Table 8). For the above reasons, it has been supported that calcium antagonists are the drugs of choice. The use of CCBs after the recovery of cold ischemia time acute tubular necrosis (ATN) and normalization of graft function must target to normal levels of systolic blood pressure (< 130 mmHg) because the afferent arteriolar dilatation conveys the systemic blood pressure into the glomerulus and in long term may result in kidney damage if the systolic blood pressure is not well controlled. However, in a comparative clinical trial, it was found that a calcium antagonist, an ACE-I and an a-blocker were equally effective in reducing blood pressure⁵⁷ and patient and graft survival did not show difference with the use of b-blockers and / or calcium antagonists in a 5-year follow up⁵⁸. In a recent longitudinal study it has been suggested that beta blockers as well as ACEIs may have a beneficial effect on cardiovascular mortality and on patient and graft survival over calcium antagonists⁵⁹.

Table 8. Characteristics of CCBs⁶⁰.

Isradipine (Lomir) and nifedipine (Coracten, Macorel, Adalat) are probably the most effective drugs among calcium channel antagonists and do not cause increase of cyclosporine levels as it happens with diltiazem, verapamile and nicardipine^{24, 61, 62}. These drugs are potent vasodilators and may cause dizziness, flushing, headache, leg oedema and gum hyperplasia^63–65.

These adverse effects (Table 9) can be minimised by the use of slow release formulations or with agents of a slow onset of action. It has been reported that short – acting calcium antagonists, given in non-transplanted patients, may increase the mortality in those with a recent history of acute myocardial infarction or coronary heart disease⁶⁶. Recently, safety has proved not to be a problem with calcium channel blockers in hypertensives treated in the ALLHAT study even in those with chronic renal failure⁶⁷. CCBs present robust antihypertensive action even in the presence of concomitant salt consumption. Clinical trials have shown that nondihydropyridine CCBs are more effective in reducing proteinuria compared with dihydropyridines (such as nifedipine). The combination of CCBs with an ARB or ACE-I reduces further the proteinuria^{68, 69}.

Table 9. Dose, renal effects, dosage adjustment and toxicity of the more commonly used CCBs in renal transplantation.

GH: Gingival Hyperplasia, HD: Headache, OE: oedema, FL: Flashing, CA: Conduction abnormality

Angiotensin converting enzyme inhibitors (ACE-I)

The basic haemodynamic effect of ACE-I is vasodilatory via suppression of angiotensin II production and inhibition of bradikinin inactivation (Table 10). Also, it has been suggested that ACE inhibitors retard the evolution of glomerulosclerosis and chronic decline of renal function, controlling arterial blood pressure and possibly normalizing intraglomerular hemodynamics^{70, 71}.

Table 10. Characterists of ACE-I⁷²,⁷³.

The use of ACE-Is in post-transplant hypertension had been a matter of debate for a long time. In recent clinical studies with a long term follow up in renal transplant patients, ACE-Is have been shown to be effective in the treatment of post-transplant hypertension. There was no difference between ACE-Is’ and calcium antagonists’ antihypertensive effect. Also adrenal plasma flow and GFR were similar in both groups of patients^{70, 74}. Mourard compared nifedipine plus atenolol with lisinopril plus furosemide and found no differences between the two groups as far as the antihypertensive efficacy, the adverse drug reaction profile, the effect on plasma renal flow and GFR. It has been shown that ACE-Is reduce significantly the proteinuria of transplanted patients with chronic allograft nephropathy⁷⁵.

The decline of renal function (20% - 30%) is due to foll of glomerular capillary pressure and GFR. If there is a more than 30% decrease after treatment with ACE inhibitors it is possibly related to the existence of renal artery stenosis or it may happen in grafts with normal parenchyma when the patient is dehydrated^76–78. The use of these drugs has been connected with hyperkalemia, especially in diabetics, and anemia⁷⁹ (Table 11).

Table 11. Dose, renal effects, dosage adjustment in renal failure and toxicity of most commonly used ACE-Is in renal transplantation.

CA:conduction abnormality, C:cough, A:angioedema, H:hyperkalaemia, An:anaemia

Angiotensin II receptor antagonists (ARBs)

ARBs reduce the capillary pressure, the GFR and the systemic blood pressure by blocking the physiological response to angiotensin II^{80, 81} (Table 12). It is best to start these drugs during the posttransplant period when kidney function and immunosuppression is stable.

Table 12. Angiotensin receptor blockers.

The recent successful use of angiotensin II receptor antagonists type I has added a new group of drugs in the treatment of renal transplant hypertension^{71, 82, 83}.

These agents have a significant control on the blood pressure, reduce the need for other antihypertensive agents^{82, 83} and reduce statistically significantly proteinuria (Figure 4, Table 13) of patients with chronic allograft disease⁸⁴. These agents do not seem to interfere with any of the immunosuppressive agents.

Figure 4. The systolic blood pressure six months before and six months after valsartan treatment Vergoulas G, et al. Hippokratia 2001; 5:61-68.

Table 13. Proteinuria and number of antihypertensive drugs at baseline and six months after treatment with ARBs⁸⁴.

Stimulation of AT1 receptors of erythroid progenitor cells by Ag II is believed to increase red blood cell mass independently from circulating erythropoietin. AT1 blockers cause statistically significant fall of Ht and Hb (Figure 5) and are very useful in hypertensive patients with erythremia^{82, 83}. It is believed that the blockade of AT1 receptors results in a decrease of red blood-cell mass independently of erythropoietin and initial haemoglobin levels^{85, 86}.

Figure 5. Hb levels six months before and six months after valsartan treatment. Vergoulas G, et al. Hippokratia 2001; 5:61-68.

In some patients supplementation with erythropoietin may be required and some may consider this as an inappropriate trade-off. However the opportunity to reduce both kidney and cardiovascular risks simultaneously in patients with greater cardiovascular burden may be an important consideration.

These drugs have the ability to lower significantly the levels of TGF-β1 in the plasma of transplanted patients with chronic allograft nephropathy⁸⁷. Usually, they do not cause hyperkalemia or hyperuricaemia and cause a slight but significant rise of serum creatinine level⁸⁸ (Table 14). A rise of serum creatinine of 20-30% is acceptable but always must be kept in mind the possibility that the rise is due to rejection. The reduction of GFR correlates with stabilization of kidney function over time possibly due to an anatomical protection of kidney⁸⁹. Serum creatinine level increase by more than 30% could indicate diminished effective arterial blood volume because of diuretic use or renal artery stenosis. From the first four drugs of this class of antihypertensives (losartan, valsartan, irbersartan, candesartan) it seems that losartan has the weaker antihypertensive effect and candesartan the stronger^90–92.

Table 14. Dose, renal effects, dosage adjustment in renal failure and toxicity of ARBs in renal transplantation.

The drugs of this category could be proved valuable not only for the treatment of hypertension of renal transplant recipients but also for the intervention in the evolution of chronic allograft nephropathy by interfering with profibrogenic and scarring processes within the kidney^93–95 and this possibly is the great difference between ARBs and ACE-Is because much production of angiotensin II takes place by non-ACE pathways both systemically and at the tissue level. These alternative pathways include direct formation from angiotensinogen, cathepsin G, and tissue plasminogen activation. Angiotensin I also can be converted to angiotensin II at the tissue level by chymase and cathepsin G. These local pathways are very important because tissue levels of angiotensin II are nearly 1,000 times greater than the levels in the circulation. Angiotensin II converting enzyme inhibitors have no effect on angiotensin II formed by these alternate pathways^96–100. Another point in favour of ARBs is the high percentage of patients that can not tolerate ACE-I^{101, 102}.

There have been some concerns about the early administration of ACEIs and ARBs after transplantation because of the fear of ATN development or DGF. Recently it has been supported that the early administration of ACEis/ARBs after transplantation is associated with faster decrease of serum creatinine levels, faster recovery time from delated graft function (DGF) and lower proteinuria¹⁰³.

It must be noticed that ACEIs/ARBs improve left ventricular function and reduce left ventricular hypertrophy due to hypertension in general population and possibly they have the same effect on the kidney transplant recipients with hypertension^104–106.

B - blockers (Table 15)

Table 15. β-Blockers¹¹¹,¹¹².

The precise mode of action of β-blockers in reducing blood pressure is not known. In a small study of the effect of β-blockers on hypertensive renal transplant recipients, a blood pressure reduction was noticed only in hypertensive patients with their native kidneys in situ¹⁰⁷. Native kidneys may play an important role in activation of renin - angiotensin system mediated by activation of the sympathetic nervous system. In a randomized study renal transplant recipients received atenolol or quinapril. In both groups blood pressure control was achieved. However quinapril lowered significantly albumin excretion¹⁰⁸.

β-Blockers may mask the symptoms of hypoglycaemia and thyrotoxicosis and cause sexual dysfunction, muscle weakness, tiredness and fatigue. Abrupt discontinuation of β-blockers may exacerbate rebound hypertension and so the dosage should be reduced slowly over a 1- to 2-week period.

They can also complicate the lipid profile in renal transplant recipients. The beneficial effect of β-blockers on transplant recipients, with a history of MI, CHD, hypertrophic cardiomyopathy or systolic heart failure outweigh the risk of their adverse effects¹⁰⁹.

The use of mTOR inhibitors may complicate further the problem of hyperlipidemia. Newer third generation β-blockers such as carvedilol (Dilatrend®) may solve the problem since they have neutral or positive effect on dyslipidemia and insulin resistance¹¹⁰. β-Blockers should be considered first choice treatment together with the ACI / ARBs for patients with a renal transplant and a history of coronary heart disease.