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NDT Advance Access originally published online on September 12, 2006
Nephrology Dialysis Transplantation 2006 21(12):3550-3554; doi:10.1093/ndt/gfl506
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Does angiotensin blockade influence graft outcome in renal transplant recipients with IgA nephropathy?

Aisling E. Courtney, Peter T. McNamee, William E. Nelson and Alexander Peter Maxwell

Regional Nephrology Unit, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB, UK

Correspondence and offprint requests to: Aisling E. Courtney, Regional Nephrology Unit, Level 11-Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, UK. Email: aecourtney{at}doctors.org.uk



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. IgA nephropathy (IgAN) is a frequent cause of end-stage renal disease (ESRD) and recurrent disease causes deterioration and graft loss in transplant recipients. No definitive management is known to reduce the risk or severity of recurrent IgAN, and the evidence to support the use of renin–angiotensin system blockade in such patients is limited.

Methods. All 1137 renal transplants performed at the Belfast City Hospital over a 27-year period were reviewed. A total of 75 patients with ESRD due to biopsy-proven IgAN were identified; 39 of them had been prescribed an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-II type I receptor blocker (ARB).

Results. The two groups were well-matched in terms of demographic details, immunosuppressive regimens and duration of follow-up (median 65 months, range 18–261 months). The 5- and 10-year graft survivals were higher in those prescribed ACEi/ARB therapy compared with those who were not, although these differences did not reach statistical significance (92.9 vs 86.5%; P = 0.34 and 81.6 vs 72.7%; P = 0.32, respectively). These results were similar when censored for death with a functioning graft. In the group where an ACEi/ARB was not prescribed, all four with biopsy-proven recurrent IgAN progressed to ESRD, compared with three out of nine in the group treated with an ACEi/ARB.

Conclusions. In transplant recipients with ESRD due to biopsy-proven IgAN, a trend towards improved 5-year and 10-year graft survival was seen in those prescribed ACEi/ARBs. All with recurrent IgAN in their grafts who were not treated with ACEi/ARB therapy progressed again to ESRD.

Keywords: IgA nephropathy; recurrent glomerulonephritis; renal transplantation; renin–angiotensin system



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
IgA nephropathy (IgAN) is one of the commonest forms of glomerulonephritis worldwide and is a frequent cause of end-stage renal disease (ESRD) in Asian and Caucasian populations [1]. Transplantation is the optimal form of renal replacement therapy, but immunohistological recurrence of IgAN is detected in up to 60% of the transplant recipients after 10 years [2]. Historically, it was postulated that recurrent disease followed a benign course and had little functional relevance [3], but it is now accepted that it is responsible for graft loss, in 3–16% of the patients [4–9].

No consensus management has been developed to reduce the risk or severity of recurrent IgAN. The European Best Practice Guidelines limit their recommendations to optimal management of the risk factors for progressive renal failure [10]. The impact of graft failure and a return to dialysis extend beyond the individual patient, adding to the dialysis population and further expanding the pool of patients awaiting transplantation. Allograft failure is now the fourth commonest cause of ESRD in the United States [11]. Given the increasing disparity between the numbers waiting for a transplant and the finite supply of donor organs, extending transplant graft survival remains a major clinical challenge. Recurrent disease is the third commonest cause of graft loss in those patients with renal failure due to glomerulonephritis, and will become increasingly important as overall graft survival improves [9].

Blockade of the renin–angiotensin system is generally accepted as being reno-protective in both diabetic and non-diabetic proteinuric renal disease, with the effects of such blockade mediated by blood pressure-dependent and independent mechanisms [12, 13]. It is established that proteinuria is a negative prognostic indicator for graft survival in IgAN [14], but evidence to support the efficacy of angiotensin blockade in this patient group is limited. The largest reported study, suggesting a beneficial effect, was based only on 10 patients [15].

We retrospectively studied patients with biopsy-proven IgAN as a cause of ESRD who received a renal transplant in our institution, to assess the influence of angiotensin blockade on graft survival, and on the course of recurrent IgAN.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Patients
All patients who had received a renal transplant at the Belfast City Hospital, UK, between 28 August 1977 and 27 April 2004 because of biopsy-proven IgAN were identified. Those with graft loss due to technical complications, (e.g. renal vein thrombosis), and rejection within the first month of transplantation were excluded from subsequent analyses. Data recorded included gender, age, previous transplant, maintenance immunosuppression, the prescription or not of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-II type 1 receptor blocker (ARB), the prescription or not of antihypertensive medication, biopsy-proven recurrence of IgAN, and graft and patient survival. The median duration of follow-up was 65 months (range 18–261 months).

Immunosuppression
Immunosuppressive regimens were individualized but general trends evolved over the 27-year period. Prednisolone and azathioprine was the usual maintenance therapy until 1989; ciclosporin introduction after 1989 allowed triple induction therapy with maintenance ciclosporin monotherapy, or dual therapy with either prednisolone or azathioprine in most patients; mycophenolate mofetil was introduced in 1998 and subsequently 26% of the patients had calcineurin inhibitor-free maintenance regimes; tacrolimus has been used as the calcineurin inhibitor of choice since 2002.

Era of transplantation
There have been significant advances in surgical technique and the immunosuppressive armamentarium over the period of this study. To allow for this variability the cohort was considered in two parts in categorical analysis: the first from 28 August 1977 until 31 December 1990 and the second from the 1 January 1991 until the 27 April 2004, (both of 160-months period).

Angiotensin blockade
If an ACEi/ARB had been prescribed for at least 12 months the patient was categorized as having received angiotensin blockade. No distinction was made between an ACEi and an ARB in the analysis.

Antihypertensive medication
A patient was recorded as receiving antihypertensive therapy if they were prescribed any of the following agents: calcium channel antagonist, ß-blocker, {alpha}-blocker, diuretic or centrally acting agents.

Graft outcome
No protocol or surveillance biopsies were performed. Clinical indications for biopsy were increasing proteinuria, rising serum creatinine values or both. The tissue was processed for light microscopy and immunofluorescence. IgAN was defined by standard criteria [16] with the recognition that the presence of IgA on immunofluorescence may occur without glomerular change and is not in itself diagnostic of IgAN. Graft loss was attributed to IgAN when there were diffuse mesangial proliferative lesions with glomerular sclerosis, and the absence of significant changes consistent with chronic allograft nephropathy, rejection or calcineurin toxicity.

Statistical analysis
Statistical analysis was performed using the chi-squared test and Fisher's exact test for categorical variables, and the independent t-test for continuous variables. The Kaplan–Meier curves and log-rank tests were used for description and comparison of graft survival, employing SPSS for Windows® (SPSS® Inc., Chicago, IL, USA) version 13.0.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Of the 1137 transplants performed in our institution between 28 August 1977 and 27 April 2004, 85 (7.5%) grafts were for patients with biopsy-proven IgAN. There were 73 Caucasian patients and one Asian patient. Eleven patients had a second transplant and were included twice. There was one post-operative death (day 1 post transplant) and five graft failures for technical complications or severe acute rejection in the first month. These were excluded from further analyses. One patient was lost to follow-up due to emigration. Data on ACEi/ARB prescription were unavailable for three patients.

Of the 75 cases for which complete data were available, 39 were prescribed angiotensin blocking medication and 36 were not. The characteristics of the two groups are summarized in Table 1. There were no significant differences in demographics, the era of transplantation, the proportion receiving their first transplant, maintenance immunosuppressive therapy or prescription of antihypertensive medication.


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  		Table 1. Characteristics of recipients who were receiving angiotensin blockade and those who were not

 
The median duration of follow-up was 70 months (range 19–261 months) for those on ACEi/ARB therapy vs 71 months (range 18–208 months) for those who were not.

There were three deaths with a functioning graft in the first 120 months after transplantation. These were due to ischaemic heart disease, malignancy and a road traffic accident. The 5- and 10-year recipient survivals were 95 and 92%, respectively.

The 5-year graft survival was higher in those prescribed ACEi/ARB therapy compared with those who were not (92.9 vs 86.5%), but the difference was not statistically significant (p = 0.34). Similarly there was a trend to improved 10-year graft survival in those prescribed ACEi/ARB treatment (81.6 vs 72.7%; p = 0.32) (Figure 1). These results were similar when censored for death with a functioning graft. In those with functioning grafts, the mean glomerular filtration rate at the end of the study period was 55.4 ml/min (SD 26.2) and 55.9 ml/min (SD 24.7) in those with and without angiotensin blockade, respectively (p = 0.95).


Figure 1
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  		Fig. 1. The Kaplan–Meier graft survival curves in renal transplant recipients with ESRD due to IgAN, with and without angiotensin blockade.

 
A similar proportion of patients were biopsied in each group, 16 (41%) in those on an ACEi/ARB and 9 (25%) in those who were not (p = 0.33). Biopsies in the first 3 months post-transplant were excluded from analysis. In patients with more than one transplant biopsy, the findings were summated so each graft was counted only once. In patients with angiotensin blockade, 10 grafts had IgA-positive immunofluorescence with nine reported as IgAN. Three have returned to dialysis (7.7% of the 39 in this group and 33% of those with IgAN). Of those without ACEi/ARB therapy, five grafts had positive immunofluorescence for IgA and four had changes consistent with IgAN. All of these progressively deteriorated to ESRD (11.1% of the 36 in this group and 100% of those with IgAN). The difference in rates of recurrent IgAN was not significant (P = 0.27). The other histological diagnoses were rejection, calcineurin toxicity and chronic allograft nephropathy. These did not differ significantly between the two groups (Table 2).


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  		Table 2. Histological diagnoses of renal transplant biopsies in recipients who were receiving angiotensin system blockade and those who were not

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Extending graft survival remains a major challenge for the transplant community. It is established that proteinuria and hypertension are adverse prognostic indicators in the transplanted kidney as well as in native kidneys [14, 17], and evidence is now emerging to support the intuitive prescription of angiotensin blockade for grafts with chronic allograft nephropathy [18].

In patients with end-stage renal disease on the basis of IgAN who receive a transplant, recurrence of the native disease is now accepted to be a significant contributor to graft failure [4, 5, 7, 8, 19]. There is limited evidence on the best therapy to minimize this risk, but it is generally accepted that calcineurin inhibitors do not alter the natural course of recurrent IgAN. A recent review of 152 patients also concluded that mycophenolate mofetil does not influence the clinical incidence or severity of recurrent IgAN [19].

Proteinuria and hypertension are common features of clinically relevant recurrent IgAN, and the use of ACEi/ARB therapy seems a logical extension of the application of these drugs in other areas of nephrology. These agents may influence graft survival and favourably modify cardiovascular disease morbidity and mortality following transplantation [20]. The data to support the use of ACEi/ARB therapy in this group of patients is limited.

In a recent review, Chandrakantan and colleagues [19] stated that ‘neither ... using an angiotensin-converting enzyme inhibitor [n]or angiotensin-II type 1 receptor blocker ameliorated the clinical course after a biopsy documented recurrent IgAN’. This conclusion was based on 13 patients treated with ACEi/ARB therapy, with a reduction of at least a third in serial urinary protein excretion in only one patient.

In contrast, Ponticelli's group [8] commented that in those with histologically proven recurrent disease, progression to ESRD occurred in seven of the 16 that were not treated with ACEi compared with three of the 21 that were. The limited patient numbers precludes meaningful statistical analysis.

Oka and colleagues [15] reported on 21 Chinese patients with recurrent IgAN, 10 of whom were prescribed ACEi therapy. There was a significant reduction in hypertension and proteinuria in this group during a mean follow-up of 12.8 months. Longer follow-up would be necessary to assess any impact on graft survival. However, the histological finding in this study of prominent glomerular hypertrophy in recurrent IgAN conceptually supports the use of angiotensin blockade in the management of hypertension and hyperfiltration in recurrent IgAN.

Our study is considerably larger than those previously reported with a total of 39 transplant recipients with a primary disease of biopsy-proven IgAN receiving ACEi/ARB therapy. The 36 transplant recipients who were not prescribed with an ACEi/ARB provide a useful comparison group. The two groups were well-matched demographically, with regard to the maintenance immunosuppression and duration of follow-up. Over 90% of the patients in both the groups were prescribed antihypertensive therapy, 49% of all those on blood pressure-lowering therapy were not on an ACEi/ARB. The grafts with primary non-function or loss in the first month were excluded from the study to prevent confounding in the data.

The 5-year graft survival was 92.9% in those prescribed angiotensin blockade vs 86.5% in those who were not, and the 10-year graft survival was 81.6 vs 72.7%, respectively. While perhaps clinically re this improvement was not statistically significant (p = 0.34 and p = 0.32). This study has a power of almost 75% to detect a 5% difference in graft survival at the statistically significant level of 5%. Therefore, although considerably larger than previous reports, the possibility of a type II error still exists. Thus, the failure to provide conclusive statistical evidence of improved graft survival with angiotensin blockade does not preclude such an effect.

The impact of angiotensin blockade was also of interest when the outcome of biopsy-proven recurrent IgAN in transplanted kidneys was examined. Overall, 17% of our patients had histologically confirmed recurrent IgAN, which is likely to be an underestimate of the actual recurrence rate given the biopsy policy of our institution. The biopsy-proven IgAN recurrence rate was comparable in both the groups. All four in the group who were not prescribed an ACEi/ARB progressed to ESRD compared with three of the nine in the group treated with an ACEi/ARB. This is similar to Ponticelli's findings [8], where a greater proportion of the patients receiving angiotensin blockade maintained self-supporting renal function despite recurrent IgAN.

The advantages of our study are the much larger patient numbers than previously reported, the presence of a valid comparison group, and the completeness and long duration of follow-up. Of interest, Choy and colleagues [5] suggested that recurrent IgAN did not become clinically relevant until at least 12 years after transplantation and with a longer follow-up period the trend for improved survival when prescribed an ACEi/ARB may become statistically significant. Registry data, where the original cause of ESRD is accurate and the cause of graft failure is diagnosed on biopsy, could help to establish the true impact of recurrent IgAN on graft outcome. The risk of graft loss from recurrent glomerulonephritis has been described from an Australian transplant registry [9], but in this report follow-up was <10 years and no data were available on the prevalence of recurrent IgAN that did not lead to graft loss.

In conclusion, this large retrospective single-centre study, with prolonged follow-up, identified all patients with ESRD due to biopsy-proven IgAN. A non-significant trend towards improved 5- and 10-year graft survival was seen in transplant recipients who were prescribed an ACEi/ARB. All of the transplant patients with recurrent IgAN in their graft who were not treated with ACEi/ARB therapy progressed again to ESRD. A larger multi-centre study should help to clarify the suggested beneficial effects of ACEi/ARB treatment on graft outcome in patients with ESRD due to IgAN.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Levy M and Berger J. (1988) Worldwide perspective of IgA nephropathy. Am J Kidney Dis 12:340–347.[Web of Science][Medline]
  2. Odum J, Peh CA, Clarkson AR, et al. (1994) Recurrent mesangial IgA nephritis following renal transplantation. Nephrol Dial Transplant 9:309–312.[Abstract/Free Full Text]
  3. Berger J. (1988) Recurrence of IgA nephropathy in renal allografts. Am J Kidney Dis 12:371–372.[Web of Science][Medline]
  4. Bumgardner GL, Amend WC, Ascher NL, Vincenti FG. (1998) Single-center long-term results of renal transplantation for IgA nephropathy. Transplantation 65:1053–1060.[Web of Science][Medline]
  5. Choy BY, Chan TM, Lo SK, Lo WK, Lai KN. (2003) Renal transplantation in patients with primary immunoglobulin A nephropathy. Nephrol Dial Transplant 18:2399–2404.[Abstract/Free Full Text]
  6. Floege J. (2004) Recurrent IgA nephropathy after renal transplantation. Semin Nephrol 24:287–291.[CrossRef][Web of Science][Medline]
  7. Ohmacht C, Kliem V, Burg M, et al. (1997) Recurrent immunoglobulin A nephropathy after renal transplantation: a significant contributor to graft loss. Transplantation 64:1493–1496.[CrossRef][Web of Science][Medline]
  8. Ponticelli C, Traversi L, Feliciani A, Cesana BM, Banfi G, Tarantino A. (2001) Kidney transplantation in patients with IgA mesangial glomerulonephritis. Kidney Int 60:1948–1954.[CrossRef][Web of Science][Medline]
  9. Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ. (2002) Risk of renal allograft loss from recurrent glomerulonephritis. N Engl J Med 347:103–109.[Abstract/Free Full Text]
  10. European best practice guidelines for renal transplantation. Section IV: long-term management of the transplant recipient. IV.2.5. Chronic graft dysfunction. Late recurrence of primary glomerulonephritides. Nephrol Dial Transplant (2002) 17:Suppl 4, 16–18.[Abstract/Free Full Text]
  11. Agodoa L, Eknoyan G, Ingelfinger J, et al. (1997) Assessment of structure and function in progressive renal disease. Kidney Int Suppl 63:S144–S150.[Medline]
  12. Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. (2003) Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 361:117–124.[CrossRef][Web of Science][Medline]
  13. Brenner BM and Zagrobelny J. (2003) Clinical renoprotection trials involving angiotensin II-receptor antagonists and angiotensin-converting-enzyme inhibitors. Kidney Int Suppl 83:S77–85.[Medline]
  14. Kimata N, Tanabe K, Ishikawa N, et al. (1996) Correlation between proteinuria and prognosis of transplant IgA nephropathy. Transplant Proc 28:1537–1539.[Web of Science][Medline]
  15. Oka K, Imai E, Moriyama T, et al. (2000) A clinicopathological study of IgA nephropathy in renal transplant recipients: beneficial effect of angiotensin-converting enzyme inhibitor. Nephrol Dial Transplant 15:689–695.[Abstract/Free Full Text]
  16. Jennette JC. (1988) The immunohistology of IgA nephropathy. Am J Kidney Dis 12:348–352.[Web of Science][Medline]
  17. Opelz G, Wujciak T, Ritz E. (1998) Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study. Kidney Int 53:217–222.[CrossRef][Web of Science][Medline]
  18. Artz MA, Hilbrands LB, Borm G, Assmann KJ, Wetzels JF. (2004) Blockade of the renin-angiotensin system increases graft survival in patients with chronic allograft nephropathy. Nephrol Dial Transplant 19:2852–2857.[Abstract/Free Full Text]
  19. Chandrakantan A, Ratanapanichkich P, Said M, Barker CV, Julian BA. (2005) Recurrent IgA nephropathy after renal transplantation despite immunosuppressive regimens with mycophenolate mofetil. Nephrol Dial Transplant 20:1214–1221.[Abstract/Free Full Text]
  20. Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ. (1996) Cardiovascular disease after renal transplantation. J Am Soc Nephrol 7:158–165.[Abstract]
Received for publication: 23. 6.06
Accepted in revised form: 31. 7.06


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