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Recurrent lupus nephritis after kidney transplantation: a surveillance biopsy study
  1. Gudrun E Norby1,
  2. Erik H Strøm3,
  3. Karsten Midtvedt2,
  4. Anders Hartmann2,
  5. Inge-Margrethe Gilboe1,
  6. Torbjørn Leivestad4,
  7. Jean Stenstrøm2,
  8. Hallvard Holdaas2
  1. 1Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  2. 2Department of Medicine, Oslo University Hospital, Rikshospitalet, Renal Section, Oslo, Norway
  3. 3Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  4. 4Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  1. Correspondence to Gudrun E Norby, Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, Oslo 0027, Norway; gudrun.elisabeth.norby{at}rikshospitalet.no

Abstract

Objectives To determine the incidence of recurrent lupus nephritis (LN) in renal transplant recipients with systemic lupus erythematosus (SLE).

Methods All patients with SLE that had undergone transplant with a functioning graft were asked in 2008 to participate in a cross-sectional study. The study included a standardised clinical examination, laboratory tests and a biopsy of the transplanted kidney.

Results A total of 41 (93%) of a cohort of 44 patients with SLE with renal transplants participated. Of the biopsies, 3 were indication biopsies and 38 were surveillance biopsies. In all, 22 patients (54%) had biopsy-proven recurrence of LN. The majority of the cases were subclinical and characterised as class I/class II LN. Proteinuria (mg protein/mmol creatinine) was significantly increased in patients with recurrence, 70.6 (104.9) mg/mmol versus 11.9 (6.7) mg/mmol in patients without recurrence (p=0.038). Lupus anticoagulant was found more frequently in the patients with recurrence, nine versus two patients (p=0.033). Recurrence of LN was associated with receiving a kidney from a living donor (p=0.049). In all, 83% (34 of 41) had chronic allograft nephropathy in the transplanted kidneys with no difference between patients with recurrence or without.

Conclusions Subclinical recurrence of LN is common in patients with renal transplants with SLE. The majority of the patients have chronic allograft nephropathy.

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Introduction

In the current era, less than 10% of patients with lupus nephritis (LN) will progress to end-stage renal disease (ESRD).1 Patients with systemic lupus erythematosus (SLE) constitute 1% to 2% of the patients with ESRD who require renal transplantation.2

There is no consensus of the recurrence rate of LN in patients with SLE with transplants. Recurrence rates have historically been considered to be low (1% to 4%), although more recent data have indicated a higher recurrence rate.3

The diagnosis of recurrent LN requires a transplant biopsy including electron microscopy and immunofluorescence.2

No studies have systematically performed surveillance biopsies in patients with SLE with transplants. In this cross-sectional study, we used surveillance biopsies to assess the incidence of recurrence of LN in the transplanted graft. We also wanted to assess chronic allograft nephropathy.4

We hypothesised that recurrence of disease would be associated with time since transplantation, clinical SLE disease activity parameters and/or clinical signs of graft dysfunction.

Patients and methods

From 5346 transplants, a total of 79 (1.4%) patients with SLE received a renal transplant at the National Transplant Centre in Norway between 1972 and 2005. All patients, except one Asian in each group, were Caucasians, and none were lost to follow-up. A total of 45 of these patients had a functioning graft in 2008 and were offered a standardised clinical examination including a protocol biopsy of the transplanted kidney. Four patients declined. In 38 patients, surveillance biopsies were performed, and in 3 patients biopsies were taken for cause.

Demographic information, transplant data and laboratory data were recorded. Urinanalysis included protein–creatinine ratio (mg protein/mmol creatinine). Glomerular filtration rate (GFR) was measured by Cr51-EDTA. High-sensitivity C reactive protein (hsCRP) was measured by using an immunoturbometric analysis (Roche Diagnostics GmbH, Mannheim, Germany).

Definitions

Of the 41 patients in the study, 39 met at least 4 of the American College of Rheumatology revised criteria for the diagnosis of SLE.5 Two of the patients had only had positive anti-nuclear antibody and positive anti-centromere antibodies; however, their pretransplant renal biopsies had histological findings consistent with LN. The definition of recurrence of LN in our study was based on biopsy findings of immune deposits by immunofluorescence and/or the demonstration of electron dense deposits of immune complex type by electron microscopy. LN was classified according to Weening et al.6 This classification system is based on biopsy of native kidneys and was modified for the transplant situation. As a graft is exposed to a variety of insults (ischaemia during transplantation, rejections, immunosuppressive treatment) that may lead to glomerular changes, globally sclerosed glomeruli were not taken into account for the determination of lupus class chronic allograft nephropathy was classified according to the Banff classification.7

The American College of Rheumatology (ACR)/Systemic Lupus International Collaborating Clinics (SLICC) damage index8 and the systemic lupus erythematosus disease activity index (SLEDAI) was used to assess SLE status.9

The characteristics for the groups were summarised and compared using independent two-sample t tests or Wilcoxon rank sums tests as appropriate for continuous variables and Fisher's exact test for categorical variables.

Results

The clinical characteristics of the patients with recurrence (RLN) and without recurrence of LN (non-RLN) are summarised in table 1.

Table 1

Demographic, clinical and laboratory characteristics

Primary immunosuppression was in principle triple treatment (ciclosporine or tacrolimus, azathioprine or mycophenolate and steroids). It is important to note that there was no difference in immunosuppressive regimes between the two groups.

The recurrence group had significant higher protein excretion than the non-recurrent group. Lupus anticoagulant was significantly more frequent in the recurrence group. Other SLE serological markers and inflammation markers were not different between the groups (hsCRP was censored for values ≥30 mg/litre). In the group with recurrence, significantly more recipients received a living donor kidney. The statistical significance persisted, although weakened to borderline significance (p=0.049) when non-related living donors were excluded from the analysis.

Of 22 patients with recurrent LN, 10 had class I mesangial lesions. Seven patients had class II. Only three patients developed proliferative recurrence with activity in two of the biopsies.

All patients, except for three in each group, had morphological changes characteristic of chronic damage to the graft (interstitial fibrosis and tubular atrophy). There was no difference between the groups (table 2).

Table 2

Transplant characteristics of the patients with and without recurrence of LN

Discussion

More than 50% of patients with transplants with SLE in our study had biopsy findings indicating recurrent disease in their grafts. This recurrence rate is substantially higher than previously reported.3 In previous studies assessing recurrent LN the majority of biopsies have been performed for clinical indications (increased serum creatinine, proteinuria or haematuria).2 However, it is reassuring that the majority of the patients had subclinical class I or II (17 of 22) and only 3 had class III or IV. Clinically manifesting recurrent glomerulonephritis is in general an important cause of deteriorating renal function in patients with renal transplants.10 The clinical significance of subclinical class I and II recurrence is uncertain, since there are no studies with longitudinal biopsy follow-up in patients with SLE with transplants. Another important finding is that the majority of patients (84%) had histological changes classified as chronic allograft nephropathy, findings in parallel with other transplant populations.4 Calcineurin inhibitors were the most commonly used immunosuppressive drugs in our population, and patients with SLE with transplants seem to be as susceptible to calcineurin inhibitor (CNI) toxicity as patients with SLE who have not had transplants.4 A major impediment to the goal of improved kidney transplant survival is a cumulative and progressive immune and non-immune injury following transplantation.4 11 There was no difference in immunosuppressive treatment in patients who were recurrent and those who were non-recurrent. In patients with SLE with transplants, ‘standard’ immunosuppression with CNI, mycophenolate mofetil and prednisolone seems to protect against clinically overt recurrence of disease, but not against chronic allograft nephropathy. It is noteworthy that ‘lupus activity’ was low in patients with subclinical recurrence. The SLEDAI and SLICC indexes were both low and did not differentiate between patients with recurrence or not, emphasising the mild degrees of renal disease activity in recurrent LN. Lupus anticoagulant was found significantly more frequently in patients with recurrence. In native kidneys lupus anticoagulant is associated with a higher risk of renal involvement12 and this appears to also be the case in transplanted kidneys in patients with SLE.

Proteinuria remains the hallmark finding suggesting clinical recurrence of glomerulonephritis after transplantation. In contrast to the significant difference in protein excretion, renal function assessed by measured GFR was not lower in patients with recurrence.

Patients with SLE with and without end-stage renal failure are at increased risk of premature cardiovascular disease, and patients with SLE with transplants benefit from statin treatment.13 Our cohort had normal levels for atherogenic lipids, reflecting the extensive use of statins as part of our standard medication.

The use of living donors in this work reflects our transplant policy. The core statistical analysis showed that use of living donor tissue was associated with recurrence of LN in the graft, but when corrected for non-related living donors the association was statistically marginal. It is well known that there is a variant with familial clustering of SLE.14 There is evidence suggesting that susceptibility genes exist but that environmental factors are probably necessary to trigger the disease.15 One inherent problem with studies in patients with SLE with transplants is the limited sample size. Although our population is relatively large, the finding of an association of recurrent LN with use of living donors must be interpreted with caution.

Potential limitations of our study merit consideration. First, this is a cross-sectional biopsy study and not a serial follow-up study. The timespan from transplantation to performing of biopsy varied considerably. The strength of the study is that the biopsies were protocol indicated and not for cause. Our findings are probably representative for a Caucasian cohort of patients with transplants with SLE, as 93% of our population with a functioning graft participated.

In conclusion, we have shown that silent recurrence of LN is more frequent than previously realised. The occurrence of recurrence may be associated with increased proteinuria, lupus anticoagulant and the use of living donors. In addition, patients with SLE with transplants demonstrate chronic immune and non-immune damage at the same rate as in patients with SLE without transplants. Longitudinal studies with serial biopsies are needed to supply information on the relevance of chronic allograft nephropathy and recurrence of LN in patients with SLE with transplants.

Acknowledgments

The authors wish to thank bioengineers Kirsten Lund, Janicke Narverud and Els Breistein for organising and collecting clinical data and administrative secretary Torhild Garen for assistance with the case record forms.

References

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Footnotes

  • Competing interests None.

  • Ethics approval This study adhered to the International Conference on Harmonization guidelines for Good Clinical Practice and in accordance with the Declaration of Helsinki. The study was approved by the Regional Ethics Committee for Medical Research (REK-Sør). All patients gave written informed consent before participation in the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent Obtained.

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