There are scarce data about clinical presentation and outcomes of posttransplant membranous nephropathy (MN), and few reports include a large number of patients. This was a retrospective cohort including adult patients with posttransplant MN transplanted between 1983 and 2015 in a single center (n=41). Only patients with histological diagnosis of MN in kidney grafts were included. Clinical and laboratory presentation, histological findings, treatment, and outcomes were detailed. Patients were predominantly male (58.5%), with a mean age of 49.4 ± 13.2 years; 15 were considered as recurrent primary MN; 3 were class V lupus nephritis; 14 were considered as
Membranous nephropathy (MN) is a common cause of nephrotic syndrome, and it is a prototype of autoimmune glomerular diseases [
There are scarce data about clinical presentation and outcomes of posttransplant MN, and few reports include a large number of patients. Thus, all additional information about this glomerulopathy can be useful in patient management. This study aimed to describe clinical, laboratorial, and histological characteristics, as well as treatment and outcomes of patients with posttransplant MN in a high-volume transplant center.
This retrospective cohort included adult patients with posttransplant MN transplanted between 1983 and 2015 in a single center that performs about 900 transplants per year. Only patients with histological diagnosis (optical microscopy and immunofluorescence) of MN in kidney grafts were included. Patients were identified through biopsies database and/or were selected from those followed in the Glomerulopathies Section. Protocol biopsies are not routinely performed in the center. Data were obtained from medical records and electronic databases. The study protocol was approved by the local Ethics Committee (CAAE: 24309913.1.0000.5505).
Proteinuria was defined as urinary protein excretion superior to 0.3 g per day in a 24-hour urine collection or 0.3g/g in protein-to-creatinine ratio (UPr/Cr) determined in a random urine specimen [
Renal function was assessed by serum creatinine (Cr) or by estimated glomerular filtration rate (eGFR) using 4-variable MDRD formula [
Partial remission was defined as Cr stabilization in a value up to 25% above the baseline level associated with decrease of proteinuria by 50% or greater and <3.0 g/g when initial values were above 3.0 g/g. Complete remission was defined as serum Cr stabilization associated with proteinuria <0.3 g/g [
The immunosuppressive therapy was individualized according to our center protocols. Induction therapy, when indicated, consisted of anti-CD25 monoclonal antibodies or antithymocyte globulin; maintenance immunosuppression was based on calcineurin inhibitor (CNI, cyclosporine or tacrolimus) plus steroid and an antiproliferative drug (mycophenolate, azathioprine, or mTOR inhibitor).
Categorical variables were expressed as frequency and percentages and compared using Chi-square or Fisher’s exact test. Continuous variables were presented as mean and standard deviation (SD) and median when indicated; comparison between groups was performed using the Student’s
Between 1983 and 2015, 12,643 kidney transplants (KT) were performed and 41 patients with posttransplant MN were identified. Patients were predominantly male (58.5%), with a mean age of 49.4 ± 13.2 years; 36.6% presented documented MN as chronic kidney disease etiology. Most patients received kidneys from living donors (63.4%) with a mean age of 38.1 ± 16.3 years.
Most patients received no induction therapy (78.1%) and the initial maintenance immunosuppressive regimen was based on calcineurin inhibitor, steroid, and azathioprine in 56.1%, in accordance with the transplant center protocol during the study period. More detailed information about demographics is available in Table
Demographic characteristics of patients with posttransplant MN.
Variables | N = 41 |
---|---|
Recipient gender – male, n(%) | 24 (58.5) |
Recipient age (years), mean ± DP | 49.4 ± 13.2 |
Pretransplant dialysis, n(%) | 40 (97.5) |
Time on dialysis (months), mean ± DP | 22.6 ± 24.1 (median = 16) |
Etiology of end-stage renal disease, n(%) | |
| 15 (36.6) |
| 2 (4.9) |
| 9 (22) |
| 5 (12.2) |
| 5 (12.2) |
| 2 (4.9) |
| 1 (2.4) |
| 1 (2.4) |
| 1 (2.4) |
Panel reactive antibodies (%), mean ± DP | 7.85 ± 22.6 (median = 0) |
Donor source, n(%) | |
| 26 (63.4) |
| 6 (14.6) |
| 16 (39) |
| 4 (9.8) |
| 15 (36.6) |
| 10 (24.4) |
| 5 (12.2) |
Donor age (years), mean ± DP | 38.1 ± 16.3 |
HLA mismatches, mean ± DP | 2.3 ± 1.8 |
Cold ischemia time (hours), mean ± DP | 25 ± 9 |
Induction therapy, n(%) | |
| 32 (78.1) |
| 1 (2.4) |
| 8 (19.5) |
Initial immunosuppressive regimen, n(%) | |
| 23 (56.1) |
| 14 (34.1) |
| 4 (9.8) |
PRED: prednisone; CNI: calcineurin inhibitor; AZA: azathioprine; MPA: mycophenolic acid; SRL: sirolimus; HLA: human leukocyte antigens.
1United Network for Organ Sharing (UNOS) criteria [
Fifteen cases were considered as recurrent primary MN as patients have chronic kidney disease (CKD) due to biopsy-confirmed MN; 3 were class V lupus nephritis: 2 of this had previous diagnosis of lupus and 1 was classified as unknown etiology for CKD; 14 had defined causes for renal disease and were considered as
The most frequent initial manifestations of posttransplant MN were proteinuria (75.6%, 3.2 ± 1.2 g) and graft dysfunction (34.1%). Proteinuria > 0.3 g/day was observed at a median time of 40 months (ranging from 4 to 74) after KT. The mean levels of serum albumin and cholesterol were 3.4 ± 0.6g/dL and 198.8 ± 58.6 mg/dL, respectively. Compared to baseline values, eGFR decreased 26.8 ± 16.4% at diagnosis. Diagnostic allograft biopsy was performed 3.7 ± 2.5 months after the onset of proteinuria and a median time of 41 months (ranging from 12.3 to 87.8) after KT. MN stage 2 was the main histological presentation (60.9%), followed by stages 1 (24.4%) and 3 (14.7%) (Table
Clinical presentation of patients with posttransplant MN.
| |
---|---|
Proteinuria > 0.3 g/g or g/24h, n(%) | 31 (75.6) |
Proteinuria1 (g/g or g/24h), mean ± DP | 3.2 ± 1.2 |
Time to onset of proteinuria > 0.3 g/g or g/24h (months), mean ± DP | 49.5 ± 49.7 (median = 40) |
Serum albumin1 (g/dL), mean ± DP | 3.4 ± 0.6 |
Serum total cholesterol1 (mg/dL), mean ± DP | 198.8 ± 58.6 |
Serum triglycerides1 (mg/dL), mean ± DP | 178.5 ± 78.7 |
Systolic blood pressure1 (mmHg), mean ± DP | 131 ± 7.8 |
Diastolic blood pressure1 (mmHg), mean ± DP | 82.2 ± 6.5 |
Graft dysfunction1, n(%) | 14 (34.1) |
Serum creatinine1 (mg/dL), mean ± DP | 1.7 ± 0.6 |
eGFR1 (mL/min/1.73m2), mean ± DP | 41.9 ± 14.3 |
eGFR decrease1 (%), mean ± DP | 26.8 ± 16.4 |
Time between proteinuria and graft biopsy (months), mean ± DP | 3.7 ± 2.5 |
Time between KT and graft biopsy (months), mean ± DP | 53.4 ± 51.5 (median = 41) |
Histological stages of MN, n(%) | |
| 10 (24.4) |
| 25 (60.9) |
| 6 (14.7) |
eGFR: estimated glomerular filtration rate; KT: kidney transplant.
1 At diagnosis.
Patients with secondary posttransplant MN received renoprotection and treatment of underlying disease. Among patients with primary forms, 15 (45.5%) received angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin II receptor blockers (ARB). Maintenance immunosuppressive regimen was modified in 20 of the 33 patients (60.6%) with primary MN: 9 patients received high oral prednisone doses (≥0.5mg/kg/day), with or without methylprednisolone pulse therapy; 4 patients were converted from azathioprine to mycophenolate; mTOR inhibitors were withdrawn in 3 patients, 2 of which were maintained temporarily on dual immunosuppressive regimen and 1 received mycophenolate instead; in 4 patients, modified Ponticelli regimen [
Fifteen patients had an apparently spontaneous remission. There were no significant differences between patients who presented spontaneous remission and those who did not remit or only remitted after immunosuppressive therapy concerning recipient age (47.6 ± 14.7 versus 50.4 ± 12.4 years old, p=0.514); donor source (living) (60 versus 65.4%, p=0.749); time since KT at diagnosis (36.8 ± 38.7 versus 62.9 ± 56 months, p=0.118); serum creatinine (1.7 ± 0.8 versus 1.8 ± 1.5 mg/dL, p=0.835); proteinuria (3.5 ± 4.4 versus 2.9 ± 2.6 g, p=0.613); posttransplant MN category (recurrence) (48.4 versus 20%, p=0.152); or maintenance immunosuppression with mycophenolate (34.6 versus 33.3%, p=1.000).
Partial and complete remissions were observed in 25 (61%) and 11 (26.8%) patients, respectively, and occurred 358 ± 180 days after diagnosis (Table
Posttransplant MN outcomes.
| |
---|---|
Time on follow-up (months), mean ± DP | 108.2 ± 52.8 |
Partial remission, n(%) | 20 (48.78) |
Complete remission, n(%) | 11 (26.8) |
Spontaneous remission, n(%) | 15 (36.6) |
Time to remission since diagnosis (days), mean ± DP | 358 ± 180 |
Proteinuria (g/g or g/24h)1, mean ± DP | 2.6 ± 3 (median = 2) |
Serum creatinine (mg/dL)1, mean ± DP | 2.2 ± 1.1 |
eGFR (mL/min/1.73m2)1, mean ± DP 1 | 38.2 ± 19.5 |
eGFR - LOCF (mL/min/1.73m2)1, mean ± DP | 34.2 ± 18.7 |
eGFR: estimated glomerular filtration rate; LOCF: last observation carried forward.
1 1 year after diagnosis.
Risk factors for posttransplant MN remission.
| | | |
---|---|---|---|
Recipient age (years old), mean ± DP | 46.8 ± 12.3 | 57.3 ± 13.2 | 0.027 |
Time after KT at diagnosis (months), mean ± DP | 54.6 ± 53.7 | 49.4 ± 46.4 | 0.782 |
Serum creatinine at diagnosis (mg/dL), mean ± DP | 1.6 ± 0.7 | 2.1 ± 2.3 | 0.351 |
Proteinuria at diagnosis (g/24h or g/g), mean ± DP | 2.9 ± 3.2 | 4.1 ± 3.5 | 0.337 |
Living donor, n(%) | 23 (74.2) | 3 (30) | 0.022 |
RAAS blockade, n(%) | 26 (83) | 9 (90) | 1.000 |
Change in maintenance IS after diagnosis, n(%) | 16 (51) | 4 (40) | 0.719 |
Treatment with high dose steroids, n(%) | 14 (45.2) | 3 (30) | 0.480 |
Treatment with Ponticelli scheme, n(%) | 1 (3.2) | 2 (20) | 0.142 |
KT: kidney transplant; RAAS:
One year after posttransplant MN diagnosis, proteinuria and serum creatinine were 2.6 ± 3 g/24h and 2.2 ± 1.1 mg/dL, respectively. Adjusting for losses and deaths, mean eGFR was 34.2 ± 18.7 mL/min (Table
As expected, one year after posttransplant MN diagnosis, patients who presented partial or complete remission showed lower serum creatinine (2.0 ± 1.0 versus 2.8 ± 1.3 mg/dL, p=0.049), higher eGFR (41.8 ± 18.9 versus 27.0 ± 12.9 mL/min, p=0.028), and lower proteinuria (1.5 ± 1.6 versus 6.1 ± 3.7 g, p<0.001). During the follow-up, there was a trend for a lower rate of deaths in patients who remitted (6.5 versus 30%, p=0.083), but the rate of graft loss was similar (35.5 versus 50%, p=0.472).
This study evaluated demography, clinical and histological presentation, treatment, and outcomes of a relatively large cohort of patients with posttransplant MN.
Unfortunately, a high proportion of patients did not have a confirmed diagnosis of chronic kidney disease (CKD) etiology (unknown and not defined chronic glomerulonephritis), which impairs the precise classification on recurrent and
More than a half of our cohort consisted of living donor transplants. This probably reflects the local practice in the early years of our transplant program, when living donor transplants were more common. The impact of the donor type on the risk of MN recurrence remains controversial [
Initial clinical and/or laboratorial presentation occurred late after KT and high proportion of patients presented nephrotic proteinuria, hypoalbuminemia, dyslipidemia, and graft dysfunction. Two patterns of MN recurrence were previously described [
Regarding specific treatment, we observed a wide variety of approaches and a lack of standardization. This was probably due to the lack of a gold standard treatment for this glomerulopathy in KT recipients, who are already on immunosuppressive therapy. More recently, good results were described with the anti-CD20 rituximab for posttransplant MN treatment and prophylaxis. However, evidence is based on small sample size noncontrolled studies. Ideal dose and safety are important aspects to be evaluated [
As expected and widely reported for MN on native kidneys and allografts, about one-third of patients presented spontaneous remission [
Although the sample did not allow robust conclusions, we observed that remission rates were more frequent in younger recipients receiving living donor kidneys. Higher remission rates in younger patients were previously reported by studies on native kidneys [
This study has some limitations that should be pointed out: (a) it is a single center, retrospective study, including patients transplanted in different decades; (b) it was not possible to estimate posttransplant MN incidence, since there was not a systematic recording or database for glomerular diseases in our center; (c) we did not assessed the antibodies against phospholipase A2 receptors (PLA2R) and thrombospondin type I domain-containing 7A (THSD7A), whose presence and intensity are related to recurrence; and (d) C4d was not routinely performed on graft biopsies. As strengths, this is a relatively large sample size, considering the low prevalence of the disease. Besides, the detailed description of diagnosis and treatment adds important information about the clinical management of such patients.
In summary late onset proteinuria, hypoalbuminemia, hypercholesterolemia, and graft dysfunction were the main clinical manifestations of posttransplant MN. RAAS blockade was common and there was not a standard treatment. The course was benign, with high proportion of remission rates and no impact on survival.
The data of this article has been presented as a poster at 54th ERA-EDTA Congress and it was published as abstract in
The authors declare that they have no conflicts of interest.
The authors are especially grateful to Professor Marcello Fabiano de Franco (