The Remission of Post-Transplant Nephrotic Syndrome Clinicopathologic Characterization

Authors


Abstract

Among 67 renal transplant recipients with nephrotic syndrome (NS), nine episodes were reversible in eight patients. Biopsies showed minimal-change disease (4), focal segmental membranous glomerulonephritis and acute glomerulitis (1), IgA nephropathy and acute glomerulitis (1) or thrombotic microangiopathy (1), and chronic transplant nephropathy with (1) or without acute glomerulitis (1). NS developed 1–4 months post transplant in the four patients with minimal-change disease, but later (33–151 months) in the others. At onset, serum creatinine was normal or elevated. Treatment included calcium-channel blockers, angiotensin-converting enzyme inhibitors, or both, together with routine antirejection therapy. Remission was achieved 4–12 months after onset, when renal function remained normal in four, improved in four, and worsened in one. At last follow-up, six patients still had remission and functional grafts. One lost graft to chronic transplant nephropathy while NS remained in remission. In the remaining patient, proteinuria, which was due to chronic transplant glomerulopathy unrelated to the initial minimal-change disease-associated NS, recurred 50 months post transplant. Remission of post-transplant NS is possible. It is often associated with minimal-change diseases and less frequently with other glomerular lesions, including acute glomerulitis. Reversible post-transplant NS does not have an adverse effect on the renal allografts.

Introduction

Nephrotic syndrome (NS) frequently develops in renal transplant recipients, and may be persistent or reversible (1–8). Persistent post-transplant NS, reported in up to 13% of renal transplant recipients, is associated with several well-known renal lesions, including de novo glomerulonephritis (GN), recurrent GN, chronic allograft glomerulopathy, chronic rejection, chronic cyclosporine A (CsA) nephrotoxicity, or de novo focal segmental glomerulosclerosis (FSGS) (1–8). Persistent post-transplant NS usually portends a poor prognosis, with 1- and 5-year graft survival rates of 75.3 and 37.5%, respectively (3,4), compared with 87.5 and 52.5% for those without NS (7).

Remission has been observed in up to 11% of post-transplant NS (7). Although reversible post-transplant NS is not rare, a comprehensive evaluation of the pathologic and clinical features of reversible post-transplant NS and its impact on the graft is not available. This is the focus of the current study.

Materials and Methods

Materials

Records of the 477 renal transplant recipients at the Methodist Hospital/Baylor College of Medicine, Houston, Texas during a 12-year period between 1988 and 2000 were reviewed to identify those with post-transplant NS. It is well known that mild, but rarely nephrotic, proteinuria often develops immediately after transplantation, but decreases rapidly and usually disappears within a month. Proteinuria in this context is probably related to preservation injury, ischemia, or acute rejection (9–12). Because of these considerations, only cases in which NS developed beyond 1 month post-transplant were included in this study. Remission of NS is defined as daily excretion of protein of less than 500 mg/day that persists during at least two consecutive assays performed at least 2 weeks apart. Sixty-seven out of 477 renal transplant recipients developed NS. Among them, nine episodes of complete and sustained remission of NS were noted in eight patients. Each of these patients underwent a renal allograft biopsy.

Methods

Protein excretion was measured in 24-h urine collections by a colorimetric method (13). During follow-up, protein excretion was monitored by the protein/creatinine ratio in spot morning urine specimens. The validity of this method has been reviewed previously (14–16). The renal transplant biopsies were subjected to light microscopy (LM) using hematoxylin & eosin, periodic acid-Schiff, and Masson's trichrome stains, immunofluorescent (IF) studies for IgG, IgM, IgA, C3, C4, lambda and kappa light chains, and electron microscopy (EM). Some biopsies were subjected to immunostaining with monoclonal antibodies against common leukocyte antigen, T lymphocytes (CD3), B lymphocytes (CD 20), or macrophages (CD 68) for phenotyping of the inflammatory cell infiltrate. The Banff schema for renal transplant biopsy was used for diagnostic categorization (17).

In order to assess the features which may account for the remission of post-transplant NS, the clinical and renal biopsy findings of the eight patients with reversible NS were compared with those of the 59 patients in whom the NS persisted. The t-test (Microsoft Excel, Microsoft, Redmont, WA, USA) was used for statistical analysis and a p-value of less than 0.05 was considered significant.

Results

Since several features of reversible post-transplant NS are best understood in structural terms, the renal biopsy findings will be reported first, followed by the clinical findings and clinicopathologic correlation.

Renal biopsy findings

Nine episodes of reversible post-transplant NS, two of which developed 55 months apart in the same patient, were noted in eight patients. Renal transplant biopsy was performed during each of these nine episodes and the main diagnoses are listed in Table 1.

Table 1. : Reversible post-transplant nephrotic syndrome renal transplant biopsy findings
Minimal-change disease4
Focal segmental membranous GN and acute glomerulitis1
IgA nephropathy and acute glomerulitis1
IgA nephropathy and thrombotic microangiopathy1
Chronic transplant nephropathy and acute glomerulitis1
Chronic transplant nephropathy1

Minimal-change disease , noted in four biopsies, was characterized by glomeruli, which were either normal or displayed minor changes including focal segmental mild mesangial sclerosis and/or hypercellularity. IF was negative or showed focal segmental weak mesangial staining for C3 and/or IgM. EM revealed global or segmental effacement of the foot processes, but electron-dense deposits were not seen. The interstitium was normal or showed features consistent with mild acute or chronic rejection, or tubulotoxic type of acute CsA nephrotoxicity.

Focal segmental membranous GN  (Figure 1), noted in one biopsy, was characterized by small subepithelial electron-dense deposits involving some, but not all glomerular capillaries (Figure 1B). There was also mild acute glomerulitis, characterized by accumulation of predominant lymphocytes in the lumen of about 10% of glomerular capillaries (Figure 1A). There was also focal tubular atrophy and mild nonspecific chronic interstitial mononuclear inflammatory cell infiltrates not diagnostic for acute or chronic rejection.

Figure 1.

Focal segmental membranous glomerulonephritis. (A) This glomerulus displays mild thickening of the glomerular capillaries. There are also mononuclear inflammatory cells within the capillary lumens, consistent with acute glomerulitis (Periodic acid-Schiff stain, × 920). (B) Small subepithelial electron dense deposits are present (electron microscopy, × 12 000).

IgA nephropathy , noted in two biopsies performed to evaluate two episodes of NS separated by 55 months in a single patient, was characterized by focal segmental mesangial hypercellularity with or without endocapillary cell proliferation, global diffuse mesangial IgA staining, and mesangial electron dense deposits (Figure 2A,B). Mild acute glomerulitis was noted in the first biopsy (Figure 2C) and thrombotic microangiopathy, probably related to CsA, characterized by fibrin thrombi in some glomerular capillaries and arterioles was noted in the second biopsy (Figure 3A,B). There was also mild, focal tubular atrophy and chronic interstitial mononuclear inflammatory cell infiltrates in both biopsies.

Figure 2.

IgA nephropathy. (A) This glomerulus displays mesangial hypercellularity and segmental endocapillary cell proliferation associated with a small crescent (Masson's trichrome stain, × 920). (B) Mesangial electron dense deposits are present (electron microscopy, × 12 000). (C) Lymphoid cells are noted in some glomerular capillaries consistent with acute glomerulitis (immunostain for common leukocyte antigen, × 920).

Figure 3.

Thrombotic microangiopathy. Thrombi are noted in both glomerular capillaries (A, arrow) and arterioles (B, arrow) (Periodic acid-Schiff and Masson's trichrome stains for panel A and B, respectively, × 920 for both).

Chronic transplant nephropathy , noted in two biopsies, was characterized by interstitial fibrosis, mild interstitial inflammation, tubular atrophy, and vascular intimal fibrous thickening. The glomeruli showed nonspecific changes including global sclerosis in up to 35% of those in the biopsies, and focal segmental ischemic injury (Figure 4A,B). In addition, mild acute glomerulitis (Figure 4C) was noted in one biopsy.

Figure 4.

Chronic transplant nephropathy. (A) A glomerulus display mild mesangial sclerosis. Patchy tubular atrophy, interstitial fibrosis and inflammation, and glomerulosclerosis are noted (hematoxylin & eosin, × 920). (B) Electron microscopy shows mesangial sclerosis, but the glomerular basement membrane is normal (×1200). (C) Lymphoid cells are noted in some glomerular capillaries consistent with acute glomerulitis (immunostain for common leukocyte antigen, × 920).

Clinical findings and clinicopathologic correlation ( Table 2 )

Table 2. : Reversible post-transplant nephrotic syndrome. Clinicopathologic features of the eight current cases
    Post-Tx NS. Remission of NSFollow-up
CaseAge
(years)/
Sex
Primary
renal
disease
DonorOnset
(mths
post-tx)
Pro
(g/d)
at Bx
S Cr
(mg/dL)
Boipsy diagnosesRX (for NS)Months
after
onset
Pro
(d/d)
S Cr
(mg/dL)
Months
post-Tx
Pro
(g/d)
S Cr
(mg/dL)
  • *

    There was no proteinuria between 8 and 32 months after transplantation. Proteinuria subsequently developed and reached 1.9 g/day at 50 months.

  • **

    This patient had two isolated episodes of reversible NS.

  • ***

    At 43 months after transplantation, this patient died of acute pancreatitis.

  • ACE = Angiotensin converting enzyme, Ca = Calcium, Cad = Cadaveric, CsA = Cyclosporin A, FSGS = Focal segmental glomerulosclerosis, GN = Glomerulonephritis, LR = Living related, NS = Nephrotic syndrome, Tx = Transplant.

125/MMalignant
hypertension
LR43.25.1Minimal-change disease
Mild acute and chronic
rejection
Increased
steroids
Ca channel blockers
402.3501.9*2.1
237/FDiabetesCad2283.1Minimal-change disease
CsA acute nephrotoxicity
Ca channel blockers80.31.7720.72.6
356/MObstructive
uropathy
Hypertension
Cad261.2Minimal-change disease
Mild acute rejection
Increased steroids
Ca channel blockers
701.3920.21.9
425/FLupus nephritisCad170.7Minimal-change diseaseIncreased steroids
Angiotensin receptor
blockers
110.30.9250.251
536/FChronic GNCad334.31.6Focal segmental
embranous GN
Acute glomerulitis
ACE inhibitors80.2243***0.21.6
6a**36/FIgA GNLR964.41.5IgA nephropathy
Acute glomerulitis
ACE inhibitors
Ca channel blockers
80.51.2See below
6b**   1518.92.3IgA nephropathy
CsA-induced thrombotic
microangiopat hy
ACE inhibitors
Ca channel blockers
110.31.51920.251.4
738/MIgA GNCad786.93.9Chronic Tx nephropathy
Caute glomerulitis
ACE inhibitors60.052.91400.48.5
855/MFSGSLR846.31.9Chronic Tx nephropathy
ACE inhibitors
Ca channel blockers120.52.61320.53.3

The patients included four men and four women, aged 25–56 years, who received five cadaveric and three living-related renal transplants, for end-stage renal disease (ESRD) of etiology not different from that of the general population of ESRD patients.

NS developed 1–4 months post transplant in the four patients with minimal-change disease, or later (33–151 months) in the others. Two episodes of reversible NS separated by 55 months, were noted in the same patient (cases 6a and b). The protein excretion ranged between 3.2 and 8.9 g/day. The serum creatinine at the time of NS was 0.7–1.6 mg/dl in four cases (cases 3, 4, 5, and 6a) and was correlated with normal or mild tubulointerstitial and/or vascular injury. The serum creatinine was 2.3–5.1 mg/dl in the other five cases. In three of these five cases, the decreased renal function was probably related to acute changes including acute rejection (case 1), acute CsA toxicity (case 2), or CsA-induced thrombotic microangiopathy (case 6b); these changes were unrelated to NS since treatment directed against them promptly restored the renal function to the baseline, whereas NS persisted. In the remaining two cases (cases 7 and 8), the decreased renal function reflected at least in part the chronic, potentially irreversible tubulointerstitial and vascular injury characteristic for chronic transplant nephropathy, which might account for a lack of improvement of renal function even when NS underwent remission.

Treatment included calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers. In addition, patients were also treated for associated conditions, including acute rejection, CsA acute nephrotoxicity, and CsA-related thrombotic microangiopathy. Remission of NS (protein excretion 0–0.5 g/day) was achieved 4–12 months after the onset, at which time the serum creatinine was stable for the four cases with initial normal or near normal serum creatinine. For the other five cases with initial increased serum creatinine, the renal function was improved in four and worsened in one.

At follow-up (25–192 months post transplant), NS remained in remission (protein excretion 0.25–0.7 g/day) and the grafts remained functional (serum creatinine 1–3.3 mg/dl) in six patients (cases 2, 3, 4, 5, 6, and 8), but one of them (case 5) died of acute pancreatitis 43 months after transplantation. One patient lost the graft due to chronic transplant nephropathy at a time when NS remained in remission. In the remaining patient, NS was in complete remission until proteinuria (1.9 g/day) recurred 50 months post-transplant, but it was due to biopsy-documented chronic transplant glomerulopathy unrelated to the initial episode of reversible NS caused by minimal-change disease.

Comparison of patients with reversible and persistent post-transplant NS (Table 3)

Table 3. : Comparison of reversible and persistent post-transplant nephrotic syndrome (NS)
 Reversible post-transplant NS
(8 cases)
Persistent post-transplant NS
(59 cases)
  1. ACE = Angiotensin converting enzyme; AG = Acute glomerulitis; Alport = Alport syndrome; CTN = Chronic transplant nephropathy; DM = Diabetic nephropathy; FSGS = Focal segmental glomerulosclerosis; GN = Glomerulonephritis; HBP = Hypertension; IgA = IgA nephropathy; MGN = Membranous GN; MPGN = Menbranoproliferative GN; NS = Nephrotic syndrome; PKD = Polycystic kidney disease; TMA = Thrombotic microangiopathy; *= One patient died at 43 months post-transplant of acute pancreatitis; **= Four patients were lost to follow-up.

Age (years)38.5 ± 4.1 (25–56)42.4 ± 1.8 (22–72)
Sex (M/F)4/435/24
Primary renal diseasesIgA (2), HBP (1), DM (1), urinary obstruction
BR (1), lupus GN (1), chronic GN (1),
FSGS (1)
Unknown (14), HBP (10), lupus GN (8), DM (5), IgA (5), crescentic GN (4), chronic GN (3), FSGS (3), NPGN (2), PKD (2), MGN (1), Alport (1)
Cadaveric/living-related donors5/338/17
Onset of NS (months post-transplant)50.1 ± 18.1 (1–151)47.3 ± 8.7 (1–291)
Protein excretion at onset of NS (g/day)6.1 ± 0.6 (3.2–8.9)4.6 ± 0.3 (3–16)
Serum Cr at onset of NS (mg/dL)2.3 ± 0.5 (0.7–5.1)3.1 ± 0.3 (0.9–9.6)
Hypertension8/8 (100%)56/59 (95%)
Hepatitis B2/6 (33%)8/42 (19%)
Hepatitis C1/5 (20%)7/36 (19%)
CMV2/5 (40%)27/52 (52%)
EBV5/7 (71%)22/35 (63%)
HIV0/7 (0%)0/39 (0%)
Causes of NSMinimal-change disease (4), MGN and AG
(1), IgA and AG (1), IgA and TMA (1), CTN
and AG (1), CTN (1)
CTN (35), recurrent GN (11), de novo GN (4), GN with primary renal diseases unknown (9)
Treatment for NSCalcium channel blocker (3), ACE inhibitors
or angiotensin receptor blockers (3), both (2)
Calcium channel blocker (22), ACE inhibitors or angiotensin receptor blockers (15), both (22)
Follow-up (months)93.2 ± 20.2 (25–192)66.1 ± 9.8 (2–342)
Protein excretion at follow-up (g/day)0.0 ± 0.3 (0–0.5)4.8 ± 0.4 (1.5–16)
Serum Cr at follow-up (mg/dL)1.8 ± 0.2 (0.9–2.9)5.6 ± 0.5 (1.1–19.9)
Graft loss1/8 (12%) *39/59 (66%) **

The age, sex, spectrum of primary renal diseases, ratio of cadaveric/living-related kidney donors, onset of NS, the frequency of hypertension, hepatitis B, hepatitis C, or cytomegalovirus infection, and treatment for proteinuria were not significantly different between the two groups. Cancer or morbid obesity was not seen in any patients of either group. At the onset of NS, the patients with reversible NS, on average, had higher daily protein excretion and lower serum creatinine than those with persistent NS (p < 0.005). The spectrum of renal lesions associated with the NS was different for the two groups (Table 3). At last follow-up, there was no or minimal proteinuria in patients with reversible NS but a mean protein excretion of 4.8 ± 0.4 g/day was noted in those with persistent NS. Graft was lost in 12% and 66% of patients with reversible and persistent NS, respectively.

Discussion

Proteinuria, which is almost always mild (less than 1 g/day), but can rarely reach nephrotic range, often develops immediately (within a week) after transplantation but subsides in most cases within a month (9–12). Remission of post-transplant NS, even when it develops beyond the immediate post-transplant period, is, however, possible. It has been reported in NS associated with isolated cases of de novo minimal-change diseases (18–24), acute glomerulitis (25,26), acute rejection (7,26), chronic rejection (7), de novo or recurrent membranous GN (27–29), and foscarnet-induced GN (30). Several large series of recurrent FSGS, a frequent cause of post-transplant NS, reported a remission rate as high as 50% (31–33).

The current study, which included only cases of NS occurring at least a month after transplantation, suggests that remission of post-transplant NS is not uncommon since it was noted in 8 out of 67 patients (11.9%), a frequency comparable to that reported by Vathsala et al. (11.3%) (7). Fontaine et al. noted that complete remission was achieved in 15% of cases with proteinuria of more than 2 g/day and with an onset beyond 3 months after transplantation (3).

The current study shows that chronic transplant glomerulopathy and recurrent or de novo GN account for almost all cases of persistent NS (Table 3), as previously reported (1,2,6), whereas a different spectrum of renal lesions was found in those with reversible NS (Table 2). Within the latter group, the most frequent lesion is de novo minimal-change disease, which was encountered in four out of nine transplant biopsies (44%). There are at least 14 other cases of de novo minimal-change disease previously reported (18–24,34), in most of which NS underwent complete remission (18–24). In cases where NS persisted (34), although the open glomeruli were normal, there was also prominent global glomerulosclerosis and chronic tubulointerstitial injury, which cast doubt on the diagnosis of minimal-change disease. Although there are no significant glomerular changes in de novo minimal-change disease (18–24), the tubulointerstitial and vascular compartments may be normal and reflect a normal renal function at the time of NS or display changes such as acute rejection, acute tubular necrosis, or acute CsA nephrotoxicity, which may account for a decreased renal function (18,24, current series). These changes, however, are probably incidental since treatment directed against them restores renal function at a time when NS persists (18,24, current series). One interesting feature of the NS associated with de novo minimal-change disease is its early onset, which falls within 4 months after transplantation for all reported cases including the current ones, except for one in which NS developed at 24 months post transplant (18); this early onset contrasts with the later onset of post-transplant NS of other causes (1–8). The pathogenesis of de novo minimal-change disease and the explanation for the frequent remission of the NS associated with it are not known. Minimal-change disease in native kidney may be related to undetermined circulating factors, probably lymphokines, that promote transglomerular capillary permeability (35). Whether the same pathogenesis is seen in the transplant setting remains unanswered. Disturbed immunoregulation in renal allograft recipients may lead to selective activation of selected population of lymphoid cells capable of synthesizing the lymphokine(s) responsible for nephrotic syndrome (36). The dynamics of lymphoid cell activation, in which activated lymphoid cells may revert to resting stage upon removal of stimulants, may also explain the frequent remission of NS associated with de novo minimal-change disease.

This study also identified other less frequent renal lesions associated with reversible post-transplant NS, including de novo membranous GN, recurrent IgA nephropathy, and chronic transplant nephropathy (Table 1). Membranous GN is the most frequent type of de novo GN in renal transplants, and NS develops in about 60% of these cases (28,37,38). Remission of proteinuria is reported in up to 33% of cases (37), but remission of NS is rare (28,37,39). IgA nephropathy recurs in 14–42% (40,41) of transplanted kidneys. Although NS develops in up to 36% of these patients (40,41), its remission has not been described. Chronic transplant nephropathy is the most frequent cause of renal allograft loss. It accounts for up to 27% of cases of post-transplant heavy proteinuria/NS (2), but remission of NS in this condition is only mentioned briefly in a single report (7). Since remission of NS is only rarely encountered in renal transplant patients with membranous GN, recurrent IgA nephropathy, or chronic transplant nephropathy, the current cases with these diagnoses were carefully reviewed to see whether there are any morphologic or clinical features that help predict the remission of NS in them. Acute glomerulitis involving less than 10% of glomerular capillaries (mild degree by the Banff classification) is noted in conjunction with one case each of recurrent IgA nephropathy, de novo membranous GN, and chronic transplant nephropathy. Acute glomerulitis, defined as accumulation of mononuclear inflammatory cells within the glomerular capillaries, is regarded as a form of acute rejection directed at the glomerulus (42–44) and may respond to antirejection therapy (45). Proteinuria was noted in up to 66% of cases of isolated acute glomerulitis (42), and NS has been described in some of these cases (25,42,43,46). Whether the proteinuria or NS associated with isolated acute glomerulitis is reversible is not known, but it is possible since acute glomerulitis itself is potentially reversible (42,45). Although the acute glomerulitis is mild in the current cases, its occurrence against a background of other glomerular lesions may both facilitate the development of NS and play a role in its subsequent reversibility.

Although the findings from this study suggest that the renal transplant biopsy findings are the major determinant of the remission of post-transplant NS, the relevance of the clinical findings to this favorable outcome was also evaluated. We found that there were no significant differences in the age, sex, spectrum of primary renal diseases, ratio of cadaveric vs. living-related kidney donors, onset of NS, or the frequency of hypertension, hepatitis B, hepatitis C, or cytomegalovirus infection between patients with reversible and persistent post-transplant NS (Table 3). Severe hypertensive nephrosclerosis, morbid obesity, or glomerular lesions associated with viral hepatitis, CMV, or cancer have occasionally been implicated as the causes of NS in general, but their roles in the development of post-transplant NS have not been established (1,4,7). Data from our study confirm this observation and further suggest that these conditions may not predicate the remission of post-transplant NS.

The treatment for heavy proteinuria/NS in renal transplant recipients traditionally includes calcium channel blockers, ACE inhibitors, and/or angiotensin receptor blockers (47–49). Whether these treatments were responsible for the remission of NS in the reported patients is not clear, since those in whom post-transplant NS persisted were treated in the same way (Table 3). Minimal-change disease or acute glomerulitis was implicated in the development of NS in most of patients with reversible post-transplant NS in this study. Since both of these conditions are thought to be related to abnormal T-cell functions (34,42), antirejection therapy, which includes steroids, may play a role in the remission of NS in these patients.

Although persistent post-transplant NS is associated with poor graft survival, the impact of reversible NS on the graft outcome is not known. The current study suggests that once remission of NS is achieved, it is sustained in most cases. Although NS may rarely recur after an initial remission, subsequent sustained remission may still be possible. This sequence was noted in a single case with recurrent IgA nephropathy in the present study and a case of minimal-change disease previously reported (23). Reversible post-transplant NS does not seem to have any adverse impact on renal allografts, since the grafts in seven out of eight patients (87%) in this study remained functional 25–192 months after transplantation, a graft survival rate comparable to that in recipients without post-transplant NS (3,4). This good outcome was also noted in previously reported isolated cases of reversible post-transplant NS (18–24).

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