Recurrence of steroid-resistant nephrotic syndrome in kidney transplants is associated with increased acute renal failure and acute rejection

Kidney International, Vol. 45 (1994), pp. 1440—1445

Recurrence of steroid-resistant nephrotic syndrome in kidney transplants is associated with increased acute renal failure and acute rejection EuN-MI KIM, JANE STRIEGEL, YOUNGKI KIM, ARTHUR J. MATAS, JOHN S. NAJARIAN, and S. MICHAEL MAUER Department of Pediatrics, SoonChunHyang University, Seoul, Korea, and The Departments of Pediatrics and Surgery, The University of Minnesota Medical School, Minneapolis, Minnesota, USA

Recurrence of steroid-resistant nephrotic syndrome in kidney trans. plants is associated with increased acute renal failure and acute rejection. We performed 73 kidney transplants in 51 patients with steroid-resistant nephrotic syndrome (SRNS) with focal segmental glomerular sclerosis (FSG) ages 18.4 12.8 (X SD) years. Recurrence of SRNS, defined by rapid onset of proteinuria, hypoalbuminemia and/or >95% epithelial

the development of recurrence of nephrotic syndrome in the renal allograft [1—ill. We had previously reported that patients

occurred in 26 grafts in 16 patients. Acute renal failure (ARF) occurred in 16 of 26 (61.5%) grafts with recurrence versus 7 of 47 (14.9%) grafts

allograft [8, 9]. We had also shown that these two variables, rapid progression to terminal ure ia and mesangial prolifera-

cell foot process effacement with or without the presence of FSG,

without recurrence (P < 0.0001). ARF occurred in 4 of 9 (44.4%) living-related donor (LRD) recipients with recurrence and 3 of 21 (12.5%) LRD recipients without recurrence (NS). ARF in cadaver donor (CAD) recipients with recurrence was 12 of 17 (70.5%) versus 4 of 23 (17.4%) without recurrence (P < 0.0001). ARF was also higher in

LRD or CAD with recurrence than in a control group of non-SRNS

whose primary renal disease took less than three years to proceed from onset to terminal uremia and patients whose native kidneys had diffuse or focal mesangial cell proliferation were at increased risk of recurrence of proteinuria in the renal tion, were frequently covariables [9]. In addition, we and others have reported increased graft loss in patients with SRNS/FSG and recurrent proteinuria in the renal allograft [3, 7—10]. How-

ever, the cause of this increased in graft loss has not been

completely explained. It is known that patients with nephrotic syndrome can be at higher risk for acute renal failure (ARF) [12—18] most often, as reviewed by Smith and Hayslett, accompanied by acute tubular necrosis (ATN) [18]. Further, it has rejection episodes occurred in all 16 patients with ARF and recurrence, been suspected that ATN may be associated with an increased in all 7 patients with ARF without recurrence, and in 7 of 10 patients risk of acute rejection in renal allograft recipients [19—211. We with recurrence without ARF compared with only 11 of 40 (28%) of had previously reported, based on a chart review study, that patients with neither recurrence nor ARF (P < 0.0001, <0.001 and about one-half of the graft loss in patients with recurrence was <0.04, respectively). A loglinear model showed associations between acute rejection and ARF (P < 0.01), recurrence and ARF (P = 0.05), due to rejection and one-half was due to recurrence per se [22]. and recurrence and acute rejection (P < 0.025). Twelve of 16 (75%) of However, in a study initiated to explore our clinical suspicion suggesting a high frequency of ARF in patients with recurrent grafts with both recurrence and ARF versus 4 of 40(10%) of grafts with neither recurrence nor ARF were lost in association with acute rejec- SRNS, we encountered an inordinate incidence of acute rejection in the first two post-transplant years (P < 0.0001). Only one graft tion. This resulted in a complete re-analysis of our SRNS/FSG was lost from recurrence of SRNS, per se. Thus, recurrence of SRNS patient material, including a review of all relevant renal allograft is associated with an increased incidence of ARF, and both ARF and recurrence are associated with greater risks of acute rejection. The pathology specimens. We report that patients with recurrence patients matched for age, sex and time of transplantation. Graft survival

at one year was lower in patients with recurrence and ARF [4 of 16 (25%)] compared to patients with recurrence and no ARF [9 of 11 (82%), P < 0.011. There was no difference in graft survival in patients without recurrence who did or did not have ARF. One or more acute

increased graft loss in recurrence is primarily due to acute rejection. As has been speculated for ARF, recurrence may result in graft changes which stimulate acute rejection.

of SRNS have a markedly increased rate of ARF and renal allograft loss from rejection compared to patients without

Patients transplanted for end-stage renal failure developing consequent to steroid resistant nephrotic syndrome (SRNS) with focal segmental glomerulosclerosis (FSG) are at risk for

Methods

Received for publication May 1, 1992 and in revised form December 29, 1993 Accepted for publication December 30, 1993

© 1994 by the International Society of Nephrology

recurrence and that these two transplant complications may be separate risk factors.

Patients Since 1965 we have performed 73 renal allograft transplants in 51 patients (25 female) with SRNS/FSG. Their ages at the time of initial transplantation was 18.4 12.8 years (X SD). Thirty-three of these allografts were from living-related donors (LRD) and 40 from cadaver donors (CAD). All of the patients previously described in our papers detailing risk factors for

1440

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Kim et a!: ARF and rejection in recurrent nephroses

Table 1. Criteria for recurrence of steroid-resistant nephrotic syndrome in 26 grafts Proteinuria an d FSG + FPE Proteinuria + FSG Proteinuria + FPE Proteinuria FPE

9 7

4 5 1

acute renal allograft rejection resulting in sufficient loss of renal function or perpetuation of primary nonfunction so as to require chronic dialysis and/or retranspiantation. Graft loss from recurrent FSG. To qualify for this category,

graft failure with advanced renal insufficiency would have occurred in association with marked glomerular abnormalities

of FSG and global glomerular sclerosis in the absence of

Abbreviations are: FSG, focal segmental glomerular sclerosis; FPE, foot process effacement.

pathologic findings of acute and chronic rejection. This criterion strictly confines graft loss from recurrent FSG to situations in which glomerular destruction from recurrent disease is clearly the dominant reason for graft failure. The adoption of this strict

recurrence of SRNS are represented here [8, 9, 22]. An additional 10 patients and 4 previously reported patients receiving new grafts are also reported here. We computer selected 67 grafts performed in 65 patients as controls (C). Selection criteria included age 4 years, sex, LRD versus CAD and primary versus subsequent grafts. Three grafts in two control patients were eliminated from further consideration because of their immediate loss from vascular accidents. The number of mismatches for HLA-A and -B in the 1.0 X SD, N = 67) and in the SRNS/FSG patients (1.8 controls (1.7 1.0, N = 60) did not differ. Similarly, HLA AB + DR mismatches in the SRNS/FSG patients (2.8 1.6, N = 1.6, N 40) were nearly identical. 46) and controls (2.6 Maximal panel reactivity exceeding 50% prior to transplantation of a given graft was present in 25% of SRNS patients and 26% of the controls. Reactivity exceeding 50% at the time of transplantation was 13% in SRNS patients and 14% in the controls. Further, by chi-square analysis, there were no significant differences in the likelihood of ATN in SRNS patients or in controls with maximal or at transplant panel reactivity of more than or less than 50%. Recurrence of SRNS (see below) was not associated with increased panel reactivity or HLA mismatches. Data describing donor age and preservation time (cold ischemic time) were recorded for cadaver grafts and analyzed as risk factors for ARF.

definition resulted in reclassification of some patients we had previously reported as having had graft loss due to recurrent disease [9, 22] to the categories of graft loss due to rejection. The hospital records and renal pathologic materials from all patients transplanted at the University of Minnesota with a diagnosis of SRNS/FSG were reviewed. The clinical course of each graft was characterized according to the criteria listed above. In addition, other causes of graft dysfunction and graft loss were noted. Statistical analysis

Statistical analysis included chi-square, Student's t-test, Fisher exact test, loglinear model associations and analysis of variance (ANOVA). Values for P 0.05 were taken to be statistically significant. Results

Incidence and criteria for recurrence of SRNS

Twenty-six grafts in 16 patients were classified as having recurrence of SRNS (Table 1). In 25 grafts the diagnosis was based upon the documentation of heavy proteinuria in the first three months post-transplantation. However, in 20 of these 25 grafts there was pathologic confirmation of this diagnosis, 7 having FSG, 9 having both FSG and extensive foot process Definitions fusion and 4 having foot process fusion alone. Thus, in all 11 Recurrent disease. Criteria for the classification of a renal grafts classified as recurrence of SRNS by the presence of early allograft as suffering recurrence (R) of SRNS included one or heavy proteinuria and where electron microscopic material was more of: (1) clinical recurrence with the post-transplant devel- available, the diagnosis was confirmed by the presence of opment of hypoalbuminemia (serum albumin <2.5 g/dl) and/or marked epithelial cell changes. Only in one case of primary proteinuria, 1 g/m2/24 hr, within 3 months of transplantation graft nonfunction was the diagnosis based on histologic criteria in the absence of clinical or histological evidence of acute alone, that of extensive foot process fusion (Table 1). FSG was rejection. All patients classified as recurrent disease based on first detected on biopsies performed between 15 days and 2 proteinuria had at least 5 g/24 hr of urinary protein; (2) histo- years post-transplantation and extensive foot process fusion logic recurrence with 95 to 100% foot process obliteration by was noted on biopsies performed within 7 days to 2 months electron microscopy [8, 9]; no patients were classified as having post-transplantation. histologic recurrence with FSG by light microscopy in the Sixteen of the 26 (61.5%) grafts in SRNS patients had ARF. absence of proteinuria as defined above (Table 1). In 37 patients with 47 grafts that did not have recurrent SRNS, Acute renal failure. ARF is defined as post-transplant renal the incidence of ARF was 14.9% (P = 0.0001, chi-square). failure with oliguria ( 1 cc/kg/hr) and uremia requiring dialysis While the incidence of ARF in cadaver kidneys with recurrence support during the first post-transplant week. Patients were was significantly greater than in cadaver kidneys with no judged not to have ARF if renal insufficiency was determined to recurrence (P = 0.002, Fisher exact test), this comparison did result from hyperacute, accelerated or acute rejection, or not reach statistical significance for the LRD recipients (Table 2). LRD with recurrence and CAD with recurrence both had vascular or urologic complications. Acute rejection. The diagnosis of acute rejection was applied higher incidences of ARF than their appropriate non-SRNS only to patients meeting renal biopsy criteria which we have controls (chi-square P <0.01 and <0.05, respectively, Table 2). previously described in detail [23]. Graft loss due to acute There were no significant differences in ARF comparing SRNS rejection was defined as one or more biopsy-proven episodes of patients without recurrence and their controls (Table 2).

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Kim et a!: ARF and rejection in recurrent nephroses

Table 2. Incidence of ARF in grafts transplanted for SRNS/FSG and controls

Recurrence of SRNS (N = 26)

ARF No ARF

No recurrence of SRNS (N = 47)

ARF No ARF

Controls (N = 64) ARF No ARF

4 (44.4) 5 (65.6) 3 (12.5) 21(87.5) 1(3.4) 28 (96.6) CAD 12 (70.5) 5 (29.5) 4 (17.4) 19 (82.6) 12 (34.3) 23 (65.7) Total 7 16 10 40 13 51 LRD

(61.5)

(38.5)

(14,9)

(85.1)

(20.3)

(79.7)

Abbreviations are: ARF, acute renal failure; SRNSIFSG, steroidresistant nephrotic syndrome with focal segmental glomerular sclerosis;

LRD, living related donor; CAD, cadaver donor. Numbers in parenthesis = %.

There was a trend toward group effects of preservation time

on the risk of ARF (P =

0.074, ANOVA). Control group cadaver recipients with ARF had longer preservation times (38 8 hr; N = 12) than those without ARF (25 12; N = 22; P <

0.005). There were no other significant group differences.

losses in patients with recurrence and ARF (Table 4). In contrast, only one patient with recurrence without ARF required early graft removal for massive nephrotic syndrome and early renal dysfunction (Table 4). Only one patient with recurrence of SRNS actually lost graft function primarily because of

destruction of the graft from the redevelopment of lesions of FSG and global glomerular sclerosis without evidence of acute or chronic rejection. The dominant causes of graft loss in patients without recurrence included acute and chronic rejection, death with a functioning graft, and noncompliance (Table 4). As expected, most of the grafts that were lost in controls were destroyed by acute or chronic rejection (Table 4). All 16 patients with recurrence and ARF had one or more acute rejection episodes in the first post-transplant year (Table 5). Also, the incidence of acute rejection was increased in patients with recurrence but no ARF and in patients with ARF without recurrence compared to the incidence in grafts with neither of these complications (Table 5). A log linear model revealed significant associations between recurrence and ARF (P = 0.05), recurrence and rejection (P < 0.025), and rejection and ARF (P < 0.01; Table 5). Thus, the incidence of acute rejection was higher in those grafts with recurrence or ARF or both compared to grafts with neither of these complications

Donor age did not influence ARF risk (ANOVA P = 0.88). Renal biopsies were performed during the ARF episodes in 9 renal allografts of SRNS patients between 4 and 30 (median 15) days post-kidney transplantation. Since, in most cases these (Table 5). Acute rejection in the first year was also more biopsies were performed when ARF persisted beyond 10 to 14 common in controls with ARF than in SRNS grafts with neither days and since ARF was usually short lived, most patients did ARF nor recurrence. However, although numerically greater, not have biopsies during their ARF episodes. All showed the incidence of acute rejection in control grafts with ARF was changes consistent with acute tubular necrosis (ATN). In one not significantly different from that in control grafts without case immediate post-transplant massive proteinuria was fol- ARF (Table 5). lowed, within 36 hours, by ARF. FSG lesions were noted at 15 Discussion days post-transplant (see above) and mild acute tubulointerstiOur studies demonstrate a marked increase in the incidence tial rejection was also noted. One graft showed ATN and moderate acute tubulointerstitial rejection at 21 days post- of ARF in patients documented to have recurrence of SRNS by transplant. This was treated successfully. However, with re- either clinical or histological criteria or both. This increased covery of graft function, there was increasing proteinuria and, incidence among SRNS patients was mainly seen in recipients five weeks later, FSG lesions and diffuse foot process fusion of cadaver kidneys with recurrent SRNS while a similar trend amongst LRD recipients did not reach statistical significance. was noted on a repeat allograft biopsy. Graft survival rates at one year and at final follow-up were However, compared to non-SRNS controls, the increase in markedly reduced in grafts with recurrence and ARF compared ARF in SRNS patients with recurrence was seen in both LRD to grafts with recurrence without ARF (Table 3). However, and CAD recipients. Our data do not allow for definitive there was no difference in graft survival rates at one year or dissection as to whether recurrence of SRNS predisposes to long-term (beyond one year) in kidneys with no recurrence ARF or whether ARF is responsible for an increased incidence comparing those with to those without ARF (Table 3). It is of recurrence. However, reports of severe ARF occurring in the noteworthy that only one of 16 grafts with recurrence and ARF native kidneys of patients with SRNS following relatively minor was functioning at the time of this analysis. Control patients provocative events [12—18] argue that the high incidence of with ARF tended to have a lower one year graft survival rate, ARF seen in the current study may be consequent to recurrence but this did not reach statistical significance (Table 3). ARF was of SRNS. Certainly, recurrence was noted in the absence of also associated with a numerically lower long-term graft sur- ARF in our patients, indicating that ARF is not a necessary vival in controls but this was not statistically significant (Table precondition for recurrence of SRNS in the renal allograft. The 3). mechanism(s) whereby recurrence of SRNS might predispose Six of the 16 grafts with recurrence and ARF (3 in a single to ARF is unknown. Glomerular filtration rate (GFR) is reduced patient) were lost when severe acute rejection ensued while the in patients with nephrotic syndrome [24, 25] and the reduction patients were still receiving dialysis support for ARF (Table 4). in GFR is proportional to the severity of glomerular epithelial

In two of these grafts massive proteinuria was documented foot process alterations [26]. Since a marked degree foot before ARF developed. Five patients had severe nephrotic process obliteration was seen in all of our patients with recursyndrome with massive proteinuria complicated by rejection rence whose biopsies were studied by electron microscopy, it is

early graft removal. Chronic rejection, acute rejection and

possible that these epithelial cell changes were associated with reduced GFR. Under these circumstances, the additional renal trauma related to the transplant process per se may have been

death with functioning graft accounted for the other four graft

sufficient to produce the extreme decline in GFR which we

episodes and elevated serum creatinine values. This combination led to the patients being extremely ill and to the decision for

1443

Kim et a!: ARF and rejection in recurrent nephroses Table 3. Survival rates of grafts with and without recurrence and in controls

ARF

P value No ARF

Controls

No recurrence

Recurrence Graft survival

1 year

long terma

4/16 (25) 0.003 9/10 (90)

1/16 (6) 0.005 4/10 (40)

1 year

long terma

4/7 (57)

4/7 (57)

NS

NS 22/40 (55)

35/40 (88)

1 year

long terma

8/13 (62)

5/13 (38)

45/51 (88)

28/51 (55)

>.05 <.1

NS

Abbreviations are: SRNS, steroid resistant nephrotic syndrome; ARF, acute renal failure; NS, not significant. Numbers in parenthesis = %. a Follow up = 5.3 4.6 (X SD) years

Table 4. Causes of graft loss SRNS

Cause Total number of grafts

RIARF 16

RINo ARF 10

NoRJARF 7

No RJNo ARF 40 —

ARF 13

Controls No ARF 51

— — — — 6 (38) ARF/Acute rejectiona — 1 (10) 5 (31) Severe NS/early RF/rejection 4 (31) 13 (25) 2 (29) 2 (20) 2 (13) 11(28) Chronic rejection 1 (6) 1 (10) 1(14) 1(3) 1(8) 1(2) Acute rejection — 5 (13) 6 (12) 3 (23) 1 (10) 1 (6) Death with functioning graft — — — — — Recurrence of SRNS/FSGS 1(10) — — — — 1 (3) 1 (2) Stopped taking medication Abbreviations are: RIARF, recurrence with acute renal failure; k/No ARF, recurrence without ARF; No RJARF, no recurrence with ARF; No k/No ARF, no recurrence without ARF; NS, nephrotic syndrome; RF, renal failure; SRNS/FSG, steroid-resistant nephrotic syndrome with focal segmental glomerular sclerosis. Numbers in parenthesis = a Patients remaining dialysis dependent after ARF developed, followed by acute rejection

Table 5. Incidence of one or more acute rejection episodes in first post-transplant year Rejection episodes %

I

II III

Recurrence/ARF Recurrence/no ARF No recurrence/ARF No recurrence/no ARF Controls/ARF Controls/no ARF

16/16 (100) 7/10 (70) 7/7 (100) 11/40 (28) 10/13 (77)

IV V VI 27/51 (53) I vs. IV, P <0.001; II vs. IV, P = 0.04; III vs. IV, P = 0.001; IV vs. V. P = 0.03 by chi-square. No other comparisons were significant. Loglinear model associations among SRNS patients are: recurrence and

ARF, P = 0.05; rejection and ARF, P < 0.01; recurrence and rejection,

P < 0.025.

defined as ARF. The greater incidence of ARF amongst cadaver as compared to LRD recipients with recurrence of SRNS in our

study is consistent with this hypothesis. This increased incidence could not be explained by influences of donor age or preservation time of cadaver kidneys in SRNS patient. This study confirmed our [8, 9] and others' [7, 10] previous observations indicating reduced early and long-term survival rates in grafts suffering from recurrence of SRNS. The current study indicates that the highest incidence of graft loss occurred in patients with both ARF and recurrence. In this group of 16 renal allografts, 15 were lost, 14 in association with rejection, and 12 early in the post-transplant course. Six grafts with ARF followed by acute rejection never functioned sufficiently to allow the patient to become dialysis-independent following transplantation. Of the 42 grafts in our series which were lost, only one was lost primarily due to severe progression of focal segmental and global glomerular sclerosis. The remainder were

primarily lost consequent to acute and chronic rejection. This conclusion, somewhat at variance with our previous writings on

this subject [9, 23], derives from the current more strict classification of graft loss due to recurrent SRNS/FSG as being limited to patients without histologic evidence of serious acute and/or chronic rejection but with advanced focal segmental and

global glomerular sclerosis. Further, the methodology of the current study involved a review of all histologic materials, resulting in some changes in the assignment of causes of graft loss compared to our earlier studies which depended on chart reviews.

Both recurrence of SRNS and ARF were independently related to an increased incidence of one or more acute rejection

episodes in the first post-transplant year. An increase in the incidence of acute rejection episodes with an associated increase in early graft loss has been previously reported in patients with post-transplant ARF [19—21], and our control patients evidenced similar trends. In addition, our studies indicate that SRNS recurrence, per se, is also associated with increased acute rejection risk. The pathogenesis of this increased acute rejection risk is unknown. Possibly acute renal injury is associated with the increased immunogenicity of the kidney [21], perhaps, as suggested by Shoskes, Parfrey and Halloran, [27], through increased expression of MHC antigens in the renal graft, leading to more efficient T cell recognition and effector response [28, 29]. Thus, Shoskes et al demonstrated increased MHC complex antigen expression in tubular epithehal cells and in inflammatory interstitial cells in mouse kidneys exposed to acute ischemic injury. Similarly, Muller et al found increased expression of HLA antigens in kidneys with a variety of glomerular disorders including in patients with SRNS/FSG [30]. The possibility that increased renal antigenicity occurs

Kim et al: ARF and rejection in recurrent nephroses

1444

consequent both to ARF and recurrence of SRNS is worthy of

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