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- Materials and Methods
Increasing numbers of patients receive kidney transplants before initiation of dialysis or shortly thereafter. Some of these patients have significant proteinuria pre-transplant making the interpretation of post-transplant proteinuria problematic. In this study, we evaluated post-transplant proteinuria in 115 patients who had urine protein measured within 3 months of transplant and assessed the association of proteinuria with allograft pathology. Proteinuria declined rapidly from 3650 ± 3702 mg/day pre-transplant to 550 + 918 at 3 weeks (p < 0.0001) and continued to decline until 1 year post-transplant (472 ± 1116, p < 0.0001 vs. 3 weeks). Proteinuria greater than 3000 mg/day was present in 48 patients (42%) pre-transplant, in 1 patient (1%) at 3 weeks and in 4 patients (4%) at 1 year. Surveillance graft biopsies were done at 1 year in 93% of patients. Proteinuria ≥1500 mg/day and/or an absolute increase in proteinuria >500 mg/day after 3 weeks post-transplant was associated with allograft glomerular pathology. In conclusion, pre-transplant proteinuria, even when high grade, declines rapidly after transplantation. Failure to decline or persistence of proteinuria greater than 1500 mg/day is indicative of allograft pathology.
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- Materials and Methods
The presence of elevated urine protein excretion after kidney transplantation is associated with poor allograft survival (1,2). Furthermore, the presence of abnormal proteinuria may be indicative of recurrent native kidney disease, which may be amenable to therapy (3). Consequently, monitoring urine protein excretion and investigating the causes of abnormal proteinuria should be an integral part of post-kidney transplant monitoring (4). In recent years, an increasing number of patients receive kidney transplants before the initiation of dialysis or within a few weeks of initiation of renal replacement therapy. These patients receive kidney allografts while they still have significant urine output and at times significant proteinuria originating from their native kidneys. This situation introduces the challenge of determining whether post-transplant proteinuria originates from the native kidneys or from the allograft? This issue was addressed in a recent study (5), which examined pre- and post-transplant urine protein excretion in 14 patients who had proteinuria pre-transplant. In that study, proteinuria declined rapidly following transplantation.
The goal of this study is to quantify the changes in urine protein excretion that occur during the first year after kidney transplantation in a cohort of patients who had proteinuria measured prior to the transplant. In addition, utilizing surveillance biopsies (6), we sought to investigate whether post-transplant proteinuria is associated with significant allograft pathology at 1 year. In agreement with previous studies, these analyses confirm the rapid decline in native urine protein excretion that occurs during the first few weeks following successful kidney transplantation. Thereafter, proteinuria continues to decline unless significant allograft pathology develops.
Materials and Methods
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- Materials and Methods
Included in this study are 115 adult kidney allograft recipients transplanted in our institution from January 1999 to December 2004. All of these patients had determinations of 24-h urine protein excretion done within 3 months of the transplant, during their initial pre-transplant evaluation. All of the patients were transplanted at least 1 year prior to this analysis. Eighty-five patients never received dialysis prior to the transplant (preemptive transplantation) while 30 received dialysis for a brief period of time, less than 3 months. Clinical and laboratory information from donors and recipients were extracted from electronic databases and from the patients' medical records. The extraction and reporting of these data were approved by the Mayo Clinic institutional review board. Graft function was assessed by serum creatinine and by iothalamate glomerular filtration rate (GFR) (7) at 3 weeks (at the time of dismissal of the patient from the early post-transplant clinic) and yearly thereafter. Proteinuria, quantified in 24-h urine collections, was measured within 3 months before the transplant, post-transplant at 3 weeks, 1 year and yearly thereafter.
As part of the routine clinical management of patients transplanted at the Mayo Clinic, surveillance allograft biopsies are done within 30 min of implantation of the graft (time 0) and at 4, 12, 24 and 60 months post-transplant. All biopsies are evaluated by one of four dedicated renal pathologists. Light microscopic findings are scored using the Banff 97 classification (8). Immunofluorescence, including C4d staining, and electron microscopy are done only if clinically indicated. The diagnosis of acute rejection is based on biopsy evidence (8). Delayed graft function is defined as the need for dialysis following the transplant.
Immunosuppression consisted of induction with Thymoglobulin (1.5 mg/kg/day for 5–7 doses) in 80% of cases; 10% received induction with anti-CD25 antibodies and 9% did not receive induction. Maintenance immunosuppression consisted of prednisone, tacrolimus and mycophenolate mofetil in 83% of the patients. The dose of tacrolimus was adjusted to achieve trough levels of 10–12 ng/mL (high-performance liquid chromatography/tandem mass spectrometry technique) during the first month post-transplant; 8–10 ng/mL from month 2–4; and 6–8 ng/mL thereafter. Nine patients (8%) received cyclosporine instead of tacrolimus and 10 (9%) received sirolimus instead of tacrolimus. Target cyclosporine levels were 200–250 ng/mL in the first 4 months and 100–150 thereafter. Target sirolimus levels were from 15–20 ng/mL for the first 4 months post-transplant and 10–15 ng/mL thereafter. During the first year, 19 patients (16%) received angiotensin converting enzyme inhibitors (ACEI) and 3 (3%) angiotensin receptor blockers (ARB).
Throughout the article, data are expressed as mean and standard deviation. Means of normally distributed data were compared by Student's t-test. Non-parametric tests were used when data were not normally distributed, such as the case with proteinuria. Proportions were compared by chi-square test.
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Table 1 displays the characteristics of the patient population. As can be seen 63 patients (55%) received kidneys from living related donors (LRD); 32 (28%) from living unrelated donors (LURD); and 20 (17%) from deceased donors (DD). Five patients were ABO blood group incompatible with their donors and 4 had anti-donor antibodies prior to the transplant (positive crossmatch transplants) (9).
Table 1. Patient characteristics
|Recipient age||52 ± 14 (range 18–82)|
|Gender (M:F)||73:42 (63%: 37%)|
|Race (N,% Caucasians)||110 (96%)|
|Dialysis pre-transplant (N,%)||30 (26%)|
|Diabetes (N,%)||24 (21%)|
|Delayed graft function||11%|
|First kidney transplant (N,%)||96 (83%)|
|Type of donor:|
| LRD||63 (55%)|
| LURD||32 (28%)|
| DD||20 (17%)|
|Type of transplant:|
| Conventional||106 (92%)|
| Positive cross match||4 (4%)|
| ABO incompatible||5 (4%)|
|Follow-up months||36 ±19 (5–78)|
Table 2 displays the etiology of the patients' chronic kidney disease and also indicates the mean level of proteinuria pre-transplant in each of the diagnostic groups. Seven patients (6%) had normal urine protein excretion pre-transplant (<150 mg/day); 32 patients (28%) had proteinuria between 150 and 1500 mg/day; 28 (24%) from 1500 to 3000 mg/day; and 48 (42%) greater than 3000 mg/day.
Table 2. Causes of native kidney disease in the study population and corresponding levels of pre-transplant proteinuria
|Cause of kidney failure||Number of patients (%)||Pre-transplant proteinuria (mg/day) (range)|
|Diabetes mellitus||14 (12%)||4934 ± 2811 (66–9780)|
|Glomerular disease||45 (39%)||5305 ± 610 (188–20446)|
| FSGS||8 (7%)|| |
| IgA nephropathy||10 (9%)|| |
| Membranous nephropathy||7 (6%)|| |
| Amyloidosis||5 (4%)|| |
| SLE||3 (3%)|| |
| Other||12 (10%)|| |
|Failing kidney allograft||19 (17%)||2602 ± 2316 (137–9141)|
|ADPKD||5 (4%)||636 ± 364 (133–1019)|
|Hypertension||5 (4%)||2789 ± 1947 (558–5166)|
|Other||22 (19%)||1531 ± 1785 (50–5977)|
|Unknown||5 (4%)||2356 ± 2338 (82–6167)|
Figure 1 displays urine protein excretion pre- and post-transplant. From its pre-transplant level of 3650 ± 3702 (range 50–20, 446) mg/day the urine protein excretion declined significantly to 550 + 918 (45–7612) mg/day by 3 weeks post-transplant (p < 0.0001, paired Wilcoxon) and declined further to 472 ± 1116 (4 – 7199) mg/day by 1 year post-transplant (p < 0.0001 vs. 3 weeks, paired Wilcoxon). This reduction in proteinuria occurred while the patients had an improvement in GFR from 14 ± 6 mL/min/m2 pre-transplant to 57±17 (20–112) mL/min/m2 at 3 weeks and 57 ± 18 (19–105) at 1 year. Eighty-five patients never received dialysis prior to the transplant. In this subgroup of patients, the decline in pre-transplant proteinuria (pre-transplant 3878 ± 4176 mg/day; 3 weeks post-transplant, 533 ± 995, p < 0.0001 Wilcoxon) was similar to that observed in the entire study population.
Figure 1. Urine protein excretion pre-transplant and at two time points after transplantation, 3 weeks and 1 year. Dashed horizontal line indicates urine protein excretion of 1500 mg/day.
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Table 3 display the changes in proteinuria that occurred after the transplant expressed as the percent of patients with different levels of proteinuria. Only those patients who had urine protein determinations at all three time points (N = 87) are included in these analyses. As can be seen, 3 weeks after transplantation there was a striking reduction in the number of recipients with high-grade proteinuria. Among the 38 patients with pre-transplant proteinuria greater than 3000 mg/day, only 1 had proteinuria in that range 3 weeks post-transplant. Furthermore, among the 61 patients with pre-transplant proteinuria greater than 1500 mg/day, only 8 had this level of proteinuria 3 weeks post-transplant. One patient had proteinuria greater than 3000 mg/day 3 weeks post-transplant and this patient had biopsy-proven recurrent focal segmental glomerulosclerosis (FSGS).
Table 3. Urine protein excretion before and after transplantation
|Urine protein level (mg/day)||Pre-transplant N (%)||Post-transplant (3 weeks) N (%)||Post-transplant (1 year) N (%)|
|0–150||5 (6)||24 (28)||43 (49)|
|151–1500||21 (24)||55 (63)||36 (41)|
|1501–3000||23 (26)||7 (8)||3 (3)|
|>3000||38 (44)||1 (1)||4 (5)|
Table 4 displays data on allograft function and blood pressure in recipients classified according to their level of proteinuria at 1 year after transplantation. For these analyses, based on the small numbers of patients with more than 1500 mg/day of proteinuria, patients were classified in three, rather than four, groups as indicated in the table. Increasing levels of proteinuria were associated with higher serum creatinine and lower GFR at 1 year. BP levels did not differ among these patients. Urine protein excretion was not significantly different in patients taking ACEI or ARB (N = 22) than in patients not taking these medications (data not shown). At 3 weeks post-transplant, urine protein excretion was not different between patients taking tacrolimus or sirolimus (data not shown). At 1 year, proteinuria was marginally higher in patients treated with sirolimus (753 + 787) than in those taking tacrolimus (487 + 1211, p = 0.056).
Table 4. Allograft function and blood pressure levels in patients classified according to their level of proteinuria 1 year after transplantation
|Parameter||Proteinuria at 1 year (mg/day)||p|
|S. creatinine (mg/dL)||1.3 + 0.3||1.6 + 0.37||2.2 + 0.85||<0.00011|
|GFR (mL/min/1.7m2)||61 + 17||52 + 19||47 + 16||0.032|
|Systolic BP (mmHg)||139 + 20||145 + 21||158 + 30||NS2|
|Diastolic BP (mmHg)||78 + 8||82 + 14||90 + 14||NS2|
Figure 2 shows the relationship between pre-transplant proteinuria and proteinuria 3 weeks post-transplant. This relationship was statistically significant (r = 0.466, p < 0.001, Spearman), indicating that higher levels of proteinuria pre-transplant are associated with higher levels of proteinuria at 3 weeks. However, Figure 2 also illustrates the profound and significant decline in proteinuria that occurs following the transplant.
Figure 2. Relationship between proteinuria pre-transplant and at 3 weeks post-transplant. Note that both the axes are logarithmic. Dashed lines indicate 1500 mg/day of proteinuria and the diagonal is the line of identity.
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Urine protein excretion declined from 3 weeks to 1 year post-transplant (550 ± 918 mg/day to 472 ± 1116, p < 0.0001). Figure 3 displays changes in proteinuria in individual patients. Sixty-seven patients (77%, identified as □ in the figure) had either no change or a decline in proteinuria; 15 (17%, identified as * in the figure) had what were considered to be clinically insignificant increases in urine protein excretion (107±92 mg/day, range 3–255); finally, 5 patients (6%, identified as ▴ in the figure) had greater than 500 mg/day increases in proteinuria. It should be noted in Figure 3 that all of these 5 patients had proteinuria of less than 1000 mg/day at 3 weeks but greater than 1500 mg/day at 1 year. All of these patients had evidence of allograft glomerular pathology, as it will be described later.
Figure 3. Relationship between the urine protein excretion at 3 weeks and 1 year post-transplants. Note that both the axes are logarithmic. Dashed lines indicate 1500 mg/day of proteinuria and the diagonal is the line of identity. Patients are classified as follow: No change or a decline in proteinuria from 3 weeks to 1 year (□); an increase in proteinuria of less than 500 mg/day during the same interval (*); and patients with an absolute increase in proteinuria of more than 500 mg/day from 3 weeks to 1 year (▴).
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One hundred and seven of the 115 study patients (93%) had surveillance allograft biopsies done 1 year post-transplant. Implantation biopsies were also available in 61 of these patients. None of these time 0 biopsies showed glomerular pathology but 4 biopsies showed mild (Banff scores = 1) interstitial fibrosis and tubular atrophy. Table 5 displays pathologic diagnoses in 1 year biopsies and the urine protein excretion for each group. Among the 38 patients with normal allograft histology, 28 had normal protein excretion (<150 mg/day); 9 had low-grade proteinuria (193–551 mg/day) and 1 patient had 1979 mg/day of proteinuria. Review of this latter biopsy confirmed the normal glomerular histology but identified protein resorption droplets in tubules suggestive of proteinuria of graft origin. Urine protein excretion was significantly lower in patients with normal histology than in patients with chronic allograft nephropathy (CAN, p = 0.01, Wilcoxon) although, as can be seen in Table 5, there is significant overlap between the levels of proteinuria between these two groups. Proteinuria was significantly higher in patients with allograft glomerular pathology than in all the other histologic groups (p = 0.009, Kruskal-Wallis). It is of interest to note that 2 of the 9 patients with glomerulopathies had normal urine protein excretion. Allograft glomerular diseases included, transplant glomerulopathy (N = 1); recurrent diseases, including IgA nephropathy (N = 1), membranous nephropathy (N = 1), anti-glomerular basement membrane nephritis (N = 1), FSGS (N = 1) and MPGN (N = 1). Three additional patients had FSGS in the allograft but their primary renal diagnosis was other than idiopathic FSGS, including IgA nephropathy, nephrotoxicity related to chemotherapy and reflux nephropathy. Seven patients had proteinuria greater than 1500 mg/day at 1 year post-transplant. Six of these patients had glomerular disease and one additional patient had 24 normal glomeruli in the biopsy and protein resorption droplets in tubules suggesting that the proteinuria originated from the allograft as noted above.
Table 5. Pathologic diagnoses in surveillance biopsies done 1 year after transplantation
|Diagnosis||Number of patients (%)||Urine protein excretion (mg/day) (range)|
|Normal||38 (36%)||186 ± 336 (4–1979)|
|Acute rejection||8 (7%)||373 ± 364 (72–1080)|
|CAN1||42 (39%)||265 ± 292 (19–1344)|
|Glomerular disease||9 (8%)||2873 ± 2711 (33–7199)2|
|Other pathologies3||10 (9%)||221 ± 240 (78–800)|
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- Materials and Methods
In agreement with previous studies (5), these analyses showed that proteinuria originating from native kidneys declines precipitously during the first 3 weeks after transplant. This decline occurred in patients with a variety of primary kidney diseases and even in patients with high levels of proteinuria prior to the transplant. Higher levels of pre-transplant proteinuria relate with higher levels of post-transplant proteinuria, suggesting that native kidneys may excrete small amounts of protein after transplantation. Despite this likely contribution of the native kidneys to the urine protein, only 9 patients (10%) had proteinuria greater than 1500 mg/day 3 weeks after the transplant and of those only 1 patient had high-grade proteinuria that was due to recurrent FSGS in the allograft. Thus, proteinuria greater than 1500 mg/day early after successful kidney transplantation is highly suggestive of new allograft pathology and rarely, if ever, can be attributed to the native kidneys.
Beyond 3 weeks post-transplant, urine protein excretion either decreases or does not change significantly in the large majority of patients (94%). In contrast to this trend, 5 patients had an increase in proteinuria of greater than 500 mg/day beyond 3 weeks post-transplant. All of these patients had new allograft pathology. It should be noted that our patients did not have proteinuria measured routinely between 3 weeks and 1 year post-transplants. Thus, the course of the proteinuria between these two time points cannot be assessed in these studies. Previous studies suggest that proteinuria from native kidneys can be present during the first 3–4 months post-transplant (5). These analyses also indicate that, considering the absolute urine protein excretion at 1 year, proteinuria greater than 1500 mg/day 1 year post-transplant most likely indicates the presence of new allograft pathology and is unlikely to originate from the native kidneys.
One year after transplantation, proteinuria between 150 and 1500 mg/day was observed in 41% of transplant recipients. All of these patients had demonstrable allograft pathology. Proteinuria was significantly lower in patients with normal histology than in patients with graft pathology and was similar in patients with acute rejection, chronic allograft nephropathy or other pathologies (see Table 5). However, we should be cautious with the interpretation of this latter observation, because of the relatively small numbers of patients in these histologic subgroups. Additional studies comparing proteinuria with allograft pathology at 1 year in a larger cohort of patients are underway.
These analyses showed an association between proteinuria at 1-year and reduced allograft function. This association is of interest but need to be confirmed in a larger cohort of patients. Ten patients in this study received sirolimus, a drug that has been associated with proteinuria (10,11). This number of patients is too small to reach firm conclusions but in evaluating post-transplant proteinuria, the possible contribution of sirolimus should be considered.
Several practical clinical lessons can be derived from these data. First, these observations provide little justification for the practice of removing native kidneys prior to the transplant in adults with high levels of proteinuria. These results would suggest that the reduction in filtration from the native kidneys that rapidly follows successful transplantation should resolve proteinuria derived from native kidneys promptly. For example, this study included 4 patients with amyloidosis and very high-grade pre-transplant proteinuria. In all of these patients, the proteinuria declined to less than 1500 mg/day 3 weeks after the transplant.
The second practical application of these results relates to the importance of both monitoring and quantitating urine protein levels following transplantation. These studies are in agreement with previous guidelines recommending this practice (4). Furthermore, these data and a previous study (2) showed the clinical relevance of relatively low levels of proteinuria post-transplantation, emphasizing the importance of precise quantitation of urine protein levels. In this study, urine protein was quantitated using 24-h urine collections. The inherent weakness of this method is that the completeness of these urine collections can be variable. Quantitation of total creatinine content in these samples may help assess the specimen's adequacy. However, this parameter was not available in our patients. Alternatively, proteinuria can be assessed by the ratio of urine protein (or urine albumin) to urine creatinine on a spot urine sample (12). However, this method does not provide precise quantitation of proteinuria.
In conclusion, proteinuria originating from native kidneys declines rapidly during the first 3 weeks following transplantation and, as a rule, continues to decline during the first year post-transplant. Failure to decline or persistence of urine protein excretion greater than 1500 mg/day cannot be attributed to the native kidneys. Rather, these clinical circumstances are indicative of allograft pathology and require investigation likely including a kidney allograft biopsy.