Albumin
Total protein
24-h (mg/day)
ACR (mg/g)
24-h (mg/day)
PCR (mg/g)
Normal
<30
<17 (men)
<300
<200
<25 (women)
Microalbuminuria
30–300
17–250 (men)
NA
NA
25–355 (women)
Albuminuria
>300
>250 (men)
NA
NA
>355 (women)
Proteinuria
NA
NA
>300
>200
Although 24-h urine collection is the gold standard for measurement of protein excretion, it is cumbersome for patients and prone to collection errors. Moreover, daily creatinine excretion is not reliable in determining completeness of the urine collection as creatinine excretion falls after transplantation. Since spot urine measurements are easier to perform and convenient, many transplant centers routinely perform spot measurements of proteinuria (or albuminuria) instead of the 24-h collection. In order to account for the dilution of protein in the urine, spot measurements of proteinuria (albuminuria) must be corrected for spot creatinine excretion giving a ratio of protein:creatinine (PCR) or albumin:creatinine (ACR). The KDIGO transplant guideline suggests that PCR and ACR are alternatives for 24-h urine collection in kidney transplant recipients. PCR and ACR thresholds are shown in Table 29.1.
Studies conducted in renal transplant population indicate the correlation of PCR to 24-h urine protein excretion to be in the range of 0.75–0.98 and the sensitivity and specificity to be 74–99 % and 73–99 %, respectively, using different cutoffs for proteinuria. Although correlation is important, it measures relative agreement and not the absolute agreement and thus it ignores bias. Although PCR may be strongly correlated to 24-h protein excretion, it may substantially over- or underestimate total protein excretion. Similarly, sensitivity and specificity provide useful information but do not inform the clinician about the quantitative accuracy of the test. Measurements of bias and accuracy are better measures of agreement than correlation, specificity, and sensitivity. In a study involving 192 kidney transplant recipients, the accuracy of spot urine measurements was modest. Only 47 % of PCR estimates were within 30 % of the 24-h value for those with proteinuria >1,000 mg/day. The results were marginally better for those with lesser amounts of proteinuria. Similarly, 38–80 % of ACR estimates (depending on the degree of albuminuria) were within 30 % of 24-h urine collection. In view of this data, we recommend using a 24-h measurement of protein excretion before making any major clinical decisions (e.g., need for biopsy) based on the presence of proteinuria.
Prevalence of Proteinuria
The cutoff used for diagnosis of proteinuria has a major impact on its prevalence. In kidney transplant studies the prevalence has varied from 7.5 to 45 % depending on the threshold used (Table 29.2). When proteinuria is defined as greater than 150 mg/day (as in nontransplant population), the prevalence of proteinuria at 12 months post-transplantation is as high as 45 %. With a higher cutoff of 1 g/day, the prevalence has ranged from 7.5 to 40 % with an average of 19 % (Table 29.2). Even nephrotic range proteinuria has been reported in the transplant population with a prevalence of 13 %. These data suggest that proteinuria is just as common a problem in the renal transplant population as it is in the nontransplant chronic kidney disease (CKD) population.
Table 29.2
Prevalence of proteinuria in kidney transplant recipients
References | Sample size | Definition of proteinuria | Time post-transplantation | Prevalence of proteinuria (%) |
|---|---|---|---|---|
Fernandez (2002), Spain | 532 | >3 g/day | >12 months | 13.7 |
Yakupoglu (2004), USA | 570 | >3 g/day | >1 week | 13.0 |
First (1984), USA | 639 | >2 g/day | >1 month | 12.1 |
Vathsala (1990), USA | 704 | >1 g/day | >1 month | 12.8 |
Kim (1994), South Korea | 204 | >1 g/day | >1 month | 27.9 |
Chung (2000), South Korea | 197 | >1 g/day | >3 months | 12.5 |
Park (2000), South Korea | 884 | >1 g/day | >6 months | 40.0 |
Karthikeyan (2003), Canada | 459 | >1 g/day | >6 months | 12.0 |
Halimi (2005), France | 484 | >1 g/day | 12 months | 20.4 |
Fernandez (2004), Spain | 3,365 | >1 g/day | 12 months | 7.5 |
Chung (2000), South Korea | 197 | >0.5 g/day | >3 months | 13.2 |
Fernandez (2002), Spain | 532 | >0.5 g/day | >12 months | 36.4 |
Fernandez (2004), Spain | 3,365 | >0.5 g/day | 12 months | 15.3 |
Halimi (2005), France | 484 | >0.5 g/day | 12 months | 35.2 |
Sancho (2007), Spain | 337 | >0.5 g/day | >3 months | 20.2 |
Amer (2007), USA | 613 | >0.5 g/day | 12 months | 15.3 |
Ibis (2007), Turkey | 130 | >0.3 g/day | 12 months | 34.3 |
Roodnat (2001), The Netherlands | 722 | >0.2 g/L | 12 months | 31.0 |
Amer (2007), USA | 613 | >0.15 g/day | 12 months | 45.0 |
Source and Causes of Proteinuria in Renal Transplant Recipients
Transplant recipients with considerable residual urine output, such as those who undergo preemptive transplantation or kidney transplantation soon after starting renal replacement therapy, may be quite proteinuric initially because of proteinuria from native kidneys. Although the mechanism remains unknown, native kidney proteinuria usually resolves at about 1 month post-transplantation. In a small study involving 14 live donor recipients, PCR was measured pretransplant and then weekly in the postoperative period. The PCR ranged from 0.5 to 9.2 (average = 2.9) pretransplant but normalized to <0.2 in all patients by 10 weeks post-transplantation. The average time to resolution of proteinuria was 4.5 weeks. Similar findings were seen in a larger prospective study involving 115 kidney transplant recipients. In this study, proteinuria fell from 3,650 ± 3,702 to 550 ± 918 mg/day at 3 weeks post-transplantation. There were 61 patients with pretransplant proteinuria values greater than 1.5 g/day and by 3 weeks post-transplantation only eight patients had this level of proteinuria. These studies suggest that proteinuria from the native kidneys resolves early post-transplantation and that persistent or increasing amounts of proteinuria should be assumed to be from the allograft.
There have been several studies that have examined the histological lesions in kidney transplant patients with proteinuria. Similar to what was seen with the prevalence data, histological diagnosis varied depending on the degree of proteinuria at the time of biopsy (Table 29.3). For patients with significant proteinuria (e.g., >1.5 or 2 g/day), glomerular pathology (e.g., recurrent and de novo glomerulonephritis and transplant glomerulopathy) seems most common. In a study involving 276 kidney transplant patients, the average proteinuria was 2.7 g/day for those with glomerular pathology compared to <500 mg/day for all other diagnoses including acute rejection and interstitial fibrosis/tubular atrophy. In fact, for patients with >1.5 g/day of proteinuria, 80 % have been found to have glomerular diseases. Transplant-specific diagnoses are more common than native kidney disease such as glomerulonephritis in renal transplant recipients with proteinuria. In the largest and most recent study to date, 58 % of transplant patients with proteinuria >150 mg/day had a transplant-specific diagnosis. The histological lesions included allograft nephropathy (also called chronic rejection or interstitial fibrosis/tubular atrophy) in 45 %, transplant glomerulopathy in 8 %, and acute rejection in 5 %. This compared to only 11 % with glomerulonephritis (Table 29.3).
Table 29.3
Allograft histology in kidney transplant recipients with proteinuria
