Proteinuria in Kidney Transplant Recipients: Prevalence, Prognosis, and Evidence-Based Management

Measuring Proteinuria 

In healthy adults, low-molecular-weight proteins and small amounts of albumin are filtered at the glomerulus and largely reabsorbed in the proximal tubule. However, in healthy individuals, approximately 40 to 80 mg of protein is excreted in urine each day.6 This includes Tamm-Horsfall protein, low-molecular-weight proteins (eg, β2-microglobulin, retinol-binding protein, and α1-microglobulin), and a small amount of albumin (∼10 mg).6, 7 Thresholds for determining normal from abnormal proteinuria have been established in the nontransplant population and are listed in Table 1. Urine from transplant recipients may contain unique proteins, peptides, and other substances that could be useful to predict allograft outcomes.8 The presence of these additional proteins might require a different threshold for defining normal. In addition, kidney transplant recipients have only 1 functioning kidney, and patients with a solitary kidney, such as living donors, often have greater levels of proteinuria.9 Nonetheless, there are no uniquely defined thresholds for proteinuria in the kidney transplant population. Therefore, it seems appropriate to use the same values established for the general population (Table 1).

Table 1. Definition of Proteinuria and Albuminuria

		Collection Method	Normal	Microalbuminuria	Albuminuria or Clinical Proteinuria
	Albumin	24-h collection (mg/d)	<30	30-300	>300
		Spot urine albumin-creatinine ratio (mg/g)	<30	30-300	>300
	Total protein	24-h collection (mg/d)	<300	NA	>300
		Spot urine protein-creatinine ratio (mg/g)	<200	NA	>200

Abbreviation: NA, not applicable. Adapted from Vassalotti et al3 and Sarafidis et al.4

There are several methods to quantify proteinuria and albuminuria, including 24-hour collection, shorter timed collection, spot urine measurements, and spot urine protein-creatinine (or albumin-creatinine) ratio.10 Given the difficulties performing 24-hour urine collections in routine practice, spot urine protein-creatinine or albumin-creatine ratios have been recommended for the determination of proteinuria in the nontransplant population.11 There are no such recommendations about the optimal method for measuring proteinuria in the transplant population.

The utility of urine protein-creatinine ratio has been studied in kidney transplant recipients.12, 13, 14 Torng et al14 found that spot urine protein-creatinine ratio correlated significantly (r = 0.793; P < 0.0001) with 24-hour protein excretion in 289 adult kidney transplant recipients. However, protein-creatinine ratio had sensitivity of only 85% to detect 24-hour protein excretion greater than 500 mg/d, and sensitivity was even lower for detection of 1 or 3 g/d of protein excretion.14 Unfortunately, 24-hour protein excretion to body surface area was not calculated in this study,15 and confidence intervals (CIs) were not provided to determine the precision of sensitivity estimates. Rodrigo et al13 also found a high correlation (r = 0.921; P < 0.0001) between protein-creatinine ratio and 24-hour protein excretion (adjusted for body surface area) in 759 kidney transplant recipients. They found high sensitivity (95.7%) to detect proteinuria greater than 3 g/d, but poor sensitivity (73.2%) to detect low levels of proteinuria. It also appears that these calculations were performed on repeated measurements in the same patients (8,277 urine samples), although this was not explicitly stated in the report.13 This would have influenced the precision of their estimates; unfortunately, no CIs were provided.13 Steinhauslin and Wauters12 analyzed the accuracy of protein-creatinine ratio in 520 urine samples from 133 kidney transplant recipients. They found a high correlation (r = 0.93; P < 0.001) with 24-hour urine collection. In a subset of 318 urine samples deemed to have been collected accurately (based on 24-hour creatinine levels), sensitivity to detect up to 250 mg/d of protein excretion was 95%, and for patients with nephrotic-range proteinuria, sensitivity increased to 99%.12 Based on the published data, the utility of protein-creatinine ratio in kidney transplant appears promising. However, further confidence in this ratio would be achieved with more data highlighting systematic bias, precision, and accuracy compared with 24-hour collection.

Prevalence of Proteinuria in Kidney Transplant Recipients 

In individual studies, the prevalence of proteinuria varies considerably, at least partly because of the threshold used to define proteinuria. Table 2 lists the major studies that have reported proteinuria in kidney transplant recipients.5, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Overall, the prevalence of proteinuria varied from 7.5% to 45% (Table 2). In studies that classified proteinuria using a high cutoff value (protein > 2 to 3 g/d), prevalence was consistent, ranging from 12.1% to 13.7%, with an average of 12.9%.5, 16, 17 When the threshold was decreased to protein greater than 1 g/d, the prevalence of posttransplant proteinuria was greater and ranged from 7.5% to 40% (average, 19.0%).18, 19, 20, 21, 22, 23, 24 In studies that defined proteinuria as protein greater than 0.5 g/d, the average prevalence of proteinuria increased to 22.6% and ranged from 13.2% to 36.4%.5, 18, 19, 20, 25, 26 Finally, when the threshold was set at just greater than the normal limit, the prevalence of proteinuria was greatest and ranged from 31% to 45%.25, 27, 28 It is evident from these studies that proteinuria occurs commonly in kidney transplant recipients. The prevalence certainly is greater than in the general population29 and approaches the level in a population of predialysis patients with chronic kidney disease.30

Table 2. Prevalence of Proteinuria in Kidney Transplant Recipients

	Reference (country)	Sample Size	Definition of Proteinuria (g/d)	Time Posttransplant (mo)	Prevalence of Proteinuria (%)
	Fernandez-Fresnedo et al,5 2002 (Spain)	532	>3	>12	13.7
	Yakupoglu et al,17 2004 (United States)	570	>3	>1wk	13.0
	First et al,16 1984 (United States)	639	>2	>1	12.1
	Vathsala et al,24 1990 (United States)	704	>1	>1	12.8
	Kim et al,22 1994 (South Korea)	204	>1	>1	27.9
	Chung et al,18 2000 (South Korea)	197	>1	>3	12.5
	Park et al,23 2000 (South Korea)	884	>1	>6	40.0
	Karthikeyan et al,21 2003 (Canada)	459	>1	>6	12.0
	Halimi et al,20 2005 (France)	484	>1	12	20.4
	Fernandez-Fresnedo et al,19 2004 (Spain)	3,365	>1	12	7.5
	Chung et al,18 2000 (South Korea)	197	>0.5	>3	13.2
	Fernandez-Fresnedo et al,5 2002 (Spain)	532	>0.5	>12	36.4
	Fernandez-Fresnedo et al,19 2004 (Spain)	3,365	>0.5	12	15.3
	Halimi et al,20 2005 (France)	484	>0.5	12	35.2
	Sancho et al,26 2007 (Spain)	337	>0.5	>3	20.2
	Amer et al,25 2007 (United States)	613	>0.5	12	15.3
	Ibis et al,27 2007 (Turkey)	130	>0.3	12	34.3
	Roodnat et al,28 2001 (The Netherlands)	722	>0.2g/L	12	31.0
	Amer et al,25 2007 (United States)	613	>0.15	12	45.0

Origin and Evolution of Proteinuria in Kidney Transplant Recipients 

Patients who undergo transplant preemptively or early in the course of dialysis therapy often have considerable residual urine output. If the original renal disease was associated with proteinuria, such as in diabetic nephropathy or glomerulonephritis, residual urine also will initially contain significant amounts of protein. In this situation, it is important to know whether the proteinuria originates from the native or transplant kidney. Two recent studies have carefully addressed this important clinical question.31, 32 D'Cunha et al32 studied 14 patients with residual urine output who received live donor kidney transplants. All patients had a urine protein-creatinine ratio measured pretransplant and then weekly posttransplant. Importantly, no patient was given an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker, or nondihydropyridine calcium channel blocker that might decrease proteinuria. Average pretransplant protein-creatinine ratio was 2.9 and ranged between 0.5 and 9.2.32 All 14 patients experienced normalization of native kidney proteinuria (ratio ≤ 0.2), which occurred an average of 4.5 weeks posttransplant (range, 1 to 10 weeks).32 The time course of proteinuria posttransplant in this study is shown in Fig 1.

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Figure 1. Time course of urine protein-creatinine ratio (UPr:Cr) posttransplant. Pretransplant UPr:Cr ranged from 0.5 to 9.2 and normalized (≤0.2) in all 14 patients by 10 weeks posttransplant. Reproduced with permission of Wiley-Blackwell from D'Cunha et al.32

In a larger study, Myslak et al31 monitored the time course of posttransplant proteinuria in 115 patients with pretransplant proteinuria. Approximately one quarter underwent transplant preemptively, and the study included both living and deceased donors. Average level of pretransplant proteinuria was 3,650 ± 3,702 mg/d of protein and decreased significantly to 550 ± 918 mg/d by 3 weeks posttransplant.31 In the 61 patients with pretransplant proteinuria greater than 1,500 mg/d, only 8 patients had this level of proteinuria by 3 weeks posttransplant.31 Furthermore, proteinuria continued to decrease or minimally increased in 94% of patients, and only 5 patients had an increase in proteinuria of more than 500 mg/d of protein beyond week 3 posttransplant.31 Transplant biopsies were performed on 93% of patients at 1 year, and a new allograft pathological state was found in all patients who had persistent proteinuria with protein greater than 1,500 mg/d or an increase greater than 500 mg/d after 3 weeks.31 It is clear from the studies by D'Cunha et al32 and Myslak et al31 that proteinuria from native kidneys decreases rapidly during the first few weeks posttransplant and persistent or increasing proteinuria should be assumed to be from the allograft.31, 32 The mechanism for this decrease is unknown; however, 2 patients in the study by D'Cunha et al32 had pretransplant and posttransplant isotopic renograms obtained. In both cases, there was a marked decrease in isotope uptake in the region of the native kidneys at 3 weeks posttransplant, indicating a significant decrease in renal blood flow.32 The mediators of this change in blood flow are speculative, but are not likely to be caused by only vasoconstriction from calcineurin inhibitors because posttransplant resolution of proteinuria has been described in the precyclosporine era.32, 33

Allograft Pathology in Patients With Proteinuria 

Several studies have examined allograft histological characteristics in kidney transplant recipients with proteinuria. As seen with the proteinuria prevalence data presented, histological diagnoses varied among studies and depended on the threshold to perform a biopsy, as well as the era of publication (Table 3). Yakupoglu et al17 performed biopsies in a series of patients with proteinuria greater than 3 g/d. Sixty-six percent had evidence of glomerular disease, including recurrent glomerulonephritis, de novo glomerulonephritis, and undefined glomerulonephritis (when the original disease was unknown).17 In contrast, Vathsala et al24 found that only 12% of patients had a glomerular lesion when the threshold to perform biopsy was decreased to 1 g/d of protein excretion. Some,24, 25 but not all,18 studies have shown a direct correlation between allograft histological characteristics and degree of proteinuria. Amer et al25 found that average proteinuria (2,716 ± 2,889 mg/d) was significantly greater in patients with glomerular pathology states compared with those with acute rejection (262 ± 389 mg/d), interstitial fibrosis and atrophy (229 ± 289 mg/d), or other histological diagnoses (239 ± 369 mg/d). In patients with proteinuria greater than 1,500 mg/d, 80% were found to have glomerular disease on biopsy.25 However, lower levels of proteinuria could not differentiate between the various pathological entities.25

Table 3. Allograft Histological Characteristics in Kidney Transplant Recipients With Proteinuria

	Reference (country)	Proteinuria at Time of Biopsy (g/d)	Sample Size With Biopsy	Allograft Nephropathy⁎ (%)	Transplant Glomerulopathy (%)	Glomerular Disease† (%)	Acute Rejection (%)	Other (%)
	Yakupoglu et al,17 2004 (United States)	>3	73	18	16	66‡	0	0
	First et al,16 1984 (United States)	>2	77	27	39	29	0	5
	Park et al,23 2000 (South Korea)	>1	81	54	0	27	7	11
	Kim et al,22 1994 (South Korea)	>1	44	20	14	41	14	11
	Vathsala et al,24 1990 (United States)	>1	63	49	24	12	15	0
	Chung et al,18 2000 (South Korea)	>0.5	26	8	8	73	0	12
	Amer et al,25 2007 (United States)	>0.15	276	45	8	11	5	31

⁎ Allograft nephropathy includes the following diagnoses: chronic allograft nephropathy, chronic rejection, interstitial fibrosis, and tubular atrophy. † Glomerular disease includes recurrent and de novo glomerulonephritis and diabetic nephropathy. ‡ A total of 65% had superimposed chronic allograft nephropathy.

Although glomerular disease (mostly glomerulonephritis) commonly is found in patients who undergo biopsy for proteinuria, transplant-specific diagnoses are more common. The prevalence of allograft nephropathy (nonspecific interstitial fibrosis and tubular atrophy that previously was referred to as chronic rejection34) ranged from 8% to 54%, with an average of 31.6%16, 17, 18, 22, 23, 24, 25 (Table 3). Transplant glomerulopathy (a unique entity defined by glomerular and peritubular capillary basement membrane duplication often associated with donor-specific antibodies34) ranged from 0% to 39%, with an average prevalence of 16.8%.16, 17, 18, 22, 23, 24, 25 In the largest and most recent study that included biopsies in patients with proteinuria, Amer et al25 found that 45% had allograft nephropathy, 8% had transplant glomerulopathy, and 5% had acute rejection. Thus, 58% of patients with more than 150 mg/d of protein excretion had transplant-specific diagnoses on biopsy compared with only 11% of patients who had glomerulonephritis.25 This finding has important implications when evaluating therapies to decrease proteinuria in kidney transplant recipients given that most studies of the nontransplant population have involved patients with diabetic nephropathy and glomerulonephritis.35, 36

Patient and Allograft Survival in Kidney Transplant Recipients With Proteinuria 

As in the nontransplant setting, proteinuria has been associated with worse kidney survival in kidney transplant recipients. In a study involving 337 patients, Sancho et al26 showed that proteinuria (> 0.5 g/d) was associated with a 5-year graft survival rate of only 69% compared with 93% for those without proteinuria. Similarly, Park et al23 found that patients with proteinuria greater than 1 g/d had a significant decrease in 5-year graft survival compared with those with no proteinuria (69.4% versus 86.5%; P < 0.01). Because graft survival is influenced by many factors, such as baseline kidney function, donor and recipient age, hypertension, and donor type, among others, it is important to determine the association between proteinuria and graft loss after controlling for such variables. Table 4 lists studies that have analyzed patient and graft survival after adjusting for potential confounding variables. Modeled as a categorical variable, proteinuria has been associated with a significantly greater risk of graft loss5, 19, 27, 28 (Table 4). In these studies, the average hazard ratio for graft failure in proteinuric patients was increased greater than 3-fold and ranged from 2.03 to 5.345, 19, 27, 28 (Table 4). Analyzed as a continuous variable, proteinuria also was associated with graft loss.20, 25, 37 Amer et al25 showed that the risk of graft loss increased 27% for each 1-g/d increase in 24-hour protein excretion. They also showed that the presence of glomerular disease on biopsy was associated with graft loss (adjusted hazard ratio, 1.58; 95% CI, 1.02 to 2.47).25 This important study was the first to show that proteinuria, independent of glomerular pathological state on biopsy and glomerular filtration rate, was associated with decreased kidney transplant survival.25 In the nontransplant setting, it has been suggested that proteinuria itself can promote injury by causing the tubules to release chemokines and cytokines leading to interstitial inflammation and fibrosis.1 It is unknown whether the detrimental effect of proteinuria on allograft survival is caused by this same mechanism.

Table 4. Association Between Proteinuria and Patient and Allograft Survival

	Reference (country)	Total Sample Size	Proteinuria Variable in Model	Adjusted Hazard Ratio for Allograft Loss (95% confidence interval)	Adjusted Hazard Ratio for Patient Death (95% confidence interval)
	Fontan et al,38 1999 (Spain)	560	Proteinuria (0.2-0.5 g/d) v none	2.30(1.10-5.40)	1.40(0.20-11.10)
			Proteinuria (0.5-2.0 g/d) v none	2.30(1.30-4.10)	1.20(0.40-4.50)
			Proteinuria (>2.0 g/d) v none	3.10(1.40-7.30)	8.60(2.60-29.0)
	Roodnat et al,28 2001 (The Netherlands)	722	Proteinuria (>0.2 g/L) v none	2.03(1.50-2.76)	1.98(1.44-2.72)
	Fernandez-Fresnedo et al,5 2002 (Spain)	532	Proteinuria (>0.5 g/d) v none	4.18(3.06-5.71)	1.92(1.27-2.89)
	Fernandez-Fresnedo et al,19 2004 (Spain)	3,365	Proteinuria (0.5-1.0 g/d) v none	2.33(1.80-3.02)	2.05(1.40-3.01)
			Proteinuria (>1.0 g/d) v none	3.47(2.74-4.40)	2.30(1.56-3.40)
	Halimi et al,20 2005 (France)	484	Per 0.1 g/d of proteinuria	1.15(1.10-1.21)	—
	Fellstrom et al,37 2005(Europe, Canada)	1,052	Per 1.0 g/d of proteinuria	1.76(1.55-1.98)	—
	Ibis et al,27 2007 (Turkey)	130	Proteinuria (>0.3 g/d) v none	5.34(1.49-19.05)	—
	Amer et al,25 2007 (United States)	613	Per 1.0 g/d of proteinuria	1.27(1.13-1.43)	—

Proteinuria also is associated with decreased patient survival in the kidney transplant population. Table 4 lists several studies examining the risk of patient death in those with abnormal proteinuria. Except for the study by Fontan et al,38 hazard ratios for patient death were fairly consistent across the studies and increased an average of 2-fold compared with those without proteinuria. In the study by Fontan et al,38 only proteinuria greater than 2 g/d was associated with patient survival, whereas amounts less than this were not predictive of mortality (Table 4). Roodnat et al28 found that proteinuria, modeled either continuously or discretely, was associated with an increased risk of patient death. For each 1-g/d of protein increase in proteinuria, the risk of death increased by 16% (P = 0.0001) after controlling for age, race, diabetes, and hypertension.28 Proteinuria was associated with an increased risk of both cardiovascular death (relative risk, 2.27; P < 0.0001) and noncardiovascular death (relative risk, 1.81; P = 0.025).28 Fernandez-Fresnedo et al5 showed that proteinuria not only was associated with patient survival, but also was predictive of cardiovascular events (ischemic heart disease and cerebrovascular or peripheral vascular disease). They found that proteinuria increased the relative risk of new cardiovascular events by 2.45 (95% CI, 1.66 to 3.62).5 As the level of proteinuria progressed (0.5 to 1, 1 to 3, and > 3 g/d), the relative risk of new cardiac events increased significantly from 1.45 (95% CI, 0.85 to 2.45) to 1.85 (95% CI, 1.1 to 2.96) to 2.88 (95% CI, 1.47 to 5.61).5

Risk Factors for the Development of Proteinuria 

Defining specific independent risk factors for proteinuria after kidney transplant has been limited by methodological issues in many articles published to date. Amer et al25 found that both systolic (r = 0.219; P = 0.018) and diastolic (r = 0.117; P = 0.048) blood pressure and serum creatinine level (r = 0.326; P < 0.0001) were associated with increasing levels of proteinuria. In addition, female donor, male recipient, and patients with acute rejection were found to have greater levels of proteinuria.25 However, adjustment for kidney function, antihypertensive medication use, and other potential confounding variables was not performed. In univariate analysis, Halimi et al20 found that donor age, donor cardiovascular death, warm ischemia time, and cold ischemia, but not delayed graft function, were associated with proteinuria at 3 months. They also found a univariate correlation with serum creatinine level and proteinuria (r = 0.3; P < 0.0001) at 1 year, but again, no multivariate adjustment was performed in this study.20 Sancho et al26 showed that proteinuric patients were more likely to have had delayed graft function (53.4% versus 31.2%; P = 0.001), but not acute rejection (27.2% versus 19.0%; P = 0.14). They also found that systolic blood pressure, body mass index, and serum creatinine level were significantly greater in proteinuric transplant recipients on univariate testing.26 Fernandez-Fresnedo et al19 showed that increasing levels of proteinuria were associated with significantly greater systolic blood pressure, diastolic blood pressure, and serum creatinine levels. In addition, they found that proteinuria was greater in patients with delayed graft function and acute rejection; however, again, no adjustment for confounding variables was performed.19 Fontan et al38 showed that delayed graft function, donor age, HLA sensitization, and acute rejection were independent predictors of proteinuria at 3 months in a multivariate-adjusted logistic regression model. Delayed graft function and serum creatinine level, both predictors in univariate analysis, were not significant after adjustment.38 Similar studies, with adjustment of important confounding variables, are needed to further clarify which clinical variables are truly associated with the development of proteinuria posttransplant.

Sirolimus and Posttransplant Proteinuria 

Unlike calcineurin inhibitors and mycophenolate compounds, sirolimus has been associated with proteinuria in kidney transplant recipients.39 This observation was noted first in patients with chronic allograft nephropathy when calcineurin-inhibitor therapy was switched to sirolimus therapy in an effort to preserve kidney function.40, 41, 42, 43 Letavernier et al44 reported on 68 kidney transplant recipients switched from a calcineurin inhibitor to sirolimus therapy. Baseline proteinuria was 0.39 ± 0.69 g/d and increased significantly to 1.44 ± 1.90 g/d by 3 months (P < 0.001).44 The increase in proteinuria persisted at 6, 12, and 24 months of therapy with sirolimus.44 At baseline, 10.3% had proteinuria greater than 1 g/d, but this increased to 46.3% by 1 year after conversion.44 Interestingly, 19 patients were switched back from sirolimus to calcineurin-inhibitor therapy because of side effects. In this group of patients, proteinuria subsequently decreased significantly from 1.95 ± 2.06 to 0.9 ± 1.41 g/d (P = 0.001).44 Ruiz et al40 reported similar findings for 149 kidney transplant recipients converted to sirolimus therapy at 5 Spanish centers. Overall, 69% had an increase in proteinuria after conversion, and average 24-hour urine protein excretion increased from 864 to 1,541 mg/d (P = 0.001).40 They also showed that patients with minimal proteinuria (< 300 mg/d) had significant worsening in mean protein excretion from 145 to 669 mg/d (P < 0.001) after the introduction of sirolimus therapy.40 Initially, it was suggested that the worsening proteinuria was caused by a hemodynamic effect induced by removing the vasoconstrictive calcineurin inhibitor. This was a reasonable hypothesis given that worsening proteinuria has been described in both heart45 and kidney46 transplant recipients who had cyclosporine therapy withdrawn, but were not given sirolimus.

A direct role of sirolimus, rather than a hemodynamic effect of calcineurin withdrawal, has emerged as a more likely hypothesis after reports of significant proteinuria in transplant recipients never exposed to tacrolimus or cyclosporine. van den Akker et al47 showed that patients randomly assigned to sirolimus conversion for skin cancer had a significant increase in proteinuria compared with control patients (1.81 ± 1.73 versus 0.29 ± 0.35 g/d; P < 0.005). Most patients in this study were converted from azathioprine therapy and were not receiving a calcineurin inhibitor.47 Diekmann et al48 reported on the development of proteinuria in 33 de novo kidney transplant recipients who received sirolimus and mycophenolate mofetil without a calcineurin inhibitor. Mean proteinuria at 1 year was significantly greater in the sirolimus group compared with the control group that received mycophenolate mofetil and prednisone (461 versus 270 mg/d; P = 0.017).48 Stephany et al49 compared 78 de novo kidney transplant recipients who received sirolimus, mycophenolate mofetil, and prednisone with 106 patients who received a standard calcineurin-inhibitor regimen. At 1 year, 37.8% of sirolimus-treated patients had protein excretion greater than 100 mg/dL on dipstick compared with only 18.4% in the calcineurin group (P = 0.004).49 On multivariate analysis, sirolimus use was independently associated with an increased odds of proteinuria at 1 year (odds ratio, 4.18; P = 0.002).49

It has been suggested that sirolimus-induced proteinuria is caused by decreased tubular reabsorption of filtered proteins.50 However, this hypothesis recently has been challenged by the finding that neither receptor-mediated endocytosis nor postendocytic processing is impaired in proximal tubular cells exposed to sirolimus.51 Although tubular defects may contribute, evidence appears to be favoring a glomerular origin for sirolimus-induced proteinuria. Kidney biopsy findings from patients with proteinuria on sirolimus therapy have shown classic glomerular diseases, including focal segmental glomerulosclerosis, minimal change, immunoglobulin A nephropathy, and membranous and membranoproliferative glomerulonephritis.52, 53, 54 Vascular endothelial growth factor, a potent enhancer of vascular permeability, was overexpressed in podocytes of a patient with focal segmental glomerulosclerosis and sirolimus-induced proteinuria.55 In addition, urine electrophoresis has confirmed a glomerular pattern with mostly albumin,39, 40 and many studies have reported new-onset nephrotic-range proteinuria after the introduction of sirolimus therapy.41, 48, 50, 52, 56, 57 Although most reports of proteinuria have been with sirolimus therapy, this likely is a class effect because similar increases in proteinuria have been reported with everolimus, another mammalian target of rapamycin (mTOR) inhibitor.58

Albuminuria in Kidney Transplant Recipients 

Only recently has the role of albuminuria been evaluated after kidney transplant. Hor and Baldwin59 measured albumin-creatinine ratios in 104 patients with pretransplant or posttransplant diabetes mellitus. They found that only 30% had a normal ratio, 43% had microalbuminuria (30 to 300 mg/g), and 27% had macroalbuminuria (>300 mg/g).59 Systolic blood pressure, glycated hemoglobin level, and serum creatinine level significantly correlated with albumin-creatinine ratio. For example, those in the the lowest quartile of systolic blood pressure (mean, 119 mm Hg) had a mean albumin-creatinine ratio of 73 mg/g, whereas those in the highest blood pressure quartile (mean, 150 mm Hg) had a ratio of 545 mg/g (P < 0.01).59 Amer et al25 measured 24-hour urine albumin excretion in 166 kidney transplant recipients at 1 year. In patients with no proteinuria (protein < 150 mg/d), 19% had abnormal albuminuria (albumin > 30 mg/d).25 For patients with up to 500 mg/d of protein excretion, 84% had evidence of abnormal albuminuria.25

Halimi et al60 measured 24-hour albumin excretion in 616 kidney transplant recipients at a minimum of 6 months posttransplant. Overall, 47.1% had normal albumin excretion, 39.8% had microalbuminuria (albumin, 30 to 299 mg/d), and 13.1% had macroalbuminuria (albumin ≥ 300 mg/d).60 Of 219 patients who had no proteinuria, 86% had normal albumin excretion and 14% had microalbuminuria.60 As seen in the analysis by Hor and Baldwin,59 increasing amounts of albuminuria were associated with significantly greater systolic blood pressures (P < 0.0001) and serum creatinine concentrations (P < 0.0001).60 After controlling for several important factors, including kidney function, age, blood pressure, and acute rejection, the presence of microalbuminuria increased the odds of graft loss by a factor of 10.19 (95% CI, 2.67 to 38.86; P = 0.0007).60 When analysis was restricted to 219 patients without proteinuria, microalbuminuria remained an independent predictor of allograft failure (odds ratio, 24.96; P = 0.039).60 These investigators also examined the relationship between albuminuria and patient death. In their fully adjusted model, microalbuminuria increased the odds of death by 4.81 (95% CI, 2.08 to 11.13; P = 0.0003).60 Interestingly, they found that microalbuminuria increased the risk of both cardiovascular- (odds ratio, 6.67; 95% CI, 1.72 to 25.93; P = 0.006) and malignancy-related (odds ratio, 8.43; 95% CI, 2.52 to 28.19; P = 0.0005) death, suggesting that albuminuria may be a marker of generalized endothelial dysfunction and inflammation, as in the general population.60

In a post hoc analysis of the Assessment of Lescol in Renal Transplantation (ALERT) trial, Fellstrom et al37 showed that 24-hour albumin excretion was significantly greater in those who reached a renal end point of graft loss or doubling of serum creatinine level compared with those who did not (0.522 versus 0.143 g/d; P < 0.0001). On univariate analysis, each 1-g/d increase in albumin excretion was associated with an increased risk of graft loss or doubling of serum creatinine level (relative risk, 2.24; 95% CI, 1.71 to 2.93; P < 0.0001), as well as an increased risk of graft loss, doubling of serum creatinine level, or death (relative risk, 1.88; 95% CI, 1.48 to 2.39; P < 0.0001).37 However, on multivariate analysis that controlled for many important factors, including total proteinuria, kidney function, blood pressure, diabetes, and age, albuminuria was no longer associated with graft failure or patient death.37 Given the conflicting data from Halimi et al60 and Fellstrom et al,37 additional studies are needed to clarify the independent association of albuminuria with patient and allograft survival.

Management of Proteinuria in Kidney Transplant Recipients 

In the nontransplant population, the goals of proteinuria reduction include symptom management (eg, controlling edema), prevention of proteinuria-related complications (eg, hyperlipidemia and venous thrombosis), and delaying progression to end-stage renal disease. The last goal has become a major focus in the nontransplant population because there is solid evidence from randomized trials that a decrease in proteinuria leads to improved renal outcomes.61, 62 Decreasing proteinuria can be achieved by using several different strategies. Data from randomized trials in nontransplant patients show that blood pressure reduction, sodium restriction, protein restriction, and treatment with ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists, nondihydropyridine calcium channel blockers, pentoxifylline, direct renin inhibitors, and combinations of these agents can effectively decrease proteinuria.36, 63, 64, 65, 66, 67, 68, 69, 70 More importantly, many of these treatments also have delayed the development of such clinically important outcomes as doubling of serum creatinine level or need for dialysis therapy.35, 36, 63 Unfortunately, a similar body of evidence based on randomized trials is not available for the transplant population. Although there are compelling theoretical reasons for blockade of the renin-angiotensin system in kidney transplant (eg, the presence of proteinuria, high cardiovascular morbidity and mortality, and constant hyperfiltration with a single kidney), it still is not known whether ACE-inhibitor or angiotensin receptor blocker use, a standard therapy in nontransplant proteinuric kidney disease, will improve patient or graft survival in kidney transplant recipients.

Observational studies have produced conflicting results about the effectiveness of renin-angiotensin system blockade in the kidney transplant population. Heinze et al71 showed that ACE-inhibitor or angiotensin receptor blocker use was associated with a significant improvement in both patient and graft survival in a cohort of 2,031 kidney transplant recipients. They found no significant interaction with baseline proteinuria, suggesting that the beneficial effect was observed in patients with and without proteinuria.71 However, greater levels of proteinuria predicted the use of an ACE inhibitor or angiotensin receptor blocker in a propensity score model.71 In contrast, Opelz et al72 showed that ACE-inhibitor or angiotensin receptor blocker use did not have a significant effect on patient or graft survival in an analysis involving 17,209 kidney transplant recipients. In subgroup analysis involving patients deemed to be at high cardiac risk (patients with diabetes or age ≥ 60 years), there still was no beneficial effect of ACE-inhibitor or angiotensin receptor blocker use.72 Unfortunately, data for proteinuria were not available in this analysis.72

Hiremath et al73 conducted a systematic review of randomized trials evaluating renin-angiotensin system blockade in the kidney transplant population. A total of 21 trials involving 1,549 patients were included in the analysis. Only 4 trials reported proteinuria that could be included in the analysis, and although all reported a decrease in proteinuria with renin-angiotensin system blockade, the pooled estimate was not statistically significant (weighted mean difference, −0.23 g/d of protein; 95% CI, −0.52 to 0.06; P = 0.12).73 When analysis was restricted to parallel trials with at least 1 year of follow-up, use of an ACE inhibitor or angiotensin receptor blocker was associated with a significant decrease in proteinuria (weighted mean difference, −0.47 g/d of protein; 95% CI, −0.86 to −0.08; P = 0.02).73 Only 1 trial, the Study on Evaluation of Candesartan Cilexetil After Renal Transplantation (SECRET), reported patient or graft survival. In this study, 502 kidney transplant recipients were randomly assigned to candesartan or placebo treatment and followed up for a median of 23 months. Cardiovascular events, graft failure, and creatinine level doubling occurred infrequently, but were not significantly different between groups.74 Patients who received candesartan had a significant decrease in proteinuria compared with the placebo group (27% versus 15%; P < 0.001).74 However, no data for absolute values of proteinuria were reported, and it was not specified whether proteinuria was a requirement for study entry.74 In addition, it is not clear whether these patients were at high risk of progressive chronic kidney disease because no data for comorbid illness, diabetic status, baseline kidney function, or proteinuria were provided. Unfortunately, this study was terminated early after the observed event rate was lower than expected. To date, this trial has only been published in abstract form in 2004.74

Although only 1 trial reported allograft survival, 12 studies reported glomerular filtration rate in the systematic review.73 The pooled estimate showed that the decrease in glomerular filtration rate was significantly greater in patients using an ACE inhibitor or angiotensin receptor blocker compared with controls (weighted mean difference, −5.7 mL/min; 95% CI, −8.7 to −2.8; P < 0.001).73 This finding was not unexpected given the known acute hemodynamic effects of ACE inhibitors and that many trials had relatively short follow-up. However, when analysis was restricted to parallel trials with at least 1 year of follow-up (median, 27 months), results were almost identical (weighted mean difference, −5.8 mL/min; 95% CI, −10.6 to −0.99; P = 0.02).73 In addition to the lower glomerular filtration rate with renin-angiotensin system blockade, significant anemia was found in the systematic review. In trials with more than 1 year of follow-up, the decrease in hematocrit was significantly greater in those using an ACE inhibitor or angiotensin receptor blocker (weighted mean difference, −3.5%; 95% CI, −6.1 to −0.95; P = 0.007).73 The well-known increase in serum creatinine level that may occur after ACE-inhibitor use might cause additional diagnostic concerns in kidney transplant recipients because this could be caused by acute rejection or polyomavirus nephropathy, rather than a drug-induced decrease in glomerular filtration rate. This might prompt additional investigations that would not normally occur in the nontransplant setting.

A randomized trial has been performed evaluating the protective effects of losartan in the kidney transplant population (ALLOGRAFT Study).75, 76 In this trial, 367 kidney transplant recipients were randomly assigned to placebo or losartan therapy (50 mg) between 4 and 8 weeks posttransplant. Treatment was for 2 years, and the primary outcome was incidence of chronic allograft nephropathy. Although patient and graft survival were not reported, mean serum creatinine levels at 2 years were similar (1.42 versus 1.41 mg/dL; P = 0.87), as were patients who developed doubling of creatinine level (3.9% versus 5.4%; P = 0.51) in the losartan and placebo groups, respectively.75 Despite a significantly lower systolic blood pressure with losartan (129.7 versus 132.7 mm Hg; P = 0.02), there was no difference in median 24-hour albumin excretion between the losartan and placebo groups (100 versus 110 mg; P = 0.12).75 Four patients in the losartan group and 12 patients in the placebo group developed proteinuria greater than 1 g/d, which was borderline significant (hazard ratio, 0.35; 95% CI, 0.11 to 1.04).75 More importantly, the incidence of chronic allograft nephropathy (losartan, 56.7% versus placebo, 52.8%; P = 0.596), as well as the severity of chronic allograft nephropathy, was not significantly different between groups.75 To date, this trial has not been published in a peer-reviewed journal.75, 76

Although it might be assumed that kidney transplant recipients would have the same benefit as nontransplant patients with renin-angiotensin system blockade, the data presented show that this still is not known. Data from the systematic review suggest that, at least in the short term, kidney transplant recipients administered an ACE inhibitor or angiotensin receptor blocker have a significant decrease in proteinuria, but also have a clinically important decrease in kidney function and hematocrit that cannot be ignored. A decrease in hemoglobin level similar to that found in the systematic review has been associated with a 24% increased risk of congestive heart failure and 16% increased risk of death in the kidney transplant population.77 To address the issue of whether proteinuric kidney transplant recipients will benefit from long-term ACE inhibition independent of blood pressure control, a multicenter randomized trial of ramipril versus placebo has been initiated in Canada.78 This trial plans to randomly assign 528 patients, and the primary outcome is a composite measure incorporating time to doubling of serum creatinine level, allograft failure, or death.78 Until results of this trial or similar trials powered to detect important clinical end points are available, it is premature to recommend treatment with an ACE inhibitor or angiotensin receptor blocker with the specific intent of decreasing allograft failure or patient death in the kidney transplant population.

Of the other possible strategies known to decrease proteinuria noted previously, only dietary protein restriction has been evaluated in randomized trials in the kidney transplant population. Two randomized crossover trials were published more than 10 years ago that produced similar findings.79, 80 Protein restriction of either 0.7 or 0.55 g/kg/d produced a statistically significant decrease in proteinuria and albuminuria.79, 80 However, the crossover design in these studies prevented examination of the effect on long-term kidney function or allograft survival. Although these trials reported positive findings, it is not clear whether a similar effect would be seen in an era with much stricter blood pressure control. In addition, the potential deleterious effect of protein restriction on overall nutritional status in the transplant population would need to be addressed thoroughly before this therapy could be recommended.

Conclusion 

Proteinuria and albuminuria are found commonly in kidney transplant recipients. Studies conducted in the early posttransplant period confirm that native kidney proteinuria decreases after transplant and persisting or increasing proteinuria should be assumed to be from the allograft. Biopsy studies have shown that causes of proteinuria in transplant recipients are very different from those in the nontransplant population. More than half the patients with proteinuria who undergo biopsy have either allograft nephropathy, transplant glomerulopathy, or acute rejection, diagnoses unique to kidney transplant recipients. Most studies to date have confirmed that proteinuria after kidney transplant is associated with decreased patient and allograft survival, as well as increased risk of cardiovascular events. There currently are fewer data regarding the prognostic value of albuminuria, and studies are conflicting about whether albuminuria is associated independently with graft loss or patient death. Proteinuria decrease can be achieved with ACE inhibitors, angiotensin receptor blockers, or dietary protein restriction in kidney transplant recipients. Whether a treatment-induced proteinuria decrease, such as from an ACE inhibitor, will result in improved patient and allograft survival is unknown and the subject of an ongoing randomized trial.