SEARCH

SEARCH BY CITATION

Keywords:

  • Kidney transplantation;
  • residual native kidney proteinuria;
  • source of post-transplant proteinuria

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

To assess the contribution of the protein content of urine from the native kidneys to post-transplant proteinuria, we prospectively studied 14 live donor transplant recipients with a pre-transplant random urine protein to creatinine ratio (UPr:Cr) >0.5. Seven patients received preemptive transplants, and seven patients were on dialysis pre-transplant (with residual urine output). Resolution of proteinuria was defined as UPr:Cr < 0.2. Immunosuppression consisted of tacrolimus, mycophenolate mofetil and corticosteroids. Anti-hypertensive drugs that might reduce proteinuria were avoided during the study. The serum creatinine was 8.7 ± 0.7 mg/dL pre-transplant, and the nadir post-transplant serum creatinine was 1.4 ± 0.1 mg/dL. The pre-transplant UPr:Cr ranged between 0.5 and 9.2 (mean = 2.9 ± 0.6). The UPr:Cr decreased to <0.2 in all 14 patients at a mean of 4.5 weeks post-transplant (range 1–10 weeks). In conclusion, in live donor renal transplant recipients with immediate graft function, proteinuria of native kidney origin resolves in the early post-transplant period. After the immediate post-transplant period, proteinuria cannot be attributed to the native kidneys, and work up for proteinuria should focus on the allograft.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

Recent studies have shown the advantage of preemptive renal transplantation over transplantation after dialysis for both patient and allograft survival. In addition, the duration of dialysis preceding renal transplantation has been shown to be an independent risk factor for inferior post-transplant outcomes (1–3). As a result, an increasing proportion of patients with end-stage renal disease are now receiving preemptive transplants, and transplant programs are also attempting to minimize the period of dialysis pre-transplant.

Preemptively transplanted patients and patients receiving transplants after being on dialysis only for a short time usually have significant residual native renal function and urine output. The mean glomerular filtration rate (GFR) has been reported to be 9.9 mL/min at the time of preemptive transplantation (3). At this level of GFR, the urine output from the native kidneys is well maintained and contains increased amounts of protein as a result of the native renal disease. The source of proteinuria following renal transplantation could, therefore, be the diseased native kidneys with residual urine output or the transplanted kidney affected by a variety of disorders such as delayed graft function, various forms of rejection, calcineurin-inhibitor nephrotoxicity and recurrent or de novo renal diseases (4,5). Delineation of the source of proteinuria (native kidneys versus allograft) is important for appropriate management.

The aims of our study were to determine the course of proteinuria of native kidney origin following transplantation and to identify the post-transplant period beyond which proteinuria cannot be attributed to the native kidneys.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

Patients

We prospectively evaluated 14 live donor renal transplant recipients. Seven of these patients received preemptive transplants and the other seven patients received transplants (with residual native urine output) after a period of dialysis ranging from 3 to 24 months. The study was approved by our institutional review board.

In each patient, the random urine protein to creatinine ratio (UPr:Cr) was determined between 4–14 days prior to and every 7–14 days following transplantation till the proteinuria resolved completely. Complete resolution of proteinuria was defined as UPr:Cr of ≤0.2. In the seven patients in the dialysis group, pre-transplant UPr:Cr was obtained between 1 and 3 days post-dialysis to avoid the effect of changing urinary creatinine levels following dialysis. To confirm the reliability of the UPr:Cr as a surrogate for the total daily urinary protein excretion, in two of the 14 patients 24-h urine collections were obtained pre- and post-transplant (after the UPr:Cr had decreased to ≤0.2), and the total protein content of these collections was measured. Two other patients had diethylenetriaminepentaacetate (DTPA) isotopic renograms of their native kidneys performed pre- and post-transplant (after the UPr:Cr had decreased to ≤0.2). In ten of the 14 study patients, the random urine albumin to creatinine ratio was measured 2–6 months after the nadir UPr:Cr had been reached. No patient was on anti-hypertensive drugs that might decrease proteinuria, such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers and non-dihydropyridine calcium channel blockers, during the study period.

Immunosuppression

The immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil and corticosteroids ± induction therapy with rabbit anti-lymphocyte globulin (Thymoglobulin®) or basiliximab (Simulect®). Target trough tacrolimus level was between 10 and 15 ng/mL during the first three post-transplant months and 5–10 ng/mL thereafter. All episodes of rejection were biopsy confirmed.

Statistical analysis

Results are expressed as mean ± standard error. The statistical significance of differences in the serum creatinine levels, GFR (calculated using the abbreviated Modification of Diet in Renal Disease study [MDRD] formula) and UPr:Cr before and after transplant was analyzed with the paired t-test using Stat View 5.0.1 (SAS Institute Inc., Cary, NC). p < 0.05 was considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

The demographic data and etiology of end-stage renal disease of the study patients are shown in Table 1. Renal allograft function improved rapidly following transplantation without the need for dialysis in all patients. The nadir post-transplant serum creatinine level was reached within 3 to 7 days in 12 patients and in 11 days in two patients. At the time the first post-transplant urine sample for measurement of the UPr:Cr was collected, the serum creatinine level had been stable at the nadir value for the preceding 3–7 days in all patients. The pre- and post-transplant serum creatinine levels and MDRD GFR values are shown in Figure 1. The trough tacrolimus level 4 weeks post-transplant was 10.1 ± 0.5 ng/mL.

Table 1.  Recipient demographics
Age (years)44 (range 21–70)
Gender (M:F)10:4
Dialysis pre-transplant
 Yes7
 No7
Type of donor
 Live related10
 Live unrelated4
Cause of renal failure
 Hypertension4
 Diabetes mellitus4
 IgA nephropathy1
 Focal segmental glomerulosclerosis1
 Reflux nephropathy1
 Henoch-Schonlein purpura1
 Membranous nephropathy1
 Chronic glomerulonephritis1
image

Figure 1. (A) Serum creatinine level pre-transplant and nadir post-transplant in the total study population. (B) The MDRD glomerular filtration rate (GFR) pre-transplant and peak post-transplant in the seven preemptive transplant recipients.

Download figure to PowerPoint

Resolution of native kidney proteinuria occurred in all patients at a mean duration of 4.5 week-post-transplant with a range of 1–10 weeks as shown in Figure 2. In the total study population (N = 14), the pre-transplant UPr:Cr of 2.9 ± 0.6 (range 0.5–9.2) decreased to 0.13 ± 0.1 post-transplant (p = 0.0007). As shown in Figure 3, the UPr:Cr in the seven patients who were on dialysis prior to transplantation decreased from 2.7 ± 0.7 pre-transplant to 0.14 ± 0.02 post-transplant (p = 0.012). In the seven preemptive transplant recipients, the UPr:Cr decreased from 3.2 ± 1.0 pre-transplant to 0.14 ± 0.2 post-transplant (p = 0.028) as shown in Figure 4.

image

Figure 2. Course of the random urine protein to creatinine ratio (UPr:Cr) in the entire study population (N = 14). Pre-transplant UPr:Cr ranged between 0.5 and 9.2 and normalized (<0.2) in all patients. The Nadir UPr:Cr was reached at a mean of 4.5 weeks post-transplant with a range of 1–10 weeks. The number of patients with UPr:Cr measurements at each time interval was as follows: Pre = 14; 1wk = 5; 2wk = 7; 3wk = 11; 4wk = 10; 5wk = 11; 6wk = 9; 7wk = 3; 8wk = 2; 9wk = 3; and 10wk = 2.

Download figure to PowerPoint

image

Figure 3. The random urine protein to creatinine ratio (UPr:Cr) pre-transplant and nadir post-transplant in the seven patients on dialysis prior to transplantation.

Download figure to PowerPoint

image

Figure 4. The random urine protein to creatinine ratio (UPr:Cr) pre-transplant and nadir post-transplant in the seven preemptive transplant recipients.

Download figure to PowerPoint

In the two patients (both recipients of preemptive transplants; cause of native renal disease diabetic nephropathy in one and hypertensive nephrosclerosis in the other) in whom 24-h urine collections were obtained; the daily protein excretion decreased from 3.1 and 1 g pre-transplant to 0.12 and 0.15 g in 3.4 and 6 weeks, respectively. The corresponding UPr:Cr in these two patients were 3.2 and 1.1 pre-transplant, and 0.13 and 0.14 post-transplant, respectively. Thus, the measured 24-h urine protein excretion in these two patients showed excellent correlation with the UPr:Cr values both pre- and post-transplant.

In all ten patients who were tested for microalbuminuria 2–6 months after normalization of the UPr:Cr, the random urine albumin to creatinine ratio was normal (15.5 ± 2 mg of albumin/gram of creatinine).

An episode of biopsy-proven acute rejection occurred in two study patients on post-transplant days 8 and 10, respectively. The Banff grading of rejection was 1B and 2A, respectively. Following successful treatment of the rejection episode, proteinuria resolved by 7 weeks post-transplant in these two recipients as well. We have observed one patient (not included in this study) in whom an elevated UPr:Cr persisted beyond 15 weeks post-transplant. This patient developed C4d-positive acute humoral rejection 31 days post-transplant. We think that the persistent proteinuria in this patient was the result of allograft glomerular damage secondary to rejection and not due to failure to resolve proteinuria of native kidney origin.

In the two patients who had pre- and post-transplant DTPA isotopic-renograms, radiotracer uptake in the native kidneys was significantly more intense in the pre-transplant images as shown in Figure 5, suggesting marked reduction in renal blood flow to the native kidneys following transplantation.

image

Figure 5. (A) DTPA renogram 1 week before transplant when the random urine protein to creatinine ratio (UPr:Cr) = 4.26. (B) Three weeks post-transplant, UPr:Cr ≤ 0.2. Marked decrease in isotope uptake by the native kidneys following transplantation is evident.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

The results of our study show that in spite of significant residual renal function and urine output at the time of transplantation, proteinuria of native kidney origin resolves within 1 to 10 weeks following successful live donor renal transplantation with immediate graft function. Thus, beyond the immediate post-transplant period, proteinuria appears to be exclusively of allograft origin in live donor transplant recipients. Whether similar resolution of proteinuria of native kidney origin occurs following deceased donor transplantation or whether delayed allograft function influences the time post-transplant at which proteinuria resolves remains to be established.

In the evaluation of native renal diseases, the UPr:Cr is increasingly replacing 24-h urine collection for quantifying protein excretion because the latter method is cumbersome and prone to collection errors. The reliability of the UPr:Cr as a surrogate for the 24-h urinary protein excretion is well established in both patients with native kidney diseases and in renal transplant recipients (6,7). One study, however, concluded that in kidney transplant recipients with daily urine protein excretion of >3.0 g, the UPr:Cr does not reliably correlate with values obtained by 24-h urine collection (8). However, the number of patients with this level of proteinuria in this study was too small to draw firm conclusions. We found excellent agreement between the UPr:Cr and the 24-h urinary protein in the two patients in whom both measurements were performed. Because of this and since the urine protein excretion did not exceed 3 g/day in any patient post-transplant, we believe that the UPr:Cr was a reliable surrogate for 24-h urine collection in our study.

Several studies over the past decade have shown that proteinuria is both a diagnostic marker and a mechanism for progression of renal failure in native kidney disease as well as the transplanted kidney (9–12). Proteinuria after transplantation is a strong predictor of graft and patient survival (13) and is an independent risk factor for cardiovascular disease (14). The delineation of the source of post-transplant proteinuria (native kidneys versus allograft) is, therefore, important for appropriate management. Proteinuria of allograft origin can develop in the early post-transplant period due to causes such as delayed graft function, acute rejection (cellular and/or humoral), calcineurin-inhibitor nephrotoxicity, thrombotic microangiopathy/hemolytic-uremic syndrome (de novo or recurrent) and rapid recurrence of native renal disease (especially focal segmental glomerulosclerosis) (5). Early post-transplant proteinuria in a patient with residual native kidney urine output might be erroneously attributed to the native kidneys. Our results are clinically important because they show that even in patients with significant residual renal function at the time of transplantation, proteinuria of native kidney origin resolves rapidly post-transplant. Thus, early post-transplant proteinuria persisting beyond a few weeks appears to be of allograft origin.

In interpreting our results, the effect of rapidly changing urinary creatinine levels on the UPr:Cr will have to be considered. By affecting the denominator of the UPr:Cr, a decrease in the urinary creatinine level will overestimate, and an increase in the urinary creatinine level will underestimate the actual urinary protein excretion. In the patients who were on dialysis prior to transplantation, we collected the pre-transplant urine sample 1–3 days following dialysis by which time the serum and urine creatinine levels would have stabilized. Thus, the measured pre-transplant UPr:Cr values in these seven dialyzed patients were unlikely to have been affected by the predictable decrease in the urinary creatinine level immediately following dialysis. The urinary creatinine level will increase as the serum creatinine level falls rapidly to its nadir value during the early post-transplant period. To avoid underestimation of the urinary protein excretion by the initial increase in the urinary creatinine level following establishment of allograft function, we ensured that the serum creatinine level was stable at its nadir value for 3 to 7 days (implying that the urinary creatinine excretion was also stable during the same period) in all our patients prior to the collection of the first post-transplant urine sample.

The reason(s) for the resolution of proteinuria of native kidney origin in the early post-transplant period is unclear. As discussed above, the rapid increase in urinary creatinine excretion with immediate graft function is an unlikely explanation for the post-transplant decrease in the UPr:Cr. The effect of the protein-free urine output from the allograft diluting the protein contained in the native kidney urine can also be discounted because the inclusion of both the urinary protein and creatinine concentrations in the UPr:Cr corrects for any dilutional effect. A number of studies performed in the pre-cyclosporine era have documented the resolution of proteinuria of native kidney origin within 12 to 120 days post-transplant (15–17). Thus, CNI-induced renal vasoconstriction causing cessation of urine output from the native kidneys is also an untenable explanation for the early resolution of native kidney proteinuria. Experimental studies have documented the presence of factor(s) in the blood of bilaterally nephrectomized animals that can induce renal hypertrophy/hyperfiltration in non-nephrectomized animals cross circulated with the nephrectomized animals (18). Furthermore, an extract of normal renal cortical tissue has been shown to have an inhibitory effect on compensatory renal hypertrophy when injected into uninephrectomized rats (19). Based on these experimental studies, we speculate that introduction of a structurally normal allograft might abolish hypertrophy, hyperfiltration and urine output in the remnant nephrons of native kidneys, possibly by suppressing the production of the putative renal hypertrophy-inducing humoral factor(s) or by releasing factor(s) that directly inhibit hyperfiltration and urine production in the native kidneys. Cessation of native kidney urine output regardless of the underlying mechanism(s) will result in the disappearance of proteinuria of native kidney origin post-transplant.

We limited our study to recipients of live donor renal transplants to ensure immediate graft function and to avoid the confounding effect that delay in the onset of renal function might have on our observations. Our findings, therefore, apply only to live donor transplant recipients with immediate graft function. Studies of deceased donor transplant recipients and patients with delayed graft function are needed before our findings can be extrapolated to all renal transplant recipients.

In conclusion, our results show complete resolution of proteinuria of native kidney origin at a mean duration of 4.5 weeks post-transplant (range of 1 to 10 weeks) in recipients of live donor kidney transplants with immediate graft function. Work up for post-transplant proteinuria should, therefore, be focused on the transplant kidney in contrast to work up for post-transplant hematuria and urinary tract infection which should focus on both the native and transplanted kidneys.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
  • 1
    Mange KC, Joffe MM, Feldman HI. Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors. N Engl J Med 2001; 344: 726731.DOI: 10.1056/NEJM200103083441004
  • 2
    Kasiske BL, Snyder JJ, Matas AJ, Ellison MD, Gill JS, Kausz AT. Preemptive kidney transplantation: The advantage and the advantaged. J Am Soc Nephrol 2002; 13: 13581364.DOI: 10.1097/01.ASN.0000013295.11876.C9
  • 3
    Mange KC, Weir MR. Preemptive renal transplantation: Why not? Am J Transplant 2003; 3: 13361340.DOI: 10.1046/j.1600-6143.2003.00232.X
  • 4
    Reichel H, Zeier M, Ritz E. Proteinuria after renal transplantation: Pathogenesis and management. Nephrol Dial Transplant 2004; 19: 301305.DOI: 10.1093/ndt/gfh002
  • 5
    Fontan MP, Rodriguez-Carmona A, Falcon TG, Valdes F. Early proteinuria in renal transplant recipients treated with cyclosporine. Transplantation 1999; 67: 561568.
  • 6
    Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med 1983; 309: 15431546.
  • 7
    Steinhauslin F, Wauters JP. Quantitation of proteinuria in kidney transplant patients: Accuracy of the urine protein/creatinine ratio. Clin Nephrol 1995; 43: 110115.
  • 8
    Torng S, Rigatto C, Rush DN, Nickerson P, Jeffery JR. The urine protein to creatinine ratio (P/C) as a predictor of 24-hour urine protein excretion in renal transplant patients. Transplantation 2001; 72: 14531456.DOI: 10.1097/00007890-200110270-00021
  • 9
    Peterson JC, Adler S, Burkart JM et al. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med 1995; 123: 754762.
  • 10
    GISEN. Randomized placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997; 349: 18571863.DOI: 10.1016/S0140-6736(96)11445-8
  • 11
    Barnas U, Schmidt A, Haas M et al. Parameters associated with chronic renal transplant failure. Nephrol Dial Transplant 1997; 12(Suppl 2): 8285.
  • 12
    Massy ZA, Guijarro C, Wiederkehr MR, Ma JZ, Kasiske BL. Chronic renal allograft rejection: Immunologic and nonimmunologic risk factors. Kidney Int 1996; 49: 518524.
  • 13
    Roodnat JI, Mulder PG, Rischen-Vos J et al. Proteinuria after renal transplantation affects not only graft survival but also patient survival. Transplantation 2001; 72: 438444.DOI: 10.1097/00007890-200108150-00014
  • 14
    Fernandez-Fresnedo G, Escallada R, Rodrigo E et al. The risk of cardiovascular disease associated with proteinuria in renal transplant patients. Transplantation 2002; 73: 13451348.DOI: 10.1097/00007890-200204270-00028
  • 15
    Laplante L, Beaudry C, Houde M. Early disappearance of proteinuria attributed to the original kidneys after kidney transplantation. Union Med Can 1975; 104: 246248.
  • 16
    Crosnier J, Antoine B, Dormont J, Debray-Sachs M, Leski M, Bach JF. Proteinuria in kidney transplantation. Bull Mem Soc Med Hop Paris 1967; 118: 233245.
  • 17
    Manuel Y, Poli S, Bernhardt JP, Revillard JP, Claudey D, Traeger J. Proteinuria in human renal allografts. Helv Med Acta 1969; 35: 319.
  • 18
    Dijkhuis CM, Van Urk H, Malamud D, Malt RA. Rapid reversal of compensatory renal hypertrophy after withdrawal of the stimulus. Surgery 1975; 78: 476480.
  • 19
    Dicker SE, Morris CA, Shipolini R. Regulation of compensatory kidney hypertrophy by its own products. J Physiol 1977; 269: 687705.