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Keywords:

  • glomerular filtration rate;
  • losartan;
  • microalbuminuria;
  • normotensive recipient;
  • renal transplantation

Abstract

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

Abstract  Aim:  Microalbuminuria is typically observed in renal transplant recipients with systemic hypertension. The effects of angiotensin II type 1 receptor antagonist (losartan) on the hypertensive recipients have been evaluated. However, the clinical background of normotensive recipients with microalbuminuria and the effect of losartan administration in those subjects have not been clarified. One of the two purposes for the present study was to investigate the clinical characteristics of normotensive recipients with microalbuminuria. The other was to evaluate the effect of losartan on urinary excretion of albumin in these patients.

Methods:  The clinical data and the change of the single kidney glomerular filtration rate (GFR) for the graft by radionuclide study were assessed in 13 normotensive recipients with microalbuminuria. These were compared with the data of 13 normotensive patients without microalbuminuria. The 13 recipients with microalbuminuria were treated with losartan for one year and urine excretion of albumin, N-acetyl-β-D-glucosaminidase (NAG) and serum creatinine (S-Cr) levels were measured.

Results:  The GFR of the grafts from donors to recipients significantly increased (30.9 to 55.2 mL/min) in microalbuminuric recipients, but did not significantly increase in the non-microalbuminuric recipients. Decreases of the urinary excretion rate of albumin (351 ± 261 at baseline to 158 ± 14 mg/gCr at 12 months), NAG (13 ± 5 to 10 ± 3 IU/gCr) and S-Cr (1.7 ± 0.6 to 1.5 ± 0.4 mg/dL) were observed in the microalbuminuric recipients with losartan administration.

Conclusions:  The present study suggests that an increased single kidney GFR of the graft from the donor in situ to the recipient might be a cause of microalbuminuria in normotensive recipients. The one-year effects of losartan were observed in terms of the decrease in urinary excretion of albumin, NAG and S-Cr levels.


Introduction

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

It has been suggested that the progression of chronic renal diseases may be mediated by glomerular hypertension and hyperfiltration states.1 Glomerular hyperfiltration in the remnant nephrons is associated with glomerular sclerosis.2 Conditions such as systemic hypertension, high protein intake and diabetes mellitus are known to enhance these hemodynamic alterations and accelerate progressive renal damage.3 In renal transplant  recipients,  glomerular  hyperfiltration  may  occur in conditions with a decreased nephron number due to previous episodes of acute rejection, prolonged ischemia, free-radical-mediated reperfusion injury, delayed graft function or drug induced nephrotoxicity either alone or in combination.4,5 Consequently, hyperfiltration nephropathy may play a pivotal role in the non-immunological event leading to late graft loss in renal transplantation.5

Glomerular hyperfiltration contributes persistent microalbuminuria.6 Microalbuminuria is recognized as the only biochemical marker for several diseases affecting the glomeurulus at early subclinical stage in diabetes mellitus, cardiovascular disease, reflux nephropathy and polycystic kidney.7–12 Therapeutic attenuation of glomerular hyperfiltration is important to prevent glomerular injury. Angiotensin converting enzyme inhibitors (ACEI) lower systemic blood pressure and glomerular capillary hydraulic pressure while preventing proteinuria, albuminuria and sclerosis in the hyperfiltrating kidneys, even in a normotensive state.13–17 Recently, angiotensin II type 1 receptor antagonist (AT1RA) was recognized as preventing proteinuria and progressive renal disease as well as ACEI.18 Also, antiproteinuric and microalbuminuric effects of AT1RA (losartan) have been reported in renal transplant recipients treated for systemic hypertension.19,20 Based on these reports, AT1RA may also have renoprotective effects in patients without systemic hypertension. However, the effect of long-term administration of losartan on urinary albumin excretion in normotensive renal transplant recipients has not been reported. Furthermore, clinical characteristics in normotensive renal transplant recipients with microalbuminuria remain to be clarified.

There were two purposes for the present study. One was to investigate the clinical characteristics of normotensive recipients with microalbuminuira compared with those without microalbuminuria. The other purpose was to evaluate the effect of a one-year administration of AT1RA on urinary excretion of albuminuria and other parameters in normotensive renal transplant recipients with microalbuminuria.

Methods

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

Patient selection

The criteria for patient selection in this study were: (i) anuria from native kidneys before transplantation; (ii) living donor transplantation; (iii) stable graft function; (iv) greater than 6 months graft survival after transplantation; (v) normotensive blood pressure (less than 140 mmHg in systolic and 80 mmHg in diastolic) without antihypertensive drugs; (vi) no prior treatment with AT1RA, ACEI, or angiotensin II receptor blocker; (vii) tacrolimus-based immunosuppression; and (viii) no recurrent or de novo glomerulonephritis proven by protocol graft biopsy. The inclusion of pretransplant anuria for criteria was designed to exclude urine protein, albumin and other excretions from the diseased native kidneys. Patients with diabetes mellitus and obvious clinical rejection episodes during the study period were also excluded.

Of the 73 renal transplant recipients at the Akita University School of Medicine, Japan, 26 recipients (16 men, 10 women) with a mean age of 38 ± 12 years and a mean post-transplant period of 35 ± 26 months matched the criteria. The 26 recipients were divided into two groups according to urinary albumin/creatinine ratio (ACR, mg/gCr) in sequential urine samples once per month as outpatients. Values over 30 mg/gCr of ACR are generally defined as microalbuminuria;21 however, in the present study, an ACR greater than 100 mg/gCr was defined as microalbuminuria. Thirteen recipients with an ACR greater than 100 mg/gCr for three successive months were regarded as normotensive recipients with microalbuminuria. Thirteen other recipients with an ACR of less than 100 mg/gCr were designated as being without microalbuminuria.

Study design

To investigate the characteristics of normotensive recipients with microalbuminuria compared with those without microalbuminuria, clinical data, biochemical parameters and changes in the single kidney glomerular filtration rate (GFR) from donor to recipient assessed by the radionuclide study were employed.

In the study of the effects of AT1RA administration, the 13 recipients with microalbuminuria were treated with losartan for longer than one year. They gave informed consent for the administration of AT1RA. Losartan was used with a single daily oral dose of 25 mg for the first month and 50 mg for the remainder of the administration period. The dose of losartan was decreased from 50 to 25 mg/day in two cases in which anemia occurred, possibly as a side-effect of losartan. Immunosuppressants were not changed during the study period.

Biochemical parameters and blood pressure measurement

The urinary concentrations of albumin (U-Alb), N-acetyl-β-D-glucosaminidase (U-NAG) and creatinine (U-Cr) were measured in single spot urine samples at 09.00 hours once per month, with serum creatinine (S-Cr) and hematocrit (Ht) levels measured at the same time. The U-Alb concentration was monitored by a photometric measurement of the antigen-antibody reaction using an immunoturbidimetric method (Wako, Osaka, Japan). The concentration of U-NAG was measured using an automated photometric assay system with 6-methyl-2-pyridyl-N-acetyl-l-thio-β-D-glucosaminide (Nittobo, Fukushima, Japan). Urinary creatinine concentrations were measured by routine techniques using an automatic analyzer (Hitachi 7170, Tokyo, Japan). Serum creatinine, Ht and other biochemical parameters such as serum electrolytes, uric acid, total serum protein and blood cell count were also measured by routine techniques using an automatic analyzer (Hitachi 7600, Tokyo, Japan) on the same day as collecting the urine samples. The ACR was calculated as U-Alb/U-Cr (mg/gCr). The excretion ratio of U-NAG (IU/gCr) was calculated in a similar fashion. The baseline levels of all biochemical parameters were obtained from the average levels for 3 months in the recipients without microalbuminuria and in those with microalbuminuria before the administration of losartan.

Blood pressure (BP) was measured at the outpatient unit. Blood pressure determinations were performed according to the World Health Organization recommendations. An automatic sphygmomanometer (TM2654, A & D, Tokyo, Japan) was used to perform two consecutive measurements at 2-minute intervals for the patients in the sitting position. The mean of the two determinations was used for calculations. Mean blood pressure (MBP) was calculated as ([systolic BP – diastolic BP]/3 + diastolic BP).

Single kidney glomerular filtration rate assessment by radionuclide study

Single kidney GFR was assessed using radionuclide imaging with 99mtechnetium diethylenetriamine pentaacetic acid (99mTc-DTPA). The normally hydrated preoperative donors and postoperative recipients were placed in the sitting-position within 3–6 months after transplantation for a computerized scintillation scan with the gamma-camera placed posteriorly and interfaced to a digital computer system. A bolus injection of 99mTc-DTPA (300 megabecquerel) was administered intravenously. The computer data acquisition was started soon after the completion of the radionuclide injection with the total acquisition time being 30 min. The values for individual renal uptake were calculated from the normalized time/activity curve for the each kidney within 3 min after the radionuclide injection. As reported previously, GFR was computed from this vascular phase renogram according to the formula developed by Gates.22,23 Single kidney GFR of the grafts was measured preoperatively in the donors and postoperatively in the recipients.

Statistical analyzes

Results are expressed as mean ± SD. Group differences for qualitative variables were performed by χ2 analysis. Comparisons of data between two groups were performed by unpaired Student's t-tests. Comparisons of data before and after the losartan administration in recipients with microalbuminuria were performed by paired Student's t-tests. Statistical significance was defined as a P-value < 0.05.

Results

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

Characteristics of patients and glomerular filtration rates

The clinical characteristics of normotensive recipients with microalbuminuria compared with those without microalbuminuria are shown in Table 1. There were no significant differences between the two groups regarding donor gender and age, recipient gender and age, body mass index of donor and recipient, transplant duration and the frequency of acute rejection before the initiation of the present study. Although there was no significant difference, a higher frequency of female donors to male recipients was observed in recipients with microalbuminuria. The baseline levels of ACR, S-Cr and Ht in recipients with microalbuminuria before losartan administration were higher than those in recipients without microalbuminuria (Table 2).

Table 1.  Clinical characteristics of the normotensive renal transplant recipients with microalbuminuira (Albuminuira) compared with those without microalbuminuria (Non-albuminuria)
 AlbuminuriaNon- albumiuriaP-value
  1. Values are expressed as mean ± SD. †From female donor to male recipient. AR, frequency of acute rejection before the initiation of this study; BMI, body mass index.

Number of patients1313 
Donor gender (% male)38.569.20.113
Recipient gender (% male)76.946.20.103
F to M (%)46.215.30.084
Donor age (years) 54 ± 14 49 ± 100.259
Recipients age (years) 36 ± 10 39 ± 150.482
Transplant duration (months) 41 ± 29 30 ± 220.267
BMI recipient 21 ± 2 22 ± 30.372
 Donor 22 ± 3 23 ± 30.191
 Recipient/ donor1.0 ± 0.20.9 ± 0.10.549
AR (time/ recipient)0.5 ± 0.70.3 ± 0.50.503
Table 2.  Clinical and biochemical data in recipients with microalbuminuria (Albuminuria) before losartan administration and those without microalbuminuria (Non-albuminuria)
 Albuminuria (n = 13)Non- albuminuira (n = 13)P-value
  1. Values are expressed as mean ± SD. Alb, albumin; Cr, creatinine; Ht, hematocrit; MBP, mean blood pressure; NAG, N-acetyl-β-D-glucosaminidase; U, urine.

U-Alb/U-Cr (mg/gCr) 351 ± 161  34 ± 390.0002
U-NAG/U-Cr (IC/gCr)13.4 ± 4.510.6 ± 3.50.1387
S-Cr (mg/dL) 1.7 ± 0.6 1.3 ± 0.30.0366
Ht (%)38.8 ± 8.531.9 ± 8.00.0413
MBP (mmHg) 107 ± 13 105 ± 140.6719

There was no significant difference in single kidney GFR for grafts between recipients with and without microalbuminuria before transplantation. In recipients with microalbuminuria, the mean GFR of the grafts significantly increased to 55.2 ± 29.1 mL/min in post-transplant recipients from 30.9 ± 10.0 mL/min in pretransplant donors. In contrast, there was no significant change between pre- and post-transplantation in the graft GFR of recipients without microalbuminuria (Fig. 1).

image

Figure 1. Changes in the single kidney glomerular filtration rate (GFR) for graft from donor (pre–transplant) to recipient (post–transplant) assessed by radionuclide study. The mean GFR significantly increased in recipients with microalbuminuria after transplantation, but not in those without microalbuminuria. *P < 0.05 compared with the pre–transplant levels. Values represent means ± SD. □, recipients with microalbuminuria; ▪, recipients without microalbuminuria.

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Alteration in ACR, U-NAG, S-Cr, blood pressure and hematocrit by losartan administration

The changes of clinical and biochemical data in recipients with microalbuminuria before and after losartan administration are shown in Table 3. The ACR in these recipients significantly decreased to 239 ± 204 mg/gCr 1 month after losartan introduction from 351 ± 261 mg/gCr at baseline and further decreased thereafter (199 ± 190 at 6 months and 158 ± 104 mg/gCr at 12 months). There was a significant decrease in the U-NAG excretion rates; from 13 ± 5 IU/gCr at baseline to 10 ± 3 IU/gCr at 6 months and 8 ± 3 IU/gCr at 12 months. The decreased ACR and U-NAG excretion rates after losartan administration was accompanied by a decrease in the S-Cr levels over 12 months (1.7 ± 0.6 mg/dL at baseline and 1.5 ± 0.4 mg/dL at 12 months). The Ht level and MBP did not significantly change during the study period.

Table 3.  Changes of clinical and biochemical data in recipients with microalbuminuria before and after losartan administration
MonthsBefore123456912
  1. Values are expressed as mean ± SD. Alb, albumin; Cr, creatinine; Ht, hematocrit; MBP, mean blood pressure; NAG, N-acetyl-β-D-glucosaminidase; NE, not examined; U, urine. *, P < 0.05 compared with the level before losartan administration.

U-Alb/U-Cr (mg/gCr)351 ± 261239 ± 204273 ± 240*235 ± 261*231 ± 196*228 ± 253*199 ± 190*172 ± 183*158 ± 104*
U-NAG/U-Cr (IC/gCr) 13 ± 5 12 ± 3 11 ± 5* 12 ± 5 11 ± 3* 10 ± 3* 10 ± 3* 10 ± 4* 8 ± 3*
S-Cr (mg/dL) 1.7 ± 0.6 1.5 ± 0.4* 1.6 ± 0.5* 1.5 ± 0.4* 1.5 ± 0.4* 1.5 ± 0.5* 1.5 ± 0.5* 1.5 ± 0.5* 1.5 ± 0.4*
Ht (%) 39 ± 9 41 ± 6 39 ± 8 41 ± 5 41 ± 4 42 ± 4 43 ± 4* 41 ± 4 42 ± 6
MBP (mmHg)107 ± 13NENE103 ± 11NENE102 ± 10NE107 ± 13

Changes of clinical and biochemical data in recipients without microalbuminuria before and after the initiation of the present study are shown in Table 4. There were no changes in ACR, U-NAG excretion rates, S-CR levels or MBP in the study period.

Table 4.  Changes of clinical and biochemical data in recipients without microalbuminuria before and after the initiation of this study
MonthsBefore123456912
  1. Values are expressed as mean ± SD. Alb, albumin; Cr, creatinine; Ht, hematocrit; MBP, mean blood pressure; NAG, N-acetyl-β-D-glucosaminidase; NE, not examined; U, urine. *, P < 0.05 compared with the level before the initial study.

U-Alb/U-Cr (mg/gCr) 34 ± 39 41 ± 72 44 ± 78 53 ± 108 33 ± 57 44 ± 73 40 ± 67 46 ± 70 37 ± 41
U-NAG/U-Cr (IC/gCr) 11 ± 4 11 ± 8 10 ± 5 10 ± 4 10 ± 5 12 ± 8 11 ± 5 11 ± 6 9 ± 4
S-Cr (mg/dL) 1.3 ± 0.31.3 ± 0.41.3 ± 0.5 1.3 ± 0.41.3 ± 0.41.2 ± 0.3 1.2 ± 0.31.2 ± 0.3 1.2 ± 0.3
Ht (%) 32 ± 8 33 ± 9 33 ± 8 34 ± 8 34 ± 8 35 ± 7 35 ± 8 37 ± 6* 38 ± 7*
MBP (mmHg)105 ± 14NENE106 ± 12NENE104 ± 11NE106 ± 12

Discussion

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

In the present study, we found that a characteristic feature of normotensive recipients with microalbuminuria was an increase in single kidney GFR for grafts after transplantation. The GFR of microalbuminuric patients with type 2 diabetes mellitus was significantly higher than non-microalbuminuric and non-diabetic patients.24 Eberhard et al. suggested that the higher prevalence of microalbuminuria in kidney donors compared with healthy patients might reflect subclinical hyperfiltration damage of the glomerulus.25 The increased GFR might be involved in the onset of microalbuminuria in the normotensive renal transplant recipients as it is present in the diabetic patients and kidney donors.

We also found the frequency of renal transplantation from female donor to male recipient appeared to be higher in the recipients with microalbuminuria than that in recipients without microalbuminuria. Neugarten et al.26 suggested that a mismatch between the nephron supply of the female donor kidney and the functional demand of the male recipient results in hyperfiltration-mediated glomerular injury, which would be responsible for the reduced survival of female allografts in male recipients. Although we failed to find any differences in the ratio of body mass index between donors and recipients in both groups, such a gender-related functional mismatch between the donor and the recipient may be a reason for the increased GFR of the microalbuminuric recipients in the present study.

Also used as a safe and effective antihypertensive, AT1RA  might  have  a  protective  effect  similar  to  that of ACEI on transplant nephropathy.27 Recently, the antiproteinuric and antimicroalbuminuric effects of AT1RA were reported in renal transplant recipients with systemic hypertension.19,20 In the present study, decreases in the U-Alb and U-NAG excretion rates and S-Cr levels for one year after losartan administration were observed in the normotensive recipients with microalbuminuria. The present study was not a randomized one. However, losartan may play a part in the decreases of U-Alb and U-NAG excretion rates and S-Cr levels in recipients with microalbuminuria, because there were no changes in the data of recipients without microalbuminuria who had no losartan administration in the study period.

The necessity of treatment with ACEI or AT1RA for microalbuminuria in renal transplant recipients has not yet been established. Kasiske et al.28 claimed that the measurement of urinary albumin excretion does not provide any diagnostic or prognostic value over that of proteinuria in the clinical practice for renal transplant recipients. However, microalbuminuria was recognized as an early marker of proteinuria in several clinical states.7,29 Hohage et al.30 demonstrated that the 5-year renal graft survival rate in the recipients with proteinuria was 58.9%, in contrast to 85.6% in those without proteinuria, and that proteinuria lasting for 12 months or longer further reduced the 5-year graft survival rate to 42.4%. It should be considered that a sustained increase in U-Alb excretion is likely to generate the abnormal glomerular permeability to protein.10,31 Improving long-term graft survival is an important issue. In this setting, the detection of microalbuminuria at a subclinical proteinuric state could be a relevant measure to introduce an early treatment to prevent the progressive proteinuria and improve long-term graft survival in renal transplant recipients.

The ACEI and AT1RA-induced anemia frequently occurs in an immunosuppressed state and they can be used as potent drugs for erythrocytosis in post-transplant recipients.32,33 We experienced losartan-induced decreases in Ht in two patients, in whom the dose of losartan was decreased from 50 to 25 mg/day. Mean BP was not significantly changed by the dose of losartan in the normotensive renal transplant recipients. The present regimen of losartan administration was considered safe in regard to AT1RA-induced anemia and hypotension.

In conclusion, the present study consisted of a small number subjects and showed that an increased single kidney GFR of the grafts from donor in situ to recipients might be a cause of microalbuminuria in normotensive recipients. The one-year effects of losartan were observed in terms of the decrease in U-Alb, U-NAG and S-Cr levels. However, the necessity of treatment with AT1RA for microalbumiuria in normotensive recipients has not yet been clarified. Further long-term follow-up studies with a large number of subjects are needed to confirm the clinical significance of losartan administration for the protection from microalbuminuria to overt proteinuria that might be responsible for the late non-immunological graft injury.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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    Klaassen RJ, Van Gelder T, Rischen-Vos J, Deinum J. Man in’t Veld AJ, Weimar W. Losartan, an angiotensin-II receptor antagonist, reduces hematocrits in kidney transplant recipients with posttransplant erythrocytosis. Transplantation 1997; 64: 7802.