| Abstract|| |
To evaluate the prevalence, risk factors, possible etiology, prognosis and management of proteinuria in renal transplant recipients, we studied 435 adult renal transplant recipient patients randomly selected from our center; 394 patients were reviewed retrospectively and 41 patients were followed-up prospectively for a period of one year. The patients were classified into three groups according to the results of urinalysis and spot urinary albumin creatinine ratio: Group A patients with normoalbuminuria; Group B patients with microalbuminuria; and Group C patients with macroalbuminuria. Persistent post-transplantation proteinuria was detected in 125 (28.8%) patients. The etiology of post-transplantation proteinuria included chronic allograft dysfunction in 44 (35.2%) patients, acute rejection in 40 (32%) patients, transplant glomerulopathy in eight (6.4%) patients, glomerular disease in 16 (12.8%) patients and other etiology in 17 (13.6%) patients. Proteinuric patients demonstrated significantly lower graft survival rates than did those without proteinuria (48.3% versus 51.7%, respectively; P = 0.017; Risk Ratio = 0.403; 95% confidence interval 0.188-0.862). We conclude that proteinuria is prevalent after kidney transplant in our population, and that it is most commonly associated with chronic allograft nephropathy, transplant glomerulopathy, glomerulonephritis and acute rejection. Post-transplant proteinuria is associated with decreased allograft survival.
|How to cite this article:|
Khedr E, El Sharkawy M, El Shahawy Y, Sany D, Sayed H. Proteinuria in Egyptian renal transplant recipients. Saudi J Kidney Dis Transpl 2015;26:161-7
|How to cite this URL:|
Khedr E, El Sharkawy M, El Shahawy Y, Sany D, Sayed H. Proteinuria in Egyptian renal transplant recipients. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2019 Jul 18];26:161-7. Available from: http://www.sjkdt.org/text.asp?2015/26/1/161/148770
| Introduction|| |
Proteinuria is a sign of renal damage and a predictor of the course of most renal diseases. Proteinuria itself plays a role in the progression of renal diseases by promoting fibrogenesis and glomerulosclerosis.  The prevalence of proteinuria in renal transplantation varies from 7.5% to 45%, at least because of the threshold used to define proteinuria. 
Proteinuria in renal transplant recipients was related to immunological and non-immunological factors.  Proteinuria in kidney transplant recipients is associated commonly with such transplant-specific diagnoses on biopsy as allograft nephropathy, transplant glomerulopathy, acute rejection and glomerulonephritis,  cyclosporine (CsA) toxicity, diabetic nephropathy and prolonged cold and warm ischemia times.  There is a strong association between proteinuria and reduced graft survival. Proteinuria provides prognostic information beyond that provided by measures of kidney function, histology and other variables associated with graft survival. ,,
Several studies have implied that proteinuria is a marker of poor long-term allograft outcome and patient survival. ,, Thus, on the basis of these findings, the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) Guidelines concluded that the use of angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers in patients with a spot urine total protein/creatinine ratio of more than 0.5 g/g may have a beneficial effect on graft survival and mortality. ,,,,,
We aimed in our study to determine the prevalence of proteinuria, the risk factors, the possible etiology, the prognosis and the management of proteinuria in renal transplant recipients.
| Patients and Methods|| |
The current study enrolled 435 adult renal transplant recipients randomly selected from the Ain Shams Specialized Hospital, Nasr Institute and Petroleum Hospital; 394 adult renal transplant recipients were reviewed retrospectively and 41 adult renal transplant recipients from living donors were followedup prospectively for a period of one year.
The patients were classified into three groups depending on the results of urinalysis and spot urine albumin creatinine ratio measured by the enzyme-linked immunosorbant assay (ELISA) into: Group A 310 patients with normoalbuminuria; Group B 49 patients with microalbuminuria; and Group C 76 patients with macroalbuminuria.
Microalbuminuria was defined according to the American Diabetes Association guidelines as 30-299 μ g/mg spot collection or 24-h collection or 20-199 μ g/min timed collection; values below the lower limit were considered as normal and above the upper limit were considered as macroalbuminuria. Because of variability in urinary albumin excretion, two of three specimens collected within a three to six month period should be abnormal before considering a patient to have crossed one of these diagnostic thresholds. The following transplant recipients were excluded from the study if they had urinary tract infection or hematuria till it resolved, acute intercurrent infection till it resolved, congestive heart failure, marked hyperglycemia, marked hypertension till it was controlled and native kidney proteinuria. All the exclusion criteria depended on the recommendations of several studies that provided guidelines to determine the origin of post-transplant proteinuria. ,,
All the patients were subjected to complete medical history and detailed clinical examination, including (A) donor-related data: Age, sex, type of donor; living-cadaveric, related-unrelated, (B) recipient-related: Age, sex, demographics, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) = (DBP +1/3 (SBP DBP), history of schistosomiasis, basal serologic status for cytomegalovirus (CMV), hepatitis C virus (HCV), hepatitis B virus (HBV), human immune-deficiency virus (HIV), original kidney disease, co-morbid diseases, dialysis modality, duration of maintenance pre-transplant dialysis, pre-transplant blood transfusions and laboratory investigations and (C) transplant-related: Number of grafts, immunosuppressive regimen, acute rejection within the first year, delayed graft function  and post-transplant diabetes mellitus (PTDM). 
The proteinuric patients were subjected to the determination of the onset of proteinuria and the amount by spot urinary albumin creatinine ratio, identification of the possible etiology and the risk factors of proteinuria  by the renal biopsy and laboratory investigations including complete blood count, liver function tests, lipid profile, kidney function tests and levels of immunosuppressive medications besides the complete medical history and the detailed clinical examination, the management of proteinuria as regards the drug prescribed for proteinuria (angiotensin-converting enzyme inhibitor, angiotensin II type I receptor blockers, calcium channel blockers), modulation of immunosuppressive drugs, antirejection therapy prescribed (pulse steroid, target therapy, plasmapheresis) and antiviral therapy for CMV, follow-up of proteinuria and follow-up of graft function for all the patients. We used the abbreviated modification of diet in renal disease (MDRD) equation to determine the estimated glomerular filtration rate (eGFR) = 170 × Serum Creatinine -0.999 × Age -0.176 × (0.762 if female) × (1.180 if black) × BUN -0.170 × Albumin +0.318 . 
| Statistical Analysis|| |
The data of the study were tabulated and statistical analysis was performed using the SPSS program V15. The data were described as mean ± standard deviation for the parametric numerical variables and as frequency and percentage for the categorical variables. The following tests were used: The independent Student "t" test was used for comparison of the parametric quantitative continuous variables for two independent groups, Chi-square test (or Fisher's exact test when appropriate) was used for comparison of the distribution of the qualitative categorical variables, one-way analysis of variant (ANOVA) test was used for comparison of the quantitative variables among more than two independent groups, least significant difference test (LSD) test was used as the post hoc test, Pearson correlation coefficient was used for testing the association between the different parametric variables and regression analysis was used as the method for performing multivariate analysis. Linear regression analysis was performed to evaluate the association between proteinuria as a continuous variable and the relevant parameters, and the logistic regression was performed to estimate the association between proteinuria as a categorical variable and relevant parameters. Graft survival rates were computed using the Kaplan-Meier method and curves were compared using the log-rank test. P-value was considered non-significant if it was >0.05 and significant if it was ≤0.05.
| Results|| |
The mean follow-up duration following transplantation was 42.9 ± 37.9 months. The mean age of the patients was 40.8 ± 11.9 years, including 310 (71.3%) males and 125 (28.7%) females, with a mean BMI of 24.7 ± 4.41 and mean MAP of 104 ± 15.1 mm Hg. There were 119 (27.4%) patients who had pre-emptive renal transplantation, while 316 patients (72.6%) had started dialysis before transplantation, with mean time on dialysis of 17.6 ± 20.5 months. The mean donor age was 30.1 ± 5.24 years, including 330 (75.9%) males and 48 (11%) donors were related to the recipients [Table 1]. The univariate analysis revealed that BMI, SBP, DBP, MAP, serum creatinine, blood urea nitrogen (BUN), HCV, bilhariziasis, CMV and acute rejection in the first year were statistically significantly different when comparing the three study groups. [Table 1] shows the comparisons of the different parameters in the three study groups during the study period and [Table 2] shows the differences during the first year of the follow-ups.
|Table 1: The mean value (±standard deviation) of anthropometric and demographic data of the three studied groups.|
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|Table 2: Comparison of the gender, donor relation, pre-transplant co-morbid disease and dialysis, bilhariziasis, HCV, CMV, number of grafts, PTDM, DGF and acute rejection in the first year among the three studied groups.|
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In the multivariate logistic regression analysis, we found that BMI, DBP, bilhariziasis, CMV and acute rejection in the first year remained statistically significant, while SBP, MAP and HCV lost their significance.
The etiology of post-transplantation proteinuria in our study included chronic allograft dysfunction in 44 (35.2%) patients, acute rejection in 40 (32%) patients, transplant glomerulopathy in eight (6.4%) patients, glomerular disease in 16 (12.8%) patients, focal segmental glomerulosclerosis in eight (6.4%) patients, membranous nephropathy in two (1.6%) patients, minimal lesion glomerulonephritis in one (0.8%) patient, lupus nephritis in one (0.8%) patient, diabetic nephropathy in four (3.2%) patients and other etiologies in 17 (13.6%) patients, including sirolimus toxicity in eight (6.4%) patients, unknown in seven (5.6%) patients, acute tubular necrosis in one (0.8%) patient and thrombotic microangiopathy in one (0.8%) patient.
There was a direct correlation between allograft histological characteristics and degree of proteinuria, P = 0.000.
We found a statistically significant difference comparing eGFR among the three studied groups during the three classified periods (P = 0.000, 0.004 and 0.000).
We also found a direct correlation between the allograft histological characteristics and the degree of proteinuria (the mean proteinuria 4529 ± 2520 μg/mg creatinine in patients with glomerular pathology states was significantly more elevated than that in the patients with acute rejection, interstitial fibrosis and atrophy and transplant glomerulopathy).
There were 29 (6.7%) patients who experienced graft loss; 14 (48.3%) patients with macroalbuminuria and 15 (51.7%) patients with normoalbuminuria. There was a statistically significant difference when comparing graft survival between the proteinuric and nonproteinuric groups (P = 0.017, RR = 0.403; 95% CI 0.188-0.862) as shown in [Table 3] and [Figure 1].
|Figure 1: Kaplan–Meier curve for graft survival in our study between proteinuric and non-proteinuric groups and between normoalbuminuric, microoalbuminuric and macroalbuminuric patients.|
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| Discussion|| |
Our results showed a correlation of proteinuria in transplant patients with pathological changes and survival. The risk factors were explored from the comparisons and univariate and multi-variate analyses. When we compared the SBP, DBP and MAP among the three studied groups, we found that those who developed proteinuria were more likely to have more MAP, mean SBP and mean DBP than non-proteinuric patients. Also, in the multivariate logistic regression analysis, the current study confirmed the independent value of DBP to predict post-transplant proteinuria. These results are comparable with those of several studies. ,,,,,,,,,,,, We also found a statistically significant difference when we compared bilharziasis between the proteinuric and non-
proteinuric groups and confirmed the independent value of bilharziasis to predict posttransplant proteinuria. We also found a statistically significant difference when we compared CMV infection between the three studied groups or between the proteinuric and non-proteinuric patients, and confirmed the independent value of CMV infection to predict post-transplant proteinuria. These results are comparable with those of many studies. ,,,,, In addition, our study showed that there was a statistically significant difference when comparing the presence of HCV infection among the patients with normoalbuminuria, microalbuminuria and macroalbuminuria, similar to the studies performed by Romero et al  and Morales et al.  However, there was no significant negative impact of HCV infection on graft survival of kidney transplant recipients in our study, comparable to many studies; ,, in contrast, our results did not coincide with other studies. ,,,, In our study, we also found that a high percentage of the proteinuric patients experienced acute rejection and, using the multivariate logistic regression analysis, the current study confirmed the independent value of acute rejection to predict post-transplant proteinuria in the first year; this was comparable to previous studies. ,,,,,,, In contrast, the study of Souqiyyeh et al  and Sancho et al  revealed that acute rejection was not a risk factor for post-transplant proteinuria. Our study coincides with Kim et al,  Myslak et al  and Amer et al,  who found a direct correlation between the allograft histological characteristics and the degree of proteinuria, in contrast with Chung et al who did not find this correlation. 
Our study revealed that 48.3% of the patients who experienced graft loss suffered from proteinuria and that all of them had macroalbuminuria, while the rest had normoalbuminuria. There was a statistically significant difference when comparing graft survival between the proteinuric and the non-proteinuric groups. Our results showed that proteinuria was a risk factor for decline in kidney function and graft loss, as shown by other studies. ,,,,,
We conclude that proteinuria is prevalent after kidney transplant in our population and that it is associated most commonly with chronic allograft nephropathy, transplant glomerulopathy, glomerulonephritis and acute rejection. Post-transplant proteinuria is associated with decreased allograft survival.
Conflict of interest: None
| References|| |
Ibis A, Akgül A, Ozdemir N, et al. Posttransplant Proteinuria Is Associated With Higher Risk of Cardiovascular Disease and Graft Failure in Renal Transplant Patients. Transplant Proc 2009;41:1604-8.
Knoll GA. Proteinuria in Kidney Transplant Recipients: Prevalence, Prognosis, and EvidenceBased Management. Am J Kidney Dis 2009;54:1131-44.
Sancho A, Gavela E, Ávila A, et al. Risk Factors and Prognosis for Proteinuria in Renal Transplant Recipients. Transplant Proc 2007;39:2145-7.
Amer H, Cosio FG. Significance and Management of Proteinuria in Kidney Transplant Recipients. J Am Soc Nephrol 2009;20:2490-2.
Amer H, Fidler ME, Myslak M, et al. Proteinuria after kidney transplantation, relationship to allograft histology and survival. Am J Transplant 2007;7:2748-56.
Cantarovich F, Martinez F, Heguilen R, et al. Proteinuria >0.5 g/d, a prevalent prognostic factor for patient and graft survival in kidney transplantation. Clin Transplant 2010;24:175-80.
Roodnat JI, Mulder PG, Rischen-Vos J, et al. Proteinuria after renal transplantation affects not only graft survival but also patient survival. Transplantation 2001;72:438-44.
Fernández-Fresnedo G, Plaza JJ, Sánchez-Plumed J, Sanz-Guajardo A, Palomar-Fontanet R, Arias M. Proteinuria: A new marker of long-term graft and patient survival in kidney transplantation. Nephrol Dial Transplant 2004;19:47-51.
Halimi JM, Laouad I, Buchler M, et al. Early low-grade proteinuria: Causes, short-term evolution and long-term consequences in renal transplantation. Am J Transplant 2005;5:2281-8.
Halimi JM, Buchler M, Al-Najjar A, et al. Urinary albumin excretion and the risk of graft loss and death in proteinuric and non-proteinuric renal transplant recipients. Am J Transplantat 2007;7:618-25.
Kang NR, Lee JE, Huh W, et al. Minimal proteinuria one year after transplant is a risk factor for graft survival in kidney transplantation. J Korean Med Sci 2009;24:129-34.
D′Cunha PT, Parasuraman R, Venkat KK. Rapid resolution of proteinuria of native kidney origin following live donor renal transplantation. Am J Transplant 2005;5:351-5.
Mysalak M, Amer H, Morales P, et al. Interpreting post-transplant proteinuria in patients with proteinuria pre-transplant. Am J Transplant 2006;6:1660-5.
Yarlagadda SG, Coca SG, Garg AX, et al. Marked variation in the definition and diagnosis of delayed graft function: A systematic review. Nephrol Dial Transplantat 2007;23:2995-3003.
KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Am J Transplant 2009;9:66.
Fernandez-Fresnedo G, Escallada R, Rodrigo E, et al. The risk of cardiovascular disease associated with proteinuria in renal transplant patients. Transplantation 2002;73:1345-8.
Kallner A, Ayling PA, Khatami Z. Does eGFR improve the diagnostic capability of S-Creatinine concentration results? A retrospective population based study. Int J Med Sci 2008;5:9-17.
Kim SC, Kang CH, Kim SK, et al. Impact of Heavy Proteinuria (>1 g/d) Following Renal Transplantation. Transplant Proc 2000;32:1894-5.
Palmer BF. Proteinuria as a therapeutic target in patients with chronic kidney disease. Am J Nephrol 2007;27:287-93.
Rose BD, Post TW. Measurement of urinary protein excretion (UpToDate 17.1). Available from: http://www.utdol.com
. [Last accessed on 2009 Jan 13].
Ibis A, Altunoglu A, Akgul A, et al. Early onset proteinuria after renal transplantation: A marker for allograft dysfunction. Transplant Proc 2007;39:938-40.
Fontan MP, Rodriguez-Carmona A, Garcia FT, Valdes F. Early proteinuria in renal transplant recipients treated with cyclosporin. Transplantation 1999;67:561-8.
Jiménez del Cerro LA, Franco A, Olivares J. Changing profiles of proteinuria in renal transplantation. Predictive factors for its appearance. Nefrologia 2002;22:356-63.
Hohage H, Kleyer U, Bruckner D, August C, Zidek W, Spieker C. Influence of proteinuria on long-term transplant survival in kidney transplant recipients. Nephron 1997;75:160-5.
Sabry A, Hassan R, Mahmoud I, Hamed M, Sobh M. Proteinuria after Kidney Transplantation, Its Relation to Hepatitis C Virus and Graft Outcome. Iran J Kidney Dis 2007;1:88-97.
Bochicchio T, Sandoval G, Ron O, Perez-Grovas H, Bordes J, Herrera-Acosta J. Fosinopril prevents hyperfiltration and decreases proteinuria in post-transplant hypertensives. Kidney Int 1990;38:873-9.
Calvino J, Lens XM, Romero R, SanchezGuisande D. Long-term anti-proteinuric effect of Losartan in renal transplant recipients treated for hypertension. Nephrol Dial Transplant 2000;15:82-6.
Halimi JM, al-Najjar A, Buchler M, et al. Microalbuminuria in hypertensive, non-proteinuric renal transplant recipients: Role of previous acute rejection episodes and sodium intake. Arch Mal Coeur Vaiss 2001;94:933-6.
Souqiyyeh MZ, Shaheen FA, Sheikh I, et al. Post-Renal transplant proteinuria: The Saudi Experience. Saudi J Kidney Dis Transplant 2005;16:556-61.
Rubin RH. Impact of cytomegalovirus infection on organ transplant recipients. Rev Infect Dis 1990;12 Suppl 7:S754-66.
Pouteil-Noble C, Ecochard R, Landrivon G, et al. Cytomegalovirus infection-an etiological factor for rejection? A prospective study in 242 renal transplant patients. Transplantation 1993;55:851-7.
The TH, Grefte JM, van der Bij W, van Son W, van den Berg AP. CMV infection after organ transplantation: Immunopathological and clinical aspects. Neth J Med 1994;45:309-18.
Reinke P, Fietze E, Ode Hakim S, et al. Lateacute renal allograft rejection and symptomless cytomegalovirus infection. Lancet 1994;344:1737-8.
Lowance D, Neumayer HH, Legendre CM, et al. Valacyclovir for the prevention of cytomegalovirus disease. N Engl J Med 1999;340:1462-70.
Juan RS, Aguado JM, Lumbreras C, et al. Impact of current transplantation management on the development of cytomegalovirus disease after renal transplantation. Clin Infect Dis 2008;47:875-82.
Romero E, Galindo P, Bravo JA, et al. Hepatitis C Virus Infection After Renal Transplantation Transplant Proc 2008;40:2933-5.
Morales JM, Domýnguez-Gil B, Sanz-Guajardo D, Fernandez J, Escuin F. The influence of hepatitis B and hepatitis C virus infection in the recipient on late renal allograft failure. Nephrol Dial Transplant 2004;19:72-6.
Einollahi B, Hajarizadeh B, Bakhtiari S, et al. Pretransplant hepatitis C virus infection and its effect on the post transplant course of living renal allograft recipients. J Gastroenterol Hepatol2003;18:836-40.
Younossi ZM, Braun WE, Protiva DA, Gifford RW, Straffon RA. Chronic viral hepatitis in renal transplant recipients with allografts functioning for more than 20 years. Transplantation 1999;67:272-5.
Giblin L, Clarkson MR, Conlon PJ, et al. Impaired renal allograft, but not patient survival, in patients with antibodies to hepatitis C virus. Ir J Med Sci 2004;173:82-4.
Lim HH, Huang CC, Huang JY, et al. Impact of HCV infection on first cadaveric renal transplantation: A singlecenter experience. Clin Transplant 2004;18:261-6.
Mitwalli AH, Alam A, Al-Wakeel J, et al. Effect of chronic viral hepatitis on graft survival in Saudi renal transplant patients. Nephron Clin Pract 2006;102:72-80.
Chung J, Park SK, Park JS, Kim SC, Han DJ, Yu E. Glomerulonephritis is the major cause of proteinuria in renal transplant recipients: Histopathologic findings of renal allografts with proteinuria. Clin Transplant 2000;14:499-504.
Dr. Yasser El Shahawy
Renal Division, Faculty of Medicine, Ain Shams University, Cairo
[Table 1], [Table 2], [Table 3]