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|Year : 2016 | Volume
| Issue : 6 | Page : 1217-1223
|Proteinuria, graft outcomes, and cardiovascular risk among kidney transplant recipients in a South African Public Hospital
Aminu Muhammad Sakajiki1, Sagren Naidoo2, P Manga3, MS Nazir3, S Naicker2
1 Division of Nephrology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; Department of Medicine, Yariman Bakura Specialist Hospital, Gusau, Nigeria
2 Division of Nephrology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa
3 Division of Cardiology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa
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|Date of Web Publication||28-Nov-2016|
| Abstract|| |
Proteinuria is a marker of poor long-term graft survival and an independent risk factor for total and cardiovascular mortality in the transplant population. We investigated the prevalence of proteinuria and its relationship with graft function and cardiovascular risk factors in kidney transplant recipients (KTRs). Adult KTRs at the Charlotte Maxeke Johannesburg Academic Hospital were recruited. Patients' records were reviewed for information on their posttransplant follow-up. Echocardiography and carotid Doppler were performed for the assessment of cardiac status and carotid intima-media thickness (CIMT), respectively. Proteinuria was analyzed both as a categorical and continuous variable. Graft dysfunction was defined as estimated glomerular filtration rate of <60 mL/min/1.73 m 2 based on the modification of diet in renal disease formula. Framingham's risk score was used to categorize patients' cardiovascular risk. Inferential and modeling statistics were applied as appropriate using Statistical Package for Social Sciences, and P ≤0.05 was considered statistically significant. One hundred KTRs including 63% males were recruited. Proteinuria was present in 51%, the mean ± standard deviation 24 h urinary protein excretion per day was 1.67 ± 2.0 g/day with a range of 0.4-9.4 g/day. Graft dysfunction was found in 52% of patients and 36% had high cardiovascular disease (CVD) risk. Proteinuric KTRs had high CVD risk, P = 0.002. Proteinuria was associated with graft dysfunction, increased left ventricular mass index, increased CIMT, and anemia. Proteinuria is prevalent; it is a marker of graft dysfunction and is associated with markers of atherosclerosis.
|How to cite this article:|
Sakajiki AM, Naidoo S, Manga P, Nazir M S, Naicker S. Proteinuria, graft outcomes, and cardiovascular risk among kidney transplant recipients in a South African Public Hospital. Saudi J Kidney Dis Transpl 2016;27:1217-23
|How to cite this URL:|
Sakajiki AM, Naidoo S, Manga P, Nazir M S, Naicker S. Proteinuria, graft outcomes, and cardiovascular risk among kidney transplant recipients in a South African Public Hospital. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2021 Dec 7];27:1217-23. Available from: https://www.sjkdt.org/text.asp?2016/27/6/1217/194655
| Introduction|| |
Proteinuria is highly prevalent after kidney transplantation and is seen in up to 45% of kidney transplant recipients (KTRs). It is associated with decreased patient and allograft survival as well as an increased risk of cardiovascular events.  The risk of death from all causes and from cardiovascular disease (CVD) increases with increasing amounts of proteinuria.  Even microalbuminuria is associated with inflammatory markers such as C-reactive protein and cardiovascular risk factors.  Sancho et al  showed that proteinuria >0.5 g/day was associated with a five-year graft survival rate of only 69% compared with 93% for those without proteinuria. Proteinuric patients are more likely to have delayed graft function (DGF; 53.4% vs. 31.2%; P = 0.001), but notacute rejection (27.2% vs. 19.0%; P = 0.14).  They also found that systolic blood pressure (SBP), body mass index (BMI), and serum creatinine level were significantly higher in proteinuric transplant recipients.  Similarly, Park et al  found that patients with proteinuria >1 g/day had a significant decrease in fiveyear graft survival compared with those with no proteinuria (69.4% vs. 86.5%; P <0.01). Both as a categorical and continuous variable, proteinuria has been associated with a significantly greater risk of graft loss. , Amer et al.  showed that the risk of graft loss increased by 27% for each 1 g/day increase in proteinuria, and this was independent of glomerular pathology on biopsy and glomerular filtration rate (GFR) and was associated with decreased kidney transplant survival. SBP, glycated hemoglobin, and serum creatinine levels significantly correlated with proteinuria.  Risk factors for increasing proteinuria included SBP, diastolic blood pressure (DBP), and serum creatinine; in addition, female donor, male recipient, and patients with acute rejection were found to have higher levels of proteinuria. , In addition, proteinuria was found to be higher in patients with DGF and acute rejection. Fontan et al  showed that DGF, donor age, human leukocyte antigen (HLA) sensitization, and acute rejection were independent predictors of proteinuria at three months in a multivariate-adjusted logistic regression model. DGF and serum creatinine level, both predictors on univariate analysis, were not significant after adjustment. 
We aim to determine the prevalence of proteinuria, its relationship with graft function and cardiovascular risk in South African kidney transplant recipients.
| Methods|| |
Patients, who received a kidney transplant from June 2005 to December 2009, were enrolled in this cross-sectional study. Information on age, gender, race, physical activity, tobacco use, age at diagnosis of renal failure, cause of renal failure, prior cardiovascular event, family history of CVD, duration on dialysis before transplant, type of dialysis, and number of transplants was collected using a structured interview form. Patients were categorized as smokers, former smokers, or nonsmokers if they never smoked. Previous CVD event was defined as a history of angina, myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention, stroke, peripheral vascular disease, peripheral angioplasty, or amputation. The type of immunosuppressants, use of blood pressure (BP) medications, statins, anti-retroviral drugs, number of HLA mismatches, and biopsy-proven rejection were all recorded. Height and weight were measured with the Detecto Scale (New York), and BMI was calculated as ratio of weight to height squared. Waist circumference was measured using the anterior superior iliac spine as the point of measurement.  Graft dysfunction was defined as estimated GFR of <60 mL/min/1.73 m 2 based on the modification of diet in renal disease formula. Framingham's risk score (FRS) was used to categorize patients into different CVD risk groups. This scoring system utilizes age, gender, smoking status, SBP, and total and high-density lipoprotein (HDL) cholesterol. Patients were categorized into low, moderate, high, and very high CVD risk. 
BP was recorded at the time of clinic visit using an Accoson mercury sphygmomanometer in the sitting position. Average BP of four clinic visits was taken as the patient's actual BP (averaged over 12 months). Pulse pressure was calculated as the difference between the SBP and DBP whereas the mean arterial pressure (MAP) was the sum of DBP and one-third of the pulse pressure.
Echocardiography was performed at the cardiology unit of Charlotte Maxeke Johannesburg Academic Hospital using the Philips iE33 machine equipped with a S5-1 1-5 MHz transducer, allowing for M-mode, two-dimensional, and color Doppler measurements (Philips Corporation, USA).
Carotid intima-media thickness
Carotid intima-media thickness (CIMT) was measured using high-resolution B-mode ultrasonography with a L3-11 MHz linear array transducer (Philips Corporation, USA). Patients were examined in the supine position with the neck hyperextended and the head turned 45° from the side being examined. Reference point for the measurement of CIMT was the beginning of the dilatation of the carotid bulb. CIMT was taken as the distance from the leading edge of the first and second echogenic lines.
Measurements were taken on the longitudinal views of the far walls of the common carotid artery, 1 cm proximal to the dilatation of the carotid bulb. The linear array transducer generates a measurement of the CIMT and displays it on the screen with a percentage success of the procedure, ranging from <50% success to 100%. For this study, a percentage success of >95% was used. The same procedure was used for each side and the mean of the right and left common CIMT was calculated.
The presence of plaques was based on encroachment of localized echogenic structures into the vessel lumen, for which the distance between the media-adventitia interface and the internal side of the lesion was ≥1.2 mm.  CIMT was measured in the plaque-free areas, and measurements were carried out on both sides.
Serum creatinine, urea, lipids, complete blood count, and urinary protein quantification were measured at the National Health Laboratory Service (NHLS) as part of the standard of care for the follow-up of patients at the kidney transplant clinic. All samples for serum chemistry were analyzed using ADVIA ® Chemistry Systems (Siemens Healthcare Diagnostics Inc.).
Serum creatinine was measured using the modified Jaffe method. The normal range for males is 62-106 μmol/L and for females is 44- 80 μmol/L at the NHLS laboratory.
Serum cholesterol and triglycerides were determined using enzymatic colorimetric methods.
The triglyceride concentration was measured based on the Fossati three-step enzymatic reaction with a Trinder endpoint. HDL cholesterol was measured after precipitation of the nonHDL fraction with phosphotungstate-magnesium, while LDL cholesterol was estimated indirectly by the use of Friedewald formula; LDL cholesterol = total cholesterol − (HDL cholesterol + triglycerides/5).
Complete blood count
Complete blood count was measured using automated hematology analyzer (ADVIA 2120 ® Philips Corporation, USA). This formed part of routine tests performed at every clinic visit.
For 24-h urine protein excretion, the ratio of the urinary protein excretion in mg/dL to that of urinary creatinine in mg/dL from a spot urine sample was used. Proteinuria was defined as urine protein to creatinine ratio (UPCR) more than 0.3 g/day. Spot UPCR has been validated as a better test than 24-h urinary protein quantification; it is not affected by urine volume or concentration, whereas the latter is prone to errors of collection; also, it is inconvenient to the patient and laboratory staff. 
| Statistical Analysis|| |
All data obtained were analyzed using the Statistical Package for Social Sciences for windows software version 17 (SSPS Inc, Chicago Il, USA). Data were reported as mean ± standard deviation (SD). Differences in means for continuous variables were compared using Student's t-test, whereas categorical variables were compared using Chi-square or Fisher's exact tests, as appropriate.
| Results|| |
Of the 100 KTRs studied, 63 were males (63%) and 37 were females (37%). The mean age of the study population was 42.2 ± 12.42 years with a range of 19-70 years. There were 77 blacks (77%), seven whites (7%), 11 colored (11%), and five Asian (5%) recipients. Ninetyfive (95%) had primary transplants whereas five (5%) were second transplants. Hypertension was the cause of end-stage renal disease (ESRD) in 53 (53%), 15 (15%) were diabetic, of these, eight (8%) had diabetes as a cause of ESRD whereas seven (7%) had new-onset diabetes after transplant (NODAT). The cause of ESRD was unknown in 18 (18%).
Proteinuria was present in 51 patients (51%); the mean ± SD urinary protein excretion was 1.67 ± 2.0 g/day with a range of 0.4-9.4 g/day. Nineteen patients were on rapamycin (19%) and 46 (46%) were on angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB). Sixty-one percent of the proteinuric KTRs were on ACEI/ARB, with only 21.6% of them on rapamycin. Graft dysfunction was found in 52% of the study population. Sixty-four (64%) had a low cardiovascular risk and 36 (36%) had a high risk for CVD.
Clinical and laboratory characteristics of the study population are shown in [Table 1].
|Table 1: Clinical and laboratory characteristics of the study population.|
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Proteinuric KTRs were older, but total steroids dose and LDL cholesterol were similar among the study population as shown in [Table 1].
Proteinuric KTRs were more likely to be males. Proteinuria was associated with high CVD risk and graft dysfunction, as shown in [Table 2].
MAP and CVD risk showed a significant correlation with proteinuria. Hemoglobin and GFR showed a negative correlation with proteinuria as depicted in [Table 3].
|Table 3: Correlation of 24-h protein excretion with cardiovascular risk variables.|
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| Discussion|| |
The prevalence of proteinuria in our study was high (51%); this was also reported by Knoll where he found a prevalence of 45%,  in contrast to a report by Fernαndez-Fresnedo et al, in which a prevalence of 15.3% was found at one-year post-transplant.  The prevalence of proteinuria in KTRs varies depending on the threshold used to define proteinuria and the period post-transplantation. Amer et al,  in the USA, found a prevalence of 45% at one-year post-transplant when they used a threshold of >0.15 g/day, but this prevalence dropped to 15% when the threshold was increased to >0.5 g/day. Halimi et al,  in France, found a prevalence of 35.2% at one-year post-transplant when they used a threshold of >0.5 g/day. This difference in prevalence could be explained by our study patients being recruited at least three years after transplantation, with some having their graft for seven years and the threshold of >0.3 g/day used to define proteinuria.
Proteinuric KTRs in this study were older and more likely to be males; Amer et al found proteinuria to be more frequent among males in their cohort of KTRs.  Proteinuric KTRs in our cohort had higher SBP, DBP, and MAP. Similar observations were reported by several other authors. ,,,
Proteinuria was associated with high CVD risk and graft dysfunction in our KTRs. Similar observations were made in other studies. , Anemia, left ventricular mass index, and high BP were found to be associated with proteinuria. These associations were also observed in the Spanish Chronic Allograft Nephropathy study.  This finding is not surprising; as graft function deteriorates, BP control becomes more difficult, and anemia becomes more pronounced, all impacting negatively on left ventricular function.
Rejection episodes were not different among the study participants; similar observations were made by Sancho et al in Spain,  though, there was a tendency toward proteinuric recipients having more rejection episodes, and this was in contrast to the finding by Halimi et al  in France, where they found higher rates of rejection among proteinuric KTRs. Rejection episodes were also reported to be more frequent in proteinuric KTRs by Amer et al  in the USA and Fernαndez-Fresnedo et al  in Spain.
Higher BMI and waist circumference were found in our proteinuric KTRs; the same finding was reported by other investigators.  The association between obesity and proteinuria has been documented in both general and transplant populations. ,
CIMT, a surrogate marker of atherosclerosis and predictor of cardiovascular events in both kidney transplant and non-transplant populations,  was found to be increased in our proteinuric KTRs. Fernαndez-Fresnedo et al  showed that proteinuria was predictive of cardiovascular events (ischemic heart disease, peripheral vascular disease, and stroke) in their KTR cohorts. The use of rapamycin, a mammalian target of rapamycin inhibitor (mTOR), was not associated with proteinuria in this study, which is contrary to existing knowledge since proteinuria has been reported to develop and worsen with the use of mTOR inhibitors.  This finding may be explained by the relatively small number of our KTRs on mTOR inhibitors. ACEI or ARB is associated with reduction of proteinuria in KTRs,  in this study; there was no difference in proteinuria between patients who were on ACEI/ ARB and those who were not.
Limitation of this study was underestimation of CVD risk by the FRS due to non-inclusion of such factors as dialysis and transplantrelated risk factors for CVD.
Another limitation of this study was that histological findings were not correlated with proteinuria, as biopsy was often indicated by features of rejection rather than the presence of proteinuria; the number of biopsies performed for proteinuria alone was too small for analysis.
| Conclusion|| |
Proteinuria is prevalent and is a marker of graft dysfunction; it is associated with increased cardiovascular risk in kidney transplant recipients in South Africa. Strategies aimed at reducing proteinuria and reductions in cardiovascular risk are encouraged.
| Acknowledgment|| |
We wish to acknowledge the contributions of Prof. Russel Britz and Dr. Ben Wambugu of the Divisions of Vascular Surgery and Nephrology, respectively, University of Witwatersrand, Johannesburg, South Africa.
The approval for this study was granted by the Human Ethics Research Committee of the University of the Witwatersrand Johannesburg, approval number: M120596.
The abstract was presented at the African Nephrology Congress in Accra, Ghana last February 2013.
Conflict of interest: None declared.
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Aminu Muhammad Sakajiki
Department of Medicine, Yariman Bakura Specialist Hospital, PMB 1010, Gusau, Zamfara State, Nigeria
[Table 1], [Table 2], [Table 3]
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