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ISSN: 2536-7153 SJMLS
SJMLS Volume 2, Number 1 March, 2017 | Page 161
Sokoto Journal of Medical Laboratory Science 2016; 1(2): 161 – 182
Original Research
SJMLS-1(2)-2016-017
Cystatin C- A Novel Biomarker for Early Detection of Renal
Impairment in Patient With HIV/AIDS
Ikpeama E A 1, Ikpeama OJ*
2, Okafor PA
3, Ikpeama, C.A.
4, Ikpeama, C.J.
5, Ogwuegbu, J.U.
6
Department of Anatomy, Anambra State University, Uli 1, Integrated Health Program Dioceses of Makurdi,
Benue State 2, School of Medical Laboratory Science, Ahmadu Bello University Teaching Hospital Zaria
3,
Federal Medical Centre Birinin Kebbi 4, Médecins Sans Frontières
5, Department of Medicine Imo State
University Owerri 6.
Corresponding Author*: [email protected]/+234-806-261-9025
Abstract Human immunodeficiency virus (HIV) - related kidney disease is one of the leading causes of death worldwide most especially in Nigeria. To access the possibility of detecting a more sensitive biomarker for the early detection of renal disease in HIV/AIDS patients., serum creatinine, Cystatin C, Urea, proteinuria and microalbuminuria were evaluated in two hundred newly diagnosed HIV seropositive patients, two hundred HIV/AIDS on therapy (CD4>250), two hundred HIV/AIDS on therapy (CD4<250) and one hundred and fifty apparently healthy HIV seronegative individuals as control. Results showed creatinine value of 0.9±0.0mg/dl, 1.3±0.4mg/dl, 1.2±0.2mg/dl and 1.3±0.0mg/dl in controls, HIV patients with CD4 ≤250, HIV patients with CD4 ≥250 and newly diagnosed HIV patients respectively. There was statistically significant difference in the mean creatinine values among the groups (p>0.05). Results shows urea value of 23±0.3mg/dl, 29±0.3mg/dl, 27±0.1mg/dl and 33±0.4mg/dl in controls, HIV patients with CD4 ≤250 cell, HIV patients with CD4 ≥250 cell and newly diagnosed HIV patients respectively. There were statistically significant differences in the mean urea values among the groups (p>0.05). Results shows Cystanin C value of 0.7±0.02mg/l, 1.5±0.1mg/l, 1.1±0.2mg/l and 1.1±0.3mg/l in controls, HIV patients with CD4 ≤250 cell, HIV patients with CD4 ≥250 cell and newly diagnosed HIV patients respectively. There was a statistically significant difference in the mean Cystanin C values among the subjects and controls (p>0.05). There was significant difference in the mean urine protein value of HIV patients when compared with control, there were no statistically significant difference in the mean value of microalbuminuria in HIV patients when compared to control. Renal disease is frequent in patients having HIV/AIDS infection.
There is need for inclusion of a sensitive (Cystatin C) renal marker as a routine check in these patients. This will help in early detection of renal diseases, thereby preventing end stage renal disease. Keywords: Cystatin C, Biomarker, Renal Impairment, HIV/AIDS
Introduction
The first report of AIDS-related renal failure, which
we now recognize as HIV-associated nephropathy
(HIVAN), was published in the mid-1980s (Nicastri
et al., 1984). Before effective anti-retroviral therapy
became available, HIVAN was so frequent, and its
clinical features were so dramatic; beginning with
heavy proteinuria, with rapid progression to end-
stage renal disease (ESRD). In immune-suppressed
patients, HIVAN became almost synonymous with
HIV-associated chronic kidney disease (CKD). As
HIV infection spread, the ESRD incidence increased
substantially, and by the early 1990s, HIVAN
became the third leading cause of ESRD in HIV
patients aged 20–64 years (Klotman et al.,1996).
Kidney disease tends to be asymptomatic and is
usually not the primary focus of a visit to an HIV
clinic (Gupta et al., 2005). The presence of kidney
disease should be anticipated; screening and proper
interpretation of the relationship between serum
creatinine level and GFR are recommended. Just as
optimal control of HIV replication is achievable for
most patients, so too is control of hypertension and
diabetes. The future holds enormous opportunities
for research in new markers for early detection of
kidney disease, prevention strategies, novel
therapeutics, and a better understanding of the
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interaction between the Black race and kidney
disease. Until that time, the incidence and spectrum
of kidney diseases in HIV-infected patients have
been altered by the widespread use of highly active
antiretroviral therapy (HAART). The clinical cause
of kidney disease is more indolent, the risk of ESRD
has been reduced by 40%–60%, the 1-year survival
rate while undergoing dialysis has increased from
25% to 75%, and kidney transplantation is a viable
option (USRDS. 2007). Despite these
improvements, risk factors for kidney disease are
highly prevalent among HIV-infected patients, and
kidney disease remains a significant cause of
morbidity and mortality, even among those patients
receiving Highly Active Anti-Retroviral Therapy
(HAART).
The kidneys are known reservoirs for persistent HIV
replication, even when the peripheral viral load is
suppressed with HAART (Winston et al., 2001).
The kidneys of patients with HIV-associated
nephropathy have a dense tubulointerstitial
inflammatory infiltrate that is primarily composed of
activated CD4+ and CD8
+ cells, and the amount of
the infiltrate appears to correlate with the degree of
clinical nephropathy (Kimmel et al., 2003). It has
been suggested that HIV-infected renal tubular
epithelial cells trigger up-regulation of
proinflammatory genes (Ross et al., 2006). This
proinflammatory renal environment may stimulate
increased immune activation in the kidneys, which
consequently may lead to heightened systemic
immune activation. Alternatively, patients with
increased systemic immune activation may be prone
to infiltration of activated T cells into the kidneys,
thereby leading to proteinuria and reduced renal
function. Chronic renal disease (CKD) is defined as
kidney damage or reduced kidney function that
persists for >3 months (Coresh et al., 2003). A
useful indicator of kidney damage is elevated
urinary protein excretion, measured qualitatively
with use of a urine dipstick or measured
quantitatively with use of a spot urine protein to
creatinine ratio (or 24-h urine collection). Kidney
function can be reliably estimated from the serum
creatinine by calculating the creatinine clearance or
glomerular filtration rate (GFR) through use of the
Cockcroft-Gault equation or Modification of Diet in
Renal Disease (MDRD) equations, respectively. A
GFR <60 mL/min meets criteria for CKD, a cutoff
supported by epidemiologic data linking lower GFR
to an increased frequency of hospitalization,
cardiovascular events, or death. MDRD equations
has been specifically validated in the HIV-infected
population. The MDRD equation was derived from
patients with low GFR and therefore can yield
variable results in persons with normal renal
function (Stevens et al., 2007). Nonetheless, these
estimates remain the most highly validated formulas
available, and both equations are more sensitive than
measurement of serum creatinine alone.
Statement of the Problem
HIV/AIDS patients are on the increase all over the
globe most importantly in Nigeria. The use of
HAART in our entire medical centers for the
management of this group of patients has
tremendously improved the well-being of this group
of patients. Early detection of renal complication
associated with HIV/AIDS could help reduce their
morbidity and mortality rate, hence there is need for
the identification of a more sensitive biomarker for
early detection of renal disease.
Justification (a)The level of serum creatinine, urea and cystatin C
in HIV/AIDS is not known in our environment.
(b)The status of urine microalbuminuria and
proteinuria in HIV/AIDS is not known in our
environment.
(c ) There is need for the use of a more sensitive
biochemical marker for accessing renal function in
patients with HIV/AIDS.
(d) The prevalence of HIV/AIDS- related renal
disease is not known in our environment
Aim
The aim of this present study was to access the
possibility of detecting a more sensitive biomarker
for the early detection of renal disease in HIV/AIDS
patients.
Objectives of the Study
To evaluate the serum creatinine, urea and cystatin
C level in newly diagnosed HIV patient, those on
therapy and the control group.
To evaluate the microalbuminuria and urine protein
(proteinuria) in newly diagnosed, those on therapy
and the control group.
To compare our findings with those reported in
other part of the world.
Materials and Methods
Description of Study Area
Seven hundred and fifty patients attending medical
treatment in St Thomas Hospital Ihugh. Ihugh is
situated in Vandeiky Local Government Area of
Benue located between latitude 70ºN by Gboko and
Buruku Local Governments Areas, in the South
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by Vandeikya Local Government, in the East by
Kwande and in the West by Konshisha Local
Government Area. In Nigeria, its geographical
coordinates are 7° 1' 0" North, 9° 2' 0" East and its
original name (with diacritics) is Ihugh. The study
included two hundred newly diagnosed HIV
seropositive patients, two hundred HIV/AIDS on
therapy (CD4≥250), two hundred HIV/AIDS on
therapy (CD4≤250) and one hundred and fifty
apparently healthy HIV seronegative individuals as
control.
Ethical Consideration
Approval for the study was obtained from St
Thomas Hospital Ihugh Medical Advisory
Committee. Verbal informed consent of the patients
was also obtained. Patient’s anonymity was
maintained; the data generated was treated with
strict confidentiality and was used for the purpose of
this research only.
Sample Size
The sample size was calculated using the formula
n = pq
[E/1.96]
2
(WHO, 1989)
Where,
n = sample size
p = Prevalence of previous studies in Kaduna
state = 4.7 (Sentinel survey 2006)
q = 100 – p
= 100 – 4.7
= 95.3
E = allowable error = 5%
N = 4.7 x 95.3
[5/1.96]
2
= 447.91
6.51
= 69 + 7 (10% for attrition)
= 76 approximately 80 patients.
Inclusion Criteria
(i) All adult HIV seropositive patients, who
consented to being included as participants in
the study were enrolled into the study.
(ii) All adult HIV seropositive patients, without
any sign and symptom of renal disease.
(iii) All adult HIV seropositive, without of any
underlying disease like diabetes, hypertension
Exclusion Criteria (i) All adult HIV seropositive patients who did
not offer a verbal informed consent to be
enrolled into the study.
(ii) All adult HIV seropositive patients with sign
and symptom of renal disease.
(iii) All adult HIV seropositive patients with
underlying disease like diabetes,
hypertension.
Collection of Samples Ten (10) ml of blood samples were collected in plain
bottle. This was allowed to clot within 30 minutes of
collection. The samples were then centrifuged at
3000 rpm for 5 minutes to obtain neat serum
samples, which were harvested into Bijou bottles
and labeled accordingly. The serum samples were
stored at 4oc until assayed. EDTA tube was used to
collect samples for the estimation of CD4 count
among the participants.
Analytical Methods
CD4 was carried out using the Partec Flow
Cytometer with an excitation light source of 488nm
or 532nm (blue or green solid state laser). The
Cyflow counter is set for counting CD4+T –cell per
µl whole cell as displayed automatically by the
instrument software which is controlled by an
operator (Fryland et al., 2004). Serum creatinine
was estimated using the method (Jaffe, 1886).
Diacethylmonoxine method was used for Urea assay
(Bruinsma et al., 2014). Protein and Microalbumin
assay was carried out using the H11-MA urinalysis
reagent strips. Cystatin C assay was carried out
using the Diazyme’s Cystatin C assay based on a
latex enhanced immuno-turbidimetric assay
(Erlandsen et al., 1999).
Statistical Analysis Data collected were entered into IBM compatible
microcomputer. Data analysis was done using
Statistical Package for Social Science (SPSS)
software package. Correlation was by Pearson’s
Correlation Coefficient. The Mean and Standard
Error of Mean (SEM) were computed and results
were expressed as mean + SEM. Student t-test was
used to compare differences between means.
Result
The results obtained in the present study are
expressed as mean ± standard error of mean (mean
±SEM) and are presented in tables 4.1 to 4.9.
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Table 1 shows the mean values of urea, creatinine
and Cystacin C in HIV patients with CD4 ≤ 250
cells/ml and control groups. There were significant
increases in the mean values of urea, Creatinine,
Cystatin C recorded in HIV patients compared with
controls (p<0.05).
Table 2 shows the mean values of urea, creatinine
and Cystatin C in HIV Patients with CD4 ≥ 250 and
controls. There were significant increases in the
mean values of urea and Cystatin C recorded in HIV
Patients with CD4 ≥ 250cells/ml compared with
control groups (p< 0.05). There was no significant
difference in the mean value of creatinine, recorded
in HIV patients compared with controls (p> 0.05).
Table 3 shows the mean values of urea, creatinine
and Cystatin C in newly diagnosed HIV patients and
controls. There were significant increases in the
mean values of urea, creatinine and Cystatin C
recorded in HIV patients compared with controls
(p<0.05).
Table 4 shows the mean±SEM values of Age (yrs),
Height (m), weight (kg), BMI of HIV patients (CD4
≤ 250) and Controls. There were significant
increases in the mean values of age, weight and BMI
recorded in HIV patients (CD4 ≤ 250) compared
with controls (p<0.05) and there was no significant
increase in the mean value of height of HIV patients
(CD4 ≤ 250) recorded compared with control group.
Table 5 shows the mean±SEM of Ages (yrs),
Height(m), weight(kg), BMI of HIV patients (CD4 ≥
250) and Controls. There were significant increases
in the mean values of age, weight and BMI recorded
in HIV patients (CD4≥ 250) compared with controls
(p<0.05).
Table 6 shows the mean±SEM value of Ages (yrs),
Height (m), weight(kg) and BMI in newly diagnosed
HIV patients and controls. There were significant
increases in the mean values of age, weight, BMI
recorded in newly diagnosed HIV patients compared
with control groups (p< 0.05). There were
significant differences in the mean values of height,
recorded in newly diagnosed HIV patients
Compared with controls (p> 0.05).
Table 7 shows the mean±SEM values of proteinuria
and microalbuminuria in newly diagnosed HIV
patients and controls. There was a significant
increase in the mean value of proteinuria recorded in
newly diagnosed HIV patients compared with
control groups (p< 0.05) and there was no
significant increase in the mean value of
microalbuminuria recorded in newly diagnosed HIV
patients compared with control group.
Table 8 shows the mean±SEM values of proteinuria
and microalbuminuria HIV patients with CD4 ≥ 250
and controls. There was no significant difference
between proteinuria and microalbuminuria HIV
patients with CD4 ≥ 250 compared with controls (p>
0.05).
Table 9 shows the mean values of protein and
microalbuminuria between HIV patients with CD4
≤250 and control group. There were significant
increases in proteinuria in HIV patients with CD4
≤250 cell compared with control (p< 0.05) and there
was no significant increase in the mean value of
microalbuminuria recorded in HIV patients with
CD4 ≤250 cell compared with control group.
Figure 1 shows strong correlation between plasma
cystatin C to Serum Creatinine. Linear regression:
CysC = 0.201SCR+ 0.512; r = 0.976; Syux = 0.622;
n=150.
Figure 2 shows strong correlation between plasma
cystatin C to Serum Creatinine. Linear regression:
CysC = 0.104SCr+ 0.514; r = 0.513; Syux = 0.322;
n=150.
Table 1: Mean values of urea, creatinine and Cystatin C in HIV patients with CD4≤ 250 cells/ml and
control groups.
Groups N Urea (mg/dl) Creatinine (mg/dl) Cystatin C (mg/l)
HIV patients (CD4 ≤ 250) 200 29±0.3 1.3 ±0.4 1.5±0.1
Controls 150 23±0.3 0.9±0.00 0.7±0.02
P-value 0.000 0.000 0.000
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Table 2 –Mean values of Urea, Creatinine and Cystatin C in HIV Patients with CD4≥ 250 and controls.
Groups N Urea (mg/dl) Creatinine (mg/dl) Cystatin C (mg/l)
HIV patients (CD4 ≥ 250) 200 27±0.1 1.0±0.2 1.1±0.2
Controls 150 23±0.3 0.9±0.0 0.7±0.02
P-value 0.6 0 0.03 0.500
Table 3: Mean values of Urea, Creatinine and Cystatin C in newly diagnosed HIV patients and controls.
Group N Urea (mg/dl) Creatinine (mg/dl) Cystatin C (mg/l)
HIV patients (newly diagnosed) 200 33±0.4 1.3±0.0 1.1±0.3
Controls 150 23±0.3 0.9±0.0 0.7±0.02
P- value 0.000 0.610 0.500
Table 4: Mean ± SEM values of Age (Yrs), Height (m), weight (kg), BMI of HIV patients (CD4 ≤ 250)
and Controls.
Group N Age (Yrs) Height(m) Weight (kg) BMI
HIV patients (CD4 ≤ 250) 200 27±0.6 1.5±0.1 57±0.9 25.3±0.2
Controls 150 25±0.7 1.6±0.1 55±0.1 21.5±0.8
P-value 0.000 0.00 0.000 0.000
Table 5: Mean ± SEM of Ages (Yrs), Height(m), Weight(kg), BMI of HIV patients (CD4 ≥ 250) and
Controls.
Group N Ages (Yrs) Height(m) Weight(kg) BMI
HIV patients (CD4 ≥ 250) 200 31±0.5 1.6±0.2 65±0.5 25.3±0.7
Controls 150 25±0.7 1.6±0.1 55±0.1 21.5±0.8
P- value 0.000 0.210 0.000 0.000
Table 6: Mean ± SEM value of Ages (yrs), Height(m), weight(kg) and BMI in newly diagnosed HIV
patients and controls.
Groups N Ages (Yrs) Height(m) weight(kg) BMI
HIV patients (newly diagnosed) 200 39±0.7 1.5±0.4 58±0.8 25.7±0.5
Controls 150 25±0.7 1.6±0.1 55±0.1 21.5±0.8
P-Value 0.00 0.01 0.92 0.000
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Table 7: Mean ± SEM values of proteinuria and microalbuminuria in newly diagnosed HIV patients
and controls.
Groups N Proteinuria (g/l) Microalbunuria (g/l)
Control group 150 0.03 ± 0.00 0.00 ± 0.00
Newly infected HIV 200 0.38 ± 0.10 0.07 ± 0.01
P-value 0.00 0.00
Table 8: Mean ± SEM values of Proteinuria and Microalbuminuria HIV patients with CD4 ≥ 250 and
controls
Group N Proteinuria(g/l) Microalbuminuria (g/l)
HIV patient CD4 ≥ 250 200 0.03 ± 0.00 0.00 ± 0.00
Control group 150 0.03 ± 0.00 0.00 ± 0.00
P-value 0.000 0.000
Table 9: Mean values of Proteinuria and Microalbuminuria between HIV patient with CD4 ≤250 and
Control group.
Group N Proteinuria(g/l) Microalbuminuria(g/l)
HIV patient with CD4≤ 250 200 0.16 ± 0.03 0.02 ± 0.00
Control group 150 0.03 ± 0.00 0.00 ± 0.00
P-value 0.000 0.000
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Figure 1. Relation of Plasma Cystatin C to Serum Creatinine.
Linear regression: CysC = 0.201SCR+ 0.512; r = 0.976; Syux = 0.622; n=150.
Figure 2: Relation of Plasma Cystatin C to Serum Urea
Linear regression: CysC = 0.104SCr+ 0.514; r = 0.513; Syux = 0.322; n=150.
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Discussion, Conclusion and Recommendation.
Discussion
HIV associated nephropathy, the most common
renal disease in HIV patients was first described in
1984 (Rao et al., 1996 and Pardo et al., 1998). Most
patients present with nephrotic syndrome,
progressive loss of renal function and without
treatment progress to end stage renal dysfunction
(ESRD) within weeks to months (Langs et al.,
1990). Although HIV associated nephropathy is
usually diagnosed late in the course of HIV
infection, renal involvement can occur earlier, even
during the acute retroviral syndrome prior to HIV
antibody seroconversion.
There were significant increases in the mean values
of age, weight and BMI recorded in HIV patients
(CD4 ≤ 250) compared with values in controls
(p<0.05). There were significant increases in the
mean values of Urea, Creatinine, Cystacin C
recorded in HIV patients compared with values
obtained in controls (p<0.05). This finding
correlates with the works of Moses and Colleagues
(2012). They reported that the mean serum Cystatin
C levels was significantly higher in the HIV-infected
patients when compared with the value in controls
(p <0.05). Direct effects of HIV appear to play a
major role in the development of HIV- associated
nephropathy, and are characterized histologically by
collapsing glomerulosclerosis, thrombotic
microangiopathy and various forms of immune
complex glomerulonephritis. Hepatitis B and C co-
infection, often co-pathogens with HIV, may affect
kidneys similarly (Agari et al., 1989). There was
significant increase in protein and microalbumin in
HIV patients with CD4 ≤250 cell when compared to
values in controls (p< 0.05). Previous reports
(Emejulu et al., 2011 and Kamga et al., (2011)
indicated that serum urea concentrations were
significantly increased (p<0.05) in both male and
female patients compared to the controls. Although
no significant difference was obtained in the serum
creatinine levels of the patients to the control,
correlation analysis however revealed a positive
association between creatinine and urea levels in
both male (r=0.63) and female (r=0.68) HIV
patients. This finding is in consonance to this study
since there were no significant increases in the mean
values of urea and creatinine recorded in HIV
patients compared with values obtained in controls
(p>0.05).
There was a significant increase in the mean value
of urea recorded in HIV patients with CD4 ≥
250cells/ml compared with control groups (p< 0.05).
There were no significant differences in the mean
values of creatinine recorded in HIV patients
compared with values in controls (p> 0.05). HIV
patients with (CD4 ≥ 250) had increased urea,
Cystatin C when compared with controls. This
finding correlate with previous report (Jerzy et al.,
2006) which indicated that HIV patients had a
significant increase in serum Cystatin C
concentration compared with apparently healthy
individuals. There were no significant differences in
urea and creatinine in both groups. Our finding is
consistent with a previous report (Kamga, et al.,
2011) in Nylon District Hospital, Douala, Cameroon
involving subjects 18 to 60 years which indicated
that there was no significant difference in the urea,
creatinine, proteinuria in HIV positives and control
groups. There was no significant difference between
proteinuria and microalbuminuria between control
and HIV patients with CD4 ≥ 250 (p> 0.05).
There were significant increases in the mean values
of Urea, Creatinine and Cystatin C recorded in HIV
patients compared with values in controls (p<0.05).
Our finding is consistent with previous report (Kara
et al., 2007) which observed renal disease (renal
insufficiency (CrCl <60 ml/min) identified in 11.5%
and CrCl <50 ml/min in 4.8% of antiretroviral-naive
HIV-infected outpatient population in Western
Kenya. Despite high correlation coefficients
between the three-renal function parameters, the
estimating equations used, when compared to
creatinine clearance as calculated by Cockcroft–
Gault indicated a lower rate of moderate to severe
renal insufficiency identified by the Modification of
Diet in Renal Disease equations. Proteinuria,
defined as a urine dipstick protein of equal to or
greater than 1+, was detected in only 23 subjects
(6.2%). Renal insufficiency is not uncommon, even
in stable patients without diabetes or hypertension.
Conversely, proteinuria was unexpectedly infrequent
in the population. In another report by Doutora et
al. (2011) that investigated the strategies for early
detection of renal injury in HIV-infected patients
indicated that 17 patients had elevated levels of
Cystatin C but with an estimated creatinine
clearance within normal range, 11 were on
antiretroviral therapy with tenofovir and/or
atazanavir. Fourteen patients were smokers and 10
patients had hepatitis C virus co-infection, which are
known causes of inflammation. In a matched control
group of 27 patients (subject) Cystatin C levels was
within normal range, the majority of patients
(subject) also were on an antiretroviral regimen of
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tenofovir and/or atazanavir. However, none of them
had hepatitis C virus co-infection. Moreover, a
statistical association was found between high levels
of Cystatin C and alanine transaminase. Differences
between biomarkers’ levels and patients on
combinations with tenofovir, ritonavir boosted
atazanavir or both were also studied. Although there
was no statistically significant difference in
creatinine and estimated creatinine clearance, with
Cystatin C, patients that were on atazanavir or
tenofovir, had a higher level of Cystatin C,
compared with patients that never were on these
drugs. For instance, in a US study looking at body
fat and metabolic changes in HIV-positive patients
(the FRAM – Fat Redistribution and Metabolic
Change in HIV Infection – cohort), investigators
conducted a cross sectional sub-study where they
compared kidney function, as measured by Cystatin
C and creatinine levels in 1,008 HIV-positive
subjects and 208 HIV-negative controls (Odden et
al., 2007). Cystatin C measurements were
consistently higher in the HIV-positive participants
(at levels that would be indicative of poor outcomes
in the general population) but creatinine-based
eGFR levels were similar in HIV-infected
individuals and controls. In a subsequent analysis of
the FRAM cohort, levels of Cystatin C were
elevated in HIV-positive patients compared to the
HIV-negative controls (mean level, 0.92mg/l vs.
0.76mg/l, p < 0.001). But creatinine levels were
similar in the two groups of patients (0.87mg/dl vs.
0.85mg/dl) (Odden et al., 2007). Cystatin C level
was elevated in HIV-infected individuals compared
to controls (p<0.001). In contrast, both mean
creatinine levels and estimated glomerular filtration
rates appeared similar in HIV-infected individuals
and controls (p=.35) and (p=.06) respectively.
Persons with HIV infection were more likely to have
a cystatin C level greater than 1.0 mg/L (p<.001), a
threshold demonstrated to be associated with
increased risk for death and cardiovascular and
kidney disease.
Another study using data from participants from the
strategies for management of antiretroviral therapy
(SMART) study found that Cystatin C and other
biomarkers of serious health problems were elevated
in people living with HIV as compared to the
general population (based on data from two large
studies monitoring the development of renal and
heart disease), even while people were taking
antiretroviral therapy (Neuhaus et al., 2010). In
summary, the investigators said, “we found that
markers of inflammation, coagulation, and renal
function were elevated in HIV-infected study
participants receiving or not receiving antiretroviral
therapy, compared with patients in two large
population-based studies.”All of this would tend to
support the fact that HIV causes kidney disorders
and this increase the risk of poor outcomes in people
living with HIV. However, a previous report (Post et
al., 2010) quite correctly point out that “although
changes in virologic control could plausibly
influence kidney function, it is also possible that
changes in Cystatin C reflect the influence of viral
replication on systemic inflammation”.
In the present study, Cystatin C showed higher
increment above control than serum creatinine in
early stages of kidney affection in HIV/AIDS-
related nephropathy. A mild degree of renal
dysfunction may develop unnoticed as creatinine
level may remain in the normal range despite a
major decline in GFR, and the use of serum
creatinine may inaccurately estimate GFR due to
dietary intake, tubular secretion of creatinine
(Kyhse-Andersen et al., 1994). These results
confirm those noticed by Coll et al. (2000). They
reported that serum cystatin C levels started to
increase when GFR was 88 ml/min/1.73 m2, while
serum creatinine level begin to increase when GFR
was 75ml/min 1.73 m2. These data indicate that
serum cystatin C may detect mild reduction in GFR
than serum creatinine. On the other hand, Shemesh
et al. (1985) reported that serum creatinine is of
little value in estimating GFR, while increased
serum creatinine with decreased GFR has been
reported in patients with several types of renal
failure (Bauer,1982). Newman and Price (1999)
have suggested that Cystatin C is the best
endogenous GFR marker.
There was a significant increase in the mean value
of age, weight, BMI recorded in newly diagnosed
HIV Patients compared with control groups (p<
0.05). It should also be noted that creatinine
production is closely related to muscle mass. Muscle
mass and GFR are dependent on age, both tending to
fall with increasing age, although it is important to
note that BMI (height/ body mass) does influence
the function of the kidney especially if BMI is ≥25 a
predisposing risk factors of hypertension which
affect the kidney directly hence increase in the
Cystatin C, Urea, and creatinine. Although there was
a statistically significant difference among HIV
infected subject (CD≥250 cell/l and CD≤250 cell/l)
when compared to control. There were no
significant differences in the mean value of height,
recorded in newly diagnosed HIV patients compared
with controls (p> 0.05).
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There was a significant increase in the mean value
of proteinuria recorded in newly diagnosed HIV
patients compared with values in control groups (p<
0.05). There was no significant increase of
microalbuminuria in the subjects. There was no
significant difference between protein and
microalbumin among HIV patients with CD4 ≥ 250
compared with controls (p> 0.05). There were
significant increases in proteinuria in HIV patients
with CD4 ≤250 compared with control (p< 0.05).
There was no significant increase of
microalbuminuria in the subjects.
Historically, microalbuminuria has been assumed to
result from alterations in glomerular filtration
secondary to changes in intraglomerular pressure
and/or structural changes of the podocyte or
glomerular basement membrane. Recent evidence in
rats, however, suggests that the normal glomerular
filter actually may leak albumin at higher levels than
previously thought, and albuminuria may result from
failure of the proximal tubule cell retrieval pathway
(Russo et al., 2007). Microalbuminuria may prove to
be a useful marker of AKI and concomitant
proximal tubular cell damage. Microalbuminuria has
previously been reported with short- and long-term
administration of nephrotoxic chemotherapeutics
such as cisplatin, ifosfamide, and methotrexate
(Kern et al., 2000 and Koch et al., 1998), as well as
antibiotics such as gentamicin (Tugay et al., 2006).
Using microalbuminuria as a marker, Leven et al.
(2007) demonstrated that N-acetylcysteine may
attenuate contrast-induced glomerular and tubular
injury. Microalbuminuria, however, may also be
caused by vigorous exercise, haematuria, urinary
tract infection, and dehydration.
Widely available, urine tests that screen for
proteinuria and albuminuria, have been shown to
identify people at higher risk of kidney disease and
other adverse outcomes in the general population
and in people living with HIV. However, a recent
study has found that the sensitivity of the cheapest,
simplest method of screening for proteinuria, the
dipstick test, may be affected by urinary
concentration (Siedner et al., 2008).
There was high correlation (r = 0.876) between
CysC and SCR that supports the concept that CysC
and SCR have similar properties as plasma markers
of GFR (Newman et al., 1994). Correlation of Cys C
measurements with measurement of GFR has been
reported in a number of previous studies (Newman
et al., 1995 and Nilsson-Ehle, 1994). Grubb et al.
(1985) first reported the correlation (r = 0.75– 0.77)
of Cys C concentrations with GFR measured by Cr-
EDTA clearance, and also found a similar
correlation (r = 0.73– 0.75) for SCr vs Cr-EDTA
clearance in renal patients ranging in age from 7 to
77 years. Stronger correlation to Cr-EDTA clearance
(r = 0.87) together with a greater distinction from
the plasma SCr correlation (r = 0.71) were reported
in a more recent study using a particle enhanced
turbidimetric assay for Cys C measurement in
patients 8–81 years of age (Nilsson-Ehle et al.,
1994). Similar numbers for the correlation of Cys C
vs Cr-EDTA clearance (r 5 0.81) were reported in
the most recent studies (Newman, 1995), but the
correlation using SCR was markedly lower (r
=0.50). According to Stickle et al. (1998) in a study
of pediatric patients there was high correlation
between Cys C vs Creatinine clearance (r = 0.77 for
4–12 years; and r = 0.87 for 12–19 years) is
comparable with the correlations obtained in
previous studies. There was a slight correlation of
Cystatin C with urea (r=0.513).
From the research, it was discovered that patient
with high serum creatinine had high urine protein,
with microalbuminuria, although some patient with
mild proteinuria never indicated any form of
microalbuminuria, some authors pointed out, that
dipstick tests only measure albumin, which is a more
specific indication of glomerular injury, such as is
seen in HIVAN (Kimmel, 2003). People with kidney
disease localized in the renal tubule may have mild
proteinuria composed of other proteins but rarely of
albumin. Thus, dipstick tests are an unreliable way
to screening for renal tubular injuries such as the
Fanconi-like syndrome that tenofovir can cause.
Risk factors associated with HIV were also strongly
and independently associated with higher Cystatin C
level, including lower CD4 lymphocyte count,
which is indicative of immune dysfunction. This
suggests that in addition to the adverse metabolic
effects of HIV, severity of HIV infection and
coinfection may exacerbate the diminished kidney
function observed in these participants. Among the
subjects, those that had higher creatinine and
Cystatin C also had proteinuria few with
microalbuminuria which is indicative of
significantly reduced renal function. The result of
the present study showed a high sensitivity of
Cystatin C and creatinine in assessing renal function
over other analyte like, urea, proteinuria and
microalbuminuria which are late makers.
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SJMLS Volume 2, Number 1 March, 2017 | Page 171
Conclusion
Cystatin C levels may be increased in inflammatory
conditions. Therefore, in HIV-infected patients,
where chronic systemic inflammation is present,
often associated to other inflammation sources, such
as chronic hepatitis C virus co-infection, the use of
Cystatin C to monitor kidney function may
overestimate kidney impairment. It is important to
develop prospective studies, in order to assess and
determine early renal dysfunction and real long-time
impact of the more recent antiretroviral drugs on
kidney function so as to take preventive measure on
kidney diseases which is the core public health
population strategies. Among the subjects those that
had higher creatinine and Cystatin C all had
proteinuria and few with microalbuminuria which is
indicative of significant reduction of renal function.
The result of the present study showed a high
sensitivity of Cystatin C and creatinine in assessing
renal function over other analyte like, urea,
proteinuria and microalbuminuria which is are late
makers.
Recommendation HIV infection appears to be a risk factor for
developing chronic kidney disease. Even in patients
with normal kidney function, the presence of
proteinuria may indicate early kidney disease. We
recommend as previously suggested (Gupta et al.,
2005) that if the initial urine analysis results are
normal, annual follow-up urine analysis are
recommended to screen for newly developed kidney
damage for the following groups, which are at
higher risk for the development of proteinuria and
poor renal outcome - African-American persons,
patients with diabetes, patients with hypertension,
patient with hepatitis C virus coinfection and
patients with HIV-RNA levels >4000 copies/l or
absolute CD4 lymphocyte counts <200/ l. An
estimate of creatinine clearance for GFR is also
recommended annually to screen for renal
dysfunction that may develop overtime and that may
herald worse overall prognosis. We recommend the
implementation of previous recommendations in
recent reports (Gardner et al., 2003 and Gupta et al.,
2004) that the baseline presence of proteinuria with
or without concomitant elevations in the serum
creatinine level is a sensitive prognostic factor of the
eventual development of chronic kidney disease.
Renal disease is frequent in patients having
HIV/AIDS infection. There is need for inclusion of a
sensitive renal marker as a routine check in these
patients. This will help in early detection of renal
diseases, thereby preventing end stage renal disease.
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