SJMLS-1(2)-2016-017 Cystatin C- A Novel Biomarker for ... · Benue State 2, School of Medical ......

ISSN: 2536-7153 SJMLS

SJMLS Volume 2, Number 1 March, 2017 | 61

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

mailto:[email protected]

SJMLS ISSN: 2536-7153

Page 162 | SJMLS Volume 2, Number 1 March, 2017

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


SJMLS Volume 2, Number 1 March, 2017 | Page 163

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.



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).


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).


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



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



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



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.



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



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.


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).

http://www.aidsmap.com/page/1429193/



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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.








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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