Assocaition of Urinary Kidney Injury molecule with Albuminuria for

early diagnosis of Nephropathy in Type 2 Diabetic Patients

Urinary Kidney Injury molecule is a better Biomarker than Albuminuria
for early diagnosis of Nephropathy in Type 2 Diabetic Patients
Abstract
Introduction :
UKIM -1 is a renal tubular injury biomarker.It’s presence in urine shows tubular damage in type
2 diabetic patients .. Early change in Diabetic Nephropathy is Glomerular hypertrophy then it
leads to gradual scaring in glomerular and tubulointestinal region. Glomerulosclerosis is
hallmark of Diabetic Nephropathy.

Aims and Objectives:

To evaluate UKIM-1 as better biomarker than Albuminuria to predict early stage of
Nephropathy in Type 2 DM patients and it’s corelation with Urinary Cretinine , Urinary
Albumin , Urinary Kim 1/Cretinine Ratio and Urinary Albumin / Cretinine Ratio

Place and Duration of Study

Department of Biochemistry and Chemical Pathology SZHL

Duration??

Materials and Methods:

The study comprised of 70 type 2 Diabetic patients , having diabeties for less than 10 years , with
or without Nephropathy. They were further divided in 2 groups on the basis of Albumin
Cretinine Ratio (ACR) . Group 1 comprised of 35 Diabetics with normoalbuminuria and Group 2
compromised of 35 diabetics with microalbuminuria. Urinary cretinine , Urinary Albumin ,
Urinary Kim 1 were estimated . Urinary Kim 1 / Cretinine Ratio and Urinary Albumin
/Cretinine Ratio also called ACR were calculated in mg/g . Comparison of Urinary Kim 1 was
done and it’s corelation with other parameters were observed .

Results:
The mean urinary Kim 1 level (ng/ml) was significantly higher in group 2 (19.83 +_ 4.78) as
compared to group 1 (10.12 +_ 3.51) (p value <0.001)

Conclusion:
Urinary Kim 1 level in this study was found to be significantly elevated in type 2 Diabeties
Mellitus patients with microalbuminuria as compared to type 2 diabetics with
normoalbuminuria . Since Urinary Kim-1 rises in case of renal tubular injury so it’s raised level
shows Nephropathy before onset of microalbuminuria which is a gold standard .Hence in
Diabetics Urinary Kim 1 levels may be performed routinely to asses development of
nephropathy at an earliar stage .

Introduction
Diabeties Mellitus is a metabolic disorder characterized by chronic hyperglycemia and
glycosuria with abnormalities in carbohydrate , fat and protein metabolism arising from a defect
in Insulin secretion and or it’s action or both .(1) Globally ,the prevalance of Diabeties Mellitus
was estimated to be 2.8% in year 2000 and 4.4% in 2030 . In Pakistan , 5.3 million people were
estimated to have diabeties while this no has increased to 13.9 million by 2030 (2). Chronic
Diabetic complications are divided into microvascular (Retinopathy , Neuropathy and
Nephropathy) and Macrovascular ( Cardiovascular, Peripheral vascular Disease and
Cerebrovascular disease ) (3).Diabetic Nephropathy is the most common micro vascular
`complication of Diabeties Mellitus(4) .It is characterized by persistant Albuminuria , elevated
Blood Pressure and Progressive decline in Kidney function leading towards End Stage Renal
Disease (5). It develops in almost 40% of al type 2 diabetic patients(6) . Diabeties Mellitus is
leading cause of Chronic Kidney Disease that further progresses to End Stage Renal Disease and
the early detection of Diabeties Mellitus related Diabetic Nephropathy is of great value .
(7)Diabetic Nephroapthy is progressive disease depending on severity of Albumin excretion rate
. (8).

In microalbuminuria an abnormally higher amount of Albumin is excreted in urine falling in

the range of 30-299mg/g cretinine . It is the earliest manifestation of renal disease in type 1 and
type 2 diabetics (9).To detect increased excretion of Urinary protein Urinary Albumin to
cretinine ratio (ACR) is measured .,Albuminuria is considered Gold Standard biomarker of
glomerular injury at present.(10)

It is of utmost importance to screen type 2 diabetics regarding the development of Diabetic

Nephropathy so that associated morbidity and mortality can be prevented and managed well in
time .(11)

UKIM-1 is a type 1 transmembrane structural glycoprotein (12) . It is located on apical

domain of renal proximal tubular epithelial cells .Tubular epithelial cells express KIM-1 once
injured by different forms of acute and chronic renal injuries (13) .KIM-1 1 is not normally
detectable in urine.It’s presence in urine is highly specific for kidney injury as it is not expressed
by any other organ.(14-15) KIM-1 is sensitive as it appears before microalbuminuria becomes
evident (16-17) . Routine monitoring of UKIM-1 might be useful to assess the development of
Diabteic Nephropathy.
 The objective of this study was to see assocation of urinary KIM- 1 and urinary albumin in
type 2 diabetic nephropathy patients and to evaluate urinary Kim 1 as a biomarker to predict
early stage of nephropathy in type 2 diabetic patients .

Materials and Methods:

Study Setting:
The study was performed in the Department of Biochemistry and Chemical Pathology , Sheikh
Zayed Hospital , Lahore in year? and patients were selected from Diabetic Endocrine Clinic and
Nephrology Department of hospital . After approval from ethical review board , patients were
selected for the study and written consent was taken from participants . The study was done
through non convinient sampling and lab values of study parameters were recorded as designed
performa.

Study Population:
70 patients having type 2 diabeties for less than 10 years between 45 to 65 years of age
comprising of equal no of male and females with and without nephropathy were included in
study according to following distribution .

Group 1: 35 patients of type 2 Diabeties having ACR <30mg/g cretinine are normoalbuminuric

Group 2: 35 patients of type 2 Diabeties having ACR 30-299mg/g cretinine are

microalbuminuric

Following individuals were excluded from the study

1)Type 2 diabetics for more then 10 years

2)Diagnosed cases of advanced chronic kidney disease or acute kidney injury

3)Renal transplant

4)Hypertension

5)Pregnancy

6)Histroy of drug intake ( ACE inhibitoes or Angiotensin receptor blockers)

7)Any other systemic illness or malignancy

8)Little or no evidence of confirmed diagnosis of type 2 diabeties mellitus

 Urinary Cretinine , Urinary Albumin , Urinary Kim 1 were performed on cell individuals .
Urinary Kim1 / Cretinine ratio was calculated .Urinary Albumin /Cretinine Ratio (ACR) was
also calculated in mg/g.

Urinary Cretinine was determined by RXL Autoanalyzer .Urinary Albumin was performed
on MINDRAY BS-400. Urinary Kim 1 was estimated by ELISA . The tests were performed in
Biochemistry lab of Sheikh zayed Hospital , Lahore

Statistical Analysis :
SPSS 20.0 was used for data entry and analysis .The data of age , duration of diabeties , Urinary
ACR were described by using mean +_ SD and median (IQR) for both groups .Comparsion
between variables was done by Mann Whitney U test .Logistic Regression model were used to
determine that age , duration and UKIM-1 were associated to predict nephropathy .P value of <_
0.05 was considered significant

Results:
There were 35 type 2 diabetic patients in Group 1(normoalbuminuric) and Group 2
(microalbuminruic) with 17 males and 18 females in both groups with mean age of 54.1+_ 6.0
and 52.1 +_ 5.1 respectively (Table 1)

The Duration of Diabeties is low is Group 1 as compared to Group 2 (p value <0.001)

Regarding Urinary Parameters Urinary Albumin , Urinary KIM-1 and Albumin Cretinine Ratio
are significantly low in Group 1 as compared to Group 2 (p value <0.001). Median Urinary Kim-
1 was significantly Higher in Group 2 as compared to group 1 (P value < 0.001).

Urinary Cretinine was high in Group 1 as compared to group 2 with the P value of 0.024.
PARAMETERS GROUP 1 GROUP 2 P VALUE

Normoalbuminuric Microalbuminuric

@ N=35 @ N=35

Gender

Male 17 17

Female 18 18

Age (years)

<_50 18 12

>50 17 23

(52.1+_5.1) (54.1+_6.0) 0.027*

Duration of DM 5 7 0.014*

(years) (5.5+_1.7) (6.5+_1.5)

Urinary 145.6 85.1 0.024*

Cretinine(mg/dl) (122.3+_44.7) 99.8+_53.6

Urinary 17.0 99.9 <0.001*

Albumin(mg/dl) (16.5+_8.3) 121.7+_81.5

Urinary Kim-1 8.83 19.85 <0.001*

ng/ml (10.12+_3.51) (19.83=-4.78)

ACR 13.21 122.20

mg/g of Cretinine (13.92+_6.82) (133.54+_82.4) <0.001*

@values are given as Median (IQR)

*p value is generated by MAN U WHITNEY TEST

*p value <0.005 is considered significant

 Discussion
The study was performed on 70 type 2 Diabetic patients grouped as Group 1
(Normoalbuminuric ) and Group 2 (Microalbuminuric) based on ACR .There were 35 patients
in each group and aim of study was to evaluate Urinary Kim 1 as an early biomarker of
Nephropathy and to correlate it’s association with Albuminuria .There were 17 males and 18
females subjects of age 45- 65 years in each group .A previous study also had same age group.
(18) The was the mean age difference was of 52.1+_5.1 in group 1 and 54.1+_6.0 in group 2
.The duration of Diabeties was less than 10 years where maximum duration was 9 years and
minimum duration was 4 years to detemine early changes before the onset of diabetic
nephropathy.Similar criteria was observed in previous study (19)

The median Urinary Cretinine was significantly higher in group 1 as compared to group 2
.The median Urinary Albumin was significantly higher in group 2 (microalbuminuric) as
compared to group 1 (normoalbuminuric) .Similarly Albumin Cretinine Ratio (ACR) found to be
greater in group 2 as compared to glroup 1 .Similar findings were seen in previous studies (20-
24).Urinary KIM-1 levels were significantly higher in group 2 as compared to group 1
(p<0.01).Some other reserchers observed similar findings in their studies .(25-28)They also
showed that Urinary KIM-1 was not detectable in healthy non diabetic subjects .However in
present study ,Urinary KIM-1 are still raised in group 1 as compared to Healthy non diabetic
subjects of other studies .A study has shown that Urinary KIM-1 levels increased progressively
in normo , micro and macroalbuminuric diabetics as compared to non diabetic healthy control
subjects .

Urinary KIM-1/ Cretinine ratio was calculated and it was significantly higher in group 2 as
compared to group 1 .A study has shown simiar results . In present study it was observed that
Urinary KIM-1/Cretinine ratio and age has predicted about microalbuminuria in type 2 diabetic
patients and this is observed by another researches as well but some reserches found a weak
corelation between them to predict nephropathy may be due to different inclusion criteria .

In the present , association of Urinary KIM-1 and Albumiurea was determined through
binary logistic regression with age and duration of diabeties mellitus to assess utilization of
Urianry KIM-1 for early diagnosis of nephropathy. Urinary KIM -1 elevated before albuminurea
and results corelated with a study .

Hence the results of current* study are in accordance with afore-mentioned studies .It is also
observed that accuracy of Urinary KIM-1 to predict microalbuminurea was 91.4% and that for
normoalbuminurea was 88.6% .

Conclusion
It may be concluded that Urinary KIM-1 was significantly high in microalbuminuric group as
compared to normoalbuminric group in type 2 diabetic patients

.Urinary KIM-1 has positive corelation with Albumin Cretinine ratio in both groups .Urinary
KIM-1 levels increased before appearence of microlbuminurea that is currently a gold standard
to diagnose nephropathy .This suggests that Urinary KIM-1 measument might be useful ,
sensitive , specific and non invasive biomarker for early diagnosis of nephropathy .

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