Clinical Epidemiology and Global Health 9 (2021) 2–6

Contents lists available at ScienceDirect

Clinical Epidemiology and Global Health

journal homepage: www.elsevier.com/locate/cegh

Diabetic kidney disease: An overview of prevalence, risk factors, and T

biomarkers
Salman Hussaina, Mohammad Chand Jamalib, Anwar Habibc,∗, Md Sarfaraj Hussaind,
Mohd Akhtare, Abul Kalam Najmie
a
Department of Pharmaceutical Medicine (Division of Pharmacology), School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
b
Department of Health and Medical Sciences, Khawarizmi International College, Abu Dhabi, United Arab Emirates
c
Department of Medicine, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India
d
Department of Pharmacognosy & Phytochemistry, R.V Northland Institute of Pharmacy, U.P, India
e
Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India

A R T I C LE I N FO A B S T R A C T

Keywords: Diabetic kidney disease (DKD) is a major public health problem characterized by elevated urine albumin ex-
Biomarkers cretion or reduced glomerular filtration rate or both. The pathophysiology of DKD involves various pathways
Chronic kidney disease like hemodynamic, metabolic, and inflammatory pathways. Increase in reactive oxygen species formation in-
Diabetes kidney disease duced by hyperglycemia through activation of electron transport chain considered as the initiators in the de-
Diabetic nephropathy
velopment of diabetes complications. Prevalence of DKD is raising continuously with disparate growth in low to
Epidemiology
India
middle-income countries and under-recognized as a global burden of disease. DKD imposes an enormous hu-
Prevalence manistic, economic, and societal burden. DKD in the initial stage is often undiagnosed until the manifestations of
serious complications. The major hurdle in the early diagnosis is limited knowledge, unroutine screening. Timely
diagnosis and appropriate interventions are the best approaches to deal with this catastrophic condition. Early
diagnosis can have lifetime benefits by controlling the progression of the disease, increasing life expectancy,
decreasing the humanistic and economic burden. Even after all these benefits; DKD cases are diagnosed when the
condition worsens. Non-availability of potential diagnostic biomarkers is the main barrier to the early diagnosis
of DKD. The present review highlights the worldwide prevalence, risk factors, and potential biomarkers for the
early detection of DKD.

1. Introduction
Diabetic kidney disease (DKD) also referred to as diabetic nephro-
pathy. The patients with diabetes and chronic kidney disease (CKD)
presented a unique cohort of DKD population, which is identified by
elevated urine albumin excretion or reduced glomerular filtration rate
(GFR) or both.1 It affects the kidney function and alters the usual
process of removal of waste products and excess fluid from the body.
Sign and symptoms of kidney disease in people with diabetes include
albuminuria (excretion of albumin in the urine), weight gain, swelling
of ankle and legs, frequent urination in the night, morning sickness,
anemia, and high blood pressure.2 DKD develops in 40% of patients
with type 2 diabetes mellitus (T2DM) and 30% of patients with type 1
diabetes. DKD is the leading cause of CKD and end-stage renal disease.3
DKD prevalence is continuously rising with disparate growth in low to
middle-income countries and under-recognized as global disease
burden.4 DKD is also associated with a high mortality rate. Kidney
disease increased mortality risk by 31.1% in patients with diabetes and
it increases with the severity of the disease.5,6 Even the mortality risk
was also higher in early DKD patients.7 Additionally, DKD imposes an
enormous humanistic, economic, and societal burden.8 DKD in the in-
itial stages is often undiagnosed until the manifestations of serious
complications.9–11 The major hurdle in the early diagnosis is limited
knowledge, unroutine screening.12,13 Early diagnosis is a cost-effective
approach to reduce the humanistic and economic burden due to DKD.
In this review, we highlighted the worldwide prevalence, risk fac-
tors, and biomarkers for the early detection of DKD.
2. Worldwide prevalence of DKD
DKD is highly prevalent across the globe. The odds of developing
CKD in patients with diabetes was reported around 1.75 (95% CI:

∗
Corresponding author. Department of Medicine, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, 110062, India.
E-mail address: anwer_habib@rediffmail.com (A. Habib).

https://doi.org/10.1016/j.cegh.2020.05.016
Received 4 May 2020; Received in revised form 23 May 2020; Accepted 26 May 2020
Available online 27 May 2020
2213-3984/ © 2020 Published by Elsevier, a division of RELX India, Pvt. Ltd on behalf of INDIACLEN.
S. Hussain, et al.
1.62–1.89).14 A cross-sectional study from a risk assessment manage-
ment program in China found 38.8% prevalence of CKD in 15856 pa-
tients with diabetes.15 A population-based study reported 2.9% pre-
valence of DKD among Chinese rural residents.16 A study conducted by
our group found 34.4% prevalence of DKD in India.13 A multicentre
study from India reported a composite prevalence of diabetic-CKD of
around 62.3%.17 Similarly, a population-based study from the United
Arab Emirates found 11.4% cumulative incidence of CKD after a follow-
up of 9 years.18 The highest prevalence rates of diabetes mellitus (DM)
and CKD-DM were observed among the elderly in the eastern Medi-
terranean region.19 Diabetes clinical data management study in Japan
revealed 15.3% of T2DM patients had low eGFR.20 Findings of United
Kingdom (U.K.) prospective diabetes study incorporating 4006 T2DM
patients revealed that 28% patients develop renal impairment after a
median follow-up of 15 years.21 The prevalence of DKD in United States
(U.S.) population was found to be 2.2% according to the cross-sectional
analysis of third national health and nutrition examination survey.22 It
also states that prevalence of DKD in the US is increasing in proportion
to the prevalence of diabetes as observed from 1988 to 2008.
3. Risk factors of DKD
3.1. Increased albuminuria
Increase excretion of albumin in the urine is a major risk factor for
the development and progression of kidney disease in people living
with diabetes. It is characterized by increased excretion of albumin/g
creatinine in the urine referred to as microalbuminuria (30–300 mg/g)
or macroalbuminuria (> 300 mg/g).
3.2. Hyperglycemia
Hyperglycemia is considered as one of the most prominent and in-
dependent risk factors of DKD.23 It increases the worsening of renal
function by altering the antioxidant system which leads to the increased
formation of advanced glycation end products. Polyol pathway activa-
tion is also postulated in the pathogenesis of DKD.24 Variability in
glycated hemoglobin (HbA1c) is associated with the development and
progression of nephropathy in both type 1 DM patients and T2DM pa-
tients.25 A similar finding was reported by the Renal Insufficiency And
Cardiovascular Events (RIACE) an Italian multicenter study.26 Evidence
from randomised controlled trials found beneficial effects of intensive
glucose control in the delayed onset as well as in preventing the pro-
gression of albuminuria in T2DM patients.27,28
3.3. Hypertension
Hypertension is a pivotal risk factor for diabetic nephropathy.
Hypertension is significantly associated with the development of dia-
betic nephropathy as confirmed by a recent meta-analysis.29 In children
with CKD hypertension is associated with cardiovascular disease.30
Hypertensive patients are at higher risk of developing diabetic ne-
phropathy as compared to non-hypertensive patients with an odds ratio
of 1.67 (95% CI: 13.1–2.14).29 This was further confirmed by a popu-
lation-based prospective study from china which states that hyperten-
sion control can reduce the incidence of end-stage kidney failure by
23%.31
3.4. Dyslipidemia
Dyslipidemia plays an important role in the development and pro-
gression of DKD. The impact of dyslipidemia on renal function im-
pairment was described by the “lipid nephrotoxicity hypothesis”.32 In
people with diabetes, dyslipidemia is characterized by a decrease in
high-density lipoprotein, and an increase in triglycerides, low-density
lipoprotein, and very-low-density lipoprotein.33 Dyslipidemia has a role
3
Clinical Epidemiology and Global Health 9 (2021) 2–6
in the development of DKD by causing apoptosis of podocytes, macro-
phage infiltration, and excessive production of extracellular matrix.34
Hyperglycemia and insulin resistance could aggravate dyslipidemia in
DKD patients.35 Evidence from epidemiological studies suggested a
positive correlation between dyslipidemia and diabetic nephropathy.
An epidemiological study on 581 T2DM patients investigating the
association between lipoprotein and DKD found a positive association.
Lipoprotein levels were found to be directly correlated with the pre-
valence of DKD.36 A Nigerian study assessing the relationship between
microalbuminuria and T2DM found a positive correlation between
urine albumin creatinine ratio (UACR) and triglycerides (p < 0.001).
LDL/HDL ratio was the independent predictor of microalbuminuria.1
3.5. Obesity
Evidence suggests a strong association between obesity and DKD.37
The mechanism by which obesity leads to DKD is not clear but it is
presumed that obesity leads to glomerular injury, glomerular hyper-
trophy, and proteinuria.38,39 A Chinese study on 264 patients with
confirmed DKD based on renal biopsy found obesity as a risk factor in
the development of nephropathy.40 Besides, a secondary analysis of
Look AHEAD randomised clinical trial suggests weight loss as an ad-
junctive treatment to delay the progression of diabetic nephropathy in
obese patients.41
3.6. Smoking
Smoking is considered as an independent risk factor in the devel-
opment and progression of diabetic nephropathy. The pathogenic role
of smoking in the development of diabetic nephropathy is multifactorial
including oxidative stress, hyperlipidemia, deposition of advanced end
glycation products, and glomerulosclerosis.42,43 Evidence form a Fin-
nish diabetic nephropathy study on 3613 type 1 DM patients found a
higher risk of albuminuria and end-stage renal disease in smokers as
compared to non-smokers.44 The risk of diabetic nephropathy was
found to be increased with the dose of smoking. This was also con-
firmed by a recent meta-analysis based on the pooling of nine cohort
studies which concludes that smoker T2DM patients are at an increased
risk of developing diabetic nephropathy.45
4. Pathophysiology of DKD
The pathophysiology of DKD involves various pathways like he-
modynamic, metabolic, and inflammatory pathways. The metabolic
pathway includes the polyol pathway, hexosamine pathway, advanced
glycation end products, and protein kinase c pathway.46 Hyperglycemia
induced kidney damage mediates through the hemodynamic pathway
by enhancing the formation of glycosylated end products, protein ki-
nase C activation, and diacylglycerol synthesis.47 An increase in re-
active oxygen species (ROS) formation induced by hyperglycemia
through activation of electron transport chain considered as the in-
itiators in the development of diabetes complications.48,49
5. Diagnosis of DKD
DKD is diagnosed based on the measurement of glomerular filtration
rate (GFR) and UACR to detect the presence of albumin in the urine. It
is clinically identified by estimated GFR below 60 ml/min per1.73 m2
or persistent excretion of albumin in the urine (albuminuria). GFR de-
creased in both T1DM and T2DM despite having normal UACR.50
Therefore, it is necessary to measure creatinine levels annually in pa-
tients with diabetes.3 There are several equations for the measurement
of estimated GFR like Chronic Kidney Disease Epidemiology Colla-
boration (CKD-EPI) equation which considered weight, transplant, and
diabetes as the potential variables.51 CKD-EPI equation categorises
people as high risk (eGFR < 90 ml/min/1.73 m2) and low risk
S. Hussain, et al.
(eGFR < 90 ml/min/1.73 m2) category.52 Another most commonly
used equation is the Modified Diet in Renal Disease (MDRD) equation
which computes GFR based on creatinine level in the serum and char-
acteristics of the patients.53 CKD-EPI equation was found to be superior
to the MDRD equation in accurately stratifying CKD risk.54 American
diabetes association guidelines recommend screening of nephropathy
inpatient with more than 5 years of type 1 diabetes and in each T2DM
patients irrespective of the duration of diabetes.55
6. Biomarkers for the early diagnosis of DKD
Timely diagnosis and appropriate interventions are the best ap-
proaches to deal with this catastrophic condition. Early diagnosis can
have lifetime benefits by controlling the progression of the disease,
increasing life expectancy, decreasing the humanistic and economic
burden.56 Even after all these benefits; DKD cases are diagnosed mostly
when the serious complications manifest. Non-availability of potential
diagnostic biomarkers is the potential barriers to the early diagnosis of
DKD. Currently, albuminuria and serum creatinine is the only available
marker in clinical practice for the identification of DKD. Published
studies raise concern on the predictive potential of albuminuria for the
identification and further progression of kidney disease to its end
stages.57 A large population-based study from the U.S. concluded al-
buminuria as a non-predictive and non-sensitive marker of DKD.57 Si-
milarly serum creatinine also lacks high predictive value because it
predicts kidney damage only if the damage is significant.58 So, there is a
need for novel biomarkers for the early diagnosis of DKD.
6.1. Galectin-3
Galectin-3 is a b-galactoside binding protein and involves in cell
growth regulation to inflammation.59 The galectin-3 level is highly
expressed in kidney tissues, heart tissues, and in inflammatory and
epithelial cells.60,61 Evidence from preclinical and clinical studies
linked higher levels of galectin-3 with incident CKD, heart failure, and
mortality. In an animal model study higher expression of galectin-3 was
found to be associated with inflammation, renal fibrosis, and kidney
damage.62 The upregulation of galectin-3 levels was observed in the
animal model with ischemic and toxic acute renal failure.63 Iacobini
et al. studied the role of galectin-3 in the pathogenesis of DKD in
knockout mice and concluded galectin-3 knockout mice had accelerated
advance glycation end products induced glomerular injury.64
Likewise, In a large population-based ARIC study which involves
1983 CKD cases found a significant and positive association between
galectin-3 and incident CKD with a hazard ratio of 2.2 (95% CI:
1.89–2.60).65 A recent cross-sectional study found higher levels of ga-
lectin-3 in T2DM patients with impaired kidney function. Independent
association was observed with the renal disease progression in T2DM
patients.66 Lastly, similar research was conducted by our research
group and found higher levels of galectin-3 in patients with poor kidney
function. We also found an inverse correlation between the galectin-3
level and estimated GFR in DKD patients.67 So based on the afore-
mentioned evidence galectin-3 could be a potential biomarker for early
detection of diabetic kidney disease.
6.2. Growth differentiation factor-15
Growth differentiation factor-15 (GDF-15) is a 40 kDa protein, be-
longs to transforming growth factor-β superfamily.68 Studies found a
connection between higher levels of GDF-15 levels with acute kidney
injury, and mortality.69 A cohort study from the Netherlands identified
GDF-15 as a clinically valuable marker for predicting the worsening of
albuminuria in T2DM patients as well as in non-diabetic hypertensive
patients. These findings were also confirmed by a well-designed study
by our group, where we found an inverse correlation between higher
levels of GDF-15 and estimated GFR.67 GDF-15 could be a potential
4
Clinical Epidemiology and Global Health 9 (2021) 2–6
diagnostic biomarker for the early detection of DKD.
6.3. Neutrophil gelatinase-associated lipocalin (NGAL)
NGAL is a lipocalin protein released from tubular cells of the kidney.
It's level increases when there is a proximal tubular injury.70 A Cana-
dian study of longevity in T1DM found intrarenal hemodynamic dys-
function in patients with an elevated level of NGAL.71 Evidence from a
cross-sectional study by Li et al. found an inverse correlation with es-
timated GFR and considered NGAL as a biomarker for normoalbumi-
nuric renal impaired T2DM patients.72 Even a meta-analysis of ob-
servational studies found the efficacy of NGAL as an early diagnostic
biomarker of DKD.73
6.4. Fibroblast growth factor-23
Fibroblast growth factor-23 (FGF-23) is a hormone derived from
bone. It promotes phosphate excretion and inhibits the breakdown of
25-hydroxy vitamin D. A large epidemiological study investigated the
impact of FGF-23 in the decline of kidney function in the general po-
pulation and conclude that higher FGF-23 levels were associated with
incident end-stage renal disease.74 Likewise, a recent study in T2DM
patients with a normal or moderate decline in kidney function found
increased cardiovascular and mortality risk in patients with higher le-
vels of FGF-23. 75
6.5. Platelet-derived growth factor (PDGF)
PDGF is a potent mitogen responsible for regulating cell growth and
cell division.76 It comprises of four different isoforms i.e. PDGF-A to D
and composed of two A subunits (PDGF-AA) as well as two B units
(PDGF-BB).76 A study from China by Wang et al.77 found a positive
correlation of urinary PDGF-BB with UACR and a negative correlation
with creatinine clearance. He also found an important role of PDGF-BB
in the initiation and progression of DKD and concluded PDGF-BB as a
marker for the early diagnosis of DKD.77 Similarly, findings from the
Egyptian study also considered PDGF-BB as a marker for the early de-
cline of kidney function in T2DM patients.78
6.6. Kidney injury Molecule-1 (KIM-1)
KIM-1 is a glycoprotein that is upregulated after acute ischemic
kidney injury.79 Evidence from published epidemiological studies found
higher levels of KIM-1 in DKD. A prospective study found a positive
association between higher levels of KIM-1 and faster decline of kidney
function in patients with early or advanced DKD.80
7. Conclusion
DKD is a medical catastrophe with high prevalence, poor diagnosis,
and a lack of novel biomarkers for the early diagnosis. Emerging plasma
and urinary biomarkers are showing promising results for the early
diagnosis which can be proved as a cost-effective tool to curtail down
the increasing prevalence rate, and to prevent the further development
of DKD to its end-stages. However, to translate these biomarkers into
routine clinical practice multination and multicentre epidemiological
studies are needed as an urgent mission to validate its potential and
applicability.
Funding
None.
S. Hussain, et al. Clinical Epidemiology and Global Health 9 (2021) 2–6

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