ORIGINAL ARTICLE
DOI: 10.5301/jn.5000152
Role of neutrophil/lymphocyte ratio in
prediction of disease progression in patients
with stage–4 chronic kidney disease
Ismail Kocyigit 1, Eray Eroglu 2, Aydin Unal 1,
Murat Hayri Sipahioglu 1, Bulent Tokgoz 1,
Oktay Oymak 1, Cengiz Utas 1
Abstract
Background: Chronic kidney disease (CKD) tends to
progress to end-stage renal disease without any inter-
vention. Neutrophil/lymphocyte (N/L) ratio may be in-
dicative of an underlying inflammatory state. We aimed
to investigate the role of N/L ratio for prediction of pro-
gression to dialysis in patients with stage 4 CKD.
Methods: We included 105 patients with stage 4 CKD in
the study. All patients were followed up from the first ad-
mission to dialysis. N/L ratio was measured during follow-
up. Patients were divided into two groups as baseline N/L
(N/Lb) ratio < 3 and N/Lb ratio ≥3 and rapid progression
was defined as > 5 mL/minute/year loss of creatinine
clearance and slow progression as < 5 mL/minute/year.
Results: Patients with N/L ratio ≥3 demonstrated high
progression rate compared to patients who had N/L ra-
tio <3 (2.6 ± 1.6 and 5.4 ± 3.3, P<.001). hs-CRP levels were
higher in patients who had rapid progression (5.6 ± 3.0
and 20.2 ± 10.6, P<.001). The sensitivity and specificity of
N/Lb were 79% and 69%, respectively, when the cutoff
level was accepted as N/L ratio ≥3 for determining rapid
progression. Furthermore, patients with a high N/Lb ratio
had worse prognosis and significantly faster progression
to the dialysis compared with those with a low N/L ratio.
Conclusion: Our results suggest that N/L ratio may
predict the progression rate of stage 4 chronic kidney
disease to dialysis. It is an easily accessible and useful
marker for monitoring CKD patients in clinical practice.
Key words: Neutrophil/lymphocyte ratio, Prediction,
Progression
358 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2013; 26 ( 02 ) : 358-365
Department of Nephrology, Erciyes University Medical
1
Faculty, Kayseri - Turkey
Department of Internal Medicine, Erciyes University
2
Medical Faculty, Kayseri - Turkey
Introduction
Chronic kidney disease (CKD) is a growing health problem
globally that results in end-stage kidney failure and car-
diovascular events. Only a small number of CKD patients,
however, progress to end-stage renal disease (ESRD) re-
quiring dialysis treatment. The heterogeneity in the risk
of progressive renal function worsening is because of
complex interactions among environmental, genetic, and
pathogenetic factors (1, 2).
Regardless of the cause of renal disease, there is strong
evidence that an acute and chronic pro-inflammatory
state exists in adults with CKD and ESRD and that in-
flammation contributes to morbidity and mortality (3, 4). In
addition, cytokines participate in pathways that enhance
the inflammatory cascade and induce renal damage. This
inflammatory response results in the generation of pro-
fibrotic factors and the progression of CKD (4, 5).
Inflammatory processes play a key role in chronic diseases
such as cardiovascular disease, cancer, chronic kidney
disease, type 2 diabetes, and Alzheimer’s disease (6). Pre-
vious studies have demonstrated that leukocyte subtype,
and neutrophil/lymphocyte (N/L) ratio are indicators of sys-
temic inflammation. Moreover, the N/L ratio has been re-
vealed to predict cardiovascular mortality and survival in
malignancies (7, 8).
Although the role of inflammation in chronic renal disease is
well known, there are no clear data in the literature about the
importance of N/L ratio on the progression of CKD. In this
study, we aimed to assess the effectiveness of the N/L ratio

in predicting the end point of progression to ESRD requiring
renal replacement therapy (RRT).
Subjects and methods
Study population
This study is a single-center, observational study. A total of
156 patients referred to and followed up as stage 4 CKD
cases at our nephrology clinic were considered for enroll-
ment in the study. We assessed subjects with overt stage
4 CKD according to the National Kidney Foundation’s clas-
sification of CKD, i.e. GFR 15 to 29 mL/min per 1.73 m2; the
patients had not yet reached ESRD at the time of the first
observation. Exclusion criteria for the study were unplanned
dialysis initiation (n=18), systemic inflammatory conditions
(n=11), leukopenia (n=7), immunosuppressive agent use
(n=6), hematologic disease (n=5), malignancies (n=2), and
autoimmune disease (n=2). Of the primary cohort of 156 pa-
tients, 105 could be followed prospectively. This study was
designed with a primary end point of progression to ESRD
requiring RRT. The study was approved by our local ethics
committee.
These patients underwent periodic clinical and biochemical
profile assessment scheduled on the basis of baseline CKD
stage as well as on renal disease progression rate.
Biochemical and hematologic parameters
Data were collected at three different time intervals during
follow-up. These data were obtained at equal time inter-
vals from first admission to the starting of RRT. Blood sam-
ples were taken in the morning after an overnight fast of
12 hours. Tripotassium EDTA-based anticoagulated blood
samples were drawn and stored at 4°C and assessed by a
Sysmex K-1000 auto analyzer within 30 minutes of sam-
pling. Hemoglobin, hematocrit, platelets, white blood cell
(WBC), differential counts (neutrophil, lymphocyte, eo-
sinophil, basophil, and monocyte) and percentages were
determined using a blood counter Sysmex K-1000 (Block
Scientific, USA).
The N/L ratio was measured in all patients at baseline and
in the follow-up period. A cutoff level of 3.0 was used for
the N/L ratio. According to N/L levels, patients were divided
into two groups as the low N/L ratio group (<3.0) and the
high NL ratio group (≥3.0). N/L ratios in patients with rapid
and slow progression were recorded at baseline (N/Lb), in
the median (N/Li) (intermediate) and predialysis period, (N/
Le) (end). WBC and mean platelet volume (MPV) were also
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2013; 26 ( 02 ) : 358-365
measured. High sensitivity C-reactive protein (hs-CRP) was
measured using a BN2 model nephlometer (Dade-Behring,
Germany). The expected values for hs-CRP in our labora-
tory ranged from 0 to 6 mg/L.
Blood urea nitrogen (BUN), creatinine, sodium, potassi-
um, calcium, phosphorus, alkaline phosphates, uric acid,
lipid profile (total cholesterol, low density lipoprotein cho-
lesterol) and 24-hour urinary protein excretion rate were
determined by the standard methods. In addition, glom-
erular filtration rate (GFR) was calculated according to the
collected 24-h urinary volume on the basis of creatinine
clearance.
Furthermore, the rate of progression (loss of creatinine
clearance on annual basis) was calculated using the follow-
ing formula:
Annual progression rate (mL/minute/year) = First GFR- last
GFR (mL/minute)/Duration of progression (months) × 12
First GFR: Value at the time of first admission,
Last GFR: The final value before dialysis
Duration of progression: The time between start to dialysis
Rapid progression defined was as > 5 mL/minute/year loss
of clearance and slow progression as < 5 mL/minute/year
loss of clearance.
Statistical analysis
Statistical analysis was performed using a standard statisti-
cal software package (SPSS for Windows, version 17; SPSS;
Chicago, IL, USA). Data are presented as mean + standard
deviation (SD). Categoric variables are presented as num-
bers and percentages. The Kolmogorov-Smirnov test was
used to assess whether the distribution of variables was
normal. Variables between progressive and nonprogressive
groups were compared with a student t test or Mann-Whit-
ney U test, while categoric variables were compared with a
chi-square test. Correlations were assessed using Spear-
man’s rank test. Comparisons of variables between various
groups were performed using unpaired student t tests, non-
parametric Wilcoxon rank sum tests, and Pearson’s v2-test.
In addition, logistic regression modeling was employed to
determine the ability of various risk factors at baseline to
predict rapid progression of disease. We used ROC analysis
to determine optimal cutoff values for the analysis of the N/L
ratio. Kaplan-Meier time-to-event curves were generated for
patients with an N/L ratio above and below the median value
(<3.0, ≥3.0) and we assessed the equality of survival distri-
butions by log-rank test. A two-tailed P<.05 was considered
statistically significant.
359
Kocyigit et al: Neutrophil/lymphocyte in disease progression

disease, use of antihypertensive drugs, serum uric acid

Results
The clinical, biochemical data and renal function measure-
ments of patients in the low and high N/L ratio groups are
shown in Table I. Age, gender, cause of end-stage renal
level, body mass index, albumin and amount of proteinuria
were similar in the two groups. However, there were statis-
tically significant differences in terms of the first creatinine
clearance (24.9 ± 4.2 mL/minute and 22.6 ± 4 mL/ minute,
P=.005), duration of progression (49.1 ± 18.1 months and 19

Table I
Clinical findings according to baseline Neutrophil/lymphocyte ratio
Low N/L ratio High N/L ratio
group (n=53) group (n=52) P
White blood cell count (mm3) 6.3 ± 1.8 7.0 ±1.9 .063
Neutrophil % 60.1 ± 8.1 70.6 ± 4.6 < .001
Lymphocyte % 30.3 ± 8.6 17.6 ± 2.9 < .001
Age (y) 55.1 ± 15.5 54.6 ± 15.1 .869
Female n/(%) 32 (60) 23 (44) .072
Smoking n/(%) 10 (18) 9 (17) .518
Baseline Creatinine clearance (ml/min)* 24.9 ± 4.2 22.6 ± 4 .005
Duration of Progression (months) 49.1 ± 18.1 19 ± 10 < .001
Rate of progression (ml/min/year) 2.6 ± 1.6 5.4 ± 3.3 < .001
hs-CRP (mg/L) 5.6 ± 3.0 20.2 ± 10.6 < .001
Uric acid (mg/dL) 7.49 ± 2.31 7.44 ± 1.85 .906
BMI (kg/m2) 25.32 ± 4.15 24.09 ± 4.48 .150
Albumin (g/dL) 3.77 ± 0.59 3.71 ± 0.56 .598
Proteinuria (g/day) 2.91 ± 3.48 3.76 ± 4.47 .297
Systolic blood pressure (mmHg) 142 ±17 146 ± 13 .721
Diastolic blood pressure (mmHg) 99.1 ± 6.6 95.8 ± 4.9 .527
Cause of end-stage renal disease n/(%)
  Diabetes mellitus 15 (28) 17 (32) .832
 Hypertension 13 (24) 11 (21) .645
 Glomerulonephritis 5 (9) 3 (5) .487
  Obstructive uropathy 5 (9) 8 (15) .551
  Polycystic kidney disease 2 (3.7) 2 (3.8) .995
 Amiloidosis 1 (1.8) 2 (3.8) .995
 Unknown 11 (20 ) 10 (19 ) .812
Use of antihypertensive drugs n/(%) 46 (86) 41 (79) .661
 ACEI/ARBs 15 (28) 14 (27) .995
  Calcium-channel blockers 7 (13) 5 (12) .765
 Beta-blockers 6 (11) 7 (17) .765
 Diuretics 4 (8) 3 (6) .995
  Alpha blockers 4 (8) 2 (5) .681
  ACEI /ARBs+ Diuretics 8 (15) 6 (12) .995
  ARB+ Calcium-channel blockers 2 (4) 2 (4) .665

*Calculated formula by collected 24 hours urine,

BMI = Body mass index; ACEI = Angiotensin-converting enzyme inhibitors; ARBs = Angiotensin II receptor blockers; BMI = Body
mass index; hs-CRP = high sensitivity C- reactive protein; N/L ratio = neutrophil/lymphocyte ratio; y = years.

360 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428

 JNEPHROL 2013; 26 ( 02 ) : 358-365

± 10 months, P<.001), rate of progression (2.6 ± 1.6 and 5.4 ±

3.3, P<.001) and hs-CRP (5.6 ± 3.0 and 20.2 ± 10.6, P<.001)
between the two groups. Additionally, there was no statisti-
cally significant difference in terms of all the drugs used.
The predictive roles of N/L ratios, hs-CRP, age, creatinine
clearance, proteinuria, and creatinine were assessed in
univariate and multivariate analysis. In univariate analy-
sis, hs-CRP, creatinine clearance, and N/Lb were used
as predictive factors of CKD progression. However, only
N/Lb and creatinine clearance were associated with pro-
gression in multivariate analysis (Exp [β] =2.666 CI 95%=
1.640-4.332, Exp [β] =1.313 CI 95%=1.132-1.522, respec-
tively) (Tab. II).
The predictive role of N/L ratio in combined end-point was
measured in ROC analysis. The sensitivity and specificity
of N/Lb were 79% and 69% when the cutoff level was ac-
cepted as N/L ≥ 3. ROC area was measured as 0.714 (95%
CI: 0.618– 0.798, P<.0001) (Fig. 1). Progression-free survival
curves in patients with high N/L ratio and low N/L ratio were
compared using the Kaplan-Meier test. It was found that
patients with a high N/L ratio had a worse prognosis and
Fig. 1 - ROC analysis of high N/L ratio as a predictor of the
significantly faster progression to dialysis compared with rapid progression to renal end-point of CKD.
those with low a N/L ratio (median 15 months vs. 44 months
respectively) (log rank test, P<.001) (Fig. 2).
There were statistically significant positive correlations addition, there were statistically significant negative correla-
between rate of progression and N/L baseline (r=0.335, tions between the duration of progression and N/Lb (R: -.645,
P<.001), N/L intermediate (r=0.356, P<.001) and N/L end P<.001), N/Li (R: -.402, P<.001), N/Le (R: -.383 P<.001), and
(r=0.221, P=.025) and hs-CRP (r=0.317, P=.003) (Fig. 3). In hs-CRP (R: -.510, P<.001).

Table II
Univariate and multivariate analyses to assess predictors of rapid progression
Univariate Multivariate
Exp (β) P Exp (β) P
N/L baseline 1.759 (1.229-2.517) 0.002 2.666 (1.640- 4.332) <.001
N/L intermediate 1.026 (0.864 -1.220) 0.768
N/L end 0.976 (0.907-1.051) 0.522
Age 0.975 (0.949-1.002) 0.072
hs-CRP 1.064 (1.016-1.113) 0.008
Creatinine 0.972 (0.738-1.281) 0.842
Proteinuria 0.940 (0.830-1065) 0.330
Creatinine clearance 1.137 (1029-1259) 0.014 1.313 (1.132-1.522) <.001

hs-CRP = high sensitivity C- reactive protein; N/L = neutrophil/lymphocyte.

© 2012 Società Italiana di Nefrologia - ISSN 1121-8428 361

Kocyigit et al: Neutrophil/lymphocyte in disease progression
Fig. 2 - Kaplan-Meier curves of renal end points in patients
with high and low N/L ratio groups.
362 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428
Discussion
Prediction of progression of chronic renal failure is an im-
portant clinical issue. In this study, we demonstrated that
the N/L ratio is an independent predictor of progression rate
in patients with stage 4 chronic kidney disease to dialysis.
The progression rate was higher and duration of progres-
sion was shortened in patients in the ≥ 3 N/L ratio group.
During the last four decades clinical investigations have fo-
cused on determining the initial promoter and predictive fac-
tors for the progression of chronic kidney disease in order to
halt and even slow it. Most forms of progressive renal dis-
ease lead to a common histologic end point. Mesangial cells,
tubules, and glomeruli come into contact with constituents
of plasma and interact with blood-borne inflammatory cells;
these, in turn, regulate the glomerular filtration rate and con-
tribute to glomerulosclerosis by generating macrophages,
neutrophils, prostaglandins, and mediators of inflammation.
Neutrophils release chemotactic substances (e.g., interleu-
kin 8), which further promote neutrophil migration to the
kidney, activate neutrophils, and increase glomerular injury.
Fig. 3 - Correla-
tions between rate
of progression and
N/Lb, N/L i and N/
Le, and hs-CRP.

Eventually, glomerulosclerosis and decreased renal function
are associated with the infiltration of the interstitium by in-
flammatory cells (9, 10).
Numerous studies suggest that the risk factors for progres-
sion of CKD include diabetes mellitus, systemic hyperten-
sion, smoking, dyslipidemia, atherosclerotic disease, pres-
ence of inflammatory markers, obesity, and male sex (11, 12).
In spite of the large number of risk factors, several stud-
ies have recently focused on the relationship between in-
flammation and CKD. Bash et al found that inflammation
and homeostasis are important preceding pathways in
the progression of kidney disease independent of the ma-
jor traditional risk factors (13). Inflammatory state exists in
CKD and it has been demonstrated in several studies via
elevated pro-inflammatory markers. In addition to contrib-
uting to the progression of CKD, inflammation causes car-
diovascular mortality because of vascular calcification and
endothelial dysfunction (12, 14). Betjes et al found that the
presence of CD4+CD28 null T lymphocytes are associated
with increased cardiovascular risk on the basis of system-
ic inflammation (15). Additionally, Fried et al found that the
decline in estimated GFR was associated with an increas-
ing number of inflammatory and pro-thrombotic markers in
elderly individuals (12). Pereira et al reported that plasma pro-
inflammatory cytokines were elevated in adults before and
after commencing dialysis (16). In keeping with prior studies,
Kimmel et al showed that immune parameters were highly
inter-related with ESRD and that serum pro-inflammatory
cytokine levels were higher than in controls and strongly as-
sociated with an increased risk for mortality (17). In a vicious
cycle, inflammation and oxidative stress, with the induction
of pro-inflammatory cytokines and growth factors, stimulate
cell hypertrophy and the proliferation and inflammatory-
cell infiltration that contribute to maladaptive structural and
functional changes resulting in ESRD (18).
In our study, we used two main inflammation markers to
determine the effect of inflammation. One of the inflamma-
tion markers which we used to demonstrate the effect of
inflammation on progression rate was hs-CRP since it is a
significant indicator of inflammation relevant to both pro-
gression and cardiovascular events in CKD (12, 19, 20). It
has been demonstrated that hs-CRP is associated with the
prevalence, progression, and prognosis of renal dysfunction
and hs-CRP levels have been related to both prevalent and
incident CKD (20). In our study, we determined that hs–CRP
levels were higher in the patient group displaying rapid pro-
gression than in the slow progression group.
Early diagnosis and treatment of CKD is imperative to delay
or halt progression by therapeutic regimens. Many factors
have been associated with rapid progression and it is im-
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2013; 26 ( 02 ) : 358-365
portant to follow each patient’s rate of progression, as there
is wide variability in patients’ response to therapy (21). Cur-
rently there are no widely accepted predictive instruments
for CKD progression; therefore, many researchers have been
trying to determine a predictive marker or to tabulate a mod-
el for the progression of CKD. According to these recom-
mendations some of the parameters examined in several
prospective studies have included adiponectin, NT-proBNP,
fibroblast growth factor 23, asymmetric dimethylarginine,
and apolipoprotein A-IV for the prediction of CKD (22-26).
However, although all these parameters independently dem-
onstrated prediction of CKD progression after adjustment for
baseline kidney function and other variables, they were not
easily applicable in clinical practice. Nonetheless, Stum et al
revealed that uric acid is an independent predictor for CKD
progression, by excluding patients using uric acid lowering
drugs (27). Furthermore, in one meta- analysis, it was shown
that albuminuria is associated with the prognosis and pro-
gression of CKD (28). Thus, Tangri et al designed a predictive
model consisting of routine laboratory results that accurately
predicted the progression to ESRD in patients with CKD
stages 3 to 5 (29).
In this study we used the N/L ratio, which is one of the as-
says applied to identify and monitor the inflammatory re-
sponse as well as hs-CRP. In several studies, the elevated
N/L ratio was used as a predictive and prognostic marker
for cardiovascular diseases and several cancers because it is
easy to identify, simple, inexpensive, and a quick and reliable
index to determine host immunity and inflammation; it was
reported to show poor prognosis and increased mortality in
most cardiovascular diseases and malignancies (7, 8, 30).
The association between WBC counts and mortality in ESRD
was suggested nearly two decades ago. Based on the rela-
tionship between cardiovascular mortality and CKD, Reddan
et al demonstrated that an increased neutrophil count and
lower lymphocyte counts predict mortality in hemodialysis
patients (31). We aimed to show inflammatory state with N/L
ratio instead of neutrophil and lymphocyte cell count inde-
pendently from the white blood cell count, since many stud-
ies have shown that N/L ratio is quick, simple, discriminatory,
and superior to full white blood cell counts (32-36).
To the best of our knowledge, this is the first study to as-
sess the N/L ratio in the progression of CKD. We found that
patients with stage 4 CKD who had an N/L ratio ≥3 showed
more rapid progression to dialysis than patients with an
N/L ratio <3. Duration of progression was shortened in the
high N/L ratio group. As a result of these findings, we sug-
gest that the reflection of inflammation demonstrated by in-
creased N/L ratio independently predicts the progression of
CKD to dialysis. This study was also performed to examine
363
Kocyigit et al: Neutrophil/lymphocyte in disease progression
the hypothesis that an elevated N/L ratio might prove to be
a clinically useful indicator for the rapid progression of CKD.
Although many biomarkers have been defined and demon-
strated, excessive costs and technical factors such as ad-
vanced laboratory requirements can preclude their clinical
use. In contrast, simply examining the peripheral blood N/L
ratio is easily accessible and applicable for assessing pro-
gression in patients with CKD in clinical practice.
One of the limitations of our study may be the population
that we assessed. We enrolled 105 patients in this study; it
could be assessed in larger populations. Many factors affect
N/L ratio such as infection, inflammatory diseases, cancer,
and cardiovascular events. However, we tried to exclude
these factors; some subclinical cases could be incorporated
into the study population.
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364 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428
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Financial support: None.
Conflict of interest statement: None.
Address for correspondence:
Ismail Kocyigit
Erciyes University Medical Faculty
Department of Nephrology
38039 Kayseri, Turkey
iikocyigit@gmail.com
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Accepted: March 01, 2012
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