European Journal of Cardiovascular Medicine

Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for more than three months, with implications for health [1,2]. It has emerged as an important non-communicable disease worldwide [3]. The Global Burden of Disease Study 2017 estimated that 697.5 million people had CKD across all stages, a global prevalence of 9.1%, and that CKD caused 1.2 million deaths in that year [4]. A systematic review and meta-analysis reported a pooled global prevalence of 13.4% for stages 1 to 5 [5], comparable to the 13.1% reported in the adult population of the United States [6].

The burden in India is large but variably estimated. The Delhi population-based study reported a prevalence of chronic renal failure of 0.79% [7], whereas the multicentre SEEK study found CKD in 17.2% of screened adults [8]. A rural community survey from South India reported a prevalence of 6.3% [9], and studies from North India have documented a substantial prevalence of reduced glomerular filtration rate and proteinuria [10]. Reviews highlight that the true burden remains uncertain and is likely to increase [11,12]. The incidence of end-stage renal disease (ESRD) in India was estimated at 151 per million population [13], and the Indian CKD registry identified diabetic nephropathy as the leading cause of CKD, followed by chronic glomerulonephritis and hypertension [14]. Rising diabetes prevalence [15], late referral, limited access to renal replacement therapy and regional CKD hotspots of uncertain aetiology compound the problem [16,17,18,19,20].

CKD is a multisystem disorder, and haematological complications are among its earliest manifestations [21,22]. Anaemia is the most common. Its pathogenesis is multifactorial, involving relative deficiency of erythropoietin, hepcidin-mediated iron restriction, chronic inflammation, shortened red cell survival, uraemic inhibitors of erythropoiesis, nutritional deficiencies and blood loss [23,24,25,26]. The prevalence and severity of anaemia increase as glomerular filtration declines [27,28,29,30]. Anaemia contributes to fatigue, reduced exercise capacity, left ventricular hypertrophy, cardiovascular events, hospitalisation and death [31,32].

Other haematological lineages are also affected. Uraemic platelet dysfunction and thrombocytopenia predispose to bleeding [33,34], while disturbed leukocyte function and lymphopenia contribute to infection risk and the chronic inflammatory state of advanced CKD [35,36,37]. Since the introduction of recombinant erythropoietin [38], anaemia management has advanced considerably, although trials have raised concerns about higher haemoglobin targets [39,40] and guidelines now advocate individualised therapy [41,42].

In many Indian hospitals, patients present late with advanced disease, coexisting nutritional deficiencies and infections, and treatment resources such as erythropoiesis-stimulating agents (ESA) and intravenous iron are often constrained [43]. A stage-wise description of the clinical and complete haematological picture in such a setting can help physicians to prioritise screening and early intervention. The present study was therefore undertaken with the following objectives.

• To describe the demographic, aetiological and clinical profile of patients with CKD.
• To assess the haematological profile (haemoglobin, red cell indices, peripheral smear, white cell and platelet parameters and iron status) of patients with CKD.
• To correlate the haematological parameters with the stage of CKD and with biochemical markers of renal function.

Study design, setting and period

This was a hospital-based, observational, cross-sectional study conducted in the Departments of Pathology & General Medicine of a tertiary care teaching hospital in India over a period of 18 months. The study was reported according to the STROBE guidelines for observational studies [44].

Sample size and sampling

Expected prevalence of anaemia of 80% among patients with CKD, an absolute precision of 6% and a 95% confidence level, the minimum sample size calculated using the formula n = Z²pq/d² was 171. To allow for data, 200 consecutive patients fulfilling the eligibility criteria were enrolled by convenience (consecutive) sampling.

Eligibility criteria

Inclusion criteria: (i) age 18 years or above; (ii) CKD stage 3 to 5, including patients with stage 5 on maintenance haemodialysis (5D), diagnosed on the basis of KDIGO criteria, i.e. kidney damage or eGFR below 60 mL/min/1.73 m² persisting for at least three months [1,45]; and (iii) written informed consent.

Exclusion criteria: acute kidney injury or acute-on-chronic kidney disease; kidney transplant recipients; known haemoglobinopathy or haematological malignancy; chronic liver disease; active bleeding or blood transfusion within the previous four weeks; pregnancy; and current chemotherapy or immunosuppressive therapy.

Data collection

A pre-tested proforma was used to record age, sex, residence, diet, aetiology of CKD, duration of illness, comorbidities, personal habits, drug history (including NSAIDs and herbal preparations), presenting symptoms and treatment history (ESA, iron, vitamin supplementation and transfusion). General and systemic examination, including blood pressure and body mass index, was carried out. Venous blood was collected under aseptic precautions (pre-dialysis in patients on haemodialysis).

Laboratory investigations

A complete blood count (haemoglobin, haematocrit, red cell count, MCV, MCH, MCHC, RDW, total and differential leukocyte counts, platelet count) was performed on an automated five-part haematology analyser, and ESR was measured by the Westergren method. Peripheral smears were stained with Leishman stain and reported independently by pathologists. Reticulocyte count was determined by supravital staining. Serum iron, total iron binding capacity (TIBC) and ferritin were estimated in a subset of 120 patients (randomly selected from the cohort) and transferrin saturation (TSAT) was calculated. Serum urea, creatinine, electrolytes, bicarbonate, calcium, phosphorus, uric acid and albumin were measured on an automated biochemistry analyser. The eGFR was calculated with the CKD-EPI creatinine equation [46], and staging followed KDIGO recommendations [1].

Operational definitions

Table 1: Operational definitions used in the study

Ethical considerations

The study was approved by the Institutional Ethics Committee. Written informed consent was obtained from all participants, and confidentiality of data was maintained.

Statistical analysis

Data were entered in Microsoft Excel and analysed with SPSS version 26.0. Continuous variables were expressed as mean ± standard deviation (or median with interquartile range when skewed) and categorical variables as frequencies and percentages. Comparison of means across CKD stages was done by one-way ANOVA, between two groups by the independent t-test, and proportions by the chi-square test (chi-square for trend where applicable). Pearson's correlation coefficient was used to assess association between haemoglobin and other variables. A p value below 0.05 was considered statistically significant.

A total of 200 patients with CKD were included in the analysis. Of these, 82 patients (41%) were in stage 5, including 36 (18%) on maintenance haemodialysis (Table 3).

Demographic and clinical profile

The age of the patients ranged from 22 to 82 years (mean 52.4 ± 13.6 years), and 73% were in the fifth to seventh decades of life. There was a male preponderance (male : female ratio 1.6 : 1). Table 2 gives the baseline characteristics.

Table 2: Baseline demographic characteristics of the study population (N = 200)

Table 3: Distribution of patients according to CKD stage (KDIGO) (N = 200)

Table 4: Aetiology of chronic kidney disease (N = 200)

Diabetic nephropathy (38%) and hypertensive nephrosclerosis (26%) together accounted for nearly two-thirds of cases (Table 4). Hypertension was the most common comorbidity (84%), followed by diabetes mellitus (46%), as shown in Table 5.

Table 5: Comorbidities and risk factors among the patients (N = 200)

Categories are not mutually exclusive.

Fatigue and generalised weakness (82%), pallor (79%), pedal oedema (71%) and anorexia with nausea or vomiting (64%) were the most frequent presenting features. Bleeding manifestations, mostly epistaxis, gum bleeding and gastrointestinal bleeding, were seen in 13% of patients (Table 6).

Table 6: Clinical presentation of patients with CKD (N = 200)

Categories are not mutually exclusive.

Renal and metabolic profile

Mean serum creatinine and urea rose, and the eGFR fell, progressively with stage (Table 7). The overall mean eGFR was 23.0 ± 16.2 mL/min/1.73 m².

Table 7: Renal function parameters according to CKD stage (mean ± SD)

ND = not on dialysis; 5D = on maintenance haemodialysis. Differences across stages significant (ANOVA, p < 0.001).

Metabolic acidosis (69%), hypoalbuminaemia (56%), hyperphosphataemia (52%) and hypocalcaemia (48%) were common, and hyperkalaemia was found in 31% of patients (Table 8).

Table 8: Biochemical abnormalities in patients with CKD (N = 200)

Haemoglobin and prevalence of anaemia

The overall mean haemoglobin was 9.4 ± 1.9 g/dL, and 170 of 200 patients (85.0%) were anaemic. Mean haemoglobin declined significantly with advancing stage (ANOVA, F = 41.2, p < 0.001), and the prevalence of anaemia increased from 50.0% in stage 3a to 97.8% in stage 5 not on dialysis (chi-square for trend, p < 0.001) (Table 9, Figure 1). Among anaemic patients, most had moderate anaemia (Table 10).

Table 9: Haemoglobin levels and prevalence of anaemia according to CKD stage

p < 0.001 for both mean Hb (ANOVA) and prevalence (chi-square for trend).

Figure 1: (A) Prevalence of anaemia and (B) mean haemoglobin by stage of CKD.

Table 10: Severity of anaemia among anaemic patients (n = 170)

Red cell indices and peripheral smear

The mean haematocrit, red cell count and haemoglobin fell significantly with progressing CKD, while RDW rose (Table 11). MCV, MCH and MCHC did not differ significantly between stages. The mean reticulocyte count was low (1.1 ± 0.5%), and the corrected reticulocyte index was below 2 in 88% of anaemic patients, indicating a hypoproliferative response.

Table 11: Haematological parameters according to CKD stage (mean ± SD)

p values by one-way ANOVA.

On the peripheral smear, a normocytic normochromic picture was the commonest (59%), followed by microcytic hypochromic (22%), dimorphic (6%) and macrocytic (5%) pictures. Anisopoikilocytosis was noted in 44% and burr cells (echinocytes) in 31% of smears (Table 12).

Table 12: Peripheral smear findings (N = 200)

The first five categories sum to 100%; the additional findings are non-exclusive.

Iron status

Iron studies were available for 120 patients. The mean serum iron was 58.4 ± 24.6 µg/dL, mean TIBC 248 ± 62 µg/dL and mean TSAT 24.6 ± 11.8%; the median ferritin was 312 ng/mL (IQR 148-560). Overall, 62 patients (51.7%) had absolute or functional iron deficiency (Table 13).

Table 13: Iron status of patients (n = 120)

White blood cells and platelets

Leukocytosis was found in 17% and leukopenia in 6% of patients, while lymphopenia was present in 23%. Thrombocytopenia was seen in 21% and was more frequent in advanced stages (Tables 14 and 15). Clinically evident bleeding was more common among thrombocytopenic than non-thrombocytopenic patients (23.8% vs 10.1%, p = 0.03).

Table 14: Leukocyte and platelet abnormalities (N = 200)

Table 15: Stage-wise distribution of thrombocytopenia

Chi-square for trend, p = 0.01.

Factors associated with haemoglobin

Mean haemoglobin was lower in diabetic than non-diabetic patients (9.0 ± 1.7 vs 9.8 ± 1.9 g/dL, p = 0.004), and anaemia was more frequent among diabetics (91.3% vs 79.6%, p = 0.02). The haemoglobin was lowest in diabetic nephropathy and highest in the miscellaneous group (ANOVA, p = 0.03). Sex-related differences were not significant (Table 16). Haemoglobin showed a moderate positive correlation with eGFR and serum albumin and negative correlations with creatinine, urea and ESR (Table 17). Of the entire cohort, only 24% were receiving ESA, 43% iron supplements and 26% had received at least one blood transfusion in the past.

Table 16: Haemoglobin according to sex, diabetes status and aetiology

Table 17: Pearson correlation of haemoglobin with other parameters

A total of 200 patients with CKD were included in the analysis. Of these, 82 patients (41%) were in stage 5, including 36 (18%) on maintenance haemodialysis (Table 3).

Demographic and clinical profile

The age of the patients ranged from 22 to 82 years (mean 52.4 ± 13.6 years), and 73% were in the fifth to seventh decades of life. There was a male preponderance (male : female ratio 1.6 : 1). Table 2 gives the baseline characteristics.

Table 2: Baseline demographic characteristics of the study population (N = 200)

Anaemia is present in the vast majority of patients with CKD attending a tertiary care hospital, and its prevalence and severity increase steadily with declining kidney function, with a substantial share attributable to absolute or functional iron deficiency. Leukocyte and platelet abnormalities are also frequent and become more marked in advanced disease. Diabetic nephropathy is the leading cause of CKD and is associated with more severe anaemia. Routine stage-wise assessment of haemoglobin, red cell indices, peripheral smear and iron indices, together with timely correction of iron deficiency, acidosis and malnutrition, should form an integral part of CKD care. Improving access to affordable anaemia therapy and early detection programmes is essential to reduce the burden of complications in India.

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