Chronic kidney disease (CKD), a common clinical problem in primary care, can be defined as any abnormality of the kidney structure and function that has been present for at least 3 months. Over the past 20 years, the incidence and prevalence of CKD have been increasing in Malaysia in line with the rising number of non-communicable diseases. At present, CKD has no cure. The treatment of CKD is very much dependent on early diagnosis and prevention of CKD progression. In this article, we aim to illustrate a practical approach to CKD in primary care, including diagnosis, evaluation, and management of CKD. 

Chronic kidney disease (CKD) spans a broad range of disease severity and heterogenicity concerning its risk of clinical progression to end-stage renal disease (ESRD). Long-term complications of CKD include ESRD, complications of ESRD, cardiovascular disease, and death.1 In Malaysia, the incidence and prevalence of CKD and ESRD have risen alarmingly over the past 20 years, which has been partly driven by the rising number of non-communicable diseases, especially diabetes mellitus. Management of CKD is largely dependent on early detection and prevention of disease progression. There is no definite cure for this disease. Because most CKD patients are managed in primary care, we aim to illustrate a practical approach to CKD in a primary care setting in the present article. 

Globally, CKD prevalence is estimated to be between 10% to 15%.2,3 An earlier population-based study in 2011 done in Peninsular Malaysia found that 9.1% of Malaysians had CKD.4 A more recent study that included the Sabah and Sarawak population found that CKD prevalence had increased to 15.5%.5 Out of this 15.5%, 6.81% had CKD stage 3 to 5. Diabetes mellitus continues to be the leading cause of ESRD in Malaysia, with 69.2% of new ESRD patients in Malaysia in 2018 resulting from diabetic nephropathy.6 The National Health Morbidity Survey 2019 estimated that 3.9 million Malaysian adults had diabetes mellitus, and 6.4 million Malaysians were hypertensive.7 It is not surprising, therefore, that the number of patients with CKD is increasing. 

Besides mortality and morbidity, CKD also contributes to a significant burden in terms of health care costs. Based on data reported in 2019, the estimated cost of hemodialysis per patient per year was RM39,791, while the cost for peritoneal dialysis reached RM37,576.8 In total, RM1.12 billion was spent on ESRD in 2016.9 Given these serious public health impacts, diagnosing CKD early to prevent progression to ESRD is therefore essential for primary care practitioners.

1.0 Diagnosis of CKD 

1.1 Definition of CKD 

CKD can be defined as any abnormality of kidney structure and function that has been present for at least 3 months.10 (See Table 1.)Notably, CKD is not defined solely based on glomerular filtration rate (GFR), as other markers of kidney damage must be taken into consideration. These indications include pathological abnormalities, structural abnormalities, or increased urinary albumin excretion. Additionally, the persistence of abnormalities for at least 3 months is necessary to distinguish CKD from acute kidney injury (AKI).10

Table 1: Criteria for diagnosis of CKD 

Notably, CKD is not defined solely based on glomerular filtration rate (GFR), as other markers of kidney damage must be taken into consideration. These indications include pathological abnormalities, structural abnormalities, or increased urinary albumin excretion. Additionally, the persistence of abnormalities for at least 3 months is necessary to distinguish CKD from acute kidney injury (AKI).10

1.2 Staging of CKD 

The International Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend the classification of CKD based on cause, GFR category, and albuminuria category (Tables 2 and 3).10 Identifying the cause and staging of CKD can help in predicting outcomes and guiding disease-specific treatment. The degree of albuminuria has also been shown to portend poorer outcomes in terms of cardiovascular issues, mortality, and the kidneys.11 Together, these factors (cause of CKD, staging, and degree of albuminuria) facilitate predicting the prognosis of kidney disease.

1.3 Screening for CKD 

As there is no definite cure for this illness, early detection is vital to help delay the progression of CKD. Population-based screening is currently not recommended.12 A more targeted approach to screening can be more practical and cost-effective. Specifically, screening should be focused on individuals with risk factors for CKD (Table 4).13 Screening methods include examining serum creatinine (to estimate the GFR) and urine for albumin secretion. 

Table 4: Risk factors for CKD that require CKD screening

2.0 Evaluation of CKD 

2.1 Clinical Evaluation 

Most patients with CKD who are seen in the primary care setting are often in the early stages. Hence, these patients are frequently asymptomatic and typically unaware of their CKD and its seriousness.14 These factors make it imperative for primary care doctors to identify individuals at risk. Clinical evaluation of these patients starts with a full medical history, a detailed drug and dietary history, the person's history of past blood pressure (BP) and sugar control, and a physical examination. Investigations include renal function tests and collecting urine for microscopy and albuminuria. 

Some patients may present to the primary care setting with a more advanced stage of CKD. They may have non-specific signs and symptoms of uremia, such as fatigue, loss of appetite, weight loss, sleep disturbances, and poor concentration.15 Meanwhile, those who present with acute medical emergencies, such as acute pulmonary edema, seizures, or uncontrolled hypertension, will need to be referred for hospital care immediately. After the diagnosis of CKD is confirmed and the cause and stage of the disease have been established (Table 5), patients should then be treated and managed according to the stage of CKD. However, unless the patient presents early in the course of CKD, the cause of the CKD may not be confidently ascertained. 

2.2 Blood test 

Serum creatinine is affected by many factors, such as age, gender, muscle mass, and protein meals. That said, it is an insensitive marker of GFR early in the course of CKD, as an initial rise in serum creatinine indicates about 50% loss of GFR.16 Hence, detection of CKD based on estimated GFR is a more accurate assessment of renal function than serum creatinine.1 A normal GFR is approximately 120 to 130 ml per minute per 1.73 m2 in young adults, decreasing by an average of 1 ml per minute per 1.73 m2 per year beginning at the age of 30-40 years.17

Estimated GFR (eGFR) can be derived from serum creatinine based on several equations (Table 6). The more commonly used formulas for GFR estimation in daily practice are the modification of diet in renal disease (MDRD) equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The highly recommended CKDEPI represents the current standard of care, as it provides a more accurate eGFR in a normal individual or GFR >60 ml/min/1.73 m2. 18

The Cockcroft-Gault formula is now used only for adjusting medication dosage.12 Serum cystatin C-based GFR is most beneficial when false positive decreased GFR is suspected.12 However, this latter test is more expensive than other options and is not widely available. 

Table 6: Equation to derive eGFR

A few caveats should be noted when applying these equations for eGFR. The eGFR is not accurate in the setting of AKI, as kidney function is not in a steady state.1 It is also less accurate in patients with extreme muscle mass, malnutrition, or liver disease. 

2.3 Urine examination

A urine examination is performed to detect proteinuria or microscopic haematuria. Proteinuria, which refers to increased excretion of any urinary protein, has both diagnostic and prognostic value in CKD.17 Persistent proteinuria is often a defining marker of renal injury and a sign of glomerular or tubular disease. Notably, patients with proteinuria may still have normal eGFR. Prognostically, the presence of proteinuria also signifies a higher risk of cardiovascular disease and death.12 Several methods that are available to evaluate for proteinuria include urine dipstick, automated urinalysis, albumin-to-creatinine ratio (ACR), urine protein-to-creatinine ratio (PCR), and 24-hour urine protein (Table 7). A urine dipstick analysis is an inexpensive and widely available test. This simple semiquantitative test can be employed in the primary care setting. However, it is important to keep in mind the possibility of false positivity in the event of concentrated urine, gross haematuria, or the presence of antibiotics.19 Apart from false positivity, the urine dipstick test is relatively insensitive to non-albumin protein. Automated urinalysis in this setting will help improve predictive value for significant proteinuria. 

Moderately increased albuminuria is defined as a urinary albumin excretion rate of 30-300 mg/day and is often the earliest sign of diabetic kidney disease. Moreover, a urine albumin measurement provides a more sensitive and specific measure of changes in glomerular permeability than total urine protein.8 A single early morning urine sample for ACR is a sufficiently sensitive test to detect moderately increased albuminuria.20 In contrast, urine spot PCR also includes tubular secreted proteins, as well as plasma protein from disease processes and infection, making it a less sensitive test.12 Routine 24-hour urine quantification for protein is both cumbersome and often poorly performed. Hence, the KDIGO guidelines recommend urine ACR as an initial screening test for proteinuria.

Table 7: Different tests that can be used to detect proteinuria or albuminuria

In addition to tests aimed at identifying proteinuria, urine examination is also used to evaluate microscopic haematuria, which can be caused by structural renal tract disease or glomerular disease. Common causes of microscopic haematuria include urinary tract infection, benign prostatic hyperplasia, and urinary calculi.21 A patient with isolated microscopic haematuria should be evaluated for urological causes of haematuria. The presence of hypertension, elevated creatinine, cellular cast, and proteinuria should prompt a nephrology referral, as these may indicate glomerular disease.21

2.4 Ultrasound

All patients with CKD should undergo an ultrasound. This procedure can provide the following information: a) Renal size, shape, and location – small kidney size may suggest chronicity of kidney disease. Renal size assessment is an important consideration before renal biopsy. It may detect abnormal anatomy, such as horseshoe kidney.22 b) Renal cortex and echogenicity – a thin renal cortex and increased renal echogenicity are signs of CKD.22 c) Obstruction – the presence of hydronephrosis and hydroureter is suggestive of renal tract obstruction. d) Structural pathology – renal calculi and polycystic kidney disease can be diagnosed from an ultrasound.  

2.5 Causes of CKD 

Once the diagnosis of CKD has been established, the next step is to look for the cause. Causes of CKD can be broadly classified according to their pathophysiological mechanism (Table 8). Such mechanisms include pre-renal, renal vascular, glomerular, tubulointerstitial, hereditary, and obstructive causes. In the case of pre-renal causes, clinical evaluation may elucidate the patient's history and detect the presence of signs and symptoms of chronic heart failure or chronic liver disease. The presence of dysmorphic red blood cell cast, proteinuria, and haematuria points towards a possible glomerular cause of CKD. If a glomerular disease is suspected, a serologic workup is indicated.1 A renal biopsy may be needed to establish the underlying glomerular disease since specific treatment may be given depending on the histopathological diagnosis. Those with CKD of uncertain cause may need a nephrologist consult. Meanwhile, obstructive causes of CKD should be referred to urology for intervention. 

Table 8: Common causes of CKD

2.6 Referral to nephrologist 

Primary care physicians play a central role in referring patients to nephrologists promptly,1 especially since a timely referral can facilitate intervention to delay CKD progression and allow time to prepare the patient for RRT. Timely referral has been shown to improve the preparation for RRT, lower the use of a dialysis catheter, reduce emergency dialysis, and improve survival (Table 9). 

Table 9: Indication for nephrology referral