Last updated: Lesson of the Month - April 2014…
on 26 Apr 2014

Chronic Kidney Disease (CKD)

Definition, Classification and Prevalence

Stephanie Stringer, Sarah de Freitas and Paul Cockwell

Chronic kidney disease is described by KDIGO (Kidney Disease: Improving Global Outcomes) as ‘evidence of damaged renal parenchyma as demonstrated by active urinary sediment and/or structural abnormality (this must be present for stages 1 and 2 CKD) and/or evidence of decreased kidney function as demonstrated by a reduced glomerular filtration rate (GFR) and chronicity to distinguish it from acute kidney injury (AKI).’

Active urinary sediment refers to the presence of haematuria and/or proteinuria;  the presence of haematuria or proteinuria may indicate glomerular pathology and the importance of proteinuria as a risk factor for CKD progression and CVD has become increasing recognised with time and will be described later in this topic. Structural abnormalities of the renal tract include kidney stones, cysts, renal scars. Individuals with structural kidney disease are at risk of progression and even in the absence of evidence of reduced GFR should be considered to have CKD. The current  definition of CKD by KDIGO (Levey et al; 2011) comprises :

(i) presence of kidney damage for ≥ 3 months, with kidney damage defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies and/or

(ii) GFR <60 ml/min/1.73m2 for ≥ 3 months with or without kidney damage.

The definition of CKD has led to the development of a classification system for CKD. This has entered widespread use and provides a system that is helpful both for clinical practice and for clinical and epidemiological research. The current classification system for CKD is shown in the table below.

*Chronicity is confirmed by the presence of abnormal kidney function by eGFR or proteinuria for >3 months

The majority of people with CKD are elderly and have sustained kidney damage as a consequence of vascular disease comprising one or more of hypertension, macrovascular disease and diabetes. For mild-moderate CKD the dominant causes are diabetes and hypertension. However as CKD progresses to severe (stage 4 and stage 5) CKD, there is a change of prevalence in causes of kidney disease with an increased proportion of younger patients with glomerulonephritis and genetic causes of CKD. This is because these diseases progress more rapidly and elderly patients have a major competing risk of early death as a consequence of CKD. A summary of the major causes of kidney disease in patients with advanced CKD is shown in table 1. For information on the causes of kidney disease in patients who are starting treatment for end-stage kidney disease then please see page 23 table 7 of the hyperlink.

It is unusual for people to get overt symptoms associated with CKD; and overt symptoms that are demonstrably associated with CKD are restricted to people with advanced CKD. The symptoms associated with advanced CKD are discussed later in this article.

Historically there has been a lack of recognition of CKD as a highly important chronic disease, both for the individual patient and in terms of the organisation of clinical services and the health economic implications of the disorder. In the past 10-years these shortfalls have systematically addressed. As a consequence of this there is now evidence developing from the UK and other countries that outcomes for people with CKD are Improving (UK Renal Registry report; 2010). There are also major health economic implications associated with CKD, a high proportion of health care funding is used in managing patients with CKD.

What is the basis for classifying CKD?

One of the developments that facilitated the introduction of a classification system was increased accuracy in kidney function testing as a consequence of the adoption of the creatinine based Modification of Diet in Renal Disease (MDRD) study formula to produce an estimated glomerular filtration rate (eGFR) that provides a measurement of excretory kidney function of sufficient accuracy for use in clinical practice.

The MDRD equation was used by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) to frame the classification system that has become widely adopted in clinical practice, the current version of this is shown above. Guidelines were then developed (KDIGO 2002) that were based on observations that to improve the outcomes of patients on dialysis required a focus on the health of patients at risk of ESKD and that it may be possible to slow the rate of progression and reduce the complications of CKD by early identification and directed management.

The prevalence of and risk factors for CKD

The formalised reporting of eGFR led to better identification of the prevalence of kidney disease, with estimates of CKD in the developed world of up to 16% of the adult population. In the UK a recent report that utilised epidemiological data identified the prevalence of all CKD as 14% in men and 13% in women. The prevalence of CKD where there was a demonstrable reduction in excretory kidney function as defined by an eGFR of <60ml/min/1.73m2 (stage 3-5 CKD) was 6%. Advanced CKD is uncommon; around 0.4% of the adult population has stage 4 CKD and 0.2% has stage 5 CKD.

End-stage kidney disease (ESKD) is rare, with new cases being very unusual. In 2009, the incidence of ESKD was 109 per million population (pmp) in UK adults, with 6730 new patients.

Key point: A renal unit that serves a million people, will start 2 patients with ESRF on dialysis per week.

Prevalence was 794 pmp, with 49,080 ESRD patients. With an estimated UK population of 62, 262,000 in 2010, ESRD occurs in 1 in 1270 people, ie about 0.1% of the population. So,

Key point: A GP with a practice of 8000 patients, will have around eight patient with ESKD

Risk factors

CKD is more common in women than in men, although men are more likely to progress to ESKD. The prevalence increases by age so that by the 8th decade of life over 30% of people have stage 3-5 CKD. However there is concern that there is over-classification of CKD in the elderly as a consequence of a component of the physiological decline in kidney function with age being assessed as pathological. Other risk factors for CKD include all cardiovascular disease groups and smoking. There are significant ethnic differences in CKD. People who are non-white are at increased risk of progressing to ESKD when they have CKD.

Pathophysiological considerations

Irrespective of the cause of kidney disease there are common processes that are characteristic of CKD and contribute to the progressive decline in kidney function that is seen in many patients. Loss of nephrons is associated with glomerular hypertension in the remaining glomeruli and progressive interstitial fibrosis, peritubular capillary loss and inflammation, including infiltration of mononuclear cells.

The pathophysiology of CKD has been reviewed by  Yu (2003)Metcalfe (2007) and López-Novoa (2011).


Glomerular Filtration Rate and Proteinuria/Albuminuria

How is kidney function measured?

Until the development of the K/DOQI guideline, kidney function was primarily assessed by direct measurement of serum or plasma creatinine, formed from creatine phosphate metabolism in skeletal muscle, to produce an approximation of kidney function. However serum creatinine levels are variably effected by other factors including muscle mass, dietary protein load, gender and direct renal tubular excretion. As a consequence (i) identical serum creatinine levels represent different levels of kidney function in different individuals and (ii) the relationship between creatinine levels and kidney function is a non-linear relationship

Whilst not a direct measurement of GFR, creatinine can be utilised in combination with correction factors that are specific for the individual under assessment to produce an estimated (e)GFR. The importance of eGFR in providing a readout of kidney function that is used in routine clinical practice is based on the principle that true GFR is the most accurate assessment that we have available for measuring the excretory function of the kidneys.

What is Glomerular Filtration Rate (GFR) and how is it measured?

Glomerular filtration rate is defined as the volume of fluid filtered from the glomerular capillaries in a specified period of time; any substance that is freely filtered at the glomerulus, and is neither secreted nor absorbed by the kidney, can be used to measure GFR; in routine clinical practice creatinine is the molecule that is utilised for this purpose. Creatinine is freely filtered at the glomerulus, is not protein bound and is not metabolised by the kidney, however as previously noted both tubular secretion and variable production is dependent upon factors that are unrelated to the underlying kidney disease and are important confounders (Perrone et al; 1992). Some of these confounders can be corrected for by utilising equations into which they are incorporated to produce a calculated or e(GFR).

True or measured GFR can be obtained using inulin clearance (the gold standard method). The inulin clearance method requires intravenous infusion and timed urine collections over a number of hours and is therefore complex, costly and inconvenient. Furthermore inadequate urine collections can cause inaccuracy of the obtained measurement (Shannon and Smith; 1935).

More commonly, for assessment of measured GFR, isotopes such as [51Cr]EDTA and 125I-iothalamate can be used. However, these are also impractical to use in routine clinical practice, as they are time consuming for the patient, expensive, require a specialised organisational infrastructure (special licensing and regulation of handing and waste disposal of the radioisotope) and exclude certain patient groups (e.g. pregnant women) (Chantler et al; 1969). To overcome these obstacles other exogenous substances have also been used to measure GFR, these include the radiocontrast agents iohexol and iothalamate (Krutzen et al; 1984, Gaspari et al; 1992). Both iohexol and iothalamate have been shown to correlate closely with gold standard measures of kidney function with excellent reproducibility and minimal renal toxicity (Brandstrom et al; 1998). However there is evidence that measured eGFR does not perform better than eGFR when clinically relevant outcomes were studied (Hsu et al; 2011).

The GFR obtained from tests that provide a measured GFR produces normal values for men of around 130 ml/min/1.73m2 and for women of around 120 ml/min/1.73m2; with increasing age these ‘normal’ values decline. The use of measured GFR is currently restricted to situations where a precise measure of kidney function is required (for example in individuals wishing to be considered as living kidney donors) and eGFR is the current clinical standard. The current formula used to calculate eGFR in routine clinical practice is the four variable modification of diet in renal disease (MDRD) equation.

The MDRD formula and other formulas for estimating GFR

The MDRD equation has replaced the Cockcroft-Gault (CG) (Cockcroft and Gault; 1976) formula, which was developed against creatinine clearance, introduced in 1976 and was subsequently used by many clinical services in routine practice. Indeed, the formula continues in use as it was used for the purposes of defining dose adjustments for many drugs that have significant renal clearance. However it requires knowledge of the weight of the patient (and this may not be routinely available) and it may provide an overestimation of GFR in some groups (Levey et al 1999).  Furthermore the CG formula is less accurate than MDRD and can vary from measured GFR by >30%.

 The Cockcroft-Gault Formula for the estimation of GFR

  (140-Age) x weight (in kg)]/72 x Serum creatinine (in mg/dL)*

*Multiply by 0.85 if female

The MDRD formula was developed in 1999 when Levey et al developed formulae to estimate GFR using serum creatinine and other readily available data as a component of a randomised controlled trial designed to assess the effect of protein restriction and blood pressure control upon the progression of CKD (Beck et al; 1991). 1628 patients with kidney disease were recruited and the study protocol included measurement of GFR with 125I-iothalamate, a 24-hour urine collection and a single measurement of serum creatinine (Levey et al; 1993). The recruited population were young, predominantly male and 88% were of white ethnicity. A stepwise regression model was utilised to predict GFR utilising training and validation samples. Seven equations were assessed and these are listed below

The equations compared in the MDRD study for the estimation of GFR

Equation 1: GFR = 0.69 x [100/PCr]

Equation 2: GFR = 0.81 x [Cockcroft-Gault formula]

Equation 3: GFR = 0.81 x [CCr]

Equation 4: GFR = 1.11 x [(CCr + Curea)/2]

Equation 5: GFR = 1.04 x [CCr]+0.751 x [Curea]+0.226 x [1.109 if patient black]

Equation 6: GFR = 198 x [PCr]-0.858 x [age]-0.167 x [0.822 if patient is female] x [1.178 if patient is black] x [SUN]-0.293 x [UUN]+0.249

Equation 7: GFR = 170 x [PCr]-0.999 x [age]-0.176 x [0.762 if patient is female] x [1.180 if patient is black] x [SUN]-0.170 x [Alb]+0.318

(Abbreviations: Alb = serum albumin; CCr =creatinine clearance (mL/min/1.73m2);Curea = urea clearance (mL/min/1.73m2);PCr = serum creatinine concentration (mg/dL); SUN = serum urea nitrogen concentration (mg/dL); UUN = urine urea nitrogen concentration (g/d))

The equation that resulted in the maximum R2 value (91.2%) included urine biochemistry variables (equation 6) but is not useful for clinical practice as it requires 24-hour urine collection. Therefore equation 7 was  used to interpret the study as it was the precision of the equation was close to that of equation 6 (R2 90.3%) and it included routinely collected clinical data. The inclusion of variables associated with creatinine production (age, ethnicity and gender) contributed to the accuracy of the equation, although the equation was not validated in individuals with normal renal function or the elderly (patients over 70 years of age were not included in the MDRD study), these omissions may limit the utility of the equation as an estimation tool across a CKD population.

The K/DOQI working group abbreviated MDRD equation 7 by removing blood urea nitrogen and serum albumin from the calculation. The resultant abbreviated, “4-variable MDRD” formula although not validated by the MDRD group, performed well compared to 125I- iothalamate in an analysis of 1775 patients recruited to the African American Study of Kidney Disease and Hypertension (AASK) (Lewis et al; 2002) . This equation formed the basis for the classification system that informed the 2002 CKD guideline. The stage of CKD that were created  were based upon the eGFR; although patients with stage 1 and stage 2 CKD required additional evidence of kidney damage for classification

The four variable MDRD equation for estimating GFR from serum creatinine 

eGFR = 32788 x sCr (mmol/L)-1.154 x age-0.203 x [1.212 if black] x [0.742 if female]

The CKD-Epi formula

In 2009, in an attempt to improve the accuracy of eGFR, the CKD-Epi formula was developed from a pool of more than ten studies which produced a total of 8254 patients (2/3 of whom were randomly selected for formula development and 1/3 for validation; a further 3896 patients were then used for external validation purposes) (Levey et al; 2009). The new formula performed better than the MDRD formula, especially at higher GFRs, and there is also some evidence that it provides better cardiovascular disease (CVD) risk stratification than the MDRD formula (Matsushita et al; 2010). At present this formula is under consideration by guideline development groups for incorporation into clinical practice.

Work is continuing in this area and includes other markers of kidney function. A recent large community based cohort study including individuals aged >65 years (in contrast to the MDRD study), calculated the prevalence of CKD using the MDRD and CKD-Epi equations, with CKD-Epi GFR estimated both by creatinine and by cystatin-c. The data obtained suggested a variance in the prevalence of CKD dependant upon the equation used, although the cystatin-c based CKD-Epi estimate appeared to be the most specific (Rotenbacher et al; 2012). While this was a large study, it was limited by being a cross-sectional analysis and by the absence of a gold standard measure of GFR against which the estimating equations were compared.

The CKD-Epi equation for estimating GFR from serum creatinine (Levey et al; 2009)

eGFR = 141 x min(sCr/k,1)a x max(sCr/k,1)-1.209 x 0.993age x (1.018 if female) x (1.159 if black)

sCr, serum creatinine, k = 0.7 for women and 0.9 for men, a = -0.329 for women

Proteinuria and albuminuria

The term proteinuria is usually used to refer to the presence of albuminuria; while not all proteinuria is albuminuria it is important to note that semi-quantitative methods to identify proteinuria such as dip stick testing are most specific for the identification of albuminuria and other proteins may not be detected by this method (Pugia et al; 1999). While much of the risk associated with proteinuria refers to albuminuria, the urinary excretion of other proteins may also be implicated in progressive CKD and CVD risk.


Albumin is the most common protein present in the urine in health and in disease; this is a function of albumin as the most prominent plasma protein, and of the molecular weight of the molecule (which ensures that around 1% of albumin is filtered by the glomerulus in health) (Bourdeau and Carone; 1974). Glomerular filtered albumin is almost completely resorbed in health by proximal tubular epithelium. However when there is excess filtration of albumin by the glomerulus and/or a decrease in the re-absorptive capacity of proximal tubular epithelium, albuminuria (pathological levels of albumin in the urine) can develop (Pollock and Poronnik; 1999). In addition to being a marker of risk, albuminuria may be directly injurious to intrinsic renal cells and so contribute to the progression of CKD (Nelson et al; 1997), the relationship between albuminuria and eGFR with CVD and mortality is an area of great importance (Matsushita et al; 2010).

Traditionally albuminuria was quantified using 24 hour urine collections, as the amount of albumin excreted in the urine varied during the day; a major disadvantage of this method was that it was inconvenient for patients and collection was frequently incomplete resulting in inaccuracy. It is now acceptable to quantify albuminuria using spot urine tests, either for albumin creatinine ratio (ACR) or protein creatinine ratio (PCR), the sample does not have to be a first void sample although if one is available this is preferable as it correlates most closely with 24-hour measurements and can exclude orthostatic proteinuria (Keane et al; 1999). The K/DOQI reference ranges for albuminuria using ACR and the equivalent in both PCR and 24-hour urine results are shown in the table

ACR; Albumin creatinine ratio, PCR; protein creatinine ratio, AER; Albumin excretion rate, PER; Protein excretion rate

Albuminuria has traditionally been divided into microalbuminuria and overt albuminuria; the term microalbuminuria being first coined in the early 1980s by Viberti and Svendson and was defined as albuminuria that was below the level detectable on urine dip-stick testing but at a level that was predictive of the development of overt nephropathy (Viberti et al; 1982). Subsequently there has been a great deal of research confirming that microalbuminuria (defined as 30-300mg/24 hours) is both a renal and cardiovascular risk factor, however in recent years there has been an understanding that even albuminuria below the microalbuminuria cut off and into the normal range is a risk factor for cardiovascular events and progression to overt nephropathy (Gerstein et al; 2001).  This more sophisticated appreciation of albuminuria as a continuous risk factor has led some to call for an end to the distinction between microalbuminuria and overt albuminuria (Forman and Brenner; 2006). This has led to the description of albuminuria as normal, high or very high as shown in the above table.

Albuminuria can result from a primary renal pathology (such as intrinsic glomerular disease), from any pathology that affects the glomeruli (such as diabetic glomerulosclerosis) or as a result of hyperfiltration where discrete nephron loss leads to compensatory hyperfiltration of surrounding nephrons, these hyperfiltrating nephrons contribute to an increase in urinary albumin secretion. Albuminuria can be considered not only as contributing to the risk of progressive CKD and as an early marker of kidney damage but also as a CVD risk factor (Brenner et al; 2001, de Zeeuw et al; 2004).

Cardiovascular Disease, CKD and clinical outcomes

Cardiovascular disease

Over the past decade it has been increasingly clear that the major risk to people with CKD is of cardiovascular disease (CVD) (Foley et al; 1998). In 2002 the Hoorn study reported that individuals with mild kidney impairment (estimated using serum creatinine, the Cockcroft-Gault formula and the MDRD formula) were at risk of increased cardiovascular mortality (Henry et al 2002).

The following year, in data derived from a community based observational study, Atherosclerosis Risk In Communities (ARIC), where the majority of participants had preserved kidney function, the rate of cardiovascular events over the follow up period of around six years was higher in individuals with a reduced eGFR than those with a normal eGFR (Manjunath et al; 2003). The risk was incrementally higher for people with a lower eGFR fand was more pronounced for individuals of African American ethnicity than White ethnicity and was independent of other CVD risk factors (Manjunath et al; 2003).

In a large cohort of community dwelling Americans Go et al reinforced this observation and demonstrated an independent, graded increase in risk of CVD, risk of death and hospitalisation as eGFR fell in a study with a follow up period of just under three years (Go et al; 2004). This increased risk started with an eGFR below 60mL/min and increased with the severity of CKD. While this study did not contain information about other potential CVD risk factors it indicated that individuals with even minor degrees of renal impairment were at significant CVD risk and that a component of this risk was likely to be independent of other comorbidities that are associated with CKD (Go et al; 2004).

The reasons for the association between CKD and CVD are only partly understood; although many risk factors for CVD are also causes or complications of CKD (diabetes, hypertension and vascular calcification), not all of this enhanced risk is explained by these traditional risk factors and it has been hypothesised that non-traditional risk factors are implicated in CVD development (Menon et al; 2005).

The natural history of CKD was initially assumed to involve a predictable progression to ESKD; however there is now an acknowledgment that this is only the case in a minority of patients (Hallan et al; 2006). Where progression does occur there is an increased risk of CVD in addition to the risk associated with baseline and stable impairment of kidney function (Shiplak et al; 2009).  An analysis of the CVD health study showed that patients whose eGFR declined by more than 3mL/min/1.73m2/year were at increased risk of all cause and cardiovascular mortality (Rifkin et al; 2008). In another analysis of the same cohort the association between cardiovascular events and rate of decline of kidney function was examined; the incidence of all types of cardiovascular events was higher in those patients with a more rapid decline of kidney function, this was independent of demographic factors, CVD risk factors and baseline kidney function (Shiplak et al; 2009).

The importance of CKD as a CVD risk factor, and the hypothesis that the enhanced CVD risk could be mitigated by early identification of CKD with treatment of known risk factors for CKD; the commonest of these is hypertension.

Hypertension and CKD

It has long been understood that hypertension is both a cause and a consequence of CKD and that as blood pressure (BP) rises the relative risk of development of ESKD increases correspondingly. There is a strong evidence base to show that management of BP to defined targets improves long-term survival and protects against the progression of CKD in people with renal disease (Klag et 1996; Weiner et al; 2004). As the treatment of hypertension has improved, the relative risks of CVD and progressive CKD have fallen, further confirming a patho-physiological relationship  (Klag et 1996; Weiner et al; 2004). The presence of proteinuria in hypertensive patients is also of prognostic significance; these patients are at highest risk of progressive decline in kidney function as well as CVD (Samuelsson et al; 1995). For this reason the guidelines included recommendations on the treatment of hypertension for patients with CKD and patients with proteinuria (usually measured as albuminuria) have more aggressive BP targets than those without proteinuria (CKD Nice guideline; 2008). The principle that albuminuria is a known risk factor for both progressive CKD and CVD was first explored in patients with diabetes (Borsch-Johnsen et al; 1987).

Albuminuria and cardiovascular disease in CKD

The pathophysiology of CVD in patients with CKD is complex as so many of the risk factors are inter-related, albuminuria is an excellent example of this, the figure illustrates some of these inter-relationships associated with albuminuria.


The relationship between kidney function, albuminuria and mortality was explored in the HUNT II study, a community based health study with prolonged follow up (Hallan et al; 2007).  Participants were asked to provide three urine samples in which the ACR was measured; they also underwent estimation of GFR (by MDRD) and collection of data pertaining to medical history, anthropomorphics and blood pressure. Cardiovascular events and deaths were tracked and found to be strongly correlated with both impaired kidney function and increased urinary albumin excretion, the risk was additive suggesting that when both albuminuria and impaired kidney function are used for risk stratification more accurate estimates are achieved.

In another community based study Astor et al reported data from the NHANES III cohort, urine samples were obtained for ACR measurement and GFR was estimated using the MDRD formula, data pertaining to cardiovascular risk factors were also collected (Astor et al; 2008). Lower eGFR was associated with increased cardiovascular events and all cause mortality, when eGFR and albuminuria were considered together the association with all cause mortality and cardiovascular events was significant.

Albuminuria and progressive CKD

In 1976 Kussman et al observed that the number of patients with diabetes who were reaching ESKD was rising and the natural history of kidney disease in these patients was not clear; to investigate this a retrospective analysis of juvenile patients with diabetes reaching ESKD was performed (Kussman et al; 1976). They reported that at the time of identification of proteinuria there were few complications of diabetes present but as time progressed the amount of proteinuria increased and kidney function fell in tandem with the development of multiple diabetic complications, they concluded that proteinuria is an early marker of diabetic nephropathy but was unlikely to be treatable by any means other than renal replacement therapy when the need arose.

The relationship between proteinuria and progressive CKD was described in 1984 by Mogensen et al in a cohort of patients with type 2 diabetes, urinary albumin excretion was measured and a comparison was made between the outcomes of normal controls, patients with diabetes and albumin excretion of 30 -140μg/mL and patients with diabetes and “heavy proteinuria” (>140μg/mL urinary albumin excretion) after 9 years of follow-up (Mogenson et al; 1984). The group with 30-140μg/mL albuminuria were more likely to have progressed to clinically detectable proteinuria than the normal controls and were also at increased risk of death, the group with baseline overt proteinuria had the poorest outcomes.

When Verhave et al reported data in 2004 on the association between microalbuminuria and CKD risk in non-diabetic subjects they were the first to do so (Verhave et al; 2004). The PREVEND study was drawn from the general population of Groningen in the Netherlands, 6022 individuals underwent estimation of GFR (using both the Cockcroft-Gault and the MDRD formulae) and measurement of urinary albumin excretion (using the mean of two 24 hour urine collections) at baseline and after four years. At the follow up visit just over 4% of the cohort had a new finding of an eGFR<60mL/min/1.73m2 and higher baseline urinary albumin excretion was independently predictive of the development of impaired eGFR.

In another large community study, carried out in Alberta, Canada, nearly 1 million adults underwent estimation of GFR (using the MDRD equation) and urinary albumin excretion (using a single spot sample for ACR or urine dip stick testing with mild proteinuria being defined as trace or 1+ and heavy proteinuria being defined as 2+), all baseline measures were repeated over a six month run in period (65).  Adjusted all cause mortality was higher in those with a lower eGFR or proteinuria, as was progression to ESKD or doubling of serum creatinine (Hemmelgarn et al; 2010).

The natural conclusion of the K/DOQI classification system and the increased understanding of the cardiovascular implications of CKD was the development of best practice guidelines for the management of patients with CKD. These included recommendations on blood pressure targets and which anti-hypertensive agents should be used, and a focus on the monitoring and management of secondary complications of CKD (NICE CKD Guideline; 2008).

The end-points utilised in CKD studies

Clinical end-points

A clinical end point is a definitive physical event that a patient has reached; this may be a cardiovascular event, progression to ESKD and requiring RRT or death. While a clinical end point provides certainty that the pathological process in question has occurred and the use of categorical outcomes makes analysis less complex, patients may take many years to reach an end point and this can make associations difficult to assess and studies of intervention very expensive. It can also be argued that by the time an end point has occurred any opportunity to reverse the pathological process has been missed. Another disadvantage of a clinical end point is that patients who do not meet them (either because their disease has progressed slowly or they have died before they were able to reach them) are not considered to have “progressed”. However this might not be a genuine reflection of their risk; the use of composite end points that include death goes some way to overcome this.

Surrogate end-points

For these reasons surrogate end points are often used; a surrogate end point is one where a stage that is intermediate to the end point is identified and measured, this might include a change in kidney function (68) or the development of albuminuria. Biomarkers such as creatinine (used in estimating equations) and albuminuria are often used as surrogate end points, with a biomarker described as a substance measured in a biological sample that is related to a pathological process, although other physiological markers can also be described as biomarkers; for example, fever is a biomarker of infection. Finding a marker that is genuinely an intermediate step in the process, that is unaffected by any other process and that is reliably and reproducibly measureable is a challenge and may explain why surrogate end points are not as robust as clinical end points. Despite this the use of biomarkers can enable relatively rapid assessment of efficacy of a certain diagnostic technique or intervention.

In studies of renal interventions or of novel biomarkers both clinical and surrogate end points have been utilised, these can be broadly divided into end points related to markers or measures of renal function or markers related to proteinuria.

Kidney function based clinical and surrogate end points

There are both clinical and surrogate end points that rely that are based on changes in kidney function, the most commonly used clinical end point being progression to ESKD and commencement of RRT. Surrogate end points include rate of change of kidney function through slope based analyses; the utility of this approach is limited by the fact that kidney function rarely declines in a linear fashion (Stevens et al; 2006).

Another surrogate end point is the absolute change in kidney function between two time points, a doubling of serum creatinine or halving of eGFR is often utilised. Whilst the pattern of decline of kidney function is not a limitation, the variability of the most commonly used marker of kidney function (a creatinine eGFR) means that a difference in eGFR on two occasions may not represent a genuine change in GFR between those time points (Levey et al; 1993). The variability in creatinine based estimates of GFR may not simply be related to factors associated with creatinine production but may be a feature of the intra-test variability of creatinine; in the MDRD study this was quoted as 9.4%.  In effect a surrogate marker of kidney function is being used to define a surrogate end point.

Albuminuria based surrogate end points

While albuminuria is known to be of pathophysiological relevance to the progression of CKD it is not a proven intermediate step in the path to ESKD, as not all patients with significant albuminuria will progress to ESKD (Foster et al; 2007). Using albuminuria as a surrogate end point has been popular in interventional studies of patients with diabetes where the disease process is known to involve the development of albuminuria. While there is a strong and significant association between albuminuria and progressive CKD it cannot be definitively stated that the effect of a certain intervention on albuminuria is the same as its effect on renal progression (Stevens et al; 2006). Another potential limitation is the intra-test variability of measures of albuminuria (using the ACR) which can be as high as 60% (Dyer et al; 2004).

Risk stratification in CKD

The disparity in clinical outcomes of individuals with CKD makes accurate risk stratification a holy grail of CKD management; being able to accurately predict which patients will remain stable, which will experience a slow linear or stepwise decline and which are at risk of an inexorable, accelerated decline towards ESKD would allow clinicians to focus treatment on those at highest risk.

It is clear that there are many factors that influence risk of progression (a likely combination of nephron loss, inflammation and endothelial dysfunction causes by both traditional and non-traditional risk factors); the observation that a single insult (e.g. unilateral nephrectomy) is usually associated with good renal outcomes supports this (Nenov et al; 2000).  Any risk scoring system would necessarily include clinical and laboratory variables in combination with sophisticated mathematical modelling similar to that used to construct the Framingham cardiovascular risk scoring system (Kannel and Larson; 1993).

In an analysis of data from the RENAAL study (reduction of renal end points in patients with diabetic nephropathy using the angiotensin blocker Losartan), a proposed risk stratification system for arrival at ESKD included urinary ACR, serum albumin, creatinine and haemoglobin. The formulae for risk of progression to ESKD and death is shown below (Keane et al; 2006). The authors concluded that the use of the formulae improved the prediction of arrival at ESKD from 50% when only albuminuria was included, to >80% when all four clinical variables were included. It is important to note that this formula was developed from a diabetic cohort and may not be applicable to the non-diabetic population.

ESKD = (1.96 x log[ACR])-(0.78 x sAlb[g/dL])+(1.28 x sCr[mg/dL])-(0.11 x Hb[g/dL])

Death = (1.14 x log[ACR])-(.061 x sAlb[g/dL])+(0.97 x sCr[mg/dL])-(0.07 x Hb[g/dL])+(0.08 x HbA1C[%])

ACR, albumin creatinine ratio; sAlb, serum albumin; sCr, serum creatinine; Hb, haemoglobin; HbA1C, glycated

In another attempt to devise a renal risk stratification tool Tangri et al used a variety of routinely collected demographic, clinical and laboratory data in two independent cohort studies where there was a variety of distribution of renal impairment and causes of renal impairment  (Tangri et al; 2011). The total population was large (n=8391) and the end point used was progression to ESKD (identified from national registry data); the development cohort consisted of 3449 individuals and the validation cohort of 4942 individuals, the two cohorts did not materially differ from one another at baseline. They used seven different equations (the composition of which are shown below) and compared them to determine which provided the most accurate prediction of risk of progression.

Model 1: Age and Gender

Model 2: Baseline eGFR, age and gender

Model 3: Baseline eGFR, age, gender and log urine ACR

Model 4: Baseline eGFR, age, gender, log urine ACR, diabetes and hypertension diagnoses

Model 5: Baseline eGFR, age, gender, log urine ACR, systolic BP (per 10mmgHg), diastolic BP (per 10mmgHg) and body weight (per 10kg)

Model 6: Baseline eGFR, age, gender, log urine ACR, serum albumin (per 0.5g/dL), serum phosphate (per 1.0mg/dl), serum bicarbonate (per 1.0mEq/L) and serum calcium (per mg/dL)

Model 7: Baseline eGFR, age, gender, log urine ACR, systolic BP (per 10mmgHg), diastolic BP (per 10mmgHg) and body weight (per 10kg), serum albumin (per 0.5g/dL), serum phosphate (per 1.0mg/dl), serum bicarbonate (per 1.0mEq/L) and serum calcium (per mg/dL)

The C statistic was higher for model 6 compared with models 2 and 3 and no further improvement in sensitivity or specificity was observed by the additional of extra clinical variables (model 7), the hazard ratios for model 7 and model 6 were 0.835 (95% CI 0.819-0.851) and 0.851 (95% CI 0.825-0.857) respectively(84). An equation based on model 6 is consequently the one used in a smart phone risk stratification tool developed by the authors(85). While this is a very promising risk stratification tool it has yet to be validated in other cohorts and may be limited by its lack of ethnic diversity and inclusion of referred patients only.

Variability in eGFR and ACR

In the MDRD study the intra-test variability of the creatinine based eGFR was 9.4%, the variability being greatest at the extremes of GFR (Levey et al; 1999). In a study examining the accuracy of creatinine based eGFR equations in clinical studies in comparison to iothalamate based GFR measurements, Levey at al in 1993 recommended that to reduce the intra-test variability at least four measures should be used (Levey et al; 1993). This approach has now been validated by a number of studies and there is consensus that using between four and six eGFRs collected over a period of at least one year is a more accurate way of assessing decline than percentage change in creatinine based on two results (Hemmelgarn et al; 2006).

The presence of significant albuminuria is also part of the inclusion criteria, early work on urinary albumin creatinine ratio measurement found that there was significant intra-test variability associated with this method (around 60%) (Dyer et al; 2004). This variability should be remembered in clinical practice.


Clinical considerations

Aim of History

The aim of the history is to establish: (1) whether the patient has CKD or AKI; (2) if CKD, its cause; (3) renal pathology; and (4) complications.

Key Point: as a general rule, if the patient looks reasonably well, it is CKD. Most patients with AKI look unwell.

We will now suggest some questions that you may need to ask. Few patients will require all these questions.

Questions Related to CKD

  • How are you feeling? – fatigue? When did you last feel reasonably well?
  • Any shortness of breath, ankle swelling, breathing problems at night, cough, blood in your sputum?
  • Any loss of appetite, weight loss, nausea?
  • Any itching? Any rashes?
  • Any urination at night? How many months/years have you had to get up to pass urine at night?
  • Any aches or pains? If so, is it the muscles or your joints? Which joints? Any history of gout?
  • Any problems with your ears, nose or throat? Any sore throats?

Questions Related to Causes of CKD

  • Childbirth/pregnancy
  • Did you have any severe illnesses as a small child?
  • Did you have any urinary infections as a child?
  • Women: If you have been pregnant did you have any problems when you were pregnant? Did your blood pressure go up? Did your kidneys leak protein? Did you get pre-eclampsia? History of miscarriage (Anti-Phospholid Antibody Syndrome)? Did you have any urine infection whilst pregnant?
  • Men: Any problems with the urinary stream? Do you have to wait to get going/have a weak stream/dribbling at the end of the stream?
  • Have you ever seen blood in your urine? Had kidney stones or have a family history of kidney stones?
  • Does your urine ever look frothy as if there was soap or washing up liquid in it?
  • Have you ever had abnormal urine dipstick? (eg insurance medical)

Past Medical History

  • Do you have diabetes? If so, for how long, and do you have any complications of the diabetes? (eg retinopathy, neuropathy)

Notes: complications of DM are associated with CKD; record when DM started

  • Do you have high blood pressure? When did it start? (record that too)
  • Any other major operations or illnesses? eg previous malignancy, autoimmune conditions known to cause CKD (eg Systemic Lupus Erythematosus) 
  • History of TB/TB contact?
  • Any history of jaundice or hepatitis?
  • Have you ever had malaria? How ill were you?


  • What medications do you take? Do you take painkillers? Do you take ibuprofen/brufen/voltarol or any other anti-inflammatory pain killers? When did you start these medications?
  • Do you take a drug that ends in '-pril' or '-sartan'?
  • <
  • Have you had any recent antibiotics or herbal remedies?

Social and Family History

  • Have you ever smoked (Renovascular Disease)? Ever been a regular heavy drinker (IgA Nephropathy)?
  • Have you ever take drugs (recreational)? Which ones? Have you ever injected? When did you last inject?
  • Tattoos? Partners and sexual habits? Transfusions abroad? (Membranous Nephropathy, Mesangiocapillary Glomerulonephritis and FSGS are associated with Hepatitis B, C and HIV  respectively)
  • Any family history of kidney problems? (Alports Disease, Polycystic Kidney Disease). Anyone else in your family ever had kidney failure, dialysis or a transplant?


Key point: patients with mild renal impairment (CKD1-3) are usually asymptomatic. Symptoms vary between patients and tend to occur between CKD 4 and CKD 5.

  • Anorexia, nausea, vomiting, stomatitis, and an unpleasant taste in the mouth
  • Tiredness, loss of libido, loss of concentration, insomnia and restless legs
  • Pruritus may be especially uncomfortable
  • Shortness of breath (secondary to fluid overlaod, anaemia, or acidotic breathing, or a combination of all three) and ankle swelling
  • Chest pain (pericarditis?)
  • Urine output. You will also need to know how much urine the patient is producing. Patients find this difficult to assess (how much urine have you passed today?). Ask whether they have noticed a change in the amount of urine they have been passing recently. Nocturia is common, principally due failure to concentrate urine
  • Bone pain (from renal bone disease)
  • Late symptoms (of advanced CKD; patients now rarely appear at this stage)
  • Coarse muscular twitches, peripheral sensory and motor neuropathies, muscle cramps and seizures (usually the result of hypertensive or metabolic encephalopathy)


Key point: There may be no signs on examination.

Nonetheless. A full examination and detailed general examination is required, especially abdominal, cardiovascular and respiratory systems. The following signs may be present:

  • Anaemia (not usually obvious)
  • Excoriation marks (common)
  • Note the type and distribution of any rashes
  • Signs of fluid overload (pulmonary oedema, tachycardia, leg oedema) (rare in CKD1-3). JVP: This is the most important sign in a patient with renal disease. Fluid overload may be due renal retention of Na and water, and activation of the renin-angiotensin-aldosterone system. Hypertension and IHD may also contribute. Severe CCF may be due to amyloidosis
  • Blood pressure. This is essential for several reasons, including fluid state assessment. Hypertension is present in > 80% of patients with CKD4-5
  • Examine the heart carefully, listening for a pericardial rub (pericarditis)
  • Palpate (ballot) the kidneys, to check for large kidneys (polycystic kidney disease). Tumours, or large obstructed kidneys, are rarely palpable
  • Check for any other organomegaly (polycystic patients may also have hepatomegaly from liver cysts)
  • Palpate for an enlarged bladder (obstructive uropathy). If palpable, proceed to digital rectal examination (in males) to check prostate size and consistency
  • Listen for epigastric and femoral bruits (renovascular disease)
  • Finally check the fundi, for signs of hypertension and diabetes

Late Signs of Advanced CKD (rare)

  • Brown nails
  • Discoloration of the skin from uraemia (yellow-brown)
  • Undernutrition leading to muscle wasting
  • ‘Uraemic frost’ - urea from sweat crystallises on the skin
  • Hyperreflexia, pericardial rub, GI ulceration and bleeding

Acute-on-Chronic Deterioration

Assess the patient to see if there has been any acute (and reversible) cause that can be treated to prevent further damage. If an acute-on-chronic deterioration has occurred, proceed with investigation as you would for Acute Kidney Injury (AKI). Even if the patients' underlying renal function is poor, preserving their remaining renal function may delay dialysis for an extra year or so, which will: 

1.  Greatly enhance the quality of their life
2.  'Buy time’ to prepare access for dialysis and transplant ‘work-up’. A pre-emptive Living Renal Transplant is often the best option for fitter patients

Does the Patient Need Dialysis?

Even in a well patient (without AKI), it is important to finish the assessment by asking the question ‘does this patient require renal replacement therapy (dialysis), and if so, when?’ This will depend on their current renal function, and the presence of life-threatening complications such as:

  • Hyperkalaemia, fluid overload (or acidosis) resistant to medical treatment
  • Severe ‘uraemia’ (causing pericarditis, hiccoughs or bleeding)
  • Hypervolaemia
  • Acidosis
  • Failure to thrive (poor appetite, weight loss)

Ensure Patient Safety

The above should form the basis of 'the renal assessment'. Most importantly - at the end of your assessment - you must make sure the patient does not have a potentially life threatening disorder. If they do, you must treat it appropriately.

For example, if the patient is found to have hyperkalaemia, is acidotic or severely uraemic, or has symptomatic pulmonary oedema, do NOT waste time trying to establish the cause of their renal failure (this is true for acute and chronic kidney disease). You can do this once you have made sure the patient is safe, if necessary with emergency dialysis.

When a patient presents with renal impairment, it is important to decide whether this is acute or chronic. This is straightforward if the patient has recent blood tests, which show either a gradual decline in renal function or an acute change - but often a single set of blood results is all that is available.


Differentiating AKI from CKD is partly done by the initial assessment (history and examination) described above. Then a complete renal 'work up' is necessary to define the level of renal impairment, and the pathological diagnosis. This will also involve a variety of other blood tests and imaging studies.

The following blood tests are usually done, depending on the presentation - often as part of a ‘renal screen’. Make sure if you are asked to perform such a screen you know exactly what is required, as different patients will require different investigations.

In a well patient, these tests are organised in the outpatient department. Many renal units run 'one-stop clinics', where tests are organised before the first appointment, allowing a senior to make a probable diagnosis on this first visit.
Note: it is important to know the results in an appropriate time period, not just send them off

Key point: patients with CKD and diabetes mellitus have a greater tendency to suffering with anaemia and hyperkalaemia.

Aim of Investigation

Initial investigation has 3 primary aims:

1. Quantify renal impairment
2. Make a pathological diagnosis
3. Exclude easily reversible causes (eg obstructive nephropathy, and some glomerulonephritides)

Blood Tests


  • U&E’s – Potassium - normal or high (occasionally low). If very high (or very low), ensure correct patient, not a spurious result, and that electrolytes are ‘safe’. Do NOT accept a ‘haemolysed K’ as 'OK' (and check tomorrow). Recheck it today. Sodium - normal or low.
  • Random blood glucose - high in diabetes. But glucose can fall in advanced CKD as insulin is renally excreted. This may require dose reduction (or stopping) anti-diabetic agents.
  • Calcium, phosphate, alkaline phosphate, PTH – calcium usually low (but can be normal or high) and high phosphate, alk phos and PTH. All suggest CKD (see CKD-MBD)
  • Albumin - low in nephrotic-range proteinuria or malnutrition
  • Bicarbonate - low
  • Lipids - dyslipidaemia is common


  • Full blood count (and look at MCV). Normocytic anaemia with a Hb <11 g/dL is typical of CKD4-5 (except if patient has PCKD). WC and platelets are normal. But thrombasthenia contributes to bleeding tendency

Note: don’t be caught out: There are other causes of anaemia and renal failure, so keep an open mind; and ensure the anaemia is not caused by acute or insidious GI bleed, or some other disease not yet diagnosed. Severe anaemia may suggest myeloma

  • Iron stores – different units prefer different measure of iron status, eg ferritin, transferring saturation, serum iron or total iron binding capacity. Use local guideline
  • B12 and folate levels


  • ANCA (MPO and PR3) - for ANCA positive vasculitis (see glomerulonephritis)
  • ANA and dsDNA - for SLE
  • C3 and C4 complement levels - eg low in SLE, cryoglobulinaemia and mesangiocapillary glomerulonephritis
  • Rheumatoid factor - for RA and other connective tissue disorders
  • Serum protein electrophoresis and serum free light chains - dysproteinaemia (eg myeloma)

Recent Biomarkers

Recent renal biomarkers discovered include neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and liver-type fatty acid-binding protein. These have been reviewed by Fassett (2011)


Key point: significant proteinuria (>1g/L, or PCR >100 mg/mmol) is the hallmark of glomerular disease.

  • Dipstick urinalysis – simple, quick and cheap. May show blood/protein, or evidence of infection. Remember proteinuria if present is due to albuminuria. So, myeloma (which can be associated with significant tubular proteinuria) may have a normal dipstick
  • Urine protein quantification
  • Microscopy and sensitivity


  • A chest x-ray
  • An ultrasound scan of the renal tract (kidneys, ureters, bladder) is usually necessary; looking for evidence of obstruction, number of kidneys, kidney size, cortical thickness, polycystic disease. Small echogenic kidneys are often seen in patients that present late with advanced renal failure
  • Intravenous pyelogram (IVP) and CT/CTA - not often used because of potential for contrast nephropathy
  • MRI/MRA - not often used in view of risk of nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy (NSF/NFD) in patients with renal failure. This has been related to high doses of gadolinium-containing contrast agents
  • Nuclear medicine scans (DMSA, DTPA, MAG3) - different scans useful for diagnosis of reflux nephropathy or % contribution of renal function
  • Isotope GFR - gold-standard measurement of GFR, but not widely available

Note: simple bone x-rays are now rarely done to look for evidence of renal bone disease

Invasive Tests

Key point. Renal biopsy - unexplained CKD, in a patient with two normal sized kidneys, and significant proteinuria (>1 g/L, or protein-creatinine ratio (PCR) >100), often warrants a renal biopsy. A tissue diagnosis is also useful for prognosis (see renal biopsy).

Renal angiogram – occasionally may be necessary if renal artery stenosis is suspected
Note: both of these tests carry significant risks - ie they are senior decisions



Aims of Treatment of CKD

  • Exclude reversible causes (especially obstructive nephropathy and some glomerulonephritides)
  • Avoid Nephrotoxic Drugs
  • Reduce rate of progression of CKD (especially by controlling BP tightly,  using ACE inhibitors or ARBs where indicated
  • Manage complications
  • Prepare for dialysis and transplantation, if necessary

Withdrawal of Nephrotoxic Drugs

Review all medication including over-the-counter drugs; particularly consider recent additions (eg ACEi/ARBs, diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), or any drug capable of causing interstitial nephritis (such as penicillins, cephalosporins, mesalazine, diuretics). Usually stop metformin if eGFR <30 ml/min.

All Stages of CKD

General health advice is recommended: smoking cessation, weight loss, aerobic exercise, limiting alcohol intake, limiting sodium intake. Several studies have shown an association between smoking and CKD, and studies of patients with CKD have shown smoking increases speed of decline in GFR to ESRD, independent of the underlying cause .

Weight reduction is recommended for obese patients. Weight reduction has been shown to decrease proteinuria. It also improves blood pressure control. Avoidance of nephrotoxins - eg IV radiocontrast agents, NSAIDs, aminoglycosides.

Cardiovascular prophylaxis. For patients with 10-year risk of cardiovascular disease of >20%, consider aspirin treatment.  Consider cholesterol lowering treatment (SHARP study).

Key point: In all causes and stages of CKD, BP should be tightly controlled. The following information represents clinical guidelines based on the current evidence base in the area

Blood Pressure Targets (see NICE Hypertension Guideline for how to measure and detail) and drug guidelines in CKD

<140/90 (clinic) in non-diabetic patients with an ACR of <30 mg/mmol (<150/90 if >80 years old

<130/80 in people with diabetes or when the ACR is ≥30 mg/mmol

Maximise BP agent use at each stage before adding in a further agent

First line

CCB in all ≥55 and all people of Black ethnicity

ACEi or ARB if any of

  • Age <55 except people of Black ethnicity
  • Diabetes
  • ACR ≥30 mg/mmol

If person already on a thiazide and BP well controlled don’t switch

Second line

If on CCB add in an ACEi or ARB (ARB preferred if black)

If on ACEi or ARB add CCB

Third line

If eGFR ≥30 ml/min use a thiazide diuretic (Indapamide  MR or Chlorthalidone)

If eGFR <30 ml/min use furosemide

Fourth line

Beta blocker

Alpha blocker

Spironolactone (but get informed consent) if eGFR ≥30 ml/min and K+ <4.5 mmol/l

Consider seeking expert advice

5th line (options)

Consider seeking expert advice

Specific considerations for ACEi and ARBs

The NICE CKD guideline recommendation is the ACEi should be used first and ARBs used if ACEi are not tolerated.

The evidence base for an additional effect over the anti-hypertensive benefit for ACEi/ARBs in people with CKD is in:

  • People with diabetes and high or very high albuminuria (microalbuminuria or more; ACR >3 mg/mmol))
  • People with non-diabetic CKD and very high albuminuria (ACR of >30 mg/mmol)

The BP target in these high-risk groups is <130/80 and they should be used at the maximum tolerated dose within the dosing recommendations of the BNF

  1. They should not be used in combination and they should not be used in combination with a renin inhibitor
  2. Avoid NSAIDs in people who are maintained on an ACEi or an ARB
  3. Test eGFR and serum potassium before treatment with an ACEi or ARB and repeat after 1–2 weeks of treatment and after each dose increase.
  4. If there is an eGFR decrease of < 25% or plasma creatinine increase < 30% following ACE inhibitor/ARB introduction or dose increase: do not modify the dose and repeat the test after 1–2 weeks.
  5. If there is an eGFR increase of ≥ 25% or an increase of plasma creatinine ≥ 30% stop the ACEi/ARB and refer to nephrology
  6. If serum K+ is significantly above the normal reference range (typically > 5.0 mmol/l) do not start an ACEi/ARB; exclude and treat other factors that promote hyperkalaemia and recheck serum K+.
  7. If K+ is ≥5.5-5.9 mmol/l on an ACEi/ARB consider a small dose of furosemide
  8. If K+ is ≥6 mmol/l on an ACEi/ARB stop the drug
  9. ACEi/ARBs should be withheld at the time of an acute intercurrent illness
  10. In people with an accelerated decline of renal function (>10 ml/min over 3 years – stop the ACEi/ARB and refer to nephrology​

Angiotensin converting enzyme inhibitors (ACEi) and angiotension receptor blockers (ARBs) in patients with declining kidney function

Many patients with CKD are treated with ACEi or ARBs and in some patients (e.g. those with proteinuria and/or diabetes) there is good evidence to show that these drugs should be first line treatment. However there is uncertainty about their use in patients who sustain a continuing decline in kidney function on these drugs. This brief summary overviews the current status of the area and includes a guideline on the use of ACEi or ARBs in CKD.

Current status

Initial studies showed that ACEi and ARBs reduced the doubling time of creatinine in patients with type I and type II diabetes over a 3 year period. Further studies then showed that ACEi and ARBs reduced the progression of renal disease in non-diabetic patients; some data suggested that the effect of the drugs is best seen when started early (eGFR<50 ml/min). These studies suggesting that these agents are renoprotective in patients with CKD have formed the basis of guidelines which recommend the use of ACEi/ARBs in patients with proteinuria and/or diabetes, and have been transposed to apply to advanced CKD.

In 2006, a Cochrane Review included 49 studies on the utility of ACEi/ARBs in patients with diabetes and kidney disease. The authors found that both drugs improved renal outcomes. Further, when compared to placebo, use of ACEi at maximum tolerated doses appeared to decrease mortality in patients with diabetic kidney disease (RR 0.78; 95% CI 0.61 to 0.98). These mortality data were not found with ARBs. However the study cautioned against concluding that ACEi and ARBs prevent CKD progression and suggested that the beneficial effect seen may mainly reflect their anti-proteinuric effects (and therefore could not be applied to people without proteinuria), and that there was little robust evidence of benefit in advanced CKD.

In fact renoprotection from ACEi/ARB may be lost in more advanced disease where significant ischaemic nephropathy is present. This hypothesis is supported by reports in both diabetic and non-diabetic patients with CKD indicating that ACEi/ARBs may actually accelerate renal progression; in some patients with advanced CKD the intrarenal haemodynamic effects of ACEi/ARBs may decrease the time to renal replacement therapy. Furthermore, combined ACEi/ARB treatment has been shown in one large study to worsen renal outcomes in patients at high cardiovascular risk.

A recent study  (Ahmed et al) demonstrated that ACEi/ARB withdrawal in 52 patients with advanced CKD led to an overall mean increase in eGFR of 10ml/min/1.73m2 over 12 months, and an increase or stabilisation in eGFR in all but 4 patients. Further evidence of the problems associated with ACEi/ARBs in advance kidney disease emanates from data from a retrospective cohort study which evaluated risk factors for adverse drug events and found factors such as hyperkalaemia and renal impairment as indications for discontinuation of the medication. In this study of 2,225 out-patients administered ACEi, 19% of the initial group discontinued ACEi therapy due to adverse events.

Trial evidence on the effectiveness and safety of ACEi/ARB discontinuation in advanced CKD is lacking; this is reflected in current guidelines that provide no specific instructions regarding ACEi/ARB in relationship to the severity of CKD. One indication of the uncertainty of this area is that the MRC have recently funded a study to identify if withdrawal of ACEi/ARB in people with CKD 4 and CKD 5 is beneficial to kidney function and other markers of outcome.

Additional Management for CKD3

  • Annual measurement of FBC, U+E, glucose, LFT, Bone
  • If Hb <10 g/dL and other causes excluded, treat with erythropoiesis-stimulating agents (ESA) to maintain Hb 11-12 g/dL
  • Immunise against influenza and pneumococcus
  • For Bone Chemistry - see CKD MBD chapter
  • Correction of metabolic acidosis (eg with PO SODIUM BICARBONATE 1.2g tds) has been shown to slow the progression of CKD (Mahajan, 2010). Kraut (2011) has reviewed the effects of metabolic acidosis in CKD
  • Follow the NICE CKD guidelines

Additional Management for CKD Stages 4-5

Key point: patients with CKD 4 or 5 (eGFR <30), significant proteinuria, haematoproteinuria are at higher risk of progressing to ESRD and specialist nephrology referral is recommended.

Patients should be seen within 6 weeks. If urgent, within a week, or today. Exceptions may include:

  • Patients with another terminal illness
  • Patients with stable function in whom all the appropriate investigations and management interventions have been performed and who have an agreed and understood care pathway
  • Patients in whom further investigation and management are clearly inappropriate

Note: these three groups may warrant a phone call to a nephrologist to discuss the patient 

Key point: focus on rapid treatment of reversible causes (especially obstructive nephropathy and some glomerulonephritides).

After this has been done, follow-up is required, including:

  • 3-monthly tests: FBC, U+E, bicarbonate, glucose, LFTs, Bone and PTH
  • Dietary assessment
  • Early referral to a weight management clinic is useful if transplantation is being considered. Bariatric surgery may be necessary
  • Low protein diet? The main conclusion from the MDRD (Klahr, 1994) is that there no evidence that (previously used) low protein diet delays RRT, but they may control symptoms. The study is controversial and has subsequently been re-interpreted with different conclusions (Levey, 1999)
  • Immunisation against Hepatitis B
  • Timely provision of dialysis access (and/or transplant work-up) depending on treatment choice
    Renal Replacement Therapy

Indications for renal replacement therapy (haemodialysis, peritoneal dialysis or renal transplantation) include:

  • CKD5, serum creatinine > 500 mmol/L, or urea > 50 mmol/L
  • Severe metabolic disturbance (potassium >6.5 mmol/L or bicarbonate less than 15 mmol/L) resistant to medical therapy
  • Symptoms: pericarditis, encephalopathy, peripheral neuropathy, intractable gastrointestinal symptoms, failure to thrive and malnutrition




Top Tip: In all stages of CKD, BP should be focused on

1. 'Normal' serum creatinine and eGFR are unknown. In one study, median eGFR (using the MDRD
equation) decreased from 90–100 ml/min (age 18–24 years) to 60–65 ml/min (age 85+ years). CKD
is classified into 5 stages, based on eGFR
2. In a stable patient, consider a diagnosis of CKD3, if on more than one occasion eGFR <60 mls/min
3. CKD is common: 5-10% of the population if a biochemical definition is used
4. Patients with mild renal impairment (CKD1-3) are usually asymptomatic but even minor CKD is
associated with increased cardiovascular death and morbidity
5. Cardiovascular risk modification probably helps to reduce the risk of CKD progression as well as
protecting patients against cardiovascular disease. Therefore GPs should lead CKD care in the
majority of cases
6. Symptoms vary between patients and tend to occur between CKD 4 and CKD 5
7. Patients with CKD 4 or 5 (eGFR <30), significant proteinuria, haematoproteinuria are at higher risk
of progressing to ESRF and specialist nephrology review is recommended
8. End Stage Kidney Failure (ESRF) (ie requiring dialysis) is rare, affecting about 0.1% of the
9. In all causes and stages of CKD, BP should be tightly controlled. If urinary PCR < 100 mg/mmol:
threshold for initiation (or increase) of treatment = 140/90 mm Hg, target 130/80 mm Hg. If PCR >
100 mg/mmol: threshold 130/80 mm Hg, target 125/75 mm Hg. ACE-I and ARBs should be
10. Significant proteinuria  or unexplained CKD with normal sized kidneys, may warrant a renal biopsy
11. Patients with CKD and diabetes mellitus have a greater tendency to suffering with anaemia and
12. Patients who progress when empowered early to make choices have better outcomes. Their
choices include conservative management (medical management), dialysis (and the choice between
peritoneal and haemodialysis) and transplantation. Better preparatory time impacts on morbidity and


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Key Documents for Reference

ACE inhibitor and ARB information