Definition of a Risk Factor

A risk factor is a variable that has a causal association with a disease or disease process such that the presence of the variable in an individual or population is associated with an increased risk of the disease being present or developing in the future. Thus, risk factors may be useful for identifying subjects at increased risk for a disease or particular outcome due to a disease process. In the course of epidemiologic research, many variables may show associations with a disease of interest but these may be chance associations, noncausal associations, or causal associations (true risk factors). The Bradford Hill criteria provide minimum requirements to be fulfilled to identify a causal relationship between a putative risk factor (exposure) and a disease (outcome; Table 22.1 ). In complex diseases such as CKD that result from the combined effects of multiple factors, it is likely that many risk factors will not fulfill all the criteria. Nevertheless, they do provide a useful framework for assessing the strength of a proposed causal relationship between risk factor and disease.

Epidemiologic Methods for Identifying Risk Factors

Studies to investigate associations between putative risk factors and a disease may be classified as observational or experimental. Observational studies include cross-sectional, case-control, and cohort studies, whereas the randomized controlled trial is the main experimental study.

Susceptibility Factors

These are risk factors associated with an increased risk of an individual developing CKD after exposure to a factor that has potential to cause renal damage. An example is a reduced nephron number after uninephrectomy, which is associated with an increased risk of developing diabetic nephropathy if the individual develops diabetes. Studies to identify susceptibility factors should recruit subjects free of CKD at baseline who have been exposed to an initiating factor and followed over a prolonged period to allow ascertainment of outcomes. This could be achieved through a cohort study or subgroup analysis of an RCT.

Initiation Factors

Initiation factors directly cause or initiate kidney damage in a susceptible individual. Examples include exposure to nephrotoxic drugs, urinary tract obstruction, or primary glomerulopathies that may provoke CKD in some (but not all) exposed individuals. Studies investigating initiation factors should aim to recruit subjects without CKD at entry or known susceptibility factors, with variable exposure to a putative initiating factor. A cohort study design is best suited to investigate outcomes in subjects exposed versus not exposed to the factor of interest, or an RCT design could be used to assess the potential nephrotoxicity of a new drug.

Progression Factors

These are factors that contribute to the progression of kidney damage once CKD has developed. An example is hypertension, which exacerbates raised intraglomerular hydraulic pressure and therefore accelerates glomerular damage. Studies investigating progression factors should recruit subjects with relatively early-stage CKD in a cohort study design. RCTs may also be used to study progression factors if the intervention being investigated modifies a putative progression factor. Outcomes may therefore be compared between the group in whom the risk factor was modified versus a control group. Unfortunately, however, many interventions alter several risk factors, and it may therefore not be possible to attribute an improved outcome to changes in a single risk factor.

Age

The prevalence of CKD increases with age and is reported to be as high as 56% in those 75 years of age or older. Longitudinal studies of subjects without kidney disease have observed a decline in GFR with increasing age in some subjects, implying that nephron loss may be regarded as part of normal aging. On the other hand, aging is associated with an increase in several other risk factors for CKD, including hypertension, obesity, and cardiovascular disease, which may contribute to the rise in CKD prevalence. Several population-based studies have found a higher incidence of proteinuria and CKD as well as ESKD with increasing age. Similarly, the incidence of a decline in renal function over 5 years was greater among older patients with hypertension. One study reported that advanced age is a negative predictor of ESKD among patients with CKD, although older age was associated with a greater rate of decline in GFR. This apparent contradiction is most likely explained by the competing risks of death and ESKD in older patients, illustrated by the observation from one longitudinal study that for patients 65 years and older, the risk of ESKD exceeded the risk of death only when the GFR was 15 mL/min/1.73 m ² or less ( Figure 22.2 ). On the other hand, another study found that in patients with CKD stage 4 or 5, renal function in those 65 years or older was associated with a slower decline than in those younger than 45 years.

Baseline estimated glomerular filtration rate (eGFR) threshold. Below this the risk for end-stage kidney disease (ESKD) exceeded the risk for death in each age group among 209,622 U.S. veterans with chronic kidney disease stages 3 to 5 followed for a mean of 3.2 years.

(From O’Hare AM, Choi AI, Bertenthal D, et al: Age affects outcomes in chronic kidney disease. J Am Soc Nephrol 18:2758-2765, 2007.)

A large individual-level meta-analysis that included data from 2,051,244 participants in 46 cohort studies has provided robust data regarding the effect of age on the risks associated with CKD. In general population and high cardiovascular risk cohorts, the increase in relative risk of mortality associated with lower GFR declined with increasing age but the increase in absolute risk of death was higher in older age groups. Similar trends were observed for the mortality risks associated with albuminuria. On the other hand, the relative increase in risk of mortality did not decrease with increasing age in data from CKD cohorts. Furthermore, there was no attenuation of the risk of ESKD with increasing age in any of the cohort categories. Thus, older age is a susceptibility factor for CKD, and the associated increase in risk of death and ESKD is observed at all ages. These observations suggest that targeted screening for CKD in older subjects would be a cost-effective strategy, but further studies are required to investigate the extent to which the risks associated with CKD in older adults may be attenuated by intervention. For further discussion of CKD in older age groups, see Chapters 24 and 85 .

Gender

In experimental studies, male rodents were more susceptible to age-related glomerulosclerosis than females, an observation that was independent of glomerular hemodynamics or hypertrophy and was attributable to a specific androgen effect. Data regarding the effect of gender on the risk of CKD and progression in humans are, however, somewhat contradictory. Many reports have indicated that male gender is associated with worse renal outcomes. Studies have reported a higher incidence of proteinuria and CKD among men in the general population and an increased risk of ESKD or death associated with CKD, a higher risk of decline in renal function in male hypertensive patients, a lower risk of ESKD in female patients with CKD stage 3, and a shorter time to renal replacement therapy (RRT) in male patients with CKD stage 4 or 5. In addition, most national registries, including the U.S. Renal Data Service (USRDS), have reported a substantially higher incidence of ESKD in males (413 per million population [pmp] in 2003) versus females (280 pmp). Previous meta-analyses have, however, yielded conflicting results, with one reporting a higher rate of decline in GFR in men and another reporting a higher risk of doubling of the serum creatinine level or ESKD in women after adjustment for baseline variables, including blood pressure and urinary protein excretion.

The largest meta-analysis to date included data from studies of 2,051,158 participants investigating the impact of gender on CKD-related outcomes. Whereas the risk of all-cause and cardiovascular mortality was higher in men than women, the relative risk of mortality increased with lower GFR and higher albuminuria in both, and the slope of increase in risk was steeper in women than men. Importantly, the relative risk of ESKD increased with lower GFR and higher albuminuria in both sexes and there was no evidence of a difference in the increase in risk between men and women ( Figure 22.3 ). One limitation of many of the studies quoted is that menopausal status of the women was not documented. Nevertheless, it is clear from the most robust data published that CKD is associated with at least the same relative increase in risk of death and ESKD in women as in men. The reasons for the higher absolute incidence of renal replacement therapy in men versus women require further investigation. For further discussion of the impact of gender on CKD, see Chapter 20 , Chapter 21 , Chapter 52 .

A, B, Hazard ratios of end-stage kidney disease according to estimated glomerular filtration rate. C, D, Urinary albumin/creatinine ratio in men versus women in chronic kidney disease cohorts. A, C, Gender-specific hazard ratios, including a main effect for male gender at the reference point. B, D, Hazard ratios in each gender, thus visually removing the baseline difference between men and women. Hazard ratios were adjusted for age, gender, race, smoking status, systolic blood pressure, history of cardiovascular disease, diabetes, serum total cholesterol concentration, body mass index, and estimated glomerular filtration rate splines or albuminuria.

(Adapted from Nitsch D, Grams M, Sang Y, et al: Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis . BMJ 346:f324, 2013.)

Ethnicity

African Americans are overrepresented in the U.S. dialysis population, suggesting that ethnicity is a strong risk factor for the progression of CKD to ESKD. Population-based studies have found a higher incidence of ESKD among African Americans that was attributable only in part to socioeconomic and other known risk factors. Similarly, the risk of early renal function decline (increase in serum creatinine ≥ 0.4 mg/dL) was approximately threefold higher (odds ratio [OR], 3.15; 95% confidence interval [CI], 1.86 to 5.33) among black versus white diabetic adults, but 82% of this excess risk was attributable to socioeconomic and other known risk factors. The risk of renal function decline over 5 years among hypertensive patients was greater in African Americans, and African ancestry was independently associated with a greater rate of GFR decline in the MDRD study. Interestingly, data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort Study have shown a lower prevalence of estimated GFR (50 to 59 mL/min/1.73 m ² ) among African American versus white subjects but a higher prevalence of estimated GFR (10 to 19 mL/min/1.73 m ² ), suggesting that African American ethnicity acts as a progression factor but not as a susceptibility factor. A 2012 report from the USRDS showed a substantially higher incidence of ESKD in African Americans (3.3 times higher than whites), Hispanics (1.5 times higher than non-Hispanics), and Native Americans (1.5 times higher than whites). Similarly, the prevalence of ESKD in 2012 was higher among minority groups: African Americans, 5671 pmp; Native Americans, 2600 pmp; Hispanics, 2932 pmp; Asians, 2272 pmp; and whites, 1432 pmp. CKD and ESKD have also been reported to be more prevalent in other ethnic groups, including Asians, Hispanics Native Americans, Mexican Americans, and Aboriginal Australians.

A large meta-analysis that included data from 940,366 participants in 25 general population cohort studies investigated the impact of ethnicity on the risks associated with CKD in blacks, whites, and Asians. The absolute risk of all-cause or cardiovascular mortality (after adjustment for age) and ESKD was higher in black versus white versus Asian participants. However, the relative risk of all-cause or cardiovascular mortality and ESKD increased to a similar degree with lower GFR or greater albuminuria in all the ethnic groups. Thus, the risk between lower GFR or greater albuminuria and mortality or ESKD was not modified by ethnicity. The mechanisms underlying the associations between ethnicity and CKD remain to be elucidated, but possible explanations include genetic factors (see below, “ Hereditary Factors ”), increased prevalence of diabetes mellitus, lower nephron endowment, increased susceptibility to salt-sensitive hypertension, and environmental, lifestyle, and socioeconomic differences. Ethnicity and CKD are discussed further in Chapter 20 , Chapter 21 , Chapter 52 .

Decreased Nephron Number

Acquired Nephron Deficit

In experimental models of acquired nephron deficit, severe nephron loss (5/6 nephrectomy) alone initiates a cycle of progressive injury in the remaining glomeruli, mediated primarily through glomerular hypertension and hyperfiltration. In 14 patients subjected to similarly large reductions in nephron number following partial resection of a single kidney, 2 developed ESKD and 9 developed proteinuria, the extent of which was inversely correlated with the amount of renal tissue remaining. Lesser degrees of acquired nephron loss, such as removal of one of two previously normal kidneys (uninephrectomy), may not be sufficient to cause CKD in most subjects. However, nephrectomy for renal cell carcinoma is associated with an increased risk of developing CKD that is greater after radical nephrectomy than partial nephrectomy, suggesting that in the presence of subclinical kidney damage, acquired nephron loss may provoke CKD, and that the risk is proportional to the number of nephrons removed.

Nephron loss may also predispose individuals to CKD if they are also exposed to other risk factors. This is perhaps best illustrated by the observation that uninephrectomy exacerbates renal injury in experimental diabetic nephropathy and, in diabetics, uninephrectomy increases the risk of developing diabetic nephropathy.

The interaction between nephron loss and other risk factors is further illustrated by the observation that in a study of 488 people who had surgery for renal cell carcinoma, radical nephrectomy (compared to partial nephrectomy), diabetes, and increased age were each independently associated with an increased risk of developing CKD at least 6 months after surgery. In those who had a partial nephrectomy but no additional risk factors, only 7% developed CKD, but this increased to 24%, 30%, and 42% in those 60 years of age or older, those with hypertension, and diabetics, respectively.

In most forms of human CKD, initial nephron loss due to primary renal disease, multisystem disorders that involve the kidney or exposure to nephrotoxins is focal, but hemodynamic adaptations in the remaining glomeruli are thought to contribute to nephron loss by provoking further glomerulosclerosis (see Chapter 52 ). Several epidemiologic studies have supported this hypothesis by showing that patients with a reduced GFR are at increased risk of a further decline in renal function. Two large meta-analyses of cohort studies identified baseline GFR as a strong predictor of ESKD. Among 845,125 participants from the general population, the estimated GFR (eGFR) was independently associated with an increased risk of developing ESKD when it fell below 75 mL/min/1.73 m ² . For groups of patients with average eGFRs of 60, 45, and 15 mL/min/1.73 m ² , the hazard ratios for developing ESKD were 4, 29, and 454, respectively, when compared to a reference group with an eGFR of 95 mL/min/1.73 m ² . Similar findings were reported in a further 173,892 participants selected for being at increased risk of developing CKD ( Figure 22.4 ). Among 21,688 patients selected for having CKD, a lower eGFR was an independent risk factor for ESKD, such that a fall of 15 mL/min/1.73 m ² below a threshold of 45 mL/min/1.73 m ² was associated with a pooled hazard ratio of 6.24. Further analyses by the CKD Prognosis Consortium have confirmed that the association between reduced GFR and increased risk of ESKD persists independently of gender, age, ethnicity, diabetes, and hypertension. Additionally, analysis of data from 1,530,648 participants has shown that change in GFR over time is strongly predictive of future risk of ESKD (and mortality), suggesting that a GFR decline of 30% may be useful as a surrogate marker of CKD progression in clinical trials. Thus, in different contexts, acquired nephron deficit may be regarded as a susceptibility factor (e.g., after donor nephrectomy in a healthy kidney donor), initiation factor (when severe nephron loss provokes glomerulosclerosis in remaining previously normal glomeruli), or progression factor (when nephron loss accelerates pre-existing damage in remaining glomeruli).

Pooled hazard ratios (95% CI) for end-stage kidney disease (ESKD) according to spline estimated glomerular filtration rate (eGFR) (upper panels) and albumin/creatinine ratio (lower panels), adjusted for each other and for age, gender, and cardiovascular risk factors (continuous analyses). Reference categories are eGFR of 95 mL/min/1.73 m ² and albumin/creatinine ratio of 5 mg/g or dipstick-negative or trace. Left panels, Results for general population cohorts. Right panels, High-risk cohorts. Dots represent statistical significance, triangles represent nonsignificance, and shaded areas are 95% confidence interval. ACR, Albumin/creatinine ratio; GP, general population; HR, high risk.

(From Gansevoort RT, Matsushita K, van der Velde M, et al; Chronic Kidney Disease Prognosis Consortium: lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes in both general and high-risk populations. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int 79:1341-1352, 2011.)

The importance of GFR as a risk factor has emphasized the need for more accurate methods to estimate it. Adoption of the MDRD equation improved detection of CKD and made possible much of the epidemiologic research on CKD, but it was recognized from the outset that the MDRD equation was imperfect and, in particular, tended to underestimate true GFR at values above 60 mL/min/1.73 m ² . This is important because this is the threshold below which CKD may be diagnosed without other evidence of kidney damage. Several other equations have been developed to estimate GFR from serum creatinine concentration, culminating in a recommendation by KDIGO that the MDRD equation should be replaced by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, which is more accurate than the MDRD equation and results in less bias, particularly at GFR values above 60 mL/min/1.73 m ² . Further analysis by the CKD Prognosis Consortium found that the eGFR determined by the CKD-EPI equation results in a lower prevalence of CKD stages 3 to 5 (8.7% vs. 6.3%) and affords better risk prediction than the MDRD equation. Among those classified as having an eGFR of 59 to 45 mL/min/1.73 m ² by the MDRD equation, 34.7% were reclassified by the CKD-EPI as having an eGFR of 89 to 60 mL/min/1.73 m ² , and those reclassified had a lower incidence of adverse outcomes versus those not reclassified (e.g., incidence of all-cause mortality 9.9 vs. 34.5/1000 person-years).

The limitations of creatinine as a marker of GFR due to nonrenal factors that affect serum creatinine concentration, including muscle mass and diet, have prompted a search for alternatives. Cystatin C, a peptide produced by all nucleated cells and therefore not affected by muscle mass, has emerged as the most promising alternative. The production of reference material to standardize cystatin C assays has greatly improved the potential for clinical application, and equations have been developed to estimate the GFR from the serum cystatin C concentration or from creatinine and cystatin C levels together. The combined equation and CKD-EPI (creatinine) equation have similar bias, but the combined equation yields better precision and accuracy. Further work by the CKD Prognosis Consortium has reported that when cystatin C is used to estimate GFR, reclassification to a higher GFR category (higher than that assigned by eGFR creatinine) is associated with a lower risk of all-cause mortality, cardiovascular mortality, and ESKD. It should be noted, however, that in this analysis, CKD was defined by a single eGFR value. It therefore remains to be established whether the use of cystatin C will improve risk prediction in those with CKD defined by two eGFR values determined at least 90 days apart, as required by the KDIGO definition.

Blood Pressure

Hypertension is an almost universal consequence of reduced renal function but is also an important factor in the progression of CKD. In the hypothesis of CKD progression presented in Figure 22.1 , it is clear that elevated systemic blood pressure transmitted to the glomerulus would contribute to glomerular hypertension and thus accelerate glomerular damage. Hypertension has been shown to be predictive of ESKD risk in several large population-based studies. Furthermore, a close association between the magnitude of increased risk and level of blood pressure has been reported in several studies, so that even elevations in blood pressure below the threshold for the diagnosis of hypertension were associated with increased risk of ESKD.

Among patients with CKD in the MDRD study, higher baseline mean arterial pressure (MAP) independently predicted a greater rate of GFR decline. These observations have led to the suggestion that blood pressure be viewed as a continuous rather than dichotomous risk factor for CKD, with less emphasis on traditional definitions of hypertension and normotension. Despite these close associations, the causality criterion for a risk factor requires evidence from an RCT. Three large RCTs have sought to investigate the effect on CKD progression of intensive versus standard blood pressure lowering. Whereas the primary analysis of data from the MDRD study found no significant difference between the rate of decline in GFR between patients randomized to intensive blood pressure control (target MAP < 92 mm Hg, equivalent to <125/75 mm Hg) versus standard blood pressure control (target MAP < 107 mm Hg, equivalent to 140/90 mm Hg), a secondary analysis did show benefit associated with the low blood pressure target in patients with higher levels of baseline proteinuria. Further secondary analysis showed that the lower achieved blood pressure was also associated with a slower GFR decline, an effect that was more marked in patients with higher baseline proteinuria. Furthermore, long-term follow-up (mean, 6.6 years) of patients from the MDRD study reported a significant reduction in the risk of ESKD (adjusted HR, 0.68; 95% CI, 0.57 to 0.82) or a combined end point of ESKD or death (adjusted HR 0.77; 95% CI, 0.65 to 0.91) in patients randomized to low blood pressure targets, even though treatment and blood pressure data were not available beyond the 2.2 years of the original trial.

In the African American Study of Kidney Disease and Hypertension (AASK), no significant difference in the rate of GFR decline was observed between subjects randomized to MAP goals of ≤92 mm Hg or lower versus 102 to 107 mm Hg. It should be noted, however, that patients in AASK generally had low levels of baseline proteinuria (mean urine protein, 0.38 to 0.63 g/day) . Furthermore, prolonged follow-up of the AASK cohort after completion of the randomized trial found no significant differences in the primary outcome for the whole cohort; however, it did show a significantly reduced risk of creatinine doubling, ESKD, or death in subjects with a baseline urine protein/creatinine ratio more than 0.22 g/g who were initially randomized to intensive blood pressure control. Thus, the MDRD and AASK study results suggest a significant interaction between blood pressure and proteinuria as risk factors for CKD progression.

In a third study, additional blood pressure reduction with a calcium channel blocker in patients with nondiabetic CKD on ACE inhibitor (ACEI) treatment failed to produce additional renoprotection, but the degree of additional blood pressure reduction was modest (4.1/2.8 mm Hg) and may have been insufficient to improve outcomes in patients already receiving optimal ACEI therapy. A recent RCT has reported significant benefit associated with a lower blood pressure target in young people with autosomal dominant polycystic kidney disease (age < 50 years) and GFR higher than 60 mL/min/1.73 m ² . Participants randomized to a low blood pressure target (110/75 to 95/60 mm Hg) evidenced a slower rate of increase in kidney volume and a greater decrease in albuminuria and left ventricular mass index than those randomized to usual blood pressure control (120/70 to 130/80 mm Hg). Interestingly blood pressure was not an independent predictor of ESKD in diabetic patients in the RENAAL study or in predominantly nondiabetic subjects in the Chronic Renal Insufficiency in Birmingham (CRIB) study. This is likely due to the fact that blood pressure was well controlled in all subjects (in the RENAAL study) and illustrates how risk factors may vary in importance, depending on the population studied.

Taken together, there is convincing evidence that elevated blood pressure is an important risk factor for progression of CKD, although unequivocal evidence from RCTs is lacking, and some uncertainty remains regarding optimal treatment targets. It is hoped that the ongoing Systolic Blood Pressure Intervention Trial (SPRINT; NCT01206062 at www.clinicaltrials.gov ), which randomized more than 9000 subjects, including about one third with nondiabetic CKD, to systolic blood pressure targets of less than 120 or 140 mm Hg, will yield new data to guide future recommendations.

Obesity and Metabolic Syndrome

In experimental models, obesity is associated with hypertension, proteinuria, and progressive renal disease. Micropuncture studies have confirmed that obesity is another cause of glomerular hyperfiltration and glomerular hypertension that can be predicted to exacerbate the progression of CKD. Furthermore, several other factors associated with obesity and the metabolic syndrome may contribute to renal damage, including hormones and proinflammatory molecules produced by adipocytes, increased mineralocorticoid levels and/or mineralocorticoid receptor activation by cortisol, and reduced adiponectin levels. In humans, severe obesity is associated with increased renal plasma flow, glomerular hyperfiltration, and albuminuria, abnormalities that are reversed by weight loss. Obesity, as defined by increased body mass index (BMI), has been associated with increased risk of developing CKD in several large population-based studies. Furthermore, one study has found a progressive increase in relative risk of developing ESKD associated with increasing BMI (RR, 3.57; 95% CI, 3.05 to 4.18 for BMI of 30.0 to 34.9 kg/m ² vs. BMI of 18.5 to 24.9 kg/m ² ) among 320,252 subjects confirmed to have no evidence of CKD at initial screening.

There is evidence that obesity may directly cause a specific form of glomerulopathy characterized by proteinuria and histologic features of focal and segmental glomerulosclerosis, but it is likely that it also acts as a risk factor in the development of several other forms of renal disease. One study has identified childhood obesity as a risk factor for CKD in adulthood. Among 4340 participants born in one week in 1946, pubertal-onset obesity and obesity throughout childhood were associated with an increased risk of CKD (defined by eGFR < 60 mL/min/1.73 m ² or albuminuria) at age 60 to 64 years. Interest has also focused on the role of the metabolic syndrome (insulin resistance), as defined by the presence of abdominal obesity, dyslipidemia, hypertension, and fasting hyperglycemia, in the development of CKD. An analysis of data from the Third National Health and Nutrition Examination Survey (NHANES III) data found a significantly increased risk of CKD and microalbuminuria in subjects with the metabolic syndrome as well as a progressive increase in risk associated with the number of components of the metabolic syndrome present. Furthermore, a large longitudinal study of 10,096 patients without diabetes or CKD at baseline identified metabolic syndrome as an independent risk factor for the development of CKD over 9 years (adjusted OR, 1.43; 95% CI, 1.18 to 1.73). Again, there was a progressive increase in risk associated with the number of traits of the metabolic syndrome present (OR, 1.13; 95% CI, 0.89 to 1.45 for one trait vs. OR, 2.45; 95% CI, 1.32 to 4.54 for five traits). In another study, patient hip/waist ratio, a marker of insulin resistance, was independently associated with impaired renal function, even in lean individuals (BMI < 25 kg/m ² ), among a population-based cohort of 7676 subjects.

The effect of obesity on the progression of established CKD is less well documented. Increased BMI has been identified as a risk factor for CKD progression among subjects with immunoglobulin A (IgA) nephropathy, renal mass reduction surgery or renal agenesis, and renal transplants. On the other hand, BMI was unrelated to the risk of ESKD among a cohort of patients with CKD stage 4 or 5. It is widely recognized that weight loss is difficult to achieve in obese individuals, but surgical intervention in the form of gastric banding or bypass appears to offer the most effective long-term outcomes. Two large cohort studies have shown significant survival benefit in subjects who underwent bariatric surgery, but unfortunately renal end points were not reported in these studies. Beneficial renoprotective effects of weight loss have been reported in a meta-analysis of observational studies that found an association between weight loss and reduction in proteinuria independent of blood pressure, as well as smaller studies that reported improvement or stabilization of renal function or reduction in proteinuria following bariatric surgery in subjects with CKD.

The best method for assessing obesity in CKD remains to be determined. A further systematic review analyzed the effects of weight loss achieved by bariatric surgery, medication, or diet in 31 studies and found that in most studies, weight loss was associated with reductions in proteinuria. In people with glomerular hyperfiltration, the GFR tended to decrease with weight loss, and in those with a reduced GFR, it tended to increase. BMI is the most widely applied method but does not take body composition into account. One study has reported a high sensitivity but relatively low specificity of BMI to detect obesity in subjects with CKD.

High Dietary Protein Intake

Protein feeding provokes an increase in GFR in rodents and humans. Consistent with the hypothesis that the glomerular hemodynamic changes associated with hyperfiltration accelerate glomerular injury, experimental studies have reported that a high-protein diet accelerates renal disease progression, whereas dietary protein restriction results in normalization of glomerular capillary hydraulic pressure as well as SNGFR and marked attenuation of glomerular damage. Observational studies in humans have reported an increased risk of microalbuminuria associated with higher dietary protein intake in subjects with diabetes and hypertension (OR, 3.3; 95% CI, 1.4 to 7.8) but not in healthy subjects or those with isolated diabetes or hypertension, again illustrating the interaction between risk factors for CKD. In another study, high intake of protein, particularly nondairy animal protein, was associated with a greater rate of GFR decline among women with an eGFR of 80 to 55 mL/min/1.73 m ² but not in those with an eGFR of more than 80 mL/min/1.73 m ² . Randomized trials investigating the effects of high protein are lacking, but several studies have sought to examine the potential renoprotective effects of dietary protein restriction. In the MDRD study, primary analysis revealed no significant difference in the mean rate of GFR decline in subjects randomized to low- or very low-protein diets, but secondary analysis of outcomes according to achieved dietary protein intake indicated that a reduction in protein intake of 0.2 g/kg/day correlated with a 1.15-mL/min/year reduction in the rate of GFR decline, equivalent to a 29% reduction in the mean rate of GFR decline. On the other hand, long-term follow-up of participants in study 2 of the MDRD trial found no renoprotective benefit among those randomized to very low-protein diet in the original study, but did report a higher risk of death in this group (HR, 1.92; 95% CI 1.15 to 3.20). Nevertheless, three meta-analyses of smaller studies have all reported a significant renoprotective benefit associated with dietary protein restriction. The role of dietary protein restriction in the management of CKD is discussed further in Chapters 52 and 61 .

Pregnancy and Preeclampsia

Physiologic adaptations during pregnancy provoke glomerular hyperfiltration that usually does not cause renal damage. In the context of preexisting CKD, however, the glomerular hyperfiltration of pregnancy can be predicted to exacerbate proteinuria and glomerular injury. Several studies have shown an increased risk of CKD progression during pregnancy, particularly when the pregestational serum creatinine is 1.4 mg/dL or higher (≥124 µmol/L). In one study of 82 pregnancies in 67 women with primary renal disease and serum creatinine level of 1.4 mg/dL or more, blood pressure, serum creatinine, and proteinuria increased during pregnancy. In 70 pregnancies with postpartum data available, persistent loss of maternal renal function at 6 months was reported in 31%, and by 12 months 8 women had progressed to ESKD. Adverse obstetric outcomes included preterm delivery in 59% and low birth weight in 37%, although fetal survival was 93%.

In a more recent series of 49 women with CKD stage 3 to 5 before pregnancy, the mean GFR declined during pregnancy (from 35 ± 12.2 to 30 ± 13.8 mL/min/1.73 m ² ), but there was no change in the mean postpartum rate of GFR decline. Nevertheless, a pregestational GFR less than 40 mL/min/1.73 m ² , combined with proteinuria of more than 1 g/day, was associated with a more rapid postpartum GFR decline and a shorter time to ESKD or halving of GFR and low birth weight. Although earlier reports suggested good outcomes, one recent study has reported adverse effects associated even with early-stage CKD. In 91 pregnancies with predominantly CKD stages 1 and 2, modest increases in hypertension, serum creatinine, and proteinuria were observed. An increase in adverse obstetric outcomes, including preterm delivery, lower birth weight, and admission to a neonatal intensive care unit versus low-risk pregnancy controls was also reported; this remained true, even when only those with CKD stage 1 were considered, although there were no perinatal deaths. On the other hand, pregnancy was not associated with a more rapid decline in the GFR over 5 years in a cohort of 245 women of childbearing age with IgA nephropathy and serum creatinine level of 1.2 mg/dL or lower (in the majority).

Complications of pregnancy and, in particular, hypertension and preeclampsia, may also cause renal damage. In one large population-based study, renal outcomes were assessed in 570,433 women who had had at least one singleton pregnancy. Only 477 women developed ESKD at a mean of 17 ± 9 years after the first pregnancy (overall rate, 3.7/100,000/women/year), but preeclampsia was associated with a significant increase in the risk of ESKD, ranging from a relative risk of 4.7 for preeclampsia in a single pregnancy (95% CI, 3.6 to 6.1) to a relative risk of 15.5 for preeclampsia in two or three pregnancies (95% CI, 7.8 to 30.8). The risk was further increased if the pregnancy resulted in a low-birth weight or preterm infant. Causes of ESKD were glomerulonephritis in 35%, hereditary or congenital disease in 21%, diabetic nephropathy in 14%, and interstitial nephritis in 12%. Similarly, in women with diabetes prior to pregnancy, preeclampsia and preterm birth were associated with significantly increased risks of ESKD and death, illustrating how different risk factors for CKD may interact to increase risk.

A large cohort study reported an increased risk of multiple adverse health outcomes after hypertension during pregnancy, including cardiovascular disease, diabetes mellitus, and CKD (HR, 1.91; 95% CI, 1.18 to 3.09). Similarly, a very large case-control study found that hypertension during pregnancy was associated with a substantially increased risk of subsequent CKD (HR, 9.38; 95% CI, 7.09 to 12.4) or ESKD (HR, 12.4; 95% CI, 8.53 to 18.0). In both these studies, the risks of CKD were substantially higher if preeclampsia developed during the pregnancy. Possible explanations for these observations include the presence of pathogenic factors common to CKD and preeclampsia, including obesity, hypertension, insulin resistance, and endothelial dysfunction, exacerbation by preeclampsia of preexisting subclinical CKD, and effects of preeclampsia on the kidney that increase the risk of CKD later in life. That preeclampsia may provoke renal damage has been suggested by several studies showing an increased incidence of microalbuminuria after preeclampsia. A meta-analysis of seven of these studies reported a 31% prevalence of microalbuminuria at a weighted mean of 7.1 years after preeclampsia versus 7% in a control group with uncomplicated pregnancies. Further research is required to identify which mechanisms are most relevant but, even without further information, preeclampsia should be regarded as a risk factor for the development and progression of CKD.

Diabetes Mellitus

Diabetic nephropathy has rapidly become the single most common cause of ESKD worldwide. Diabetes was associated with a substantially increased risk of ESKD or death associated with CKD in one population-based study of 23,534 subjects (HR, 7.5; 95% CI, 4.8 to 11.7), as well as an increased risk of moderate CKD (estimated creatinine clearance < 50 mL/min) in another study of 1428 subjects with an estimated creatinine clearance of more than 70 mL/min at baseline. Evidence that glycemic control is a key risk factor for the development of diabetic nephropathy has been shown in randomized trials that found a reduced risk of developing nephropathy in subjects with type 1 and type 2 diabetes randomized to tight glycemic control. The pathogenesis of diabetic nephropathy is complex and involves multiple mechanisms, including glomerular hemodynamic factors, advanced glycation end product formation, generation of reactive oxygen species, and upregulation of profibrotic growth factors and cytokines. In at least one study, diabetic nephropathy was associated with more rapid progression to ESKD than other causes of CKD. Thus, diabetes may be regarded as a susceptibility, initiation, and progression risk factor for CKD. For further discussion of the pathogenesis of diabetic nephropathy, see Chapter 39 .

Urinary Protein Excretion

Abnormal excretion of protein in the urine indicates dysfunction of the glomerular filtration barrier and is therefore a marker of glomerulopathy and an index of disease severity. Experimental evidence has suggested that proteinuria may also contribute to progressive renal damage in CKD (see Chapter 53 ). A large body of evidence attests to a strong association between proteinuria and the risk of CKD progression, as well as cardiovascular and all-cause mortality. Mass screening of a general population of 107,192 participants by dipstick urinalysis identified proteinuria as the most powerful predictor of ESKD risk over 10 years (OR, 14.9; 95% CI, 10.9 to 20.2). Similarly, among 12,866 middle-aged men enrolled in the multiple risk factor intervention trial (MRFIT), proteinuria detected by dipstick test was associated with a significantly increased risk of developing ESKD over 25 years (HR for 1+ proteinuria, 3.1; 95% CI, 1.8 to 3.8; HR for ≥2+ proteinuria, 15.7; 95% CI, 10.3 to 23.9). Furthermore, detection of 2+ proteinuria or more increased the hazard ratio for ESKD associated with an eGFR less than 60 mL/min/1.73 m ² from 2.4 without proteinuria (95% CI, 1.5 to 3.8) to 41 with proteinuria (95% CI 15.2 to 71.1).

Similar associations have been reported for measurements of urinary albumin in the general population. In the Nord-Trøndelag Health (HUNT 2) study, which included 65,589 adults, micro- and macroalbuminuria were independent predictors of ESKD after 10.3 years (HR, 13.0 and 47.2, respectively) and combining reduced eGFR with albuminuria substantially improved the prediction of ESKD. In the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, albuminuria was an independent predictor of a decline in eGFR to less than 60 mL/min/1.73 m ² .

Among patients selected for having CKD from a wide variety of causes, baseline proteinuria has consistently predicted renal outcomes. In three large prospective studies that included patients with nondiabetic CKD (MDRD study, Ramipril Efficacy In Nephropathy [REIN] study, and AASK), higher baseline proteinuria was strongly associated with a more rapid decline in GFR. Similarly, among patients with diabetic nephropathy, the baseline urinary albumin/creatinine ratio was a strong independent predictor of ESKD in the RENAAL study and Irbesartan in Diabetic Nephropathy Trial (IDNT). The findings of these individual studies have been confirmed by two large meta-analyses. In one analysis, which included nine general population cohorts ( N = 845,125) and eight cohorts with increased risk of developing CKD ( N = 173,892), urine albumin/creatinine ratios of more than 30, 300, and 1000 mg/g were independently associated with progressive increases in the risk of ESKD, progressive CKD, and AKI, respectively (see Figure 22.4 ). Among 21,688 patients known to have CKD from 13 studies, an eightfold higher urine albumin/creatinine or protein/creatinine ratio was associated with increased all-cause mortality (pooled HR, 1.40) and risk of ESKD (pooled HR, 3.04). Further meta-analyses by the CKD Prognosis Consortium have shown that the magnitude of proteinuria remains a risk factor for ESKD independent of gender, ethnicity, age, diabetes, or hypertension.

Secondary analyses of prospective RCTs have found that the extent of residual proteinuria that persists, despite optimal treatment with an ACEI or angiotensin receptor blocker (ARB), also predicts renal prognosis. In the REIN study, percentage reduction in proteinuria over the first 3 months and the absolute level of proteinuria at 3 months were strong independent predictors of the subsequent rate of decline in GFR. In the IDNT, a greater reduction in proteinuria at 12 months was associated with a greater reduction in the risk of ESKD (HR, 0.44; 95% CI, 0.40 to 0.49 for each halving of baseline proteinuria). In the AASK study, a change in proteinuria from baseline to 6 months predicted subsequent progression. Similarly, a meta-analysis of data from 1860 patients with nondiabetic CKD showed that during antihypertensive treatment, the current level of proteinuria was a powerful predictor of the combined end point of doubling of the baseline serum creatinine level or onset of ESKD (relative risk [RR], 5.56; 95% CI, 3.87 to 7.98 for each 1.0-g/day increase in proteinuria). Furthermore, a meta-analysis of 21 randomized trials of drug treatment in CKD, which included 78,342 participants, found that for each 30% initial reduction in albuminuria on treatment, the risk of ESKD decreased by 23.7% (95% CI, 11.4% to 34.2%) independent of the class of drug used for treatment. These data support the proposal that proteinuria, like blood pressure, should be regarded as a continuous risk factor for CKD progression. Proteinuria thus appears to be a powerful predictor of renal risk in the general population, in patients with CKD prior to treatment, and in CKD patients on treatment. Recognition of the importance of proteinuria as a risk factor in CKD prompted the addition of an albuminuria category (A1 to A3) to the CKD classification proposed by KDIGO.

These important observations raise the question of how best to measure proteinuria. As discussed, all measurements of proteinuria have been reported to predict renal outcomes, including dipstick urinalysis, urine albumin/creatinine ratio or protein/creatinine ratio (ACR and PCR) and 24-hour urinary albumin or protein excretion. A secondary analysis of data from the RENAAL trial found that urine ACR measured on the first morning void was better than 24-hour urinary protein or albumin concentration as a predictor of time to doubling of the serum creatinine level or ESKD among patients with diabetes and CKD. On the other hand, retrospective analysis of data from 5586 patients with CKD reported similar HRs associated with urinary ACR and PCR for the outcomes of all-cause mortality, start of renal replacement therapy, or doubling of serum creatinine. Further analysis of these data identified a cohort of patients with a normal urine ACR but elevated urine PCR in whom the risk of ESKD or death was intermediate between the groups with both urine ACR and PCR abnormal or normal. Analysis of data from the CRIC study also reported that urine ACR and PCR had similar associations with complications of CKD. Together, these data imply that any measure of proteinuria is better than no measurement. If the goal is to detect and monitor low levels of albuminuria (category A1 and A2), the urine ACR measured on the first morning void is best. For patients with CKD, urine ACR or PCR may be used, and there is some evidence that there may be added information gained by requesting both.

Serum Albumin

Serum albumin levels are widely regarded as a marker of nutritional status but may also be reduced due to proteinuria or inflammation. Several studies have identified lower serum albumin levels as a risk factor for CKD progression. In the MDRD study, higher baseline serum albumin was associated with slower subsequent rate of GFR decline but, in a multivariable analysis, this was displaced by a similar correlation with baseline serum transferrin levels, another marker of protein nutrition. Three studies have found associations between serum albumin and renal outcomes in patients with type 2 diabetes and CKD. Among 182 patients with a mean serum creatinine of 1.5 mg/dL at baseline, hypoalbuminemia was an independent risk factor for ESKD. In a long-term follow-up of 343 patients, lower baseline serum albumin was an independent predictor of CKD progression and, in the RENAAL study, lower serum albumin was an independent predictor of ESKD. Similar observations have been reported in other forms of CKD. In a large cohort of patients with IgA nephropathy ( N = 2269), lower serum total protein (composed largely of albumin) was an independent risk factor for ESKD. In a cohort of 3449 patients with CKD referred to a nephrology service, lower serum albumin was an independent risk factor for ESKD. In these studies, the predictive value of serum albumin was independent of and additional to that of proteinuria, indicating that it was not merely acting as a marker of albuminuria.

Anemia

Chronic anemia due to inherited hemoglobinopathy is associated with increased renal plasma flow, glomerular hyperfiltration, and subsequent development of proteinuria, hypertension, and ESKD. Anemia is a common complication of CKD from any cause, and several studies have shown that it is also an independent predictor of CKD progression. In the RENAAL study, baseline hemoglobin was a significant independent predictor of ESKD among diabetic patients—each 1-g/dL decrease in hemoglobin was associated with an 11% increase in the risk of ESKD. Baseline hemoglobin was also one of four variables included in the renal risk score developed from the RENAAL data. Similarly, a higher hemoglobin level was independently associated with lower risk of progression to ESKD (halving of GFR or need for dialysis) or death among 131 patients with all forms of CKD (HR, 0.778; 95% CI, 0.639 to 0.948 for each 1-g/dL increase). Furthermore, time-averaged hemoglobin of less than 12 g/dL was associated with a significantly increased risk of ESKD among 853 male veterans with CKD stages 3 to 5 (HR, 0.74; 95% CI, 0.65 to 0.84 for each 1-g/dL increase in hemoglobin).

Two other cohort studies have identified lower hemoglobin as an independent risk factor for a more rapid decline in GFR in patients with CKD stage 4 and ESKD in patients with CKD stage 3 or 4. Consistent with the hypothesis that anemia contributes directly to CKD progression, two small randomized studies have reported a renoprotective benefit associated with erythropoietin therapy. Among patients with serum creatinine of 2 to 4 mg/dL and hematocrit less than 30%, erythropoietin treatment was associated with significantly improved renal survival. In nondiabetic patients with serum creatinine of 2 to 6 mg/dL, early treatment (started when hemoglobin < 11.6 g/dL) with erythropoietin alpha was associated with a 60% reduction in the risk of doubling the serum creatinine level, ESKD, or death versus delayed treatment (started when hemoglobin < 9.0 g/dL).

On the other hand, two other studies that had left ventricular mass as their primary end point and the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) found no effect of a high versus low hemoglobin target on the rate of decline in the GFR. Several studies have, however, reported adverse outcomes associated with normalization of hemoglobin in patients with CKD. In the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) study, randomization to a higher hemoglobin target (13 to 15 mg/dL) was associated with a shorter time to initiation of dialysis than a lower target (10.5 to 11.5 mg/dL). In TREAT, randomization to a higher hemoglobin target was associated with an increased risk of stroke and, in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study, a higher hemoglobin target was associated with an increased incidence of the combined end point of all-cause mortality, myocardial infarction, or hospitalization for congestive cardiac failure.

Dyslipidemia

Lipid abnormalities are common in patients with CKD, and several studies have identified dyslipidemia as a susceptibility and progression factor for CKD. In population-based studies, several lipid profile abnormalities have been associated with an increased risk of developing CKD, including an elevated low-density lipoprotein (LDL) to high-density lipoprotein (HDL) cholesterol ratio, higher triglyceride and lower HDL cholesterol levels, lower HDL cholesterol levels and elevated total cholesterol, low HDL cholesterol, and elevated total to HDL cholesterol. Several observational studies have reported dyslipidemia as a risk factor for CKD progression. In the MDRD study, lower HDL cholesterol levels independently predicted a more rapid decline in GFR ; in a smaller study of patients with CKD, total cholesterol, LDL cholesterol, and apolipoprotein B levels were all associated with a more rapid decline in the GFR. Among 223 patients with IgA nephropathy, hypertriglyceridemia was independently predictive of CKD progression. Hypercholesterolemia was reported to predict loss of renal function in patients with type 1 or 2 diabetes and, among nondiabetic patients, CKD advanced more rapidly in those with hypercholesterolemia and hypertriglyceridemia.

RCTs of lipid lowering have produced mixed results with respect to renal outcomes. Subgroup analysis of a prospective randomized trial of pravastatin treatment in patients with previous myocardial infarction found that pravastatin slowed the rate of decline in patients with an eGFR less than 40 mL/min/1.73 m ² , an effect that was also more pronounced in those with proteinuria. Similarly, in the Heart Protection Study, patients with previous cardiovascular disease or diabetes randomized to simvastatin treatment had a smaller increase in serum creatinine than those who received placebo. In a placebo-controlled, open-label study, atorvastatin treatment in patients with CKD, proteinuria, and hypercholesterolemia was associated with preservation of creatinine clearance, whereas it declined in those receiving placebo. On the other hand, lipid lowering with fibrates was not associated with renoprotection in two studies, although one study did show a reduced incidence of microalbuminuria in patients with type 2 diabetes receiving fenofibrate.

One meta-analysis of 13 small controlled trials found that lipid-lowering therapy was associated with a significantly slower rate of GFR decline (0.156 mL/min/month; 95% CI, 0.026 to 0.285; P = 0.008) among patients with CKD. On the other hand, several other studies found no association between dyslipidemia and risk of CKD progression. Analysis of data from a relatively small subgroup of studies with renal end points recorded in a meta-analysis found that statin therapy was associated with a reduction in proteinuria but with no improvement in creatinine clearance in participants with CKD. Furthermore, analysis of data from 3939 participants in the CRIC study found no association between total or LDL cholesterol and the risk of ESKD or 50% reduction in eGFR. Indeed, among participants with proteinuria of less than 0.2 g/day, higher LDL and total cholesterol were associated with a lower risk of reaching this end point. The Study of Heart and Renal Protection (SHARP) is the largest RCT to investigate the cardiovascular and renoprotective effects of lipid lowering in CKD. Patients with CKD or undergoing dialysis were randomized to treatment with simvastatin and ezetimibe or placebo. In 6245 participants with CKD not requiring dialysis, treatment resulted in an average reduction in LDL cholesterol of 0.96 mmol/L but was not associated with a reduction in the primary outcome of ESKD or secondary outcome of ESKD or creatinine doubling. Similarly, a meta-analysis of 38 studies, which included 37,274 participants with CKD, found that statin therapy was associated with a reduction in mortality and cardiovascular events but no clear effect on CKD progression. Together, evidence that dyslipidemia is a risk factor for CKD progression remains mixed, with the most recent studies indicating no association. Mechanisms whereby dyslipidemia may contribute to CKD progression are discussed in Chapter 52 .

Serum Uric Acid

Hyperuricemia is a common consequence of chronic renal failure and may also contribute to CKD progression. Several cohort studies have investigated uric acid as a risk factor in CKD and were summarized in a recent review. Most but not all population-based studies have identified hyperuricemia as an independent risk factor for the development of incident CKD. Similarly, most cohort studies that included people with CKD have identified a higher serum uric acid level as a risk factor for CKD progression. Possible mechanisms whereby hyperuricemia may contribute to CKD progression are exacerbation of glomerular hypertension, endothelial dysfunction, and proinflammatory effects. On the other hand, it is possible that an elevated uric acid concentration is acting as a marker of reduced kidney function or oxidative stress—uric acid is produced by xanthine oxidase, which also generates reactive oxygen species.

To date, only small studies investigating the effect of uric acid–lowering therapy on CKD progression have been published. A meta-analysis of eight trials found no difference in the eGFR among participants treated with allopurinol versus those with no treatment or placebo in five trials, whereas three trials that reported only serum creatinine reported benefit in favor of allopurinol. In five trials that measured proteinuria, no benefit was observed. Together, published evidence suggests that an elevated serum uric acid level may act as a susceptibility and progression risk factor in CKD, but large randomized trials are still required to determine whether treatment of hyperuricemia is beneficial for slowing CKD progression.

Serum Bicarbonate

Studies in animal models have shown that acidosis may promote the progression of CKD through several mechanisms, including activation of the alternative complement pathway by elevated cortical ammonia levels, increased production of endothelin and aldosterone, and calcium deposition. At least five studies have investigated serum bicarbonate as a risk factor in human CKD. In all except the MDRD study, lower serum bicarbonate levels, even within the normal range, were independently associated with an increased risk of CKD progression. Two small randomized trials have reported slowing of CKD progression with bicarbonate supplementation, and another trial found that correction of acidosis with oral sodium bicarbonate or a diet rich in fruits and vegetables was associated with a lower rate of GFR decline. Bicarbonate supplementation is already recommended for patients with levels below 22 mEq/L, but several studies are underway to investigate further whether it is beneficial in the setting of less severe acidosis.

Plasma Asymmetric Dimethylarginine

Asymmetric dimethylarginine (ADMA) is formed by the breakdown of arginine methylated proteins and acts as an endogenous inhibitor of nitric oxide synthase to reduce nitric oxide production. The increased ADMA levels observed with a reduced GFR have been proposed as one mechanism for the endothelial dysfunction associated with CKD. Elevated ADMA levels are associated with CVD and cardiovascular mortality in patients with CKD. In animal models, administration of ADMA was associated with the development of hypertension, increased deposition of collagen I and III and fibronectin in glomeruli and blood vessels, and rarefaction of peritubular capillaries. Conversely, the overexpression of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme responsible for degradation of ADMA, was associated with reduced ADMA levels and amelioration of renal injury in rats after 5/6 nephrectomy, implying that ADMA may also promote CKD progression.

Several relatively small studies have identified increased ADMA levels as a risk factor for CKD progression. Among 131 patients with CKD, a higher plasma ADMA level was an independent risk factor for ESKD or death (HR, 1.20; 95% CI, 1.07 to 1.35 for each 0.1-µmol/L increase). In 227 relatively young patients with mild-to-moderate nondiabetic CKD, higher ADMA levels predicted progression to the combined end point of creatinine doubling or ESKD (HR, 1.47; 95% CI, 1.12 to 1.93 for each 0.1-µmol/L increase). Finally, retrospective analysis of data from 109 patients with IgA nephropathy showed associations between ADMA levels and glomerular and tubulointerstitial injury. Furthermore, the plasma ADMA level was an independent determinant of annual GFR reduction rate.

Serum Phosphate

When rats were fed a high-phosphate diet after uninephrectomy, renal calcium and phosphate deposition, as well as tubulointerstitial injury, were observed within 5 weeks. Furthermore, in animals and humans with CKD, dietary phosphate restriction or treatment with oral phosphate binders was associated with reductions in proteinuria and glomerulosclerosis and attenuation of CKD progression. Together, these data suggest that phosphate loading and/or hyperphosphatemia exacerbate renal injury in CKD. In addition, higher levels of the phosphatonin fibroblast growth factor 23 (FGF23) have been identified as an independent predictor of CKD progression. Three cohort studies of patients with CKD have identified higher serum phosphate levels as an independent risk factor for progression. On the other hand, the largest study to date, which included 10,672 participants with CKD, found no independent association between higher serum phosphate and risk of progression. It should be noted, however, that the number of ESKD events was low, and the study therefore had limited power to detect a moderate association between serum phosphate levels and CKD progression.

Other Biomarkers

A number of other biomarkers are currently being investigated as risk factors in CKD. Although many have been reported to be associated with adverse outcomes, the challenge is to identify biomarkers that add to the predictive power of established risk factors. For a comprehensive discussion of novel biomarkers, see Chapter 30 .