The prevalence of CKD increases with age and is reported to be as high as 56% in those 75 years or older. Longitudinal studies of subjects without kidney disease have observed a decline in GFR with advancing age in some individuals, implying that nephron loss may be regarded as part of normal aging. Additionally, aging is associated with an increase in several other risk factors for CKD including hypertension, obesity, and CVD, 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 older age. Similarly, the incidence of a decline in kidney function over 5 years was greater among older compared with younger patients with hypertension. One study reported that older age is associated with a lower risk of treated kidney failure among patients with CKD, even if they have accelerated decline in eGFR. 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 ( Fig. 19.2 ). By contrast, it has been reported in another study that a more rapid decrease of eGFR was associated with CKD in persons of a younger age, which in turn is associated with an increase in the 1-year mortality rate.

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 . 2007;18:2758–2765.

A large individual-level meta-analysis that included data from 2,051,244 participants in 46 cohort studies has provided robust data regarding the role of age on risks related to CKD. In the general population and high cardiovascular risk cohorts, the increase in relative risk of mortality associated with lower GFR was more pronounced in younger persons, but the increase in absolute risk of death was more pronounced in older persons. Similar trends were observed for the mortality risks associated with albuminuria. By contrast, using data from CKD cohorts, the relative increase in risks of mortality and ESKD associated with eGFR and albuminuria were similar among older and younger patients.

Thus older age is a susceptibility factor for CKD, and the associated increase in risk of death and ESKD with the presence of CKD 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 Chapter 21 , Chapter 60 .

Data regarding the role of sex on the risk of CKD and progression are somewhat contradictory. Studies have reported a higher incidence of proteinuria and CKD among males in the general population and an increased risk of ESKD or death in males with CKD, ^{, ,} a higher risk of decline in kidney function in males with hypertension, a lower risk of ESKD in females with CKD stage 3, and a shorter time to renal replacement therapy (RRT) in males with CKD stage 4 or 5. In addition, most national registries including the U.S. Renal Data Service have reported a substantially higher incidence of ESKD in males (413 per million population [pmp] in 2003) compared with females (280 pmp). Previous meta-analyses have yielded conflicting results, with one reporting an accelerated rate of decline in GFR in males and another reporting a higher risk of doubling of serum creatinine or ESKD in females 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 role of sex on CKD-related outcomes. Whereas the risks of all-cause and cardiovascular mortality were significantly higher in males than females and the relative risk of mortality was higher with lower eGFR and higher albuminuria in both sexes, the gradient was steeper in females than males. The relative risk of ESKD was higher with lower eGFR and higher albuminuria in both sexes, and there was no evidence of a difference in the increase in risk between males and females ( Fig. 19.3 ). One limitation of many of the studies quoted is that the menopausal status of the females 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 females as in males. The reasons for the higher absolute incidence of RRT in males versus females require further investigation and may be related to treatment preferences for RRT rather than biological differences in disease progression. For further discussion of the role of sex on CKD, see Chapter 22.

( A and B) Hazard ratios of end-stage kidney disease according to estimated glomerular filtration rate (eGFR).

(C and D) Urinary albumin-to-creatinine ratio (ACR) in men versus women in chronic kidney disease cohorts. (A and C) Gender-specific hazard ratios including a main effect for male gender at the reference point. (B and 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. CI, Confidence interval.

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. 2013;346:f324.

African Americans are overrepresented in the U.S. dialysis population, suggesting that race may be 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 kidney function decline (increase in serum creatinine ≥0.4 mg/dL) was approximately threefold higher (odds ratio [OR], 3.15; 95% CI, 1.86 to 5.33) among Black versus White adults with diabetes, but 82% of this excess risk was attributable to socioeconomic and other known risk factors. The risk of kidney function decline over 5 years among patients with hypertension was more pronounced in African Americans, and African ancestry was independently associated with an accelerated rate of GFR decline in the Modification of Diet in Renal Disease (MDRD) study. Interestingly, data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort Study have shown a lower prevalence of eGFR (50 to 59 mL/min/1.73 m ² ) among African American persons but a higher prevalence of eGFR (10 to 19 mL/min/1.73 m ² ) among white persons, suggesting that African American race acts as a “progression factor” but not as a “susceptibility factor.” A 2012 report from the U.S. Renal Data Service showed a substantially higher incidence of ESKD in African American persons (3.3 times higher than whites), Hispanic persons (1.5 times higher than non-Hispanics), and Native American persons (1.5 times higher than whites). Similarly, the prevalence of ESKD in 2012 was higher among minority groups: African American, 5671 pmp; Native American, 2600 pmp; Hispanic, 2932 pmp; Asian, 2272 pmp; and white, 1432 pmp. CKD and ESKD have also been reported to be more prevalent in other ethnic groups, including Asian, Hispanic, Native American, Mexican American, and Aboriginal Australian. A large meta-analysis that included data from 940,366 participants in 25 general population cohort studies investigated the associations of race and ethnicity with CKD. The absolute risk of all-cause or cardiovascular mortality (after adjustment for age) and ESKD was higher in Black versus White versus Asian persons. However, the relative risk of all-cause or cardiovascular mortality and ESKD increased to a similar degree with lower GFR or higher albuminuria in all the race/ethnicity groups.

Thus the associations among lower GFR or higher albuminuria and mortality or ESKD were not modified by race or ethnicity. The mechanisms underlying the associations between race and ethnicity with CKD remain to be elucidated, but possible explanations include genetic factors ( APOL1 gene variants account for 40%, see the “Hereditary Factors” section); prevalence of DM; nephron endowment; susceptibility to salt-sensitive hypertension; and environmental, lifestyle, and socioeconomic differences. Race and ethnicity with CKD are discussed further in Chapters 18, 20, and 50 .

Hypertension, which is defined as an increased systolic blood pressure >130 mm Hg and/or diastolic blood pressure >80 mm Hg, or the need for pharmacologic therapy to achieve BP targets, is an almost universal consequence of impaired function. From a CKD-focused standpoint, this is due to sodium retention, hypervolemia, and neurohormonal activation associated with progressive decrease in GFR. However, hypertension itself is also known to be an important factor in the progression of CKD toward ESKD. In the hypothesis of CKD progression presented in Fig. 19.1 , 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 associated with ESKD 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 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) was independently associated with a more rapid 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. Whereas the primary analysis of data from the MDRD study found no significant difference between the rate of decline in GFR among patients randomized to intensive blood pressure control (target MAP <92 mm Hg, equivalent to <125/75 mm Hg) and standard blood pressure control (target MAP < 107 mm Hg, equivalent to 140/90 mm Hg), a secondary analysis did show benefit associated with the lower 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. Thus the MDRD study results suggest a significant interaction between blood pressure and proteinuria as risk factors for CKD progression.

The Systolic Blood Pressure Intervention Trial, which randomized nearly 10,000 patients older than 50 years of age with hypertension, without diabetes, and increased risk of CKD including about one-third with CKD, showed that targeting systolic blood pressure <120 mm Hg, as compared with <140 mm Hg, resulted in fewer fatal and nonfatal CVEs and death. A subgroup analysis of the 2646 participants with CKD showed no difference in the primary renal outcome of ≥50% decline in GFR or ESKD, though there was a more pronounced decrease in GFR after 6 months (–0.47 vs.–0.32 mL/min/1.73 m ² per year) among patients randomized to the lower SBP target. The risks of all-cause mortality (HR, 0.72; 95% CI, 0.53–0.99) and CVE (HR, 0.81; 95% CI, 0.63–1.05) were lower in the more intensive SBP-lowering group and there was no overall increase in serious adverse events, though AKI, hypokalemia, and hyperkalemia were increased in the more intensive SBP-lowering target group. An additional analysis of two intensive systolic blood pressure lowering trials also found a threefold increase in incident CKD among patients without CKD at baseline, although no change in tubular injury markers was observed. In the HALT Progression of Polycystic Kidney Disease (HALT-PKD) study, targeting a blood pressure of ≤120/70 mm Hg in patients with autosomal dominant polycystic kidney disease (ADPKD) through use of lisinopril and telmisartan allowed for a slower increase in total kidney volume, no overall change in eGFR, a more pronounced decline in left ventricular mass index, and a more pronounced reduction in albuminuria.

Taken together, there is convincing evidence that elevated blood pressure is a risk factor for progression of CKD. While lowering SBP reduces the risk of CKD and death, it is unknown whether more intensive control of hypertension reduces (or increases) the risk of progressive CKD.

In experimental models, obesity is associated with hypertension, proteinuria, and progressive kidney 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 kidney damage including hormones and proinflammatory molecules produced by adipocytes, elevated 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 elevated body mass index (BMI), has been associated with an increased risk of developing CKD in several large population-based studies. ^{, ,} Indeed, one study found a progressive increase in the relative risk of developing ESKD associated with higher BMI (relative risk, 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 ³ ) among 320,252 subjects confirmed to have no evidence of CKD at initial screening.

Evidence indicates 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 kidney disease. One study has identified childhood obesity as a risk factor for CKD in adulthood. Among 4340 participants born in 1 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 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 survey participants 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 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, 1.18–1.73). Again, there was a progressive increase in risk associated with the number of traits of the metabolic syndrome present (OR, 1.13; 95% CI, 0.89–1.45 for one trait vs. OR, 2.45; 95% CI, 1.32–4.54 for five traits). In another study, patient hip-to-waist ratio, a marker of insulin resistance, was independently associated with impaired kidney function, even in lean individuals (BMI <25 kg/m ³ ), among a population-based cohort of 7676 individuals.

Surgical intervention in the form of gastric banding or bypass appears to have evidence in improving long-term outcomes. 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.

In recent years, there has been an accumulation of evidence that treatment of obesity in patients with or without diabetes with GLP1 receptor agonists can improve kidney and cardiovascular outcomes. Previous CV outcome trials of liraglutide, dulaglutide, and semaglutide that included secondary analyses of kidney outcomes showed GLP1 receptor agonists reduced major adverse cardiovascular events (MACE) by 14% (HR, 0.86; 95% CI, 0.80–0.93) and hospital admissions for heart failure by 11% (HR, 0.89; 95% CI, 0.82–0.98). Additionally, the risk of various kidney disease outcomes including macroalbuminuria, increased serum creatinine, a ≥40% decline in eGFR, receival of kidney replacement therapy, or death due to kidney disease was reduced by 21% (HR, 0.79; 95% CI, 0.73–0.87). Findings from the FLOW trial were published in May 2024 and conclusively demonstrated a benefit of semaglutide, such that major kidney disease events including onset dialysis, transplantation, reduction of eGFR to <15 mL/min/1.73 m ² , or death from kidney- or cardiovascular-related causes was reduced by 24% (HR, 0.76; 95% CI, 0.66–0.88) after weekly 1.0 mg subcutaneous dose of semaglutide. Further, the risk of MACE was reduced by 18% (HR, 0.82; 95% CI, 0.68–0.98). This evidence supports the measurement/evaluation of obesity in patients with CKD and suggests that medical therapy with GLP1 agonists is likely to modify both kidney and cardiovascular risk.

The best method for assessing obesity in CKD remains to be determined. A 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.

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 kidney 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 patients with diabetes and hypertension (OR, 3.3; 95% CI, 1.4–7.8) 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 dietary protein intake, particularly nondairy animal protein, was associated with a more rapid 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 >80 mL/min/1.73 m ² . Randomized trials investigating the effects of high-protein diet are lacking, but several studies have sought to examine the potential renoprotective effects of dietary protein restriction. In the MDRD study, the 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. By contrast, 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 reported a higher risk of death in this group (HR, 1.92; 95% CI, 1.15–3.20). As such, dietary protein restriction cannot be routinely recommended for patients with CKD. Additional discussion on the role of dietary protein restriction in the management of CKD is available in Chapter 55 .

Physiologic adaptations during pregnancy provoke glomerular hyperfiltration that usually does not result in kidney 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 (≥124 μmol/L). In one study of 82 pregnancies in 67 females with primary kidney disease and serum creatinine concentrations ≥1.4 mg/dL, blood pressure, serum creatinine, and proteinuria increased during pregnancy. In 70 pregnancies with postpartum data available, persistent loss of maternal kidney function at 6 months was reported in 31%, and by 12 months eight (14%) females 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 females 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 <40 mL/min/1.73 m ² , combined with proteinuria of >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 study has reported adverse pregnancy outcomes 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 pregnancy 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 (GFR >90 mL/min/1.73 m ² ) were considered, although there were no perinatal deaths. By contrast, pregnancy was not associated with a more rapid decline in the GFR over 5 years in a cohort of 245 females of childbearing age with IgA nephropathy and serum creatinine level of ≤1.2 mg/dL (in the majority).

Complications of pregnancy and, in particular, hypertension and preeclampsia may also contribute to kidney 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, 3.6–6.1) to a relative risk of 15.5 for preeclampsia in two or three pregnancies (95% CI, 7.8–30.8). 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 before 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 CVD, DM, and CKD (HR, 1.91; 95% CI, 1.18–3.09). Similarly, a large case-control study found that hypertension during pregnancy was associated with a substantially increased risk of subsequent CKD (HR, 9.38; 95% CI, 7.09–12.4) or ESKD (HR, 12.4; 95% CI, 8.53–18.0). 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 kidney 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.

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 participants (HR, 7.5; 95% CI, 4.8–11.7), as well as an increased risk of moderate CKD (estimated creatinine clearance <50 mL/min) in another study of 1428 participants with an estimated creatinine clearance of >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 participants 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 41 .

Proteinuria is an indicator of dysfunction in the glomerular filtration barrier and is therefore a marker of glomerulopathy and an index of disease severity. Proteinuria is often a result of glomerular injury and is associated with hyperfiltration, intraglomerular hypertension, glomerular hypertrophy, and glomerulosclerosis. Experimental evidence has suggested that proteinuria may also contribute to progressive kidney damage in CKD (see Chapter 29 ). A large body of evidence attests to a strong association between proteinuria and the risk of CKD progression, a relation mediated through several mechanisms including tubular injury, inflammation, and fibrosis, 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, 10.9–20.2).

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, 1.8–3.8; HR for ≥2+ proteinuria, 15.7; 95% CI, 10.3–23.9). Furthermore, detection of 2+ proteinuria or more increased the hazard ratio for ESKD associated with an eGFR <60 mL/min/1.73 m ² from 2.4 without proteinuria (95% CI, 1.5–3.8) to 41.0 with proteinuria (95% CI, 15.2–71.1). 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, microalbuminuria 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.

Among patients selected for having CKD from a wide variety of causes, baseline proteinuria has consistently predicted adverse kidney 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-to-creatinine ratio (UACR) was an independent predictor of ESKD in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and Irbesartan in Diabetic Nephropathy Trial (IDNT). ^, The findings of these individual studies have been confirmed by several 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), UACR of >30, 300, and 1000 mg/g were independently associated with progressive increases in the risk of ESKD, progressive CKD, and AKI, respectively (see Fig. 19.4 ). Among 21,688 patients known to have CKD from 13 studies, an 8-fold higher UACR or protein-to-creatinine ratio (UPCR) was associated with all-cause mortality (pooled HR, 1.40) and risk of ESKD (pooled HR, 3.04). In a meta-analysis that included more than 9 million participants, UACR was independently associated with kidney failure requiring kidney replacement therapy (and several other adverse outcomes). Other meta-analyses conducted by the CKD Prognosis Consortium have shown that the magnitude of proteinuria remains a risk factor for ESKD independent of sex, race and ethnicity, age, diabetes, or hypertension. 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.

Serum albumin concentrations are widely regarded as a marker of nutritional status but may also be reduced due to inflammation or in the setting of high-grade proteinuria. Several studies have identified lower serum albumin concentrations 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, serum albumin 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 kidney 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 these studies, the predictive value of serum albumin was seen after adjustment for urine albumin (or protein) excretion, suggesting that variation in serum albumin related to inflammation, nutritional status, and/or liver disease also contributed to ESKD risk.

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 anemia to be an independent predictor of CKD progression. In the RENAAL study, baseline hemoglobin was a significant independent predictor of ESKD among patients with diabetic kidney disease—each 1 g/dL lower hemoglobin concentration 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 concentration was independently associated with a lower risk of progression to ESKD (halving of GFR or need for dialysis) or death among 131 patients with all forms of CKD (HR, 0.78; 95% CI, 0.64–0.95 for each 1 g/dL increase). Furthermore, time-averaged hemoglobin of <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, 0.65–0.84 for each 1 g/dL higher hemoglobin).

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 <30%, erythropoietin treatment was associated with significantly improved renal survival. In patients without diabetes with serum creatinine of 2 to 6 mg/dL, early treatment (started when hemoglobin <11.6 g/dL) with epoetin alfa was associated with a 60% reduction in the risk of doubling of serum creatinine, ESKD, or death versus delayed treatment (started when hemoglobin <9.0 g/dL). By contrast, two other studies that had left ventricular mass as their primary endpoint ^, and the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) found no effect of a higher versus lower 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 (13–15 mg/dL) was associated with a shorter time to initiation of dialysis than a lower target (10.5–11.5 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 endpoint of all-cause mortality, MI, or hospitalization for congestive cardiac failure. Large randomized trials with a different class of anemia treatments (HIF stabilizers) have also found no benefit in slowing progression of kidney disease when compared with placebo or active controls.

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 concentrations, lower HDL cholesterol concentrations and elevated total cholesterol concentrations, low HDL cholesterol concentrations, and elevated total cholesterol-to-HDL cholesterol ratio. In the MDRD study, lower HDL cholesterol concentrations were independently associated with decline in GFR ; in a smaller study of patients with CKD, total cholesterol, LDL cholesterol, and apolipoprotein B concentrations were all associated with a more rapid decline in the GFR. Among 223 patients with IgA nephropathy, hypertriglyceridemia was independently associated with CKD progression. Hypercholesterolemia was reported to predict loss of kidney function in patients with type 1 or 2 diabetes ^, and, among patients without diabetes, CKD advanced more rapidly in those with hypercholesterolemia and hypertriglyceridemia.

Randomized controlled trials of lipid lowering have produced mixed results with respect to kidney outcomes. Subgroup analysis of a prospective randomized trial of pravastatin treatment in patients with previous MI found that pravastatin slowed the rate of decline in patients with an eGFR <40 mL/min/1.73 m ² , an effect that was more pronounced in participants with proteinuria at baseline. Similarly, in the Heart Protection Study, patients with previous CVD 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 creatinine clearance declined in patients receiving placebo. By contrast, lipid lowering with fibrates was unassociated with renoprotection in two studies, ^, although one study showed a reduced incidence of microalbuminuria in patients with type 2 diabetes receiving fenofibrate.

Analysis of data from a relatively small subgroup of studies with kidney endpoints recorded in a meta-analysis found that among participants with CKD, statin therapy was associated with a reduction in proteinuria but no improvement in creatinine clearance. 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 <0.2 g/day, higher LDL and total cholesterol were associated with a lower risk of reaching this composite endpoint. The Study of Heart and Renal Protection (SHARP) is the largest randomized controlled trial to investigate the cardiovascular and kidney protective effects of lipid lowering in CKD. Patients with CKD or undergoing dialysis were randomized to treatment with simvastatin + 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 did not significantly reduce the risk of ESKD or the composite endpoint of ESKD or doubling of serum creatinine. 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 50.

Hyperuricemia is a common consequence of CKD and may also contribute to CKD progression. 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 urate 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. By contrast, 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.

Two large randomized trials have examined the efficacy of urate-lowering treatments on CKD progression. These trials examined the effects of different xanthine oxidase inhibitors (allopurinol and febuxostat) and found no effects on CKD progression despite substantial reductions in serum urate concentrations. Thus it appears that while serum urate uric is a marker for impaired kidney function, it is not a modifiable risk factor for slowing CKD progression. ^,

Metabolic acidosis commonly develops in patients with CKD, particularly among diseases with extensive tubulointerstitial involvement and more generally with a reduction in functional nephron mass. As a result, there is a subsequent elevation of cortical ammonia levels, renin–angiotensin–aldosterone system activation, complement cascade activation, endothelial/aldosterone activation, and inflammation, all of which lead to impaired renal acid clearance. At least five studies have investigated metabolic acidosis as a risk factor in human CKD. In all except the MDRD study, lower serum bicarbonate concentrations, even within the population reference range, were independently associated with 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. Several randomized controlled trials have also indicated that correction of acidosis with bicarbonate supplementation results in minimal sodium loading or exacerbation of hypertension. ^,

However, these positive trials have been limited by lack of blinding and a placebo control. More recently, double-blind placebo-controlled trials were conducted, using sodium bicarbonate or veverimer (a novel intestinal hydrochloric acid binder) aiming to slow CKD progression in patients with CKD and metabolic acidosis. These higher-quality, lower-bias studies failed to show any benefit of slowing CKD progression with treatment of mild-to-moderate metabolic acidosis. Specifically, the VALOR-CKD study reported that ververimer does not slow CKD progression (defined as development of ESKD, a sustained decline in eGFR of ≥40% from baseline, or death due to kidney failure), with a hazard ratio of 0.99 (95% CI, 0.8–1.2). [CR] As such, the most recently updated KDIGO CKD guidelines recommend that patients maintain serum bicarbonate concentrations >18 mmol/L—guidance based largely on opinion rather than evidence. At present, evidence does not support treatment of metabolic acidosis to slow CKD progression. ^,

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 higher serum ADMA concentrations observed with impaired kidney function 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 resulted in 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, the enzyme responsible for degradation of ADMA, was associated with reduced plasma ADMA concentrations and amelioration of kidney injury in rats after 5/6 nephrectomy, implying that circulating ADMA may also promote CKD progression.

Among 131 patients with CKD, a higher plasma ADMA concentration was associated with ESKD or death (HR, 1.20; 95% CI, 1.07–1.35 for each 0.1 μmol/L increase). In 227 relatively young patients without diabetes with mild-to-moderate CKD, higher plasma ADMA levels predicted progression to the combined endpoint of creatinine doubling or ESKD (HR, 1.47; 95% CI, 1.12–1.93 for each 0.1 μmol/L increase). Finally, retrospective analysis of data from 109 patients with IgA nephropathy showed associations between plasma ADMA concentrations and glomerular and tubulointerstitial injury. Furthermore, the plasma ADMA concentration was an independent determinant of the annual rate of decline in GFR.

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 kidney injury in CKD. Three cohort studies of patients with CKD have identified higher serum phosphate concentrations as an independent risk factor for progression. ^{, ,} By contrast, 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 and CKD progression. In addition, higher serum concentrations of the phosphatonin fibroblast growth factor 23 (FGF23), a hormone involved in calcium and phosphate regulation through decreasing serum phosphate and 1,25-dihydroxyvitamin D ₃ , have been associated with CKD progression. ^, Along with adverse kidney effects, higher serum concentrations of FGF23 are associated with CVEs and related surrogate outcomes in patients with CKD. In the CRIC study, higher serum concentrations of FGF23 were determined to be an independent risk factor for ESKD, but more so in patients with a higher baseline eGFR (HR, 1.3; 95% CI, 1.04–1.6 if the eGFR was 30–44 mL/min/1.73 m ² ; and HR, 1.7; 95% CI, 1.1–2.4 if the eGFR was >45 mL/min/1.73 m ² ). A meta-analysis confirmed the association between elevated serum FGF23 and CVEs, as well as all-cause mortality, but suggested that the relation was not causal due to lack of an exposure-response relationship. The exact clinical significance of FGF23 is uncertain, but there appears to be potential for its use as a biomarker, specifically in patients with CKD and ESKDs.

Neutrophil gelatinase–associated lipocalin (NGAL) is an iron-carrying protein expressed throughout the distal tubule epithelium and is overexpressed in response to AKI. While it is known mostly for its role in AKI, the role of urinary NGAL in CKD progression is currently a point of interest. The Atherosclerosis Risk in Communities (ARIC) study found that baseline urinary NGAL was highest in participants with incident CKD (OR, 2.1; 95% CI, 0.96–4.6). In the CRIC study, urinary NGAL was associated with ESKD (HR, 1.7; 95% CI, 1.2–2.5) but added no significant improvement in prediction of CKD progression beyond eGFR decline and proteinuria.

Kidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein typically undetected in a normal kidney but detected in patients with AKI and CKD. One cohort study found that serum KIM-1 concentrations increased with higher CKD stage and were directly associated with eGFR decline and ESKD. The Multi-Ethnic Study of Atherosclerosis determined that doubling of urinary KIM-1 concentrations was associated with CKD and rapid eGFR decline (>3 mL/min/1.73m ² per year, OR, 1.2; 95% CI, 1.02–1.3). Studies combining KIM-1 with other markers (TNFR1, TNFR2) have also shown improvement in prediction in patients with diabetic kidney disease, but larger studies examining this approach and adjusting for cystatin C-based eGFR rather than creatinine-based eGFR, are needed. ^,

Soluble urokinase-type plasminogen activator receptor (suPAR) is a protein involved in cell adhesion and migration of endothelial and immune cells. Increased plasma suPAR concentrations have been detected in patients with glomerular disease, specifically glomerulosclerosis, as well as adverse CVEs. One study done by Hayek and colleagues using 2292 patients from the Emory Cardiovascular Bank found that higher baseline plasma suPAR concentrations were associated with CKD (eGFR <60 mL/min/1.73 m ² ). This relation was further validated using a sample of 347 patients in the Women’s Interagency Human Immunodeficiency Virus Study, where again a higher baseline plasma suPAR concentration was associated with higher incidence of CKD. Specificity may be an issue, however. For example, 30% of patients with an eGFR > 90 mL/min/1.73m ² also had an increase in baseline plasma suPAR concentrations, indicating that suPAR may be linked to inflammation or other factors in addition to kidney function. These results emphasize the need for further validation.

Uromodulin (UMOD) is a kidney-specific glycoprotein synthesized by epithelial cells found in the ascending loop of Henle. While its exact function is currently unknown, one proposed role has been in protection against urinary tract infections, innate immunity activation, and kidney stone prevention. Genome-Wide Association Studies (GWASs) indicated that single-nucleotide polymorphism (SNP) variants of the UMOD gene were associated with lower eGFR and development of CKD in European cohorts. ^, One GWAS using 3203 Icelandic patients with CKD found an association between CKD and serum creatinine with a variant adjacent to the UMOD gene on chromosome 16p12, which was strengthened with age. Whether UMOD is a marker of CKD progression remains unclear. A meta-analysis of GWAS for UMOD including six studies and 10,884 patients found that two loci located around the UMOD gene were associated with increased urinary UMOD levels. However, Shlipak and colleagues found that among 879 individuals of the Heart and Soul Study, UMOD SNP variants were associated with urine UMOD concentrations but did not affect incident CKD risk. These conflicting results indicate that further investigation is required before clinical implementation of UMOD as a CKD biomarker.

Proteomics simultaneously assess multiple proteins in blood and/or urine using electrophoresis and mass spectrophotometry in both targeted (known pathophysiology) and nontargeted (unknown pathophysiology) approaches. However, this approach poses several challenges given biosampling variability due to age, sex, diet, exercise, and other issues. Using proteomics in a Scottish cohort with type II DM, investigators for the Innovative Diabetes Tools study were able to identify at least 62 of 207 serum protein biomarkers associated with rapid progression of CKD (>40% baseline eGFR loss in 3.5 years). The use of a 14-biomarker panel (including FGF23 and KIM-1) in risk prediction models allowed for an increase in the area under the receiver operating characteristic curve (AUROC) from 0.706 to 0.868. Another study, which used capillary electrophoresis with mass spectrophotometry, looked at the utility of urinary proteomics in validating previously established biomarkers of CKD. The study used a general population cohort of 223 healthy individuals and 1767 patients with CKD (defined as eGFR <90 mL/min/1.73 m ² or urine albumin excretion >30 mg/L), finding that the proteome performed better in detection and prediction of CKD progression, improving the AUROC based on baseline eGFR and albuminuria from 0.76 to 0.82. A large proteomic study assessed 4638 plasma proteins in 3235 participants from CRIC using 50% decline in eGFR or kidney failure over 10 years as the primary outcome and validated the findings in ARIC. One hundred proteins were associated with the outcome and risk model that included 65 proteins and produced good discrimination (C-statistic [95% CI] = 0.86 [0.84, 0.89]). The use of novel serum or urinary biomarkers will likely be of value in future risk prediction models through enhancing discrimination beyond traditional risk predictors including GFR and proteinuria. Given the interplaying mechanisms that may result in any given patient with CKD, it is unlikely that any one single conventional or novel biomarker will have a large effect on risk prediction models. However, the development of biomarker panels through the use of proteomics shows potential in discriminating between disease and nondisease states, as well as risk prediction, and its future role in the clinical setting, is promising.

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.

Population-based studies have identified cigarette smoking as an independent risk factor for various manifestations of CKD including proteinuria, elevated serum creatinine concentrations, decreased eGFR, ^, and development of ESKD or death associated with CKD (HR, 2.6; 95% CI, 1.8–3.7). In the latter study, 31% of the attributable risk of CKD was associated with smoking. In a longitudinal study of 10,118 middle-aged Japanese workers, smoking was associated with an increased risk of developing glomerular hyperfiltration (eGFR ≥117 mL/min/1.73 m ² ; OR, 1.32 vs. nonsmokers) and proteinuria (OR, 1.51 vs. nonsmokers). Two other similar longitudinal studies from Japan have confirmed that smoking is associated with an increased risk of developing proteinuria but a higher mean eGFR than in nonsmokers. ^, In one study, smoking was associated with a lower risk of developing CKD stage 3. Smoking has been shown to increase the risk of progression of CKD due to diabetes, ^, hypertensive nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, and adult PKD. Randomized trials of the effect of smoking cessation on CKD progression are lacking but, in one observational study in patients with diabetes, smoking cessation was associated with less frequent progression to macroalbuminuria and a slower rate of GFR decline than continued smoking. Similarly, in CRIC, nonsmoking was associated with a reduced risk of CKD progression (HR, 0.68; 95% CI, 0.55–0.84), atherosclerotic CVEs (HR, 0.55; 95% CI, 0.40–0.75), and mortality (HR, 0.45; 95% CI, 0.34–0.60). Among 9270 participants with CKD in the SHARP, current smoking was associated with an increased risk of all-cause mortality, CVEs, and cancer but was unassociated with risk of ESRD or rate of GFR decline in 6245 participants not receiving dialysis at baseline. Possible mechanisms whereby cigarette smoking may contribute to kidney damage include sympathetic nervous system activation, glomerular capillary hypertension, endothelial cell injury, and direct tubulotoxocity.

The role of alcohol consumption as a potential risk factor for CKD remains unclear. One case-control study found a significant association between ESKD and consumption of more than two alcoholic drinks daily, whereas another similar study found no association (with the exception of “moonshine”). Some population-based studies have found that alcohol consumption is not related to CKD risk, but one study found a significant association of heavy alcohol intake (more than four drinks daily) and prevalent CKD, as well as the risk of developing CKD in participants with a normal GFR. Furthermore, heavy alcohol intake substantially increased the risk of CKD progression associated with smoking, such that participants who smoked and drank heavily had an almost fivefold increased risk of developing CKD.

Conversely, several large cohort studies have reported an inverse relation between alcohol consumption and the risk of developing CKD ^, or ESKD. Another study found that moderate-to-heavy alcohol consumption was associated with a higher risk of developing albuminuria but a lower risk of eGFR <60 mL/min/1.73m ² . This finding of a lower risk of eGFR decline is likely due to sarcopenia associated with heavy alcohol use rather than a true improvement in kidney function.

The most rigorous study published to date investigated the incidence of CKD defined by an eGFR determined using the combined cystatin C and creatinine equation or albuminuria >30 mg/day based on two consecutive 24-hour urine collections. The risk of developing CKD over a mean of 10.2 years decreased progressively with increasing alcohol consumption: HR of 0.85 (95% CI, 0.69–1.04) for occasional alcohol consumption (<10 g/week), HR of 0.82 (95% CI, 0.69–0.98) for light alcohol consumption (10–69.9 g/week), HR of 0.71 (95% CI, 0.58–0.88) for moderate alcohol consumption (70–210 g/week), and HR of 0.60 (95% CI, 0.42–0.86) for heavier alcohol consumption (>210 g/week).

The role of recreational drugs as a risk factor for CKD has not been widely studied, but one case-control study reported a positive association among heroin, cocaine, or psychedelic drug use and ESKD. Following reports of a specific renal lesion characterized by proteinuria and FSGS, termed “heroin nephropathy,” other investigators reported a wide range of inpatients with a history of heroin abuse, confirmed by biopsy. It is unclear whether the observed kidney lesions resulted from direct effects of heroin or were attributable to impurities in the drug or associated blood-borne virus infections and endocarditis. An association with renal amyloidosis, possibly due to chronic skin infections, has also been reported. Interestingly, heroin abuse was not associated with an increased risk of mild CKD in 647 hypertensive patients who showed an association between illicit drug abuse and CKD. Cocaine exerts several adverse effects that may induce kidney injury including rhabdomyolysis, vasoconstriction, activation of the renin-angiotensin–aldosterone system, oxidative stress, and increased collagen synthesis. Furthermore, chronic administration of cocaine to rats resulted in multiple renal lesions including glomerular atrophy and sclerosis, tubule cell necrosis, and areas of interstitial necrosis. Among 647 patients attending a hypertension clinic, a history of any illicit drug use was independently associated with a relative risk of 2.3 (95% CI, 1.0–5.1) for mild CKD, whereas cocaine and psychedelic drug use were associated with relative risks of 3.0 (95% CI, 1.1–8.0) and 3.9 (95% CI, 1.1–14.4), respectively. In one prospective cohort study using 2286 participants of the Life Span study, use of opiates and cocaine were both determined to be associated with eGFR <60 mL/min/1.73 m ² ; OR, 2.71 and 95% CI, 1.50–4.89 for opiates; OR, 1.40 and 95% CI, 0.87–2.24 for cocaine); cocaine use was associated with a higher odds of albuminuria (UACR >30 mg/g; OR, 1.80 and 95% CI, 1.29–2.51.

Analgesic nephropathy has been well described as a cause of CKD and ESKD resulting from abuse of combination analgesics containing aspirin and phenacetin prevalent in Australia and Switzerland until the sale of these products was restricted. Cohort studies of participants without CKD at baseline have not consistently identified associations between analgesic use and incident CKD. Among 1697 women in the Nurses Health Study, consumption of >3000 g of acetaminophen was associated with an increased risk of eGFR decline >30 mL/min/1.73 m ² over 11 years (HR, 2.04; 95% CI, 1.28–3.24); use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) was not associated with increased risk. Among 4494 male physicians from the Physicians Health Study, there was no association between occasional-to-moderate use of aspirin, acetaminophen, or NSAIDs and GFR decline over 14 years. By contrast, analgesic use may exacerbate the progression of established CKD. In one large study of 19,163 patients with newly diagnosed CKD, use of aspirin, acetaminophen, or NSAIDs was associated with an increased risk of progression to ESKD in a dose-dependent manner. Among cyclooxygenase 2 inhibitors, use of rofecoxib but not celecoxib was associated with increased risk of ESKD. In a cohort study of 4101 people with rheumatoid arthritis, chronic use of NSAIDs was not associated with a more rapid GFR decline in the entire study population, but NSAID use was independently associated with more rapid GFR decline in a small minority of patients with CKD stage 4 or 5 ( N = 17). A meta-analysis of three studies that included data from 54,663 participants with CKD stages 3 to 5 found no association between regular NSAID use and accelerated GFR decline (defined as ≥15 mL/min over 2 years) but did report an association with high-dose NSAID use (defined as 90th percentile or above in one study and not defined in the other) in two studies. The use of single-compound acetaminophen or aspirin was reported not to accelerate progression among patients with CKD stage 4 or 5, but a systematic review of the safety of acetaminophen treatment reported an increased risk of renal adverse events in three of four observational studies, in addition to an increased risk of all-cause mortality and cardiovascular and gastrointestinal adverse events in other studies.

As the authors noted, these results must be interpreted with caution due to the possibility of confounding by indication resulting from associations between the indication for prescribing selected analgesic agents and adverse outcomes.

In more tropic parts of the globe including Latin America, Sri Lanka, and India, chronic kidney disease of unknown etiology (CKDu) has been reported. Previously known as Mesoamerican nephropathy given its initial identification in Central American farmworkers, CKDu pathology is thought to be related to heat-induced dehydration. Other factors including socioeconomic status, exposure to pesticides through farm labor, and poor-quality drinking water have been considered. For a more detailed discussion of this topic, see Chapter 83 . ^{, ,}

Chronic exposure and subsequent toxicity of heavy metals, specifically lead and cadmium, has been known to result in a predominantly tubulointerstitial nephropathy. Overt lead toxicity is characterized by chronic interstitial nephritis and an association with gout. In addition, epidemiologic studies have reported that mild elevations in blood lead concentrations are associated with moderate reductions in GFR and/or hypertension in the general population. ^, Furthermore, a prospective study identified elevations in blood lead concentrations and body lead burden even within the population reference range as risk factors for CKD. Similarly, blood lead burden was a risk factor for progression among 108 patients with low-normal values and no history of lead exposure. Furthermore, randomization to chelation therapy was associated with a modest improvement in GFR over 24 months versus a small decline in those randomized to control (+6.6 ± 10.7 vs. −4.6 ± 4.3 mL/min/1.73 m ² ; P <.001).

Like lead, chronic exposure to cadmium is also associated with a distinctive nephropathy, characterized by proximal tubule damage and low-molecular-weight proteinuria. Furthermore, low-level cadmium exposure resulting from environmental contamination was associated with tubular proteinuria ; and analysis of data from 14,778 participants in NHANES showed an independent increased risk of albuminuria, reduced GFR, or both when comparing the highest and lowest quartiles of blood cadmium concentrations. Comparison of the lowest and highest quartiles for whole blood concentrations of cadmium and lead showed an even greater increased risk of albuminuria, reduced GFR, or both. In another NHANES study, blood and urine cadmium levels were directly correlated with UACR and inversely correlated with GFR. Higher blood and urine cadmium concentrations were independently associated with albuminuria, and higher blood cadmium concentrations were associated with albuminuria and a reduced GFR. Occupational or low-level environmental exposure to cadmium was associated with an increased risk of ESKD in a population-based study from Sweden.

Before clinical implementation, renal risk scores must first hold both internal and external validity, show improvement over the current risk classification system, and be easily integrated into clinical settings. The presence of internal validity indicates that the prediction model has been developed from a sample that accurately reflects the relations among the variables used in the prediction model and outcome of interest. These predictor variables must have clear definitions and be measured in each patient well before the final outcome is reached. The outcome itself, in order to avoid bias, must also be clearly defined and assessed uniformly in all patients, blind to the status of the predictor variable. In order to develop such a risk model, appropriate statistical approaches must be taken. If censoring of the variable is negligible and the follow-up period is clearly defined, logistic regression can be used. However, if there is significant censoring present, Cox proportional hazards regression is preferred. ^, Competing risk models can also be considered when there is a concomitant high risk of mortality and kidney failure in the same population, but conclusive evidence to support the routine use of a competing risk framework for CKD progression is insufficient. Finally, machine learning approaches may have some advantages for predicting progression, particularly with handling of missing data, but they should only be considered in large datasets with external validation due to concerns about overfitting. ^{, ,} In addition to the general validation issues discussed earlier, several metrics specific to performance of the prediction model are used in order to assess internal validity.