Surveillance for CKD is central in providing information on the magnitude and trends in burden of CKD that will guide disease management and prevention planning for both clinicians and public health authorities. Surveillance, defined as “the continuing scrutiny of all aspects of occurrence and spread of a disease that are pertinent to effective control”⁹, can take many forms and can focus on diagnosed, or undiagnosed, disease. For kidney disease, surveillance can monitor high risk subgroups for incident CKD in order to take clinical action, or can quantify changes in incidence or prevalence of CKD in populations to guide public health activities. In contrast to treated ESRD where both prevalence and incidence trends are available, incidence data for CKD are more limited and trends in incidence are largely unavailable. Here we focus on quantifying the total prevalence of CKD including both diagnosed and undiagnosed disease in the U.S. population. This requires a representative sample of the population and the means to determine whether individuals in the sample have CKD, regardless of previous diagnosis. Unlike ESRD, marked by clinical symptoms indicating a need for renal replacement therapy, earlier stages of CKD are mostly asymptomatic. Thus, diagnosis of CKD relies on laboratory values of markers for kidney damage, quantified by persistent albuminuria, and decreased kidney function, classified as glomerular filtration rate (GFR) < 60 ml/min/1.73 m².¹ GFR can be measured directly using urine and serum concentrations of exogenous substances such as inulin, ¹²⁵I-iothalamate, or Iohexol.¹⁰ Estimating GFR from serum creatinine, however, is the presently recommended method for CKD staging and is more feasible in the large studies that are required for accurate estimation of total CKD burden in the US.^{1, 2}

The National Health and Nutrition Examination Surveys (NHANES), conducted by the National Center for Health Statistics (NCHS), represent an ideal sample for estimating the total burden of CKD and have been used extensively for estimating CKD prevalence in the broader US population. We summarize data from a recent publication updating trends data from 1988-2004¹¹ and expand on the characteristics of subgroups within CKD Stage 3 which contains the largest number of individuals compared to any other CKD stage. The NHANES surveys include laboratory measurement of both albuminuria and serum creatinine thus allowing for the staging of CKD in a nationally representative sample, regardless of the participants' awareness, or history of diagnosis, of CKD. Surveillance requires the ability to evaluate estimates of incidence or prevalence from current data against similar estimates from comparable past data. As such, initial estimates of prevalence of CKD stages from the NHANES III (1988-1994) survey have provided a benchmark for kidney disease studies, prevention efforts, and healthcare planning.^{2, 12} Studies have compared estimates from NHANES 1999-2000 to the baseline estimates provided by NHANES III finding increased prevalence of albuminuria but no significant increase in overall prevalence of CKD. The precision of these trend estimates were constrained by the relatively small sample size of the 1999-2000 survey and may have been biased due to the limited data to establish consistent calibration of the creatinine assays over time.¹² Proper assay calibration is necessary when comparing estimates derived from laboratory data to ensure correct and unbiased comparisons, especially when assays are performed years apart and/or in different laboratories. A recent study calibrating serum creatinine in all NHANES surveys from 1988 to 2004 permitted a more rigorous examination, with less bias, of the trends in the prevalence of CKD using standardized creatinine.¹³

Urinary albumin and creatinine concentrations were assayed in the same laboratory for all surveys. Urinary albumin-to-creatinine ratio (ACR, mg/g) was computed and forms the basis for the definition of albuminuria. Microalbuminuria is defined as ACR of 30 to < 300 mg/g, and macroalbuminuria is defined as ACR ≥ 300 mg/g. All albuminuria analyses excluded women who were pregnant or were in menses. Serum creatinine was measured using a kinetic rate Jaffe method. All serum creatinine measurements were re-calibrated to standardized creatinine measurements obtained at the Cleveland Clinic Research Laboratory (Cleveland, Ohio).¹³ This re-calibration is necessary for appropriate estimation of GFR and accurate assessment of trends in prevalence over time using the different NHANES surveys.

GFR was estimated from re-calibrated serum creatinine using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation.¹⁷ The MDRD Study equation was originally developed using serum creatinine measured by a kinetic rate Jaffe method; here we use the IDMS-traceable MDRD Study equation that uses standardized creatinine¹⁸: GFR = 175 × (standardized serum creatinine)^-1.154 × (age)^-0.203 × 0.742(if the subject is a woman) × 1.212(if the subject is black). Estimated GFR is reported in ml/min/1.73 m². GFR, estimated from standardized serum creatinine, and ACR were used to define early stages of CKD according to the classification system established by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative² as follows: stage 1, persistent albuminuria with estimated GFR ≥ 90 ml/min/1.73 m²; stage 2, persistent albuminuria with estimated GFR of 60-89 ml/min/1.73 m²; stage 3, estimated GFR 30-59 ml/min/1.73 m²; stage 4, estimated GFR 15-29 ml/min/1.73 m².

Estimation of the proportion of individuals with CKD Stage 3 eligible for referral to a nephrologist followed the criteria proposed in the KDOQI hypertension guidelines.¹⁹ Using these guidelines, all individuals with eGFR < 30 ml/min/1.73 m² would be recommended for referral. Individuals with eGFR ≥ 30 ml/min/1.73 m² would be referred based on any of the following indications of increased risk for CKD progression: 1) presence of macroalbuminuria; 2) type II diabetes with microalbuminuria; 3) diabetic retinopathy; 4) hyperkalemia (serum potassium > 5.5 mEq/L); 5) resistant hypertension. For this analysis resistant hypertension was defined as systolic blood pressure > 130 mmHg or diastolic blood pressure > 80 mmHg, while taking three or more anti-hypertensive medications. This analysis excluded women who were pregnant or in menses, and was limited to NHANES III since this was the only survey with data on retinopathy.

The proportion of the US population with mild, moderate or severely reduced estimated GFR increased from 1988-1994 to 1999-2004. The combined prevalence estimate for 1999-2004 had similar precision to the 1988-1994 estimate while prevalence estimates from each of the three two year surveys had relatively wide confidence intervals (Figure 1). Moderately reduced GFR increased in prevalence from 5.4% to 7.7% (P<0.001) and severely reduced GFR increased from 0.21% to 0.35% (P=0.02). Similarly, the proportion of the overall population with microalbuminuria on a single occasion increased from 7.1% to 8.2% (P=0.01). The prevalence of macroalbuminuria rose somewhat from 1.1% to 1.3% but this difference was well within the limits of random variation (P=0.4). Subdividing the prevalence of albuminuria by different levels of estimated GFR showed that the prevalence of microalbuminuria rose significantly among individuals with normal estimated GFR while all other subgroups showed no significant rise or fall in albuminuria.¹¹

The prevalence estimate for each stage of CKD was higher in 1999-2004 than in 1988-1994 with the difference being statistically significant for CKD stages 2 to 4 and overall (Table 2). Stratified analyses by sex and race showed similar trends. The overall prevalences of CKD in 1988-1994 and 1999-2004 among men were 8.2% and 11.1%. Among women they were 12.1% and 15.0%. By ethnicity the change was from 10.5% to 13.8% among Non-Hispanic whites, 10.2% to 11.7% among non-Hispanic Blacks, and from 6.3% to 8.0% among Mexican Americans. After age adjustment prevalence odds ratios for estimated GFR < 60 ml/min/1.73 m² between 1999-2004 and 1988-1994 were of similar magnitude (between 1.4 and 1.5) and statistically significant in men, women, non-Hispanic whites and non-Hispanic blacks and Mexican-Americans. The association was somewhat weaker in the smaller number of individuals of other ethnicity. Trends over time were also similar within age categories indicating the trends were not due to age differences in the population (data not shown¹¹).

Differences in prevalence of decreased GFR and albuminuria between 1988-1994 and 1999-2004 remain substantial after adjustment for changes in the age, sex and race/ethnic composition of the US population over this time period (Table 3). The higher prevalence of diagnosed diabetes, hypertension, and higher body mass index explained some of the higher prevalence. For albuminuria trends, the higher prevalence was partly explained by the older age and high proportion of minority groups (odds ratio declined from 1.18 to 1.12 after adjustment). Further adjustment for the higher prevalence of diagnosed diabetes and hypertension and higher body mass index explained practically all of the difference (odds ratio declined to 1.03). In the fully adjusted models, the prevalence of albuminuria was strongly associated with diagnosed diabetes (OR 3.58; 95% CI 3.12-4.12) and hypertension (OR 1.70; 95% CI 1.1-1.92) as well as older age, and all race-ethnicity groups other than non-Hispanic whites (P<0.001) but not higher body mass index (P=0.1). The prevalence odds ratio of estimated GFR less than 60 ml/min/1.73 m² in 1999-2004 compared to 1988-1994 was 1.47. Age adjustment had little impact, likely because the increase in the number of older individuals was offset by a similar increase in the number of younger individuals leading the percentage of individuals aged 60+ years to remain relatively unchanged (Table 1). The prevalence odds ratio increased further to 1.53 after adjustment for age, sex and race due to the lower prevalence of decreased GFR among minority groups. The odds ratio decreased to 1.43 with additional adjustment for diagnosed diabetes and hypertension and body mass index. In the fully adjusted model, the prevalence of low GFR was strongly associated with diagnosed diabetes (OR 1.54; 95% CI 1.28-1.80) and hypertension (OR 1.98; 95% CI 1.73-2.67) as well as higher body mass index (OR 1.08; 95% CI 1.02-1.15 per 5 kg/m²) and older age but was lower among men, non-Hispanic blacks, and Mexican-Americans compared to non-Hispanic whites (P<0.001).

The conservative trends analysis showed that the difference in mean serum creatinine between surveys accounts for much but possibly not all of the higher prevalence of lower GFR in 1999-2004. In this analysis, the prevalence of CKD in 1988-1994 was higher (1.5%, 2.8%, 6.7%, and 0.23% for CKD stages 1 to 4 for a total of 11.3%). The prevalence odds ratio of estimated GFR less than 60 ml/min/1.73 m² comparing 1999-2004 to 1988-1994 was 1.17 (95% CI 1.02-1.34). After full adjustment in the conservative trends analysis the prevalence odds ratio of decreased GFR between surveys was 1.08 (0.94-1.24) indicating that the differences in mean serum creatinine, demographics, diagnosed diabetes, hypertension, and body mass index between surveys explain nearly all of the difference in prevalence of low GFR between 1988-1994 and 1999-2004 (P=0.3).

Since CKD Stage 3 includes a large number of individuals we examined the distribution of individuals in this stage across different characteristics (Table 4). As expected, the majority of individuals had a higher estimated GFR (45-59 ml/min/1.73 m² included 78.8% of all CKD stage 3 individuals adding the percentages across sex, age and albuminuria categories). Further, 61.5% of all individuals in CKD stage 3 had an estimated GFR between 45-59 ml/min/1.73 m² with no evidence of albuminuria. The table also shows the distribution of albuminuria, with 25.7% of CKD stage 3 individuals with and 74.3% without albuminuria, and age, where 22.1%, 22.7% and 55.2% were age <60, 60-69 and 70+ years. A total of 16.6% of individuals in CKD stage 3 had previously diagnosed diabetes, and slightly less than half of these had evidence of albuminuria (7.5% of all individuals in stage 3).

Surveillance for CKD should acknowledge that stages 1 to 5 differ markedly in their severity as well as prevalence. The most severe stages 4 and 5 have the lowest prevalence. However, since they have the highest rates of complications and medical costs, tracking them is vital. Given their low prevalence (~0.3% each) individuals with these stages are not well represented in population based surveys. It is also a concern that these individuals may have clinical symptoms and may be less likely to volunteer or come to an examination. Thus, alternative methods of surveillance for CKD stages 4 and 5 should be considered. We should look beyond the established surveillance for treated ESRD which combines the presence of kidney failure with the patient being offered and deciding to accept renal replacement therapy. Large health care organization and laboratory chains could be a useful way to track individuals with severe CKD, although inferences will be complicated by the non-random nature of participation in these systems. Data from the Department of Veterans Affairs _[EF2]on 2.6 million veterans age 18 to 100 with at least one outpatient serum creatinine measurement indicated that 5,300 (0.2%) had an estimated GFR of less than 15 without being on dialysis, while 14,637 (0.6%) were treated for ESRD.²⁰ The amount of time spent in stage 5 CKD without treatment is relatively short since annual ESRD incidence is 70-80% for veterans aged less than 65 and decreased to 29% after age 85. In contrast, mortality rates increased from 3% below the age of 44 to 49% after the age of 85 years.²¹

Population based surveys can be very useful for CKD stages 1-3 and with large surveys CKD stage 4. However, within these stages it would be useful to also track the distribution of albuminuria and other markers of severity and likelihood of complications and progression. For example, while the prevalence of CKD stage 3 based on NHANES 1988-1994 and 1999-2004 increased from 5.4% to 7.7%, the estimated proportion of these individuals with albuminuria decreased somewhat such the proportion of the population with both moderately decreased GFR and albuminuria increased from 1.5% to 1.9% (calculated from Table 2 of Coresh et al.¹¹).

It is useful to evaluate criteria for potential action as well as the evidence for these criteria. We evaluated a set of proposed criteria for referral to a nephrologist which suggest that while all CKD stage 4 and 5 patients (n ~ 1.1 million) should see a nephrologist only 18.6% of individuals in stage 3 (n ~ 2.9 million) should be referred. Concerning individuals with estimated GFR above 60 mg/ml/1.73 m² and albuminuria 30.8% (n ~ 3.0 million) should be referred, a majority of these due to presence of macroalbuminuria (69.2%, SE 2.3%), although these estimates do not incorporate persistence data. Further studies evaluating the evidence for such criteria and the impact of such referral are needed. However, initial estimates can be useful to assess the potential impact of recommendations, policies or ad-hoc practice patterns.