Our cohort study is the first to comprehensively examine the prevalence of CKD (stage 3 or greater) in the adult population with CF and to identify predictors of incident disease. Previous observational studies have looked at ARF (6
) or have been small and used non–guidelines-based definitions of CKD (3
Based on our results, moderate severity CKD is not uncommon in patients with CF with an annual disease prevalence of about 2% and prevalence that doubles with every 10-year increase in age. Previous studies in the general population have shown that advanced age is an independent risk factor for CKD (7
). Our age-adjusted prevalence estimates for CKD (stage 3 or greater) are about twofold higher than estimates from the United States general population using 1999–2004 National Health and Nutrition Examination Survey data (17
). Earlier stages of CKD often progress to end-stage renal disease (18
). This seemed to be the case in our cohort with up to one-quarter of cases with moderate-severity CKD requiring hemodialysis in short-term follow-up.
An important finding of this study is that CFRD requiring insulin is an important risk factor for CKD in the adult population with CF. The increase in risk with duration of disease is compatible with the natural history of diabetic microvascular complications, because diabetic nephropathy tends to arise 10–15 years after diabetes diagnosis (19
). Although it seems that we see an increase in risk much earlier, our exposure times reflect minimum values, because we were unable to capture lifetime exposure. This key finding is interesting in light of a recent statement on behalf of the American Diabetes Association and CF-related Diabetes Consensus Report Committee that the “kidneys may be somewhat protected in CFRD” because of residual insulin secretion, and the absence of other known risk factors for microvascular disease, including hypertension and hyperlipidemia (8
). Our findings support a recent study by van den Berg and coworkers (10
) comparing the microvascular complications of CFRD with type 1 diabetes. They found a similar rate of overall microvascular complications between the two types of diabetes but a much higher rate of microalbuminuria (21% vs. 4%; P
= 0.003) in CFRD. Our registry-based definition of CFRD was rigorous, because it required that the subject be on chronic insulin therapy. Although this may result in selection bias for those patients with more severe CFRD, this definition is generalizable because about 65% of patients with CFRD are chronic users of insulin as coded in the CF registry.
Cumulative number of acute pulmonary exacerbations (surrogate for cumulative IV aminoglycoside exposure) did not independently increase the risk of CKD in this study. Previous studies have found an increased risk of renal dysfunction after IV aminoglycoside exposure (3
). IV aminoglycosides are directly toxic to the kidneys but the precise mechanism leading to nephrotoxicity remains uncertain (21
). In addition to tubular damage, renal vasoconstriction and mesangial contraction are suspected to play important roles at the glomerular level (22
). There are a number of potential reasons why our findings are inconsistent with previous studies. First, we used a very crude proxy measure for IV aminoglycoside exposure because of a lack of detailed information available on this exposure in the CF Registry. Although cumulative number of IV aminoglycoside courses likely correlates with cumulative number of acute pulmonary exacerbations, we are uncertain as to what proportion of acute pulmonary exacerbations actually required IV aminoglycoside antibiotics. If this proportion was small, the impact of nondifferential misclassification of exposure may have been significant, thus leading to an underestimation of risk. We restricted our analysis to individuals with P. aeruginosa
infection because they were more likely to require IV aminoglycosides during acute pulmonary exacerbations but we still failed to demonstrate a relationship between number of acute pulmonary exacerbations and CKD risk. A more likely reason for our negative findings is that we had a relatively short exposure period and therefore we may have failed to detect an increase in risk because of limited cumulative drug exposure. In previous studies, renal function was inversely associated with lifetime IV aminoglycoside exposure (3
). We conducted a sensitivity analysis restricting to CKD cases with normal renal function on cohort entry because they had a slightly longer exposure period before CKD diagnosis but we still failed to detect an association between number of acute pulmonary exacerbations and CKD risk.
Although homozygosity for the delta F508 CFTR mutation seemed to increase the risk of CKD in age-adjusted analysis, it was not an independent predictor after adjustment in multivariate analysis. Most of the age-adjusted increased risk was likely caused by confounding by CFRD, because CFRD is a strong predictor of CKD and is also more prevalent in individuals homozygous for the delta F508 CFTR mutation. This supports previous speculation that CFTR mutations do not predispose to major renal dysfunction despite abundant expression of CFTR in the renal cortex and outer medulla (2
), and evidence of reduced renal excretion of NaCl and decreased capacity to dilute and concentrate urine (23
We found that an increase in the number of years of inhaled tobramycin use had a slightly protective effect on the risk of developing CKD. This finding is reassuring, because previous case reports have suggested nephrotoxicity related to inhaled tobramycin use (25
), which was not observed in randomized clinical trials using this drug (27
). Although speculative, a possible explanation for this observed protective effect is that individuals on maintenance inhaled tobramycin therapy are less likely to develop acute pulmonary exacerbations resulting in reduced exposure to potentially nephrotoxic IV antibiotics.
Although our study demonstrates a strong association between CFRD requiring insulin and CKD, epidemiologic studies are susceptible to biases that may influence the results and therefore we undertook multiple sensitivity analyses to ensure our results were robust. We were concerned about possible case ascertainment bias because those patients with risk factors for CKD might be more likely to have their serum creatinine measured. As an example, serum creatinine is routinely measured around the time of IV aminoglycoside use because of concerns about nephrotoxicity. Because measurement of serum creatinine is required to make a diagnosis of CKD, presence of a potential risk factor can lead to higher rates of diagnosis, thus inducing a spurious association. We thus limited our analysis to centers that monitored serum creatinine in greater than 70% of their enrolled patients to minimize this possible selection bias. Our relative risk estimates actually increased after this sensitivity analysis and therefore we do not believe case ascertainment bias was a significant issue in our analysis. The strong relative risk estimates, positive dose–response relationship, and a post hoc analysis demonstrating an even higher risk for those with CFRD complicated by microalbuminuria all support the biological plausibility of this association.
Another limitation of our study is that we relied on serum creatinine to estimate renal function. Diagnosis of earlier stages of CKD (stages 1 and 2) require evidence of kidney damage on urine or nuclear testing but this information was not available through the CF Registry (14
). Diagnosis of renal dysfunction using serum creatinine alone is subject to interpretation error because baseline serum creatinine decreases with low muscle mass and malnutrition, which are prevalent in the CF population. Therefore, we used the Cockcroft-Gault formula to estimate glomerular filtration rate as it adjusts for age, body mass, and sex. We also performed a sensitivity analysis using the abbreviated modified diet in renal disease (aMDRD) equation, which adjusts for similar factors plus ethnicity. Our CKD prevalence estimates were similar for the two estimating equations with a slightly higher rate of CKD diagnosis using the aMDRD equation. Without a gold standard available for comparison, it is difficult to know which prediction equation performs better. Unfortunately, there is no consensus on the best creatinine-based estimating equation for glomerular filtration rate in patients with CF, although one study found Cockcroft-Gault to be superior to aMDRD (32
). Choice of estimating equation is unlikely to influence the diagnosis of more advanced disease (as demonstrated in our study) but may play an important role in identifying borderline cases of renal dysfunction. Urinary biomarkers, such as N
-acetyl-β-D-glucosaminidase, may play a role in detecting earlier kidney injury (21
Another limitation of this study is the relatively short follow-up period of our cohort, with a median follow-up of just 4 years. The short follow-up period is potentially a significant limitation in the assessment of the association between our cumulative exposure covariates and CKD. Ideally, we would have looked at lifetime exposure but this was not possible with the data available in the CF Registry. For a cumulative exposure variable, such as CFRD, cumulative exposure during the short follow-up period of our cohort likely correlates with lifelong exposure because most individuals with CFRD were likely diagnosed many years previously. This is probably why we were able to establish such a strong association between CFRD requiring insulin and CKD with an exposure period of just 1–4 years. The suspected correlation between short-term and lifetime exposure observed with CFRD may not be true for acute pulmonary exacerbations, and thus remains a potential limitation.
Finally, the overall prevalence of exposure to ibuprofen was low at just 2.5%. The highest observed use of ibuprofen was in the youngest age groups also at the lowest risk for developing CKD. We thus had limited statistical power to detect an association between this exposure and CKD, leading to a possible Type II error. Therefore, we cannot exclude the possibility of increased risk of CKD after ibuprofen use.
Given the dramatic increase in disease prevalence observed with advancing age, we anticipate that the prevalence of CKD will rise with improvements in survival of the CF population. CKD diagnosis can pose a significant challenge to physicians caring for patients with CF. Doses of nephrotoxic antibiotics, such as IV tobramycin and colistin, that are relied on heavily to treat resistant strains of Pseudomonas
must be altered or sometimes avoided altogether. Earlier stages of CKD can progress to end-stage disease with its attendant complications, including the need for dialysis. More importantly, a diagnosis of CKD can result in preclusion from lung transplant consideration given the significant risk of progressive renal dysfunction in the posttransplant setting (34
), or result in worse outcomes in those transplanted with milder degrees of renal dysfunction (35
). With all these potential implications in mind, diagnosing and aggressively managing CFRD is of paramount importance to decrease the risk of CKD.
In conclusion, to assess the prevalence and predictors of incident cases of CKD in adults with CF we have longitudinally analyzed nearly 12,000 individuals with CF for a median follow-up period of 4 years from 2001–2008. During that period, 204 individuals were diagnosed with stage 3 CKD, with a disease prevalence of 2.3% and incidence rate of 4 events per 1,000 person-years. After controlling for other independent predictors and potential confounders, the results suggest that CFRD is a strong risk factor for CKD but that IV aminoglycoside exposure requires further study.