we used data from three long - term follow - up studies of the risk of esrd : two previously published studies of patients with type 1 diabetes ( t1d ) and proteinuria ( 14,15 ) and one study of patients with type 2 diabetes ( t2d ) ( 16 ) . from each study we included only patients with ckd stages 13 as determined by serum creatinine concentration and the ckd - epi formula ( egfrcreat ) the protocols and consent procedures for each study were approved by the relevant institutional review board . written informed consent was obtained from each participating patient . a brief description of each study follows . the joslin clinic is a large center for the treatment of patients of all ages with diabetes , regardless of type . most patients come to the clinic within 5 years of diagnosis , and many remain with the clinic for decades , receiving integrated care from endocrinologists , nephrologists , and ophthalmologists . about one - fourth of the 16,000 patients under the care of the clinic have t1d . between 1991 and 2004 , we recruited 423 patients with t1d and proteinuria for studies of the genetics of diabetic nephropathy . details of the selection , examination , and follow - up of this cohort were provided in a previous publication ( 14 ) . the analysis in this report includes the 364 caucasian patients with ckd stage 13 at baseline . these patients were monitored through 2008 for the occurrence of esrd or death unrelated to esrd . between 1991 and 1995 , we recruited 560 patients with t2d ( half with normoalbuminuria and half with microalbuminuria or proteinuria ) for studies of the genetics of diabetic nephropathy . details of the selection , examination , and follow - up of this cohort were provided in a previous publication ( 16 ) . the analysis in this report includes 402 patients ( 93% caucasian ) with ckd stage 13 at baseline for whom baseline serum was available for biochemical examination . the cohort was monitored through 2004 for the occurrence of esrd or death unrelated to esrd . the cohort used in this study is part of the ongoing nationwide , multicenter finndiane study . the patients included in the present analysis had their baseline examination between 1995 and 2006 . those with proteinuria at baseline were included in a study of the risk of esrd and death unrelated to esrd , the results of which were recently reported ( 15 ) . the analysis in this report includes 399 caucasian patients with ckd stage 13 at baseline , for whom baseline serum was available for biochemical measurements . the cohort was monitored through 2008 for the occurrence of esrd or death unrelated to esrd . enrollment examinations were performed by trained recruiters in all studies and included a structured interview about medical history , blood pressure measurements , and anthropometric measurements . the data obtained at the baseline examination were supplemented with clinical data from medical records ( 1416 ) . baseline characteristics of the three cohorts with diabetes in 2009 and 2010 , creatinine and cystatin c were assayed in stored baseline serum samples from the three cohorts in the advanced research and diagnostic laboratory at the university of minnesota . the method is calibrated to be traceable to an isotope dilution mass spectrometry creatinine reference method , and the calibration has been verified by regularly measuring national institute of standards and technology standard reference material ( nist srm ) no . the gfr was estimated from the serum concentration of creatinine in milligrams per deciliter with the egfrcreat formula ( 4 ) and the egfrmdrd formula ( 4 ) . serum cystatin c was measured with a particle - enhanced immunonephelometric assay using reagents from siemens - dade - behring on a bn prospec ( siemens healthcare diagnostics , inc . , serum cystatin c assay was standardized by traceability to higher - order primary reference materials by multiplying the values obtained at the university of minnesota laboratory by 1.12 ( 17 ) . the gfr was then estimated from the serum concentration of standardized cystatin c in milligrams per liter using the published egfrcyst formula ( 9,17 ) : egfrcyst = 127.7  ( 0.105 + 1.13  standardized cystine )  age  ( 0.91 if female )  ( 1.06 if black ) . patients enrolled were monitored for the development of esrd or death by matching the study roster against the medical records of the joslin clinic , the united states renal data system and the national death index . the onset of esrd was recorded as the date of the first renal transplant ( if it was preemptive kidney transplant ) or renal dialysis . the most recent query took place in october 2010 and covered all incident cases of esrd between 1991 and the end of 2008 . living subjects who were free of esrd we were able to ascertain the status ( alive , esrd , or death ) of 98% of the subjects through 2008 . deaths , regardless of cause , were identified by a search of the finnish national death registry and center databases through 24 march 2009 . esrd was defined as a requirement for dialysis or kidney transplant and identified via a search of renal registries and center databases and verified in medical records . . analyses were conducted in sas 9.2 software ( sas institute , cary , nc ) . the joslin clinic is a large center for the treatment of patients of all ages with diabetes , regardless of type . most patients come to the clinic within 5 years of diagnosis , and many remain with the clinic for decades , receiving integrated care from endocrinologists , nephrologists , and ophthalmologists . about one - fourth of the 16,000 patients under the care of the clinic have t1d . between 1991 and 2004 , we recruited 423 patients with t1d and proteinuria for studies of the genetics of diabetic nephropathy . details of the selection , examination , and follow - up of this cohort were provided in a previous publication ( 14 ) . the analysis in this report includes the 364 caucasian patients with ckd stage 13 at baseline . these patients were monitored through 2008 for the occurrence of esrd or death unrelated to esrd . between 1991 and 1995 , we recruited 560 patients with t2d ( half with normoalbuminuria and half with microalbuminuria or proteinuria ) for studies of the genetics of diabetic nephropathy . details of the selection , examination , and follow - up of this cohort were provided in a previous publication ( 16 ) . the analysis in this report includes 402 patients ( 93% caucasian ) with ckd stage 13 at baseline for whom baseline serum was available for biochemical examination . the cohort was monitored through 2004 for the occurrence of esrd or death unrelated to esrd . the cohort used in this study is part of the ongoing nationwide , multicenter finndiane study . the patients included in the present analysis had their baseline examination between 1995 and 2006 . those with proteinuria at baseline were included in a study of the risk of esrd and death unrelated to esrd , the analysis in this report includes 399 caucasian patients with ckd stage 13 at baseline , for whom baseline serum was available for biochemical measurements . the cohort was monitored through 2008 for the occurrence of esrd or death unrelated to esrd . between 1991 and 2004 , we recruited 423 patients with t1d and proteinuria for studies of the genetics of diabetic nephropathy . details of the selection , examination , and follow - up of this cohort were provided in a previous publication ( 14 ) . the analysis in this report includes the 364 caucasian patients with ckd stage 13 at baseline . these patients were monitored through 2008 for the occurrence of esrd or death unrelated to esrd . between 1991 and 1995 , we recruited 560 patients with t2d ( half with normoalbuminuria and half with microalbuminuria or proteinuria ) for studies of the genetics of diabetic nephropathy . details of the selection , examination , and follow - up of this cohort were provided in a previous publication ( 16 ) . the analysis in this report includes 402 patients ( 93% caucasian ) with ckd stage 13 at baseline for whom baseline serum was available for biochemical examination . the cohort was monitored through 2004 for the occurrence of esrd or death unrelated to esrd . the cohort used in this study is part of the ongoing nationwide , multicenter finndiane study . the patients included in the present analysis had their baseline examination between 1995 and 2006 . those with proteinuria at baseline were included in a study of the risk of esrd and death unrelated to esrd , the results of which were recently reported ( 15 ) . the analysis in this report includes 399 caucasian patients with ckd stage 13 at baseline , for whom baseline serum was available for biochemical measurements . the cohort was monitored through 2008 for the occurrence of esrd or death unrelated to esrd . enrollment examinations were performed by trained recruiters in all studies and included a structured interview about medical history , blood pressure measurements , and anthropometric measurements . the data obtained at the baseline examination were supplemented with clinical data from medical records ( 1416 ) . in 2009 and 2010 , creatinine and cystatin c were assayed in stored baseline serum samples from the three cohorts in the advanced research and diagnostic laboratory at the university of minnesota . the method is calibrated to be traceable to an isotope dilution mass spectrometry creatinine reference method , and the calibration has been verified by regularly measuring national institute of standards and technology standard reference material ( nist srm ) no . the gfr was estimated from the serum concentration of creatinine in milligrams per deciliter with the egfrcreat formula ( 4 ) and the egfrmdrd formula ( 4 ) . serum cystatin c was measured with a particle - enhanced immunonephelometric assay using reagents from siemens - dade - behring on a bn prospec ( siemens healthcare diagnostics , inc . , serum cystatin c assay was standardized by traceability to higher - order primary reference materials by multiplying the values obtained at the university of minnesota laboratory by 1.12 ( 17 ) . the gfr was then estimated from the serum concentration of standardized cystatin c in milligrams per liter using the published egfrcyst formula ( 9,17 ) : egfrcyst = 127.7  ( 0.105 + 1.13  standardized cystine )  age  ( 0.91 if female )  ( 1.06 if black ) . patients enrolled were monitored for the development of esrd or death by matching the study roster against the medical records of the joslin clinic , the united states renal data system and the national death index . the onset of esrd was recorded as the date of the first renal transplant ( if it was preemptive kidney transplant ) or renal dialysis . the most recent query took place in october 2010 and covered all incident cases of esrd between 1991 and the end of 2008 . living subjects who were free of esrd we were able to ascertain the status ( alive , esrd , or death ) of 98% of the subjects through 2008 . deaths , regardless of cause , were identified by a search of the finnish national death registry and center databases through 24 march 2009 . esrd was defined as a requirement for dialysis or kidney transplant and identified via a search of renal registries and center databases and verified in medical records . patients enrolled were monitored for the development of esrd or death by matching the study roster against the medical records of the joslin clinic , the united states renal data system and the national death index . the onset of esrd was recorded as the date of the first renal transplant ( if it was preemptive kidney transplant ) or renal dialysis . the most recent query took place in october 2010 and covered all incident cases of esrd between 1991 and the end of 2008 . living subjects who were free of esrd we were able to ascertain the status ( alive , esrd , or death ) of 98% of the subjects through 2008 . deaths , regardless of cause , were identified by a search of the finnish national death registry and center databases through 24 march 2009 . esrd was defined as a requirement for dialysis or kidney transplant and identified via a search of renal registries and center databases and verified in medical records . analyses were conducted in sas 9.2 software ( sas institute , cary , nc ) . demographic clinical characteristics of the two t1d cohorts were similar , whereas those of the joslin t2d cohort were quite different . age at diabetes diagnosis was almost 30 years older ; current age was older , and duration of diabetes was shorter . body weight and blood pressure were higher , whereas urinary albumin excretion ( measured as the albumin - to - creatinine ratio ) was lower and egfr was higher . moreover , the incidence rate of esrd was lower and the mortality rate due to death unrelated to esrd was higher than in the t1d cohorts . the three cohorts differed to some degree in endogenous markers of renal function . in the finndiane cohort , the concentration of creatinine was higher than in the t1d joslin cohort , whereas the concentration of cystatin c was lower . as a consequence of these differences , mean egfrcreat and egfrmdrd were slightly lower in the finndiane cohort ( p = 0.02 ) than in the joslin cohort ( p = 0.01 ) and mean egfrcyst was higher ( p = 0.02 ) . as expected , serum concentrations of creatinine and cystatin c in the joslin t2d cohort were substantially lower than in the t1d cohorts . the distributions of patients in each cohort according to ckd stage determined by egfrcreat and then partitioned by egfrcyst stage are reported in table 2 . for example , in the joslin t1d cohort , those numbers ( 87 + 55 + 75 ) add to 217 , which is 60% of the cohort ( n = 364 ) . concordance was similar in the joslin t2d cohort ( 65% ) and somewhat higher in finndiane ( 73% ) . however , discordant staging in the finndiane cohort differed from that in the joslin cohorts . it was symmetric in the finndiane cohort ( egfrcyst stage higher for 16% and lower for 11% ) but very asymmetric in both joslin cohorts ( egfrcyst stage was higher than egfrcreat stage for 35% and lower for only 3% ) . this difference in the pattern of discordant classification in the joslin and finndiane cohorts was highly significant ( p < 0.0001 ) . distribution of patients according to ckd stage defined by egfrcreat and partitioned by egfrcyst stage we determined the esrd incidence rate in each cell of table 2 to assess what effect the partitioning of egfrcreat stages according to egfrcyst stages had on the risk of esrd . the incidence rates are reported in table 3 . the partitioning produced subgroups within each egfrcreat stage with a gradient of increasing esrd risk ; moreover , the gradient was very similar within each of the three cohorts . thus , despite the differences among the cohorts , staging each egfrcreat stage by egfrcyst stage , consistently , added information about the risk of esrd . by contrast , the partitioning by egfrcreat ( along the columns ) of patients within an egfrcyst stage did not result in comparable gradients . incidence rate of esrd in each cohort according to ckd stage defined by egfrcreat and partitioned by ckd stage defined by egfrcyst the incidence rates of esrd during follow - up that were reported in table 3 can also be summarized by actuarial methods as 10-year cumulative risks of esrd ( fig . this representation of esrd risk is probably easier for clinicians and patients to interpret when considering prognosis . figure 1 shows the combined results from a stratified modeling of the joslin and the finndiane t1d cohorts . relative to the subgroups where the egfrcyst and egfrcreat stages agree ( bars ) , the 10-year risks were lower ( bars ) if the egfrcyst stage was lower than the egfrcreat stage , and higher ( bars ) if the egfrcyst stage was higher . for t2d , the 10-year risks were also higher if the egfrcyst stage was higher than the egfrcreat stage , but if it was lower , the 10-year risk could not be estimated because no esrd occurred among the few patients there ( data not shown ) . the analyses in tables 2 and 3 were repeated using ckd stages based on egfrmdrd and the pattern of esrd risk was the same ( supplementary tables 1 and 2 ) . ten - year cumulative risks of esrd in patients with t1d were calculated by actuarial methods according to ckd stages determined jointly by egfrcrea and egfrcyst . the pattern of differences was similar in the joslin and finndiane cohorts of t1d , so the cohorts were pooled as a single cohort . we tested the statistical significance of differences presented in table 3 using a cox proportional hazard model of time to esrd with adjustment for cohort differences in urinary albumin excretion and ace inhibitor / angiotensin receptor blocker use . because the results within each cohort were similar ( table 4 ) , we tested for significant heterogeneity of the hazard ratios ( hrs ) across cohorts in a joint model and found none ; therefore , the cohorts were combined for the final analysis . for patients with concordant staging by both egfrcyst and egfrcreat , the summary hr for a one - step increase in ckd stage was linear ( 3.3 [ 95% ci 2.74.0 ] ) . for patients with discordant staging , the risk of esrd for patients with an egfrcyst stage higher than their egfrcreat stage was significantly higher than for those with concordant stages ( summary 2.3 [ 1.83.1 ] ) . similarly , the risk for patients with an egfrcyst stage lower than their egfrcreat was significantly lower than that for those with concordant stages ( summary 0.30 [ 0.130.68 ] ) . analysis of time to onset of esrd in each cohort according to ckd stage defined by egfrcreat and partitioned by egfrcyst stage altogether , only 159 deaths were unrelated to esrd in the three cohorts , and cardiovascular deaths accounted for approximately two - thirds ( supplementary table 1 ) . we analyzed the mortality rate in the same way as the incidence rates of esrd . the patterns of findings were similar to those for esrd , but the effect of partitioning of egfrcreat stages according to egfrcyst had a smaller effect on the mortality rates ( supplementary tables 1 and 2 ) . the number of cvd deaths was too small to perform a separate analysis for such deaths . patients with diabetes have a very high risk of developing esrd as well as a high risk of dying without developing esrd . in this report , we show for the first time that , for young or middle - aged diabetic patients in ckd stages 13 ( based on routine measurements of serum creatinine ) , a secondary assessment of renal function based on serum cystatin c significantly improves esrd risk stratification . this finding applies to caucasian patients with t1d and t2d in boston as in finland and is true regardless of whether the initial ckd stage is based on the ckd - epi or mdrd study formulas . ckd staging by both egfrcreat and egfrcyst resulted in significant discrepancies in approximately 2535% of patients . in the joslin cohorts , this is consistent with the evidence that creatinine - based formulas underestimate gfr in the normal range . therefore , it is the symmetric pattern of discordant staging in the finndiane cohort that is unexpected . although the reason for this difference is unclear , we hypothesize that the modestly higher serum creatinine in the finndiane cohort was responsible . factors other than gfr are known to influence serum creatinine , so population differences most likely exist . they may be due to differences in muscle mass or diet and do not necessarily imply population differences in kidney function . estimates based on a population with a different distribution of serum creatinine concentrations , such as the finndiane cohort , will be biased . if the higher creatinine in finndiane is due to something other than gfr ( as seems most likely ) , the ckd - epi formula underestimates their gfr and overestimates their ckd stage . this would counter the tendency of egfrcreat to underestimate renal function and result in the symmetric pattern of discordance in the finndiane cohort . although the difference between the distributions of serum creatinine concentrations in the joslin and finndiane cohorts raises concerns about the applicability of the mdrd and ckd - epi formulas across diverse populations , the significantly improved esrd risk stratification provided by a secondary assessment of renal function based on serum cystatin c is robust against these population differences . the partitioning of each egfrcreat stage by egfrcyst stage distinguishes a significant gradient of risk , with the risk increasing as egfrcyst stage increases . interestingly , although the pattern of discordant ckd stages depends on whether the egfrcreat ( ckd - epi ) or egfrmdrd ( mdrd ) formula is used , the pattern of a risk gradient with egfrcyst stage within each egfrmdrd stage persists ( data not shown ) . should measurement of serum cystatin c replace measurement of serum creatinine in clinical settings or supplement it in selected patients is a question that arises . first , one must take into account that patients with diabetes have a much higher risk of esrd than the general population and may require special consideration . second , although ckd staging based on the serum creatinine concentration and the mdrd or ckd - epi formula is inexpensive and already in routine clinical use , secondary ckd staging based on serum cystatin c concentration of patients with normal or nearly normal gfr improves stratification of esrd risk and limits the extra expense to the subset of patients who can benefit most . whether this extra expense is justified depends on the cumulative risk of esrd ( as illustrated in fig . 1 ) and the value of improved detection of patients at high risk of esrd . the question deserves a formal cost - benefit analysis , which is beyond the scope of this report . it is unclear that we can attribute the ability of egfrcyst to refine a prediction of esrd based on egfrcreat simply to an improved estimate of renal function and , hence , a more accurate determination of how much renal function must be lost to reach esrd . only a marginal difference between egfrcreat and egfrcyst has been found in cross - sectional comparisons of them with a direct measurement of gfr ( iothalamate clearance ) in nondiabetic individuals ( 911 ) . another possibility is that serum cystatin c concentration carries additional information about the risk of other adverse outcomes . in the elderly general population , for example , the serum concentration of cystatin c is a more accurate predictor of death due to cvd than serum creatinine ( 12 ) . possibly , variation in serum cystatin c reflects a mechanism or risk factor involved in cvd that is unrelated to renal function ( 18 ) . the multi - ethnic study of atherosclerosis ( mesa ) and cardiovascular health study ( chs ) demonstrated that for patients with ckd stages 3 according to the creatinine - based ckd - epi equation , an adverse prognosis was limited to the subset of patients who had ckd stages 3 according to egfrcyst ( 13 ) . the adverse outcomes included death , cardiovascular event , heart failure , and kidney failure . in a recent analysis of the reasons for geographic and racial differences in stroke ( regards ) study of middle - aged individuals , adding cystatin c to measures of creatinine and urinary albumin excretion improved the predictive accuracy for all - cause mortality and esrd ( 19 ) . there is general agreement between our results and those obtained in these other studies , namely , that measurement of serum cystatin c has value in assessing risk of esrd and death . the studies in nondiabetic patients with ckd 3 ( by egfrcreat ) showed that egfrcyst is a predictor of esrd and death . our study in patients with diabetes showed that discordant ckd staging by egfrcreat and egfrcyst added particularly to the prediction of esrd risk , the principal risk for this population . thus , its utility is not diminished by the fact that the relationship of serum cystatin c with mortality risk in diabetes , so well documented in nondiabetic subjects ( 12,13,19 ) , is only marginally confirmed in our diabetic cohorts . in summary , the risk of esrd increases with each stage of ckd , but partitioning of each egfrcreat stage by egfrcyst stage distinguishes a significant gradient of risk , with the risk increasing as egfrcyst stage increases . the information gained from discordant ckd staging can be important clinically for advising patients about their risk of esrd or to tailor interventions to their level of risk . this finding applies to caucasian patients with t1d and t2d in boston as in finland and is true regardless of whether the initial ckd stage is based on the ckd - epi or mdrd study formulas .
objectivepatients with diabetes have a high risk of end - stage renal disease ( esrd ) . 
 we examined whether prediction of this outcome , according to chronic kidney disease ( ckd ) staging by creatinine - based estimates of the glomerular filtration rate ( egfrcreat ) , is improved by further staging with serum cystatin c  based estimates ( egfrcyst).research design and methodspatients with diabetes in ckd stages 13 were selected from three cohorts : two from joslin diabetes center , one with type 1 diabetes ( n = 364 ) and one with type 2 diabetes ( n = 402 ) , and the third from the finnish diabetic nephropathy ( finndiane ) study of type 1 ( n = 399 ) . 
 baseline serum concentrations of creatinine and cystatin c were measured in all patients . 
 follow - up averaged 810 years and onsets of esrd ( n = 246 ) and death unrelated to esrd ( n = 159 ) were ascertained.resultsalthough ckd staging by egfrcyst was concordant with that by egfrcreat for 62% of joslin patients and 73% of finndiane patients , those given a higher stage by egfrcyst than egfrcreat had a significantly higher risk of esrd than those with concordant staging in all three cohorts ( hazard ratio 2.3 [ 95% ci 1.83.1 ] ) . 
 similarly , patients at a lower stage by egfrcyst than by egfrcreat had a lower risk than those with concordant staging ( 0.30 [ 0.130.68 ] ) . 
 deaths unrelated to esrd followed the same pattern , but differences were not as large.conclusionsin patients with diabetes , ckd staging based on egfrcyst significantly improves esrd risk stratification based on egfrcreat . 
 this conclusion can be generalized to patients with type 1 and type 2 diabetes and to diabetic patients in the u.s . and 
 finland .