the incidence of end - stage kidney disease ( esrd ) requiring renal replacement therapy ( rrt ) due to type 2 diabetic nephropathy ( dn ) in the medicare esrd program is 3550% , reported by the united states renal data system ( usrds ) . at rrt initiation , type 2 diabetes mellitus ( dm ) with renal manifestations ( code 250.40 ) is the most frequently reported primary cause of esrd on the centers for medicare & medicaid ( cms ) esrd medical evidence report form ( cms2728 ) , accounting for over 40% of all incident esrd in 2013 , with an incidence of approximately 0.2% of the us diabetic population per year . most receive the diagnosis on clinical presentation alone , based on a well - described and specific disease course , and few have a renal biopsy . although dn has characteristic biopsy findings , there is no specific treatment once established , other than blood pressure and glucose control , and treatment with renin diagnosis is defined by the 2007 kidney disease outcomes quality initiative ( kdoqi ) practice guidelines . patients must have either ( i ) macroalbuminuria ( albumin to creatinine ratio   > 300  mg / g ) or ( ii ) microalbuminuria ( 30300  mg protein / g creatinine ) and associated diabetic retinopathy , with no evidence of another glomerular or systemic disease associated with esrd . this includes sudden presentation with nephrotic range proteinuria , active urine sediment or rapid glomerular filtration rate ( gfr ) decline . it is unknown what percentage of patients identified on the cms2728 as having type 2 dn as the primary cause of esrd actually meet these diagnostic criteria . because usrds reports on the causes of esrd are highly cited and may be used to justify allocation of resources , including research , further scrutiny is warranted . the usrds annual data report includes the paragraph ,  primary cause of esrd : a cautionary note , acknowledging that reliability of clinician - assigned primary causes of esrd is not well established . even among patients with glomerular disease diagnoses established by renal biopsy , agreement between the cms2728 primary cause of esrd and biopsy results were low , with the cause of esrd field left blank in 57% of forms . we hypothesized that the cms2728 would tend to overestimate , rather than underestimate , type 2  dm as a cause of esrd . to investigate this hypothesis , we performed a single center , retrospective cohort study to determine the incidence of type 2  dm reported as the primary cause of esrd ( code 250.40 ) on all adult patients who had a cms2728 form submitted at rrt initiation over a 9-year period . we further determined the percentage of patients so identified who met kdoqi criteria for type 2 dn , and compared their demographic and clinic characteristics with those who did not meet kdoqi criteria . this was a retrospective , cohort study of all adult military health care beneficiaries ( aged 18 years or older ) whose cms2728 form was submitted at initiation of rrt ( including kidney transplant ) at walter reed army medical center / walter reed national military medical center , located in esrd network 5 . the beginning of this time period coincided with implementation of the present cms2728 . on the form , the study was reviewed and approved by the walter reed national military medical center institutional review board ( study # 413443 ) , as a minimal risk protocol with waiver of informed consent . subjects were identified from the nephrology service social work cms2728 database , during the time period above . if their rrt modality changed , individual esrd patients may have had more than one cms2728 form submitted . in individual patients who had forms dated within 90 days of one another , the earliest dated form was included , and the other(s ) excluded . if forms were dated  > 90 days apart , both submissions were counted toward the incidence denominator . the database was sorted to identify all those who received a diagnosis code 250.40 ( diabetes with renal manifestations type 2 ) , who were then counted for the incidence numerator , and entered as subjects into the subsequent part of the study . patients with esrd secondary to type 1  dm ( code 250.41 ) were excluded . copies of the cms2728 for each of these were reviewed , as well as the information from the electronic medical record in the years preceding rrt initiation , extending back to 2003 . pertinent demographic and clinical data were collected to include age at esrd , sex , race , year of rrt initiation , type of rrt ( peritoneal dialysis , hemodialysis or transplantation ) , year of type 2  dm diagnosis , year of dn diagnosis , diabetes medications , hgba1c at rrt initiation , body mass index at rrt initiation , history of smoking and history of hypertension / years of hypertension at rrt initiation . clinical and historical information were collected to determine whether the subjects met kdoqi 2007 criteria for diagnosis of type 2 dn : serum creatinine , imaging studies , urine sediment at diagnosis , other renal diagnoses , macroalbuminuria at diagnosis ( and amount ) , microalbuminuria at diagnosis ( and amount ) , retinopathy diagnosis and date of positive or negative ophthalmologic examination , neuropathy diagnosis and date , gastropathy diagnosis and date , chf diagnosis and date , presence of vascular disease and manifestation . type 2 dn as the cause of esrd was based on the kdoqi 2007 criteria , and was deemed present if : ( i ) biopsy diagnosis of dn was present , ( ii ) macroalbuminuria ( albumin to creatinine ratio  >  300 mg / g ) was present or ( iii ) microalbuminuria ( 30300  mg protein / g creatinine ) and associated diabetic retinopathy was present . the diagnosis of type 2 dn was questioned if the subject presented initially with nephrotic syndrome , active urine sediment , an alternative diagnosis , rapidly declining estimated gfr ( egfr ) , or was without micro- or macroalbuminuria . overall demographic and clinical features of the subjects with the 250.40 diagnosis are presented using descriptive statistics : mean    standard deviation or median ( range ) . patients who did not meet kdoqi clinical or biopsy criteria for dn as primary cause of esrd were compared with those who did meet criteria using t - test for normally distributed variables , and fisher s exact test or the mann we conducted exact logistic regression , due to small sample size , to evaluate whether retinopathy was independently associated with type 2 dn based on kdoqi criteria , adjusted for age , sex and race . inter - rater agreement between the primary and secondary reviewer was quantified using the kappa statistic . analyses were performed using stata 13se ( college station , tx , usa ) or graphpad quickcalcs ( san diego , ca , usa ) online software . overall demographic and clinical features of the subjects with the 250.40 diagnosis are presented using descriptive statistics : mean    standard deviation or median ( range ) . patients who did not meet kdoqi clinical or biopsy criteria for dn as primary cause of esrd were compared with those who did meet criteria using t - test for normally distributed variables , and fisher s exact test or the mann we conducted exact logistic regression , due to small sample size , to evaluate whether retinopathy was independently associated with type 2 dn based on kdoqi criteria , adjusted for age , sex and race . inter - rater agreement between the primary and secondary reviewer was quantified using the kappa statistic . analyses were performed using stata 13se ( college station , tx , usa ) or graphpad quickcalcs ( san diego , ca , usa ) online software . there were 299 cms2728 forms submitted between march 1 2006 and 31 march 2015 ( 9.09 years ) , representing 297 patients , two of whom had two cms2728 forms each submitted   > 90 days apart ( 5 years and 6 years ) . of these 299 cms2728 forms , 56 were coded as representing esrd due to type 2  dm [ international classification of diseases ( icd)-9 code 250.40 ] . this represents an incidence of 18.7% over 9.09 years , and was the third most common cause of esrd coded by our program . for comparison , incidence of esrd secondary to hypertension ( icd-9 code 40391 ) was 27.8% , and for primary and secondary glomerulonephritis ( gn ) , 20.1% ( codes 5820 , 5821 , 5829 , 5831 , 58321 , 58381 , 7100 , 7101 , 7598 , 2870 , 44620 , 44621 , 58391 ) . in all , 95% ( 53/56 ) were documented as having been seen by a nephrologist prior to esrd . of the 56 patients , 12 ( 21.4% ) did not have type 2  dm as the primary cause of esrd using kdoqi 2007 criteria upon review of health records ( table 2 ) . of these 12 , two ( 16.7% ) one ( case 1 ) had nephropathy secondary to type 1  dm , and should have been coded as icd-9 code 250.41 . the other ( case 2 ) had originally had type 2  dm as the primary cause of esrd , but lost a subsequent kidney transplant to biopsy - confirmed bk virus - induced nephropathy , and should have been coded as icd-9 code 99681 . table 1demographic and clinical features of patients coded as 250.40 ( type 2 diabetes with renal manifestations ) as cause of esrd on cms2728 ( those meeting kdoqi 2007 guideline criteria for type 2 dn versus those who did not meet kdoqi criteria are compared)met kdoqi 2007 criteria for type 2 dn as cause of esrdp - valueyesno(n = 44)(n = 12)age ( years)66.8  9.561.8  10.30.12sex0.33  male29 ( 65.9%)6 ( 50.0% )  female15 ( 34.1%)6 ( 50.0%)race  white6 ( 13.6%)0 ( 0%)0.32  african  american30 ( 68.2%)8 ( 66.7%)1.00  asian0 ( 0%)2 ( 16.7%)0.04  other8 ( 18.2%)2 ( 16.7%)1.00rrt type43 ( 98% ) hd12 ( 100% ) hd1.00body mass index , kg / m31.4  7.329.8  4.20.48history of hypertension44 ( 100%)12 ( 100%)1.00history of cardiovascular disease30 ( 68%)9 ( 75%)0.73history of smoking13 ( 30% ) ( n = 43)5 ( 42%)0.50years since diagnosis of type 2  dm19 ( 840 ) ( n = 33 ) ( n = 11 unknown)11 ( 320 ) ( n = 8) ( n = 3 unknown , n = 1 type 1  dm)0.007active urine sediment0 ( 0%)3 ( 27% ) ( n = 11)0.006developed macroalbuminuria prior to esrd44 ( 100%)9 ( 82% ) ( n = 11)0.037microalbuminuria only prior to esrd0 ( 0%)0 ( 0%)1.00retinopathy38 ( 86%)4 ( 36% ) ( n = 11)0.002biopsy12 ( n = 11)0.099hd , hemodialysis.adata are presented as mean    standard deviation , as median ( range ) or as number ( percentage ) . patient records were reviewed by a primary and secondary provider , with a third provider in the event of disagreement , as per materials and methods.bdefined as history of coronary artery disease , cerebrovascular disease and/or peripheral vascular disease.call patients with active urine sediment had associated hepatitis c.dbiopsy results : one patient had bk nephropathy in transplant kidney ; one patient had membranoproliferative glomerulonephritis with cryoglobulinemia and background diabetic changes.ebiopsy results : consistent with diabetic nephropathy.table 2characteristics of patients coded as having type 2 dn as the primary cause of esrd , but who did not meet kdoqi 2007 criteria#probable primary cause of renal failure ( icd-9-cm code)macro- albuminuriamicro- albuminuria aloneretinopathyactive urine sediment?biopsy1diabetes with renal manifestations type 1 ( 25041)yesnoyesnono2complications of transplanted kidney ( 99681 ) bk nephropathy on transplant biopsyyesnoyesnoyes3unknown ; patient without proteinuria ( 7999)nonoyesnono4probable hepatitis c - associated gn with previous aki ( 58391)yesnonoyesno5adpkd ; tophaceous gout with obstructive nephrolithiasis ( 75313)yesnononono6possible drug - associated aki with subsequent ckd ( 7999)nonononono7esrd presumed 2 to htn , presenting with hypertensive urgency ( 40391)yesnononono8probable renal vascular disease ; small kidneys , cortical thinning , and renal arterial calcifications ( 40391)yesnononono9probable hepatitis c - associated gn ; history of malignant hypertension ( 58391)yesnonoyesno ( offered)10mpgn with cryoglobulinemia 2 to hepatitis c on biopsy ; diabetic changes also present ( 58391)yesnoyesyesyes11hypertensive kidney disease ; small kidneys bilaterally and renal vascular disease ( 40391)yesnononono12insufficient data to make diagnosis ; presented at esrd post - stroke ; presumed 2 to type 2  dm ( 7999)unknownunknownunknownunknownunknownaki , acute kidney injury ; htn , hypertension ; adpkd , autosomal dominant polycystic kidney disease ; mpgn , membranoproliferative glomerulonephritis . demographic and clinical features of patients coded as 250.40 ( type 2 diabetes with renal manifestations ) as cause of esrd on cms2728 ( those meeting kdoqi 2007 guideline criteria for type 2 dn versus those who did not meet kdoqi criteria are compared ) data are presented as mean    standard deviation , as median ( range ) or as number ( percentage ) . patient records were reviewed by a primary and secondary provider , with a third provider in the event of disagreement , as per materials and methods . all patients with active urine sediment had associated hepatitis c. biopsy results : one patient had bk nephropathy in transplant kidney ; one patient had membranoproliferative glomerulonephritis with cryoglobulinemia and background diabetic changes . characteristics of patients coded as having type 2 dn as the primary cause of esrd , but who did not meet kdoqi 2007 criteria aki , acute kidney injury ; htn , hypertension ; adpkd , autosomal dominant polycystic kidney disease ; mpgn , membranoproliferative glomerulonephritis . of the remaining 10 patients , although all had type 2  dm , none appeared to have dn by kdoqi 2007 criteria ( table 2 ) . three appeared to have hypertensive chronic kidney disease ( ckd ) , two of which had probable renal vascular disease . two had no history of micro- or macroalbuminuria , and the cause of ckd was unclear . one , who presented at esrd after a stroke , had no records available to verify the diagnosis . patients who had kdoqi - predicted dn had a type 2  dm diagnosis more years than those who did not [ 19 years ( 840 ) versus 11 years ( 320 ) , p  =  0.007 ] . those who did not have kdoqi - predicted dn were more likely to have an active urine sediment ( p  =  0.006 ) , and less likely to have developed macroalbuminuria ( p  =  0.037 ) or retinopathy ( p  =  0.002 ) prior to esrd . on exact logistic regression ( adjusted for age , sex and race ) , retinopathy was significantly associated with kdoqi - predicted dn [ odds ratio   =  19.16 ( confidence interval 2.76223.7 ) , p  =  0.0009 ] . prevalence of type 2  dm in the usa is 12% for 4564 year - olds , and 22% among those 6574 years . in our single - center study , 18.7% of incident esrd patients were coded on the cms2728 as having type 2 dn as the primary cause of esrd , substantially lower than the national percentage of  > 40% . however , even in this cohort , over 20% of patients appear to have been incorrectly assigned per kdoqi 2007 clinical criteria . two were miscoded ( one had type 1  dm and one had biopsy - proven bk nephropathy in a renal allograft ) . seven of the 10 who were not miscoded had other , more likely renal diagnoses ( including hepatitis c - associated gn , hypertension / renal vascular disease and polycystic kidney disease ) , and had esrd type 2 dm is so common that it is likely that some patients starting rrt are indicated as having esrd secondary to dn merely because they have concurrent type 2  dm , especially when the patient is not well known to the nephrologist completing the form , as is often the case in patients who begin chronic rrt concurrent with an acute hospitalization . over - assignment of type 2  dm as the cause of ckd is suggested by several studies that identify patients with ckd and type 2  dm who do not have significant proteinuria , one of the clinical diagnostic criteria for dn [ 79 ] . in a biopsy study of patients with type 2  dm and ckd ( egfr  < 60  ml / min/1.73 m ) , normoalbuminuric patients were less likely to have typical glomerular changes of dn , but more likely to have arteriosclerosis and tubule - interstitial fibrosis alone . normoalbuminuric patients without the glomerular changes of dn may have progressive ckd , but this may be due to hypertension , obesity and intrarenal vascular disease rather than dn nephropathy , and the diagnosis can only be clarified by biopsy [ 11 , 12 ] . biopsy series of patients with atypical dn presentations ( with or without proteinuria ) demonstrated that 3560% had other causes of glomerular disease , and up to 1/3 had nondiabetic renal disease only , including acute tubular necrosis , hypertensive nephrosclerosis and focal segmental glomerulosclerosis [ 13 , 14 ] . two out of 34 patients ( 6% ) with type 2  dm with a typical clinical course and  >  500  mg/24  h proteinuria ( who would have met the kdoqi 2007 criteria for dn , and had been entered into a clinical trial ) did not have dn on biopsy . thus , it is likely that some patients with esrd associated with , but not caused by , type 2  dm , are incorrectly assigned a diagnosis of dn . the cms2728 assesses only one component of the kdoqi criteria for dn  diabetic retinopathy . history of macro- or microalbuminuria is not ascertained . according to the usrds annual data report , in 2013 , 14.1% of patients who had type 2  dm reported as the primary cause of esrd were also reported as having diabetes with retinopathy . among patients who had other causes of esrd , 2.8% were recorded as having diabetes with retinopathy . for purposes of comparison , the other cms2728 measures of diabetes as a comorbid condition ( como_dm_ins , como_dm_nomeds , como_dm_oral , for diabetes as a comorbid condition with use of insulin , no medications or oral medications , respectively ) when assessed together , were present in 90.5% of patients coded as having type 2 dn as the primary cause of esrd , and were present in 28.6% of patients with other causes of esrd ( excluding type 1 or unspecified dm ) . comorbid conditions in cms2728 do not distinguish between type 1 and type 2  dm . however , given the small fraction of type 1 diabetics presenting at esrd nationally , comorbid diabetes tracks very closely , if not identically , with type 2 dn as a cause of esrd . study limitations include small sample size , single center series and differences in patient population , suggested by the higher incidence of hypertension and primary / secondary gn in our cohort . our patient population consists of younger active duty and retired military members and their families , which may account for the greater percentage of incident patients who had esrd secondary to primary or secondary gn . nationally , type 2 dn - associated esrd incidence is six times that of esrd secondary to gn , while in our cohort , esrd incidence secondary to gn is slightly greater than type 2 dn . thus , our study may not be able to be extrapolated to the general esrd population . however , those who received the diagnosis of type 2 dn were demographically similar to those receiving the diagnosis in esrd network 5 , where our center is located . in 2014 , the mean age among incident network 5 esrd patients was 62.7 years and 57.3% were male . in all , 83% of incident esrd patients in the district of columbia , and 53% in maryland , were african  american . the criteria are grade b  moderately strong evidence recommendations , especially for patients with type 1  dm . for type 2 diabetics , micro- and macroalbuminuria are not as strongly predictive of typical diabetic glomerular changes on biopsy , and are not as strongly associated with retinopathy [ 810 , 12 , 15 , 17 ] . although the positive predictive value of retinopathy concurrent with macroalbuminuria is 67100% , the negative predictive value is quite variable at 2084% . a weakness of national registry and health record data is that the kdoqi criteria of albuminuria and diabetic retinopathy may not be recorded in a fashion that facilitates ready retrieval . thus , similar analyses will depend on manual validation , in the absence of significant advances in natural language analytics . if the 20% over - assignment of type 2 dn as the primary cause of esrd seen in our cohort were replicated in other or larger populations , there could be substantial implications for diagnosis and management of esrd . research funding could be affected , as many global and national institutes allocate resources based on the frequency of esrd causes . a 20% reduction in type 2 dn as a primary esrd cause would result in an incidence not much greater than that of hypertensive renal disease , a diagnosis itself in substantial doubt due to recognition of apol1-mediated renal disease , undiagnosed glomerular disease among all races and other factors . therapeutic nihilism for dn , due to limited specific treatment options , may unfortunately lead to diagnostic nihilism , especially if finding a condition requiring specific treatment is felt to be unlikely . in our cohort , active urine sediment was a particularly important discriminator and was associated with hepatitis c - related renal disease , a curable condition with specific therapy . the original legislation authorizing health and human services renal disease registry , of which the usrds is a primary component , the 1986 omnibus budget reconciliation act and section 1881 of the social security act , specifically called for research on the causes of end stage renal disease. over the years , the usrds annual data report and independent investigators have contributed substantially to those efforts . one of the implications of over - ascertaining type 2 dn as a primary cause of esrd is under - ascertaining other causes of esrd . these could include treatable diseases , such as hepatitis c and glomerular disease , as well as new and unsuspected causes due to environmental or other exposures , exemplified by mesoamerican nephropathy . non - traditional causes of ckd may go unrecognized in the usa due to the huge penumbra of clinically associated type 2 dn and hypertension . the logical next step would be a comparable study in a large health system with queryable health records , including comparison with patients who were not coded as having type 2  dm as the cause of esrd . if these findings were replicated , there may be work to do investigating the causes of esrd and ckd . although type 2  dm is an important cause of ckd and esrd , in many cases it may be an exacerbating factor rather than primary contributor . in particular , these data emphasize the importance of biopsy in patients with atypical features , since all of those with active urine sediment likely had a diagnosis other than type 2 dn . the presence of active urine sediment is not ascertained in current registries and is difficult to abstract from health records . we conclude that in a single - center setting , reported cms2728 diagnoses of type 2  dm as a cause of esrd were overestimated by approximately 20% when kdoqi 2007 diagnostic criteria for dn were applied . because of the high prevalence of esrd reported as secondary to type 2  dm in the usa , similar overestimation nationally ( if validated in larger cohorts ) could indicate an opportunity to recognition of such conditions , if treatable , could potentially lower the rate of ckd progression and the incidence of esrd .
abstract 
 background : end - stage renal disease ( esrd ) incidence due to type 2 diabetic nephropathy ( dn ) is 3550% , according to the united states renal data system . 
 methods : a single - center , retrospective cohort study to determine incidence and diagnostic accuracy for type 2 dn as the primary cause of esrd ( code 250.40 ) on the center for medicare & medicaid ( cms ) medical evidence report form ( cms2728 ) submitted at renal replacement therapy initiation . 
 all patients  18 years of age with a cms2728 submitted between 1 march 2006 and 31 march 2015 at a single academic military medical center ( esrd network 5 ) were included . 
 medical records of those with a code 250.40 diagnosis were reviewed to determine whether they met the kidney disease outcomes quality initiative ( kdoqi ) 2007 criteria for dn . 
 results : esrd incidence secondary to type 2 dn was 18.7% ( 56/299 individual cms2728 submissions over 9.09 years ) . in all , 12/56 ( 21.4% ) did not meet kdoqi criteria for type 2 dn . although all had diabetes , those not meeting criteria had shorter disease duration ( p  =  0.007 ) , were more likely to have active urine sediment ( p  =  0.006 ) , and were less likely to have macroalbuminuria ( p  =  0.037 ) or retinopathy ( p  =  0.002 ) prior to esrd . on exact logistic regression , retinopathy 
 was significantly associated with kdoqi - predicted dn [ odds ratio  =   19.16 ( confidence interval 2.76223.7 ) , p  =  0.0009 ] . 
 conclusions : in this single - center cohort , 21.4% identified as having type 2 dn as the primary cause of esrd were incorrectly assigned per kdoqi 2007 clinical criteria . 
 if replicated in larger populations , this could have substantial implications regarding the epidemiology of esrd in the usa .