KDIGO CKD GL Public Review Summary Report

Transcription

1 KDIGO CKD GL Public Review Summary Report Stakeholder Section Statement No. Comments Developer s Response Definition of CKD 1.1 Reviewer Comment Albuminuria is rarely quantified in children and adolescents and even when measured does not pick up very high levels of low molecular weight proteins, as seen in the low molecular weight proteinuria in children that appears to predate Dent's Disease in adults. Unless the criteria are intended just for adults it would be advisable to add UP/C > 0.2 on a first morning urine to account for children with CKD. I think this was the subject of a similar discussion many years ago Andrew?? Reviewer Comment UAE should also be used to define albuminuria. 2. Should hematuria be a marker of kidney damage? In the patients with asymptomatic bacteriuria, hematuria is common. Reviewer Comment I believe that only the GFR below 60 ml/min is not evidence of CKD. Thank you for your comment. Nonalbumin proteinuria in Dent disease is an example of Electrolyte and other abnormalities due to tubular disorders in Table 1, and is now mentioned explicitly in Table 2. Testing for nonalbumin proteinuria is included in We define increased albuminuria as AER (synonymous with UAE) in Tables Thank you for your comment. This has been clarified in Tables 1 and 2. The choice of a GFR threshold <60 ml/min/1,73m2 was driven by large population studies examining prognosis. Whilst we would agree that in the absence of proteinuria and other markers of kidney damage a GFR<60 is associated with less risk of adverse outcome than in the presence of proteinuria nevertheless there is still an increased risk. Reviewer Comment Method of egfr? Definition is based on GFR, not egfr. Methods for measurement and estimation are discussed later. Reviewer Comment Urine sediment abnormalities and low level albuminuria too broad and will lead to many misdiagnosed with CKD. Thank you for your comment. We debated these comments long and hard and beg to differ. The definition and classification was driven by prognosis and the presence of even low levels of albuminuria increases risk of all adverse outcomes (mortality, cardiovascular disease, AKI and ESRD).

2 Reviewer Comment It should be mentioned how many of the markers should be detected e.g., two or more of the markers to be more applicable. Reviewer Comment Why not to include Total Protein (quantitative) estimation instead of Albuminuria? Reviewer Comment I find the albuminuria, electrolyte, and GFR criteria most practical for my population of elders. Reviewer Comment The presence of simple cysts without albuminuria qualifies as criteria for CKD? Reviewer Comment The inclusion of microscopic hematuria in kidney damage deserves a more throughout discussion. The presence of microscopic hematuria does not equal to kidney damage in many instances. Thank you for your comment. Only 1 marker is required. This is clarified in Table 1. Thank you for your comment. Whilst we have recommended a hierarchy for proteinuria testing (see statement ), the recommendation to replace urinary total protein with albumin as the test of choice in testing for proteinuria is consistent with most, but not all, current national and international guidance. It is accepted that cost pressures may affect implementation of this recommendation and may differ across the world. We also accept that there are circumstances where alternatives will need to be used (see statement ). Thank you for your comment. Thank you for your comment. We agree that simple cysts are not criteria for a diagnosis of CKD and this is now explicit on page 10. Thank you for your comment. See Reviewer Comment 2. Reviewer Comment For me hematuria is not a marker of kidney disease. Thank you for your comment. See Reviewer Comment 2. Reviewer Comment Wrong statement albuminuria more than 3mg/gm creatinine Thank you for your comment. Reviewer Comment 13 Very clear definition. Thank you for your comment, which we very much appreciate. Reviewer Comment Clear and concise. Thank you for your comment, which we very much appreciate. Reviewer Comment Spot urine for albuminuria. Thank you for your comment. The definition is based on AER. Methods for measurement are discussed later. Reviewer Comment Albuminuria must not be expressed as mg/day, is not suggested and can be confused - The history of kidney transplantation is not a marker of kidney disease. Maybe, it can be proposed like another item of criteria for CKD. Normative values for albuminuria and proteinuria are generally given as loss rates (excretion rates). This is clarified on page 9. See rationale for history of kidney transplantation on p 10.

3 Reviewer Comment Structural abnormalities may include simple cysts which do not result in CKD. Also I have colleagues who have egfrs of <60 ml/min but nil else to find clinically, biochemically and on urinalysis. Function stable and nil to suggest TIN and no obstruction on U/S. I am not too sure what to suggest about this situation? Reviewer Comment How we can consider the history of kidney transplant per se is a marker of CKD regardless of the evaluation of graft function? Reviewer Comment I do not think that a UACR of mg/d in the absence of any other abnormality (isolated microalbuminura) is a real kidney disease. I do not think that an isolated egfr (MDRD or CKD-EPI) of 45-59ml/min/1.73m2 in absence of albuminuria or other structural abnormalities in an elderly person (especially a woman) is real kidney disease. Reviewer Comment Albuminuria >30 for 3 months does not = CKD as this is often spontaneously reversible and may be postural and benign. More clarity is needed in this criterion. Reviewer Comment Hematuria should be clearly classified in case of over diagnosis. Reviewer Comment Urine abnormalities may be due to no progressive disease, similarly electrolyte disturbances not evidence based. Kidney histology is not always available and can be sampling error cannot be followed up. Imaging not standardized. Therefore to me GFR and urine albumin excretion are acceptable. Reviewer Comment An addendum should be inserted barring time frame of 3 months if there is radiologic evidence of polycystic kidneys or shrunken kidneys. Thank you for your comment. See replies to Reviewer Comments 3 and 9. Normative values for albuminuria and proteinuria are generally given as loss rates (excretion rates). This is clarified on page 9. See rationale for history of kidney transplantation on p 10. See replies to Reviewer Comments 3 and 5. See reply to Reviewer Comment 5. Thank you for your comment. See reply to Reviewer Comment 2. We agree that the strength of evidence is stronger for some of the criteria than others. Table 2 has been clarified to indicate that duration can be based on documentation of inference. Reviewer Comment Most appropriate definition at present. Thank you for your comment, which Reviewer Comment I have some reserves /sic/ regarding definition of CKD. First: Structural abnormalities is a vague term. What do we refer while saying structural abnormalities? For example unilateral renal agenesis is a structural abnormality but patients may be completely healthy without reduced GFR and proteinuria. This term should be more specific. It may include longitudinal length of kidney, cortex echogenicity and cortex thickness. we very much appreciate. Table 2 provides details.

4 Reviewer Comment Second: I am confused with history of renal transplantation. Is it due to generally low GFR values after renal transplantation or due to single functioning kidney? Excellent kidney function may be attained with renal transplantation in some patients, thus, automatically categorize these patients as having CKD may be misleading. We should be more specific here. Reviewer Comment : Just a clarification (Structural abnormalities detected by imaging) - So this means that anyone with 'increased or slightly increased echogenicity of the kidneys suggestive of medical renal disease' reading by a radiologist is classified as having CKD? Reviewer Comment Any albuminuria is kidney damage and endothelial dysfunction. Reviewer Comment This definition assumes that the patient has been seen regularly by medical professionals, at least over a 3 month period, and has lab work, imaging, and other object medical data, for at least a 3 month period. The definition needs to clarify the time period to include those patients who have not been followed by medical professionals and whose CKD is just being discovered/uncovered. Reviewer Comment GFR estimation should be standardized by suggesting a calculation method as the CKD-EPI. Reviewer Comment 31 I think definition should be more inclusive to hopefully capture all cases of CKD. To this effect using [albumin/creatinine] and [protein/creatinine] ratios may be preferable than 24 hour urine determinations (of either microalbumin or protein). Reviewer Comment I understand the rationale for CKD, however, I do wish it had been called something else like CKI or CRI : I still have many a patient who asks me where they caught the disease from. I try and educate them regarding the definition of disease but they mainly equate it to the flu or chicken pox! Reviewer Comment History of nephrolithiasis (cystinosis, oxalosis) can be a marker for kidney damage. Reviewer Comment The threshold of GFR <60 could be modified according to the interracial divergence. Because even healthy Japanese people have lower GFR compared to Caucasian counterparts, Japanese CKD patients should have lower threshold. There must be some room for the definition of CKD. See reply to Reviewer Comment 16. We agree that this can be a difficult distinction. On page 10, the text states significant. Clinical context is required for action. See reply to Reviewer Comment 23. See reply to Reviewer Comment 4. See reply to Reviewer Comment 15. The workgroup carefully debated the pros and cons of using the term disease vs. other terms. This was considered. In the absence of a current stones or other marker of damage, we did not consider a history of stones to be a marker of kidney damage. Abnormal renal handling of electrolytes is included as a marker. We are not aware of solid evidence of substantial interracial divergence in measured GFR.

5 Reviewer Comment The statement (with implication of health) will exclude large number of patients who are eligible for the rest of the definition) for example, children with congenital renal disorders may be discovered accidentally and remain asymptomatic for long time. Reviewer Comment Thanks for including the issue of tubular disorders. We agree that there is variability in the clinical course of these abnormalities. Since some children with these abnormalities do have complications, we would consider the abnormalities to have implications for health. Reviewer Comment Urine sediment should add WBC and WBC cast as well. This is included in Table 2. Reviewer Comment Markers of Kidney damage: Urine sediment abnormalities (e.g., GLOMERULAR hematuria) Decreased GFR: included dosage methods (e.g., MDRD equation, etc.) Reviewer Comment But! Please, note that the finding of red cell casts in the urinary specimen is a sign of active/acute glomerulonephritis/vasculitis! Should therefore prefer to use granular casts; Urine sediment abnormalities (e.g. hematuria, granular casts etc.). Reviewer Comment Electrolyte and other abnormalities due to tubular disorders is not clear. Ex glucosuria may be a result of tubular disorder and a result of diabetes without tubular dysfunction. That may be confusing. See reply to Reviewer Comment 2. See reply to Reviewer Comment 2. Glucosuria would not qualify as a marker of kidney damage unless it is due to a tubular disorder. Reviewer Comment Improved by use of functional correlations. Thank you for your comment which we very much appreciate. Reviewer Comment Would add proteinuria, either [Protein/Creatinine] ratio or See justification on pages 7-8. presence in urinalysis. Reviewer Comment Fig 3: The horizontal line is not reported. This referee suggests replacing the term "sex" with "gender." This should be valuable for all pages. Fig 5: Triangles are not reported. Fig 3 is corrected. Triangles are reported in legends to Figs 4-5. Reviewer Comment Not probable that a PCP will detect tubular abnormalities. Too many markers for population screening. Reviewer Comment Hematuria due to urological causes should be excluded in the definition. Reviewer Comment Not always the markers above mentioned are associated with CKD. Reviewer Comment The criteria >3months is not considering that kidney structure can't be verified at 3 months "abnormalities of kidney structure or function, present for 3 months," and I propose: CKD is defined as proven kidney structure fibrosis or abnormalities of kidney function present for 3 months... Reviewer Comment Need to explain the role of albumin-to-creatinine ratio and protein-to-creatinine ratio testing. Can they be used interchangeably, or is one recommended over the other? Guideline is for broader use than PCP and population screening. Also useful for specialists. See reply to Reviewer Comment 2. See reply to Reviewer Comment 2. See reply to Reviewer Comment 23. See reply to Reviewer Comment 15.

6 Reviewer Comment The lower limit for albuminuria (>30 mg/day) seems very low and a lot of elderly or patients with inflammation may be marked with the stigma of CKD. Perhaps some other markers such as hs-crp might be of extra value before labeling CKD, especially in categories G1 and G2. Reviewer Comment My concern is that GFR is being calculated based solely on creatinine and age without adjustment for body size on routine labs. Reviewer Comment Should add a category of patients at risk with silent disease: genetic nephropathy, diabetics. Reviewer Comment Several times across the guideline you use >3 months and not "> or equal 3 months." Reviewer Comment Perhaps a little discrepancy between the information on Table 2 (page 8, row 22): "Decreased estimated GFR can be confirmed by measured GRF if required" and the statement "We suggest using additional test (such as cystatin C or a clearance measurement) for confirmatory testing in specific circumstances (2B)." See reply to Reviewer Comment 5. With regard to classification, we only considered kidney measures. We agree that many other measures may influence prognosis. See Table 8. See reply to Reviewer Comment 4. By definition, the category of at increased risk for CKD would not be included as CKD. It has been corrected to be > 3 months, not > or equal to 3 months. Thank you for pointing this out. We have now clarified in Table 2 that egfr refers to GFR estimated by creatinine or cystatin C. Reviewer Comment Table 2 (page 9, row 13): stones are better detected by imaging than histology. Reviewer Comment I have doubts regarding the inclusion of the term abnormalities detected by histology. If there are no other markers of kidney damage, a kidney biopsy is not justified and no information on histology would be available. If a partial nephrectomy is performed because of a tumor, the surrounding kidney tissue sometimes discloses global glomerulosclerosis and some interstitial fibrosis, particularly in the elderly. This should not qualify for kidney damage. To avoid such erroneous ideas, I would leave out the histology. Reviewer Comment Page 8, table 2 on Kidney Damage: To be consistent with the rest of the paper the value Urine ACR > 2000 mg/g should be 2200 mg/g i.e, page 27: bottom of Table 5, page 28, page 32; AND IT MAY BE MAY BE accompanied by signs or symptoms of nephrotic syndrome since in Secondary Glomerulosclerosis, such level of albuminuria may NOT Be accompanied by nephrotic syndrome /sic/. Reviewer Comment This should explicitly state that kidney donors may have a GFR<60 but not have CKD. This has very important insurance consequences. We are referring to examples of causes of tubulointerstitial disease. Table 2 has been modified. We disagree. If the tissue surrounding a tumor contained evidence of kidney disease, it would be considered as CKD. Thank you for pointing out the discrepancy. Table 2 has been changed. This is discussed on page 12.

7 Reviewer Comment May modify as "CKD is defined as abnormalities of kidney structure or function, or presence of markers of kidney damage, present for 3 months, with implications for health (see below)." When only structure or function abnormalities are mentioned, those do not necessarily reflect markers of damage. Reviewer Comment Page 7, Definition of CKD: Should specify that any of the markers of kidney damage are sufficient for the diagnosis. It is not completely clear whether one, some or all are required. Suggest specify that one or more markers qualify for the diagnosis. Albuminuria should be 30 mg/day Reviewer Comment Page 8, Table 2 refers to > 3 months where the definition specifies 3 months. This is clarified in the text as >90 days but the document should be clear and consistent. Reviewer Comment Page 8, Table 2, kidney damage. As the term microalbuminuria is now discouraged, suggest either removing it from the table, or adding a phrase such as... corresponds to microalbuminuria, now referred to as moderately increased (as per table on page 29). Similarly the term macroalbuminuria should be indicated as being now termed severely increased. The term clinical nephropathy is not used elsewhere in the document and perhaps could be omitted from this table. The specific criteria listed in Table 1 reflect abnormalities of structure or function. See reply to Reviewer Comment 6. Thank you. See reply to Reviewer Comment 52. We have made the suggested changes. Reviewer Comment Table 2, kidney damage: Albuminuria should be ACR 30 Thank you. mg/day, 3 mg/mmol and 30 mg/g. There is variation on the exact cutoffs for ACR throughout the document which should be standardized. Reviewer Comment Table 2, kidney damage: Dot point 3 should be 300 mg/g. Thank you. Reviewer Comment Page 14, albuminuria: All mentions of >30 mg/day should be 30 mg/day to be consistent with the table. Reviewer Comment Pages 15 and 16: Suggest a reference for each of the conditions starting with Urine sediment abnormalities. This would increase the utility of the document. Reviewer Comment Page 16, History of kidney transplantation: Suggest specifying as recipients of kidney transplants in first sentence to clearly avoid applying this criteria to donors. Reviewer Comment Page 18: d) isolated albuminuria. Change >30 mg/g to 30 mg/g. We have not meant for the guideline to be a textbook. Thank you. Thank you. Thank you.

8 Reviewer Comment Page 18, d) dot point 2: Can an equivalent to 1g/24 hour total protein in albumin mg/day also be provided (70 mg/mmol as per NICE or 700 mg/g or 700 mg/day). Also recommend using mg/d rather than g/24 hours for consistency. Thank you. Reviewer Comment Page 19, f): Suggest 60 ml/min/1.73m2. Agree. Reviewer Comment Page 19, 2nd last paragraph: Suggest specify that it is body surface area normalized GFR that reaches adult levels at about 2 years of age to ensure no confusion with raw GFR in ml/min. Reviewer Comment Page xi and page 7: Table- Albuminuria>30mg/day should be albuminuria 30mg/day We have made the suggested changes. Thank you. Reviewer Comment Page 14: AER>30mg/day should be AER 30 mg/day. Thank you. Reviewer Comment Page 18: ACR>30mg/g should be ACR 30 mg/g. >1g/24h total protein should be 1g/24h. Thank you. Reviewer Comment Page 19: albuminuria >30mg/day should be 30 mg/day. Thank you. Stakeholder Section Statement No. Comments Developer s Response Staging of CKD 1.2 Reviewer Comment I think a notion of progression of CKD must be included in alongside of albuminuria and GFR and etiology. That is important in relation to arterial hypertension control as well. Reviewer Comment In the guidelines of NKF, we always understand that the CKD is independent of cause. We specifically debated these considerations. We decided that CKD should be classified by kidney measures only. This is now explained on page 14. We also decided that classification should be based on measures at a single point in time. Classification can be revised at later time points. We have retained the KDOQI concept that the definition of CKD is independent of cause. We have modified the KDOQI concept that cause is now included in the classification of CKD. Reviewer Comment : consider, systemic disease with presence or absence We were not sure that this is clearer

9 of damage in target organs of these systemic diseases. than what is written. Reviewer Comment Statement 1.2.2: Possibly to include 2,8-Dihydroxyadenine We have removed oxalosis. deficiency in Table 3 (Page 22 Row 22) because it is more frequent than oxalosis, especially in some populations (See citations PMID: ; ) Reviewer Comment Page 22 line 1: "in developed nations" should be "in developed countries." For Fig. 8 and the other figures, this referee suggests replacing green with white color and increasing the intensity of the yellow color. Please report Fig. Thank you for your suggestions. We have not changed the colours from the original publications. We cite Figure 8 here. 10 in the rationale. Reviewer Comment : The statement seems to be unclear We ve clarified it. Reviewer Comment I like the idea of introducing cause into the staging system as an ungraded statement. This is clearly of practical importance for clinical assessments. Reviewer Comment Page 21: It is important to distinguish between OBSERVED or PRESUMED pathologic anatomic findings (whether a renal biopsy was performed or not). This is particularly important in the diagnosis of DIABETIC NEPHROPATHY (either clinically or pathologically diagnosed) or NEPHROANGIOSCLEROSIS (either clinically or pathologically diagnosed). Reviewer Comment Page 27: NONSENSE...a better rationale should be provided to consider nephrotic range albuminuria equally than albuminuria around 300 mg/g. An additional category > mg/g should be considered as it is reflected in the publication of Levey AS, Coresh J Lancet 379 (9811):165-80, Nephrotic syndrome (>2200 mg albumin UNITS? 3000 mg protein UNITS?) is rare in general practice, and the simplicity of the AER was preferred BUT A4 would be helpful for specialists and future studies. THIS RANGE OF PROTEINURIA IS RELATIVELY COMMON in GLOMERULAR SCLEROSIS and also impairs prognosis. Additionally in page 32 it is stated that it is clearly recognized that these very high levels of proteinuria carry a different risk than lower values within the same category. This must be considered even for future research and epidemiological studies to avoid important biases. Reviewer Comment Need to classify GFR as moderately decreased, not mild to moderate - this understates how much renal function Thank you. We agree. We specifically debated whether to consider an additional category for nephrotic range albuminuria, but decided against it, based on considerations of simplicity and practicality, as had been recommended at the 2009 London conference. This is discussed also on page 26. The footnote to Table 6 has been expanded to provide more details. We selected the terms to match the description of former Stage 3 (30-59) as moderate. is lost. Reviewer Comment Regarding 1.2.3: May add stage 5 T for transplantation. We have clarified that we have not retained the T in the revised classification system. Reviewer Comment CKD 3b should be defined based on egfr<45, whereas CKD 3a (45-<60) should require the same criteria as CKD 1 This is a comment about the definition, not the classification. Please see

10 and 2 need, so that overdiagnosis of CKD 3a be avoided. reply to Reviewer Comment 3. Reviewer Comment I would prefer "Stage 1-5" instead of G1-5. We considered this. Reviewer Comment More studies are still required to confirm outcome difference between G3a and G3b. We considered the strength of evidence of current studies to be satisfactory. Reviewer Comment I appreciate classification based on GFR rather than egfr. Thank you. This is NOT changed Reviewer Comment In older male and female, egfr can be less than 60. Without albuminuria, hematuria or any other factor, they should not be designated as CKD. Simply having a GFR less than 60 cannot be accepted as CKD. Reviewer Comment : In South Asia, especially among young females, a GFR between is not rare. Caution is advised regarding generalization of category G2 among different populations. from previous KDOQI guideline. Please see reply to Reviewer Comment 86. GFR category G2, without evidence of kidney damage, is not considered CKD. Reviewer Comment G0 may be added as increased risk for renal disease. Please see reply to Reviewer Comment 51. Reviewer Comment Page 23, table 4: Category G1 should be 90. Suggest asterisk against mildly decreased should either be against categories G1,2,3a,3b and 4 or next to Terms. As noted in the text all are relative to young adults. Thank you. We carefully considered the location of the asterisk. We felt that the terms for categories G3-5 were appropriate for older as well as Reviewer Comment Page 26. Figure 8: Suggest place units either in legend or on graphs. ACR and GFR can be referred to in different units. Also suggest categories of egfr are not overlapping. e.g., 15 29, 30-44, 45-59,60-74 etc. (note the ACR do no overlap). Reviewer Comment For 1.2.3, I find it too confusing to break category G3 into 2 sections. Most health practitioners I see are barely aware of staging CKD as it is. Again, for 1.2.4, I prefer the existing categories. They define what's "normal." Reviewer Comment , Will G1/2, A2 without structural evidence of kidney damage = CKD- if so I do not agree. Reviewer Comment , Same comments as for The lower limit for albuminuria (>30 mg/day) seems very low and a lot of elderly or patients with inflammation may be marked with the stigma of CKD. Perhaps some other markers such as hs-crp might be of extra value before labeling CKD, especially in categories G1 and G2. Reviewer Comment , I think this is sensible and may provoke a little more thought in diagnosis. Although the CKD grading is ingrained did the for younger adults. Figure 8 is reproduced from another publication, so it is not edited here. This was discussed extensively. While some prefer a simpler classification, others preferred to have more detail. The audience for the guideline is wide. We felt this is our best compromise. We recognize that implementation will vary by population, intent, and across countries. See reply to Reviewer Comment 86. See reply to Reviewer Comment 86. Thank you.

11 concept of G1-G6 get considered rather than a/b classification? The alerting and quantifying of albuminuria is essential and I am pleased it has been included. Reviewer Comment Albuminuria categories may be integrated with the respective proteinuria excretion rate as in the KDIGO on BP management in CKD. Agree. Reviewer Comment You may include the ACR using mg/mg. This is easy to perform and it was validated, the paper appeared in AJKD. We have elected to use mg/g to avoid decimals. Reviewer Comment Not sure how well these are interchangeable. Low muscle mass -elderly may have high ACR but normal 24 hr. Needs discussion. Agree that these are not exactly interchangeable. This is discussed on page 23. Reviewer Comment Proteinuria categories should be added. In Japan, albuminuria is not covered by public insurance except for early stage of diabetic nephropathy. Corresponding proteinuria categories are described in Table 6. We appreciate that implementation will vary across countries. Reviewer Comment This appears to remove the term microalbuminuria. Agree. Reviewer Comment I think there should be 4 grades to albuminuria, since 300 to 1500 g/g Cr should be differentiated from greater amounts; exact cut point however is not in the literature. Area for research? Reviewer Comment It is not given the opportunity to calculate albuminuria through ratio of urinary albumin/creatinine. Reviewer Comment The traditional threshold for proteinuria which as an isolated finding warrants a possible renal biopsy is 1g per day. This equates to ACR >75mg/mmol. Setting the threshold for severely increased at >30mg/mmol makes it impossible to highlight this valuable further threshold of >75. Why not have A0 as <3, A1: 3-75, A2: and A3: >220? Reviewer Comment Note the new Australian consensus statement on albuminuria continues the historic approach of gender specific cut points for ACR. There is a strong rationale for this although the clinical advantage in this approach is not well established and the simplicity of non-gender specific cut points is appreciated. Reviewer Comment I am wondering whether measuring albuminuria rather than proteinuria is a true advantage. There is a substantial risk of underdiagnosing myeloma or tubular injuries. In the table, See reply to Reviewer Comment 83. Approximately equivalent ACR terms are provided. Calculating AER from ACR requires measurement of creatinine excretion rate. If a timed urine collection is available, then AER can be measured directly. Alternative methods for estimation of CER were felt to be beyond the scope of the guideline. Please see reply to Reviewer Comment 83. Thank you for the comment. We considered this. The rationale for not using sex specific cut-offs is provided on page 11. Detection of non-albumin proteinuria is discussed in Abbreviations included.

12 the meaning of the abbreviations (AER, ACR mg/d mg/mmol etc. ) should be detailed. Reviewer Comment Considering the risk of progression with urinary albumin level of 400 mg is not equivalent to nephrotic range proteinuria, I think the nephrotic range proteinuria should be in another category such as A4. Reviewer Comment That means that a check for what we call microalbuminuria must be done for all people who can present CKD. If A2 in CKD, what about repeating this microalbuminuria check since it is not validated as marker of prognostic in CKD out of diabetic nephropathy? Reviewer Comment Since AER is not equal to ACR especially at lower protein excretion, using the same definition will lead significant misclassification. Moreover, albumin excretion estimation is not available especially in developing countries like India. I suggest that we should use ACR only. Reviewer Comment 112 Good, comprehensive definition! Thank you. See reply to Reviewer Comment 83. This is a comment about definition, not classification. Data on higher relative risk for A2 category holds for people without diabetes as well as in people with diabetes. See reply to Reviewer Comment 95. Reviewer Comment Regarding 1.2.4: The evidence for grade of albuminuria and outcomes is there, but not as strong. Reviewer Comment Proteinuria (mg/mmol) is missing- tubular or overflow proteinuria is not albuminuria, it is much cheaper than albuminuria and of same value. Reviewer Comment I think urine strip results cannot substitute the albuminuria measurement. Reviewer Comment : The asterisk after "Moderately increased" in category A2 with the explanation "relative to young adult level" suggests the existence of a physiologic albuminuria of the elderly. The similar design of the tables and suggest that the reduction in GFR with age and the occurrence of albuminuria in aged persons carry equivalent risk. I do not agree with this idea. Reviewer Comment Page 28, paragraph 2: The use of a single cut point for males and females is a judgment call. I would note that the use of a single cut point will have the effect of making increased ACR more common in females than males. Perhaps the document could allow the use of sex-related decision points where there are the resources are available. Given the fact that patient sex is almost always available information, e.g., in a laboratory computer system or on a request form, this would seem reasonable. Reviewer Comment Page 28, 3rd paragraph: 60 ml/min/1.73m2. Also on the 4th last line units should be mg/d for albumin and protein. Reviewer Comment Page 28 or page 14: Suggest make a statement that ACR is preferred over AER in most situations. This is based on Relative strength, compared to GFR categories, varies across populations. See reply to Reviewer Comment 108. Cost is an implementation issue and is expected to vary across countries. Reagent strip results are an approximation (mentioned in Table 2 and discussed in more detail later). We do not mean to suggest that the increase in albuminuria with aging (or the decline in GFR with aging) is physiologic. The rationale for the asterisk is that these abnormalities are more common in the elderly. See page 11. See reply to Reviewer Comment 107. Thank you. Table 2 suggests that AER can be used to confirm increased ACR.

13 patient convenience, reduced collection errors, the ability to obtain a non-ambulant (1st morning) sample and the ACR has been used in risk related studies (e.g., figure 5). The AER should be considered in cases of extreme abnormality in body composition (e.g.,emaciation, muscularity, amputations, etc) where the abnormal muscularity may affect the denominator in the ACR. Reviewer Comment Table 6: Severely increased albuminuria and proteinuria Thank you. should be include 300mg/24h and 500mg/24h, respectively. ACR and PCR need to be corrected. Reviewer Comment Page 28: ACR>30mg/g should be ACR 30 mg/day. Thank you. >300mg/d should be 300 mg/day. Nephrotic syndrome (>2200mg/albumin; >3000mg protein) should be ( 2200mg albumin; 3500mg protein). Reviewer Comment 122 Other complications also should be considered FOR See reply to Reviewer Comment 75. classification like anemia, bone diseases. Reviewer Comment 123 I am amazed that BP is not included in the classification with See reply to Reviewer Comment 75. all the evidence in the literature. The classification submitted by us is a better classification see article: Burgos-Calderon, R; Depine, S. Systematic approach for the management of chronic kidney disease: moving beyond chronic kidney disease classification. Curr Opin in Nephrology & Hypertension. 19(2): , [Mike: let me know if you need a copy of this article] Reviewer Comment 124 Too much differentiation for clinical routine. See reply to Reviewer Comment 95. Reviewer Comment 125 Reviewer Comment 126 Reviewer Comment 127 Reviewer Comment 128 Reviewer Comment 129 I think it is important to take into account the level of proteinuria in the given staging as this marker of kidney damage and independent predictor of outcome. By committing to an arbitrary 5-stage classification system and then dividing stage 3 into two sub-categories, I think we run the risk of making classification overly complex. With the addition of albuminuria, we now have 18 subcategories of CKD classification! A clear one-dimensional staging is preferable to multidimensional categories. This makes it difficult for nonnephrologists to follow and use this staging system. Find the stratification of grading system is overly complex vs the staging categories. 1. CKD stage 3 constitutes 58% (15.5 out of 26 million total CKD pop; US Renal Data System 2008 Annual Data Report). Moreover, 85% of these are in stage 3a (CKD3b was 11.7% of the CKD3 in C. P. Wen et al study, 12.3% of the CKD3 in S. L. White et al study and18.3% in Go et al study), in fact most have GFR >50. The Japanese SN estimated the prevalence of CKD 3 alone as 10.4% of Thank you. See reply to Reviewer Comment 95. See reply to Reviewer Comment 95. See reply to Reviewer Comment 95. See reply to Reviewer Comment 86.

14 Reviewer Comment 130 Reviewer Comment 131 Reviewer Comment 132 population, 7.6% within the range of ml/min per 1.73 m2. Only a minority will survive to reach CKD3b. Repeated studies showed that the age adjusted risk of CVD and total mortality is not affected GFR decline down to 30 ml (e.g.. PREVEND, Go et al in 172,144 subgroup, A. M. O Hare et al for GFR >50 etc) When we know that CKD3 mortality is occurring essentially only among its elderly population (the majority of CKD 3) mostly with GFR > 50 & at a similar rate to their similarly aged non-ckd pop, how can we attribute this death to CKD? This mortality account for the bulk of CKD related mortality? Only 15% make it to stage 3b (where still GFR has very minor role as an independent CVD risk factor). From the 26 million CKD, only 0.7 reach CKD 4 where CKD process started to have obvious pathological role. The unrealistic inflation of CKD 3 happened because of removing the additional condition of kidney damage that needs to be maintained throughout stage I could not access ref 4 that was utilized in Fig 4, but the bulk of studies (some examples indicated above) showed either no role or very minor role for the isolated GFR decline to 45 ml/min. The 1.3 HR for all-cause mortality of such CKD 3a with no MAU by CP Wen et is a reasonable/ intermediate figure (note that it was 1.0 in the studies indicated above). But Fig.4 seems suggesting HR >2 for the isolated GFR (age and albuminuria adjusted) decline to 45 ml/min. 3. In what sense we end to have the majority of CKD are females (Females are 70%, 63.2 % and 61.8% (9.4/15.4), 62% of CKD 3 in Norway study, PREVEND, NHANES data and the AusHEART study) while all literature points that male gender is a risk for rapid GFR decline both in disease and health (aging). Among the aged, the fall in GFR was reported as 8.7/decade in males vs.1.4 in females (NDT 21: , 2006). In albuminuria, we ignored ethnicity and recognized gender related U creatinine excretion differences. We made different cut off values for MAU/ pathological albuminuria. Why we didn't maintain this position toward the cut off value of CKD 3 (esp when defined independently from kidney damage condition)? 4. The note on old inactive kidney damage (e.g., unilateral nephrectomy or previous transient obstructive uropathy) vs. ongoing damaging kidney disease was indicated in note f but was not reflected in the clinical guidelines. I cannot overemphasize the clinical importance of this fact in practice. We have over-believed in the self-perpetuating hyperfiltration theory. There are clinical and lab clues for the nature of the kidney damage. History of the insult and GFR Reference 4 is a large meta-analysis. The figure is adjusted for albuminuria. Additional analyses from the same dataset are shown in Figures 7-8. See reply to Reviewer Comment 83. The variation in male to female prevalence ratios across GFR stages has many possible explanations. We did not rely solely on these data to define the GFR threshold. See reply to Reviewer Comment 83. Incorporation of these considerations into the guidelines was deemed to be too complex.

15 Reviewer Comment 133 Reviewer Comment 134 Reviewer Comment 135 Reviewer Comment 136 Reviewer Comment 137 decline rate over previous visits in addition to biomarkers as NGAL all can easily suggest the degree of activity of the renal damage. The rate of GFR decline in the CDK 3 with no albuminuria in PREVEND was just -0.2 ml/min. In Norway study: CKD 3 data: egfr decline was only 1.03 ml/min/1.73m2/yr and only 0.1% (i.e., only 4 out of 3047 patients) needed RRT during the study period; 99.9% of those labeled as CKD 3 did not need any RRT (better than ESRD risk in gen pop!). We need to add a note. Sometimes there is confusion in the units and formulas used. It would be interesting to include for the avoidance of doubt that often occur. I agree with the spirit of this guideline. By reminding physicians of the importance of cause-- not just GFR -- there will be a needed return to thinking about potentially reversible/ treatable etiologies and acknowledging that there are real differences in the natural history of kidney disease of different etiologies. I also agree with including albuminuria as an important stratification. I believe that all these classifications are simple and can be done easily in the office with minimal need for additional testing. CKD and albuminuria are not categorical entities, rather, they are continuous. It is possible to create such "categories" but these are not helpful and the kidneys do not know it. While I applaud this classification, there are not enough ICD- 9-CM or ICD-10-CM codes to capture this level of specificity. ICD-9-CM code only covers stage 3 CKD as it is current defined. I trust that concomitant with your efforts to define CKD according to e-gfr and albumin states that you will work with the ICD-10 Coordination and Maintenance committee to at least have something available as "a new disease" prior to the ICD-10 freeze. What good is it to develop new categorizations of CKD if there's no way to easily report it? You may call me at if you wish to discuss. One of the caveats of staging CKD is aging. In elderly, even if one has normal renal function and histology, clearance is decreased due to diminished muscle mass. Thus, elderly should be treated differently in this scheme. In very older patients CKD definition solely based on GFR measurements is most of the time erroneous. We should make it necessary to show structural and or biochemical renal injury in order to label a very elderly person as having CKD. Currently we are studying serum and urine NGAL levels in normal aging along with renal resistive index. We believe that this would provide We have corrected some errors. Thank you. It is common in medicine that continuous variables are categorized for medical decision making. Thank you. Efforts are underway to coordinate with ICD-10. See reply to Reviewer Comment 86. We discussed Relationship of CKD criteria to aging on page 18.

16 us with a more accurate definition of CKD in the elderly. One other potential application might be GFR nomograms according to age in the elderly. Actually this is currently being used by NICE in renal donors. Otherwise these systems will label many elderly patients as having CKD and cause heavy economic and moral burdens. Reviewer Comment 138 What is the value of quantifying albumin excretion in terms of defining and classifying CKD? Reviewer Comment 139 Basing CKD on cause might lead to a loss of every day ease of use. Reviewer Comment 140 Paed I think a note in the actual guideline should comment upon the lower limit of age that this can be applied to! Reviewer Comment 141 While acknowledging the increased vascular and, possibly, kidney risk of small increases in AER, in most community setting screening will be based on urine reagent strips. Reviewer Comment 142 Adding the "cause" is a significant advance. Thank you. Reviewer Comment 143 Appreciate thoughtful pediatric considerations. Thank you. Reviewer Comment 144 Good job! Thank you. The value is improved relationship of classification to prognosis. See reply to Reviewer Comment 95. See reply to Reviewer Comment 95. Reviewer Comment 145 Will the term stage be expunged? The guideline retains the term staging but now refers to categories rather than stages for GFR and albuminuria. Reviewer Comment 146 Reviewer Comment 147 The new CKD classification is based on cause, egfr and albuminuria. While the egfr and albuminuria categories are univocally defined, the classification of causes is not clear. An attempt of cause classification is suggested in table 3. It is rather generic, but sufficiently exhaustive. Surprisingly, table 7 reports the causes as specific diagnoses without any categorization. This approach is ambiguous because a wide number of categories (one for each renal disease) are possible. Since the CKD classification primarily has a prognostic target, an effort in this direction should be done also in cause definition. The classification proposed in table 3 follows this sense, also in the distinction between primary and secondary diseases. I suggest to validate this classification and to use it as it is. Assign cause of CKD according to systemic of pathologic findings; this will probably will work for nephrologist but in the text it is stated; this will be used to inform the need for specialists, and general medical management. However I am convinced this will complicate management for GPs. The intention of Table 7 is to provide examples of specific diseases, some of which are mentioned as specific examples in Table 3. See reply to Reviewer Comment 95. Reviewer Comment 148 Still a need to provide a table for protein to creatinine ratio. See Table 6. Reviewer Comment 149 Logically this approach makes sense but I would be See reply to Reviewer Comment 95.

17 Reviewer Comment 150 Reviewer Comment 151 concerned that it will prove cumbersome in clinical practice. 1.2 Staging should be preceded by Item 1.4 Evaluation of CKD Page 20 (and xi): Suggest heading should be Classification and staging. As refers to classification as the first item in the section. Reviewer Comment 152 Page 30, figure 9: 90 ml/min/1.73m2. Thank you. Reviewer Comment 153 Page 32: 60 and 90 ml/min/1.73m2. Thank you. Reviewer Comment 154 Reviewer Comment 155 Reviewer Comment 156 Page 32, 3rd paragraph: Suggest specifically state that the term moderate increase in albumin excretion be used in place of microalbuminuria. Page 33: It is possible to standardize on either mg/m2/d or mg/1.73m2/d for urine protein output? Page 33, 2nd last paragraph: < mg/g (<3 mg/mmol) is not internally consistent. Reviewer Comment 157 Page 32: G1(>90) should be G1( 90). Thank you. We thought it was more reasonable to define CKD and its classification first, this provides the rationale for the evaluation. We wished to retain the simpler term staging to be consistent with the prior KDOQI guidelines. Thank you for this comment. We did not wish to be too restrictive in this section. There are not sufficient data on this subject. Thank you. Stakeholder Section Statement No. Comments Developer s Response Predicting Prognosis of CKD 1.3 Reviewer Comment I would suggest stressing the importance of , i.e., identifying cause of CKD! Cause, GFR and albuminuria are stressed equally in this classification system. Reviewer Comment Table 8 is rather confusing. We have attempted to clarify it. We also cite prior versions of the table, to provide more context Reviewer Comment The text section relating the new albuminuria categories back to the traditional definitions of "micro" and "macro" is helpful in this transition phase. Also, showing the various units used is helpful since they vary by locale. Anyway to more clearly define risk categories in the summary? e.g., indicate risks associated with colours. As you know, many people only read the summary. Reviewer Comment and Acceptable, though and are too vague. Thank you.

18 Reviewer Comment Comments on Fig. 10: Multiple studies (PREVEND and R T Gansevoort et al in J Am Soc Nephrol 20: , 2009: Fig 1 and others) indicate that CKD 3 without albuminuria has better prognosis than stages 2 & 3 (such CKD 3 is equivalent to non CKD). I suggest G3a A1 to be green and G3b A1 to be yellow based on many available data. Reviewer Comment I'm not clear of the value of statement It seems to be saying "use clinical judgment", which probably does not need to be stated as a guideline. Why not use just the first and third statements? Reviewer Comment seems like a helpful tool. Thank you. Reviewer Comment I don't like colours that may mean different things to differing people, or those who are colour blind. I am unsure that all the red boxes connote equal weight. Reviewer Comment Excellent figure. It is a very good idea to put together GFR categories and albuminuria grade to establish prognosis. Reviewer Comment The colour coding is very practical, making it easy to just eyeball the risk. This is a good addition for implementation. Reviewer Comment The classification is more complex and not practical. We need a more simple classification as has been proposed by us. This figure is based on a metaanalysis that includes data from PREVEND. It is a logical follow up statement. Additional explanation added as footnote, as well as source document, which provides more detail. Thank you. Thank you. Reviewer Comment Very good image!! Thanks. See reply to Reviewer Comment 95. Reviewer Comment Need description of colour coding interpretation. See reply to Reviewer Comment 165. Reviewer Comment The introduction of green, yellow, orange and red is not clear. We cannot just tell the patients who is red and who is yellow. What is the cut point for each range? Reviewer Comment Such a matrix of risk is so artificial that the only thing that does not fit is reality. Although colourful, categorization of continuous data is a faulty train of thought and a cumbersome scheme. This is not an aide but an impediment in the decision-making. Reviewer Comment In the chart, note the risk attributable to each colour! Done. See reply to Reviewer Comment 165. Agree that it doesn t help all. For categorization of continuous variables, see reply to Reviewer Comment 135. Reviewer Comment : weak evidence to this proposition, which generalize all Statement is not graded. CKD patients. Reviewer Comment Protein excretion rates (PER) to be added in the albuminuria See Table 6. (AER) categories: most nephrologists measure PER rather than AER. Reviewer Comment The category labels of (e.g.,) G2A2 are too complicated for widespread uptake. In Australia we have gone (e.g.,) with Stage 3b with no albuminuria. Wordier but much more See reply to Reviewer Comment 95. We anticipate some variations in implementation. comprehensible for the non-nephrologist. Reviewer Comment Section 5. Perfect table, simple but very rich. A great way to Thank you.