People with diabetes, MI, and other cardiovascular disease were included. Data do not apply to people with kidney transplants. to a greater extent than atorvastatin 10 mg/day, in 3107 patients with CKD defined by eGFR o60 ml/min/1.73 m2 and pre-existing coronary artery disease (HR 0.68; 95% CI Serious adverse events and treatment disconti- nuation were increased in the high dose statin group for both people with and without CKD; the RRs of these adverse events were numerically higher in people with CKD as compared to those without, but no significance testing was performed. However, TNT participants were pretreated with 10 mg of atorvastatin during the run-in phase, and therefore were preselected for atorvastatin tolerance. In addition, the mean eGFR among TNT participants with CKD was , and patients with heavy proteinuria were excluded. Therefore, whether these findings apply to the broader population of people with CKD is uncertain. Given the potential for toxicity with higher doses of statins and the relative lack of safety data, the Work Group suggests that prescription of statins in people with eGFR o60 ml/ or RRT should be based on regimens and doses that have been shown to be beneficial in randomized trials done specifically in this population (Table 4). Patients with progressive renal dysfunction who are tolerating an alter- native regimen do not necessarily need to be switched to a regimen described in Table 4, although dose reduction may be prudent in patients with severe kidney dysfunction who are receiving very aggressive regimens. Given less concern about drug toxicity in the setting of better kidney function, (and no history of kidney transplantation) may be treated with any statin regimen that is approved for use in the general population.


Given less concern about drug toxicity in the setting of better kidney function, (and no history of kidney transplantation) may be treated with any statin regimen that is approved for use in the general population. In the judgment of the Work Group, existing evidence does not support a specific on-treatment LDL-C target and thus adjusting the dose of statin regimens based on LDL-C levels is not required. Safety data from large clinical trials suggest that the excess risk of adverse events associated with these regimens is similar among people with and without CKD. In the judgment of the Work Group, these considerations suggest that measurement of creatine kinase (CK) or liver enzyme assays is not required in asymptomatic patients. Certain medications and grapefruit juice increase blood levels of statins (Supplemental Tables 19, 20 online). If such medications are required in patients who are otherwise good candidates for statin treatment, physicians may consider one of two strategies. For medications that will be required only for short periods (such as an antibiotic), the statin could be temporarily discontinued. For medications that will be required for more than a few days, a switch to an alternative statin or reducing the statin dose could be considered to reduce the risk of drug toxicity. Patients with CKD appear to be at increased risk of adverse events when statins and fibrates are used in combination (Supplemental Tables 21 28 online). For this reason, the Work Group recommends that fibrates not be used concomitantly with statins in patients with CKD. As mentioned earlier, given that evidence of clinical benefit is greater for statins than for fibrates, the Work Group recommends that statins be prescribed in preference to fibrates when clinicians are trying to choose between the two classes of medication.


As mentioned earlier, given that evidence of clinical benefit is greater for statins than for fibrates, the Work Group recommends that statins be prescribed in preference to fibrates when clinicians are trying to choose between the two classes of medication. Statins are contraindicated in pregnant or breast-feeding females; in people with active liver disease; and in people with transaminase levels that are three times or more the upper limit of normal. There is no evidence that the risk of liver dysfunction differs in people with CKD, as compared to those without. Regardless of CKD severity, the Work Group recommends that baseline levels of transaminases be measured before initiating statin treatment. Routine follow- up measurements of transaminases are not recommended, given the low frequency of abnormalities among people without abnormal values at baseline.33 Similarly, the Work Group does not recommend measurement of CK levels at baseline or during follow-up, unless the patient develops symptoms suggestive of myopathy. 2.1.1: In adults aged Z50 years with eGFR o60 ml/min/ but not treated with chronic dialysis or kidney transplantation (GFR categories G3a-G5), we recommend treatment with a statin or statin/ ezetimibe combination. (1A) RATIONALE Data on the effects of statins and statin/ezetimibe combina- tion in non-dialysis dependent adults with eGFR o60 ml/ are presented in Supplemental Tables 6 10, 15 17 online. The SHARP trial included 9270 participants with CKD (mean eGFR of 27 ml/min/1.73 m2 ) to receive simvastatin 20 mg plus ezetimibe 10 mg daily or placebo, and followed them for 5 years.14 Thirty-three percent of participants (n 3023) were receiving dialysis at randomiza- tion and 23% (n 2094) had diabetes.


The SHARP trial included 9270 participants with CKD (mean eGFR of 27 ml/min/1.73 m2 ) to receive simvastatin 20 mg plus ezetimibe 10 mg daily or placebo, and followed them for 5 years.14 Thirty-three percent of participants (n 3023) were receiving dialysis at randomiza- tion and 23% (n 2094) had diabetes. Statin plus ezetimibe therapy led to a significant 17% reduction in the relative hazard of the primary outcome of major atherosclerotic Table 4 | Recommended doses (mg/d) of statins in adults with CKD Statin eGFR G1-G2 eGFR G3a-G5, including patients on dialysis or with a kidney transplant Lovastatin GP nd Fluvastatin GP 801 Atorvastatin GP 202 Rosuvastatin GP 103 Simvastatin/Ezetmibe GP 20/104 Pravastatin GP 40 Simvastatin GP 40 Pitavastatin GP 2 All statins may not be available in all countries. Lower doses than those used in major trials of statins in CKD populations may be appropriate in Asian countries. Note that rosuvastatin 40 mg daily is not recommended for use in CKD 1-2 non- transplant patients, as it may increase the risk of adverse renal events. Cyclosporin inhibits the metabolism of certain statins resulting in higher blood levels. Data based on 1 SHARP. Abbreviations: eGFR, estimated glomerular filtration rate; GP, general population; nd, not done or not studied. events (coronary death, MI, non-hemorrhagic stroke, or any revascularization) compared with placebo (HR 0.83; 95% CI 0.74 0.94), driven by significant reductions in non-hemor- rhagic stroke and coronary revascularization. Among the 6247 patients with CKD not treated by dialysis at randomiza- tion, treatment with simvastatin plus ezetimibe did not reduce the risk of progression to end-stage renal disease (ESRD) requiring RRT. The risk of serious adverse events was similar in participants assigned to treatment and to control.


The risk of serious adverse events was similar in participants assigned to treatment and to control. These data are supported by post hoc analyses of randomized trials of statin vs. placebo that focus on the subset of participants with CKD at baseline. In general, these analyses suggest that statins reduce the RR of cardiovascular events to a similar extent among patients with and without CKD but that the absolute benefit of treatment is larger in the former due to their higher baseline risk.34 In addition, the risk of adverse events associated with statin treatment appeared similar in participants with and without CKD. However, most of the participants with CKD in these analyses and very few had eGFR . Since the absolute risk in people who are non-dialysis- aged Z50 years is consistently greater than 10 per 1000 patient-years, in the judgment of the Work Group, knowledge of LDL-C is not required to gauge average coronary risk in this population. Although multivariable prediction instruments might yield more precise estimates of risk for individuals, the Work Group judged that the increased simplicity of an age-based approach was defensible for patients aged Z50 years based on the data presented above and would enhance uptake of the guideline. There is no evidence that ezetimibe monotherapy will improve clinically relevant outcomes in patients with or without CKD. Therefore, ezetimibe monotherapy is not recommended. The combination of findings from SHARP, post hoc analyses of randomized trials from the general population (focusing on the subset with CKD), and the large body of evidence from the general population trials collectively provide a strong rationale for this recommendation. In the judgment of the Work Group, these data warrant a strong recommendation.


In the judgment of the Work Group, these data warrant a strong recommendation. 2.1.2: In adults aged Z50 years with CKD and eGFR (GFR categories G1-G2) we recommend treatment with a statin. (1B) RATIONALE The risk of future coronary events in patients aged Z50 years with CKD is markedly increased, as compared to those without CKD, and the rate of coronary death or non-fatal MI in this population exceeds 10 per 1000 patient-years even in the absence of prior MI or diabetes (Table 3). Most patients have proteinuria and slightly reduced or normal eGFR; many such patients would have been included but not recognized in randomized trials of statins done in the general population, since many such trials did not assess proteinuria at baseline. On the other hand, this population was explicitly excluded from participa- tion in SHARP, for which the primary inclusion criterion was elevated serum creatinine [SCr] (hence, reduced eGFR). Existing data suggest that the relative benefit of statin treatment is not influenced by the presence of albuminuria: and the Cholesterol and Recurrent Events (CARE) both tested for an interaction between the presence of albuminuria and the effect of statin treatment on cardio- vascular events. Both found no significant interaction (p 0.7 and p 0.59, respectively), suggesting that the benefit of statins is similar in people with and without albuminuria. A randomized trial of pravastatin 40 mg daily vs. placebo in CKD patients with preserved GFR (i.e., eGFR categories G1-G2) but microalbuminuria found no significant risk reduction associated with pravastatin treatment on the risk of although the number of events was small (n 47).


, eGFR categories G1-G2) but microalbuminuria found no significant risk reduction associated with pravastatin treatment on the risk of although the number of events was small (n 47). A post hoc analysis of CARE participants with slightly more events (n 60) found a significant reduction in the risk of the primary outcome (CHD death or non-fatal MI) among the subset of CKD patients with eGFR categories G1-G2 (HR of pravastatin vs. placebo 0.48; 95% CI 0.28 0.83). Given these data, the high cardiovascular risk among people with CKD and eGFR categories G1-G2, the large body of evidence supporting the efficacy of statins in the general population, and the lack of an a priori reason why statins would be less effective in the presence of proteinuria (i.e., the lack of justification for a new trial done specifically in people with CKD and eGFR categories G1-G2), the Work Group judged that a strong recommendation was appropriate. 2.2: In adults aged 18-49 years with CKD but not treated with chronic dialysis or kidney transplantation, we suggest statin treatment in people with one or more of the following (2A): K known coronary disease (myocardial infarction or coronary revascularization) K diabetes mellitus K prior ischemic stroke K estimated 10-year incidence of coronary death or non-fatal myocardial infarction 410% RATIONALE As mentioned, the risk of coronary events is age-dependent in people with CKD, just as it is in the general population. Although the absolute rate of such events is lower among people with CKD who are less than 50 years of age, the co- existence of other risk factors increases the rate of coronary death or non-fatal MI substantially.


Although the absolute rate of such events is lower among people with CKD who are less than 50 years of age, the co- existence of other risk factors increases the rate of coronary death or non-fatal MI substantially. In the subset of CKD patients aged o50 years with diabetes or prior vascular disease (MI, coronary revascularization, stroke or transient ischemic attack), the rate of coronary death or incident MI (Figure 2). In the judgment of the Work Group, this rate is sufficiently high to warrant statin treatment. Similarly, some CKD patients aged 18 50 years may not have diabetes or prior vascular disease but yet have multiple cardiovascular risk factors that substantially increase their risk of future coronary events. In the judgment of the Work Group, an estimated 10-year incidence of coronary death or non-fatal MI is sufficiently high to warrant statin treatment. Since unequivocally elevated LDL-C does appear to confer an increased risk of coronary events in people with CKD (although to a lesser extent than in the general population), increased LDL-C levels should be considered when estimating coronary risk in CKD patients aged o50 years. The 10-year incidence of coronary death or non-fatal MI may be estimated using any validated risk prediction tool such as the Framingham risk score,38 or the QRISK2.42 Overall, these instruments tend to overestimate future coronary risk and usually incorporate information on LDL-C. However, since most do not explicitly consider the presence of CKD, which would be expected to increase coronary risk for any given set of traditional cardiovascular risk factors, such overestimation should be less pronounced in CKD populations.


However, since most do not explicitly consider the presence of CKD, which would be expected to increase coronary risk for any given set of traditional cardiovascular risk factors, such overestimation should be less pronounced in CKD populations. Patients whose 10-year risk of coronary death or non-fatal MI is o10% could choose to receive statin treatment if they placed relatively more value on a small absolute reduction in the risk of cardiovascular events, and relatively less value on minimizing the risks of polypharmacy and drug toxicity. On the other hand, patients valuing the potential benefits of statin treatment to a lesser extent than the potential harms might choose not to receive statin treatment even if their 10-year risk of coronary death or non-fatal MI is 410%. 2.3.1: In adults with dialysis-dependent CKD, we suggest that statins or statin/ezetimibe combination not be RATIONALE There are three large-scale RCTs of statin treatment that enrolled dialysis patients. Data from these trials are presented in Supplemental Tables 11 13, 17 online. The 4D Study (Die Deutsche Diabetes Dialyse Studie) The 4D, a multicenter, double blind, randomized trial assigned 1255 HD patients with type 2 diabetes to receive 20 mg of atorvastatin daily or placebo.43 After 4 weeks of treatment, atorvastatin reduced the median LDL-C level by difference in LDL-C level was maintained throughout the treatment period. During median follow-up of 4 years, 469 patients (37%) reached the primary endpoint (a composite of cardiac death, nonfatal MI, and fatal and nonfatal stroke): 226 assigned to atorvastatin and 243 assigned to placebo (RR 0.92; 95% CI 0.77 1.10; p 0.37). Atorvastatin had no effect on the single components of the primary endpoint with the exception of fatal stroke, in which RR was 2.03 (95% CI 1.05- 3.93; p 0.04).


Atorvastatin had no effect on the single components of the primary endpoint with the exception of fatal stroke, in which RR was 2.03 (95% CI 1.05- 3.93; p 0.04). The secondary endpoint of combined cardiac events (RR 0.82; 95% CI 0.68 0.99; p 0.03) was significantly reduced, but not all combined cerebrovascular events (RR 95% CI 0.79 1.08; p 0.33). AURORA Study (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Dialysis: an Assessment of Survival and Cardiovascular Events) In this international double-blind randomized trial, 2776 HD patients were assigned to receive rosuvastatin 10 mg daily or placebo, and followed for a median of 3.8 years.44 Despite the mean reduction in LDL-C of 43% in the intervention group, the combined primary endpoint of death from cardiovascular causes, nonfatal MI, or nonfatal stroke was not reduced (HR 0.96; 95% CI 0.84 1.11; p 0.59). Rosuvastatin did not reduce the risk of individual components of the primary endpoint, nor of all-cause mortality (HR 0.96; 95% CI 0.86- 1.07; p 0.51). SHARP (Study of Heart and Renal Protection) This international double-blind randomized trial assigned 9270 participants Z40 years old with CKD to receive simvastatin 20 mg plus ezetimibe 10 mg daily or placebo, and followed them for 4.9 years.14 Thirty-three percent of the patients (n 3023) were receiving maintenance dialysis at randomization. The remaining 6247 CKD patients had a . Mean reduction in LDL-C among the treatment group was 0.83 mmol/l (32 mg/dl), compared to placebo. Statin plus ezetimibe therapy was associated with a significant 17% RR reduction of the primary outcome of major atherosclerotic events (coronary death, MI, non-hemorrhagic stroke, or any revascularization) compared with placebo (HR 0.83; 95% CI 0.74 0.94).


Statin plus ezetimibe therapy was associated with a significant 17% RR reduction of the primary outcome of major atherosclerotic events (coronary death, MI, non-hemorrhagic stroke, or any revascularization) compared with placebo (HR 0.83; 95% CI 0.74 0.94). SHARP indicated that risk for the primary outcome of major atherosclerotic events other than death was reduced by simvastatin/ezetimibe among a wide range of patients with CKD. Combination treatment did not significantly reduce the risk of the primary outcome in the subgroup of over 3000 patients treated with dialysis at baseline. A systematic review pooling data from all available randomized trials done in CKD populations reported significant heterogeneity between dialysis and non-dialysis patients for the benefit of statins on major cardiovascular events (HR for dialysis 0.96; 95% CI 0.88 1.03; HR for non- dialysis 0.76; 95% CI 0.72 0.79; p for heterogeneity When findings from SHARP, 4D and AURORA are considered together, the clinical benefit of statins (alone or in combination with ezetimibe) in prevalent dialysis patients is uncertain. Another meta-analysis in essence confirmed the results, although the data were analyzed in a Even if statins truly do prevent cardio- vascular events in prevalent dialysis patients, it is clear that the magnitude of any relative reduction in risk is substantially smaller than in earlier stages of CKD.34 However, if this speculative benefit among dialysis patients is confirmed in future studies, the absolute benefit might be comparable to that in people with less severe CKD, due to the higher event rate among dialysis patients.46 The smaller RR reduction noted in SHARP could be due to lower compliance to study drug in the subgroup of dialysis patients.


Another meta-analysis in essence confirmed the results, although the data were analyzed in a Even if statins truly do prevent cardio- vascular events in prevalent dialysis patients, it is clear that the magnitude of any relative reduction in risk is substantially smaller than in earlier stages of CKD.34 However, if this speculative benefit among dialysis patients is confirmed in future studies, the absolute benefit might be comparable to that in people with less severe CKD, due to the higher event rate among dialysis patients.46 The smaller RR reduction noted in SHARP could be due to lower compliance to study drug in the subgroup of dialysis patients. Dialysis patients showed on average a 0.60 mmol/l (23 mg/dl) LDL-C reduction in comparison to the non- dialysis CKD group which outlined a 0.96 mmol/l (37 mg/dl) LDL-C decrease. In summary, these data suggest that despite the exceed- ingly high cardiovascular risk in dialysis patients, it is uncertain whether statin regimens lead to clinical benefit in this population. Therefore, in the judgment of the Work Group, initiation of statin treatment is not recom- mended for most prevalent HD patients. However, patients might reasonably choose statin treatment if they are interested in a relatively small, uncertain reduction in cardiovascular events. Since very high LDL-C might increase the likelihood of benefit from statin in a dialysis patient,47 patients who meet this criterion may be more inclined to receive a statin, recognizing that the benefit remains uncertain. Other factors that might influence a patient s decision to receive statin could include recent MI or greater life expectancy (both favoring treatment), and more severe comorbidity or higher current pill burden (both favoring non-treatment). 2.3.2: In patients already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, we suggest that these agents be continued.


2.3.2: In patients already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, we suggest that these agents be continued. (2C) RATIONALE SHARP, 4D and AURORA do not directly address the question of whether statins should be discontinued in patients initiating dialysis, who may be systematically different from prevalent dialysis patients. However, 2141 (34%) of SHARP patients without kidney failure at baseline commenced dialysis during the trial and were analyzed in the non-dialysis group in which overall benefit was observed.14 In the judgment of the Work Group, it is reasonable to continue statins in patients who are already receiving them at the time of dialysis initiation, recognizing that the magnitude of clinical benefit may be lower than in patients with non-dialysis-dependent CKD. Physicians should con- sider periodically reviewing the clinical status of dialysis patients and revisiting the decision to prescribe statins as required. Given the lack of direct evidence that statin treatment is beneficial in dialysis patients, this recommendation is graded as weak. Discontinuation of statin or statin/ezetimibe may be warranted in patients who place a relatively low value on a small potential relative reduction in cardiovascular events, and a relatively high value on the risks of polypharmacy and drug toxicity. 2.4: In adult kidney transplant recipients, we suggest treatment with a statin.


2.4: In adult kidney transplant recipients, we suggest treatment with a statin. (2B) RATIONALE The risk of future coronary events in kidney transplant recipients is markedly elevated: data from the placebo arm of the ALERT trial suggest that the rate of cardiovascular death or non-fatal MI is approximately 21.5 per 1000 patient- Data on the rate of non-fatal MI by age are not available for kidney transplant recipients, but a population- based study from Australia and New Zealand suggests that the rate of cardiovascular death alone is approximately 5 per 1000 patient-years even among those aged 25 44 years.49 Data on the effect of statins in adult kidney transplant recipients are presented in Supplemental Tables 29 31 online. ALERTexamined the effect of statin therapy on cardiovascular risk reduction in 2102 patients aged 30 75 years with functioning kidney transplants who were followed for 5 6 years. Fluvastatin therapy (40 80 mg/day) led to a non- significant 17% reduction in the primary outcome of coronary death or non-fatal MI, compared to placebo (RR 0.83; 95% CI 0.64 1.06). However, fluvastatin led to a significant 35% relative reduction in the risk of cardiac death or definite non- and an unblinded extension study found that randomization to fluvastatin was associated with a significant reduction in the original primary outcome after 6.7 years of follow-up. In the judgment of the Work Group, the apparent benefits observed in ALERT are consistent with the effects of statins in the general population, and suggest that statins are beneficial in patients with a functioning kidney transplant. However, the nominal lack of statistical significance in the primary analysis and the existence of a single randomized trial favor a weak recommendation.


However, the nominal lack of statistical significance in the primary analysis and the existence of a single randomized trial favor a weak recommendation. The age at which statin treatment should begin in kidney transplant recipients is uncertain: the risk of coronary events is age-dependent, and ALERT did not enroll participants younger than 30 years, However, ESRD treated by kidney transplantation is a chronic disease, with cardiovascular risk expected to increase over time even in the presence of optimal graft function. In the judgment of the Work Group, these considerations warrant treatment in all adult kidney transplant recipients. However, younger patients (for example, those o30 years and without traditional cardio- vascular risk factors) could choose not to receive statin treatment if they placed relatively less value on a small absolute reduction in the risk of cardiovascular events, and relatively more value on minimizing the risks of poly- pharmacy and drug toxicity. Considerations for International Settings In some Asian countries, doses of statins tend to be lower than those used in Western countries, due to concern about drug toxicity and clinical trial data indicating that such doses safely and improve clinical outcomes.52,53 There- fore, physicians practicing in such countries may choose to prescribe lower doses than recommended in Table 4. Suggested Audit Criteria K One year before and after the publication of this guide- line, assess the proportion of non-dialysis-dependent that receive treatment with a statin or statin/ezetimibe combination. K One year before and after the publication of this guide- line, assess the proportion of adults aged Z50 years with that receive treat- ment with a statin. K One year before and after the publication of this guideline, assess the proportion of adult kidney trans- plant recipients that receive treatment with a statin.


K One year before and after the publication of this guideline, assess the proportion of adult kidney trans- plant recipients that receive treatment with a statin. K One year before and after the publication of this guideline, assess the prevalence of statin use among non-dialysis-dependent adults aged 18 49 years with CKD and at least one of the following risk factors: known coronary disease (MI or coronary revascularization), diabetes mellitus, previous ischemic stroke, or predicted 10-year risk of CHD death/non-fatal MI 410%. KEY POINTS K Coronary risk is sufficiently high to justify prescription of statins in people aged Z50 with non-dialysis-dependent CKD or a kidney transplant. K Coronary risk in people aged o50 years with non-dialysis- dependent CKD is lower, but the presence of additional cardiovascular risk factors may increase risk to justify statin prescription. Given the evidence that treatment with statins improve vascular outcomes in this population, such treatment is suggested for patients aged o50 years with non-dialysis-dependent CKD and known vascular disease (prior MI, coronary revascularization or stroke), diabetes, or other risk factors that increase the 10-year risk of coronary death or non-fatal MI (as estimated using a validated risk calculator) to 410%. K Patients with dialysis-dependent CKD should not be initiated on statin or statin/ezetimibe treatment, given the lack of evidence that such treatment is beneficial. However, statin or statin/ezetimibe treatment should not necessarily be discontinued among existing users when dialysis treatment is initiated. K Physicians should be alert to the possibility of toxicity resulting from substances that increase blood levels of statins (e.g., grapefruit juice, certain medications).


K Physicians should be alert to the possibility of toxicity resulting from substances that increase blood levels of statins (e.g., grapefruit juice, certain medications). RESEARCH RECOMMENDATIONS K An extended observational study should be undertaken of the SHARP study cohort to determine whether the reduction in major atherosclerotic events resulting from 5 years of LDL-C lowering persists in the long-term, and whether LDL-C lowering significantly delays renal disease progression in people with non-dialysis-dependent CKD . K Given that the majority of early CKD is managed in primary care, audits of pharmacological cholesterol- lowering treatment should be undertaken in this setting. K Data from the AURORA, 4D and SHARP studies (dialysis cohort) should be pooled to undertake individual patient data meta-analysis to more comprehensively assess the benefits and risks of cholesterol-lowering treatment in people with dialysis-dependent CKD. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature.


While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. SUPPLEMENTARY MATERIAL Supplemental Table 1: Summary table of RCT examining the effect of exercise in CKD 5HD patients [continuous outcomes] Supplemental Table 2: Summary table of RCT examining low vs. mode- rate protein diet in CKD patients without DM [categorical outcomes] Supplemental Table 3: Summary table of RCT examining low vs. mode- rate protein diet in CKD patients without DM [continuous outcomes] Supplemental Table 4: Summary table of RCT examining statin therapy vs. lifestyle modification in kidney transplant recipients without DM [categorical outcomes] Supplemental Table 5: Summary table of RCT examining statin therapy vs. lifestyle modification in kidney transplant recipients without DM [continuous outcomes] Supplemental Table 6: Summary table of RCT examining statin therapy vs. usual care in patients with CKD without DM [categorical outcomes] Supplemental Table 7: Summary table of RCT examining statin therapy vs. usual care in patients with CKD without DM [continuous outcomes] Supplemental Table 8: Summary table of RCTs of statins vs. placebo in patients with CKD with and without DM [categorical outcomes] Supplemental Table 9: Summary table of RCTs of statins vs. placebo in various stages of CKD with and without DM [continuous outcomes] Supplemental Table 10: Evidence profile of RCTs examining the effect of statins vs. placebo in patients with CKD with and without DM Supplemental Table 11: Summary table of RCTs of statins vs. placebo in dialysis patients with and without DM [categorical outcomes] Supplemental Table 12: Summary table of RCTs of statins vs. placebo in dialysis patients with and without DM [continuous outcomes] Supplemental Table 13: Evidence profile of RCTs examining the effect of statins vs. placebo in dialysis patients with and without DM Supplemental Table 14: Summary table of RCT examining statin vs. placebo in patients with ADPKD [continuous outcomes] Supplemental Table 15: Summary table of RCT examining simvastatin/ ezetimibe combination vs. simvastatin/placebo in CKD patients without DM [categorical outcomes] Supplemental Table 16: Summary table of RCT examining simvastatin/ ezetimibe combination vs. simvastatin/placebo in CKD patients without DM [continuous outcomes] Supplemental Table 17: Summary table of RCT of statin ezetimibe vs. placebo in CKD patients [categorical outcomes] Supplemental Table 18: Summary table of RCT examining the effect of dose of atorvastatin in CKD patients with DM [categorical outcomes] Supplemental Table 19: Drug interactions Supplemental Table 20: Effects of grapefruit juice on statin pharmacokinetics and recommendations Supplemental Table 21: Patients on statin fibrate therapy reporting any adverse event Supplemental Table 22: Patients receiving statin fibrate therapy reporting other individual adverse events Supplemental Table 23: Patients on statin fibrate therapy reporting treatment related adverse events Supplemental Table 24: Patients on statin fibrate therapy discontinuing due to adverse events Supplemental Table 25: Patients on statin fibrate therapy with increased ALT or AST Supplemental Table 26: Patients on statin fibrate therapy with increased CK Supplemental Table 27: Patients on statin fibrate therapy with increased serum creatinine Supplemental Table 28: Patients receiving statin fibrate therapy reporting rhabdomyolysis Supplemental Table 29: Summary table of RCTs of statin vs. placebo in kidney transplant patients [categorical outcomes] Supplemental Table 30: Summary table of RCTs of statin vs. placebo in kidney transplant patients [continuous outcomes] Supplemental Table 31: Evidence profile of RCTs examining the effect of statins vs. placebo in kidney transplant recipients Supplementary material is linked to the online version of the paper at http://www.kdigo.org/home/guidelines/lipids Chapter 3: Assessment of lipid status in children with CKD 3.1: In children with newly identified CKD (including those treated with chronic dialysis or kidney trans- plantation), we recommend evaluation with a lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides).


(1C) RATIONALE have at least 10-fold higher risk for CVD mortality compared to the Many recent studies document the prevalence of CVD risk factors in children with CKD. However, due to limited follow-up, few studies demonstrate the association of dyslipidemia with clinical CVD events in adolescents or young adults, especially in the setting of CKD. In the general pediatric population, lipid levels in childhood are predictive of future lipid levels and subsequent The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study shows that initial fatty streaks seen in adolescents with normal kidney function develop into atheromatous plaques in young adults.56 Over 50% of children 10-14 years old had early fatty streaks, and 8% had fibrous plaques, thus confirming that atherosclerosis begins in childhood.56 Additional longitudinal studies demonstrate an association between childhood lipid levels and adult onset coronary artery disease.57 59 Moreover, this atherosclerotic process is likely accelerated in nephrotic syndrome, proteinuric states and chronic kidney disease due to abnormal lipid metabolism and other atherogenic risk factors, thus putting children and adolescents at risk for developing CVD as they age into adulthood. In the Bogalusa Heart Study, body mass index, LDL-C, and systolic blood pressure were associated with atherosclerotic disease of the aorta and coronary vessels of children.56,57 Recent studies of subclinical atherosclerotic CVD in children with familial hypercholesterolemia found an increase in intimal medial thickness of the aorta and carotid arteries compared to that of healthy young children.60 Thus, atherosclerotic disease appears to begin in childhood, and dyslipidemia in children may play an important role in the early pathogenesis of atherosclerosis. In children with CKD, the relationship between dyslipi- demias and subsequent atherosclerotic clinical events is not known due to short follow-up in observational studies or clinical trials.


In children with CKD, the relationship between dyslipi- demias and subsequent atherosclerotic clinical events is not known due to short follow-up in observational studies or clinical trials. Recently, the Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement from the American Heart Association Expert Panel on Population and Prevention Science stated that CVD prevention in many chronic pediatric conditions was warranted given the high risk of developing disease as adults.61 The recent National Institutes of Health Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents in 2011 addressed specific questions of screening for dyslipidemias in children and adolescents and also treatment of dyslipidemias.7 Cholesterol and its metabolism are important in children as cholesterol is the basis of cell membranes, myelin formation, subcellular organelles and steroid hormones which are all key for natural growth and development. Based on growth and development, lipid levels vary depending on age, puberty, Lipid levels are very low at birth and increase during the first year of life [mean TC of 3.9 mmol/ l (150 mg/dl), LDL-C 2.6 mmol/l (100 mg/dl), and HDL-C 1.4 mmol/l (55 mg/dl)] where they remain fairly constant till age 12 and are slightly lower in girls than boys. During puberty, there is a decrease in TC, LDL-C, and a slight decrease in HDL-C in boys. After puberty, TC and LDL-C increase to adult levels in boys and girls. Boys continue to have a slightly lower HDL-C than girls. Due to these variations in levels, former guidelines used the 95th percentile for age and gender to determine the upper limit of acceptable values. More recently, age- and gender- specific curves for lipoproteins linked to CVD risk over 15-20 years55,58 have been used instead.


More recently, age- and gender- specific curves for lipoproteins linked to CVD risk over 15-20 years55,58 have been used instead. A simplified and more practical approach has been to define acceptable, borderline high and high lipid concentration for children and adolescents based on these (see Table 5). Many studies document the prevalence of dyslipidemias among children with CKD and ESRD.63,64 As in adults, the pattern of dyslipidemias in children with CKD is greatly influenced by the underlying pathogenesis and duration of CKD, severity of proteinuria, and treatment.63,64 Due to this variability, the prevalence of hypercholesterolemia ranges from 39% to 65% in children with CKD. Among 391 children from the North American observational cohort study, CKiD (Chronic Kidney Disease in Children), TG and non-HDL-C levels increased as the measured GFR declined in this cross sectional study population.63 Conversely, HDL-C was lower for those with a lower GFR. Factors that impacted TG, HDL- C and non-HDL-C levels were primarily GFR, significant proteinuria and obesity by multivariate analyses.63 Over half the population had no evidence of dyslipidemias and of the remainder, 25% had a single abnormal lipid level, and the other 25% had at least 2 abnormal lipid levels.63 The most chapter 3 http://www.kidney-international.org & 2013 KDIGO common abnormality was hypertriglyceridemia.63 The frequency of these abnormalities suggests that clinicians should measure lipid levels at baseline in children with CKD to screen for underlying secondary causes of dyslipidemia. As for adults, there is no direct evidence indicating that measurement of lipid status will improve clinical outcomes. However, such measurement is minimally invasive, relatively inexpensive, and has potential to improve the health of people with secondary dyslipidemia.


However, such measurement is minimally invasive, relatively inexpensive, and has potential to improve the health of people with secondary dyslipidemia. In the judgment of the Work Group, children with CKD (and their families) place a high value on this potential benefit and are less concerned about the possibility of adverse events or inconvenience associated with baseline measurement of lipid levels. In the judgment of the Work Group, these considerations justify a strong recommendation despite the low quality of the available evidence. 3.2: In children with CKD (including those treated with chronic dialysis or kidney transplantation), we suggest annual follow-up measurement of fasting lipid levels. (Not Graded) RATIONALE Few data document how frequently the clinical lipid status changes in children with CKD, although it is clear that abnormal levels (once documented) are likely to persist. Unlike adults, growth and development in children have potential to influence lipid levels over time. Therefore, the Work Group recommends that fasting lipid levels be followed in children with CKD to screen for underlying secondary causes of dyslipidemia. The ideal frequency of follow-up for fasting levels of LDL-C, HDL-C and serum TGs is unknown. These levels could be assessed annually in most children with CKD. However, more frequent (or less frequent) follow-up measurements may be appropriate based on the clinical status of the patient, and the potential for such follow-up measurements to influence management.65 Possible changes in management in response to such measurements could include therapeutic lifestyle measures (see Recommendation 6.1) or statin regimens for children with very high LDL-C levels (see Recommendation 4.1). Considerations for International Settings Similar to those for Chapter 1. Suggested Audit Criteria Similar to those for Chapter 1. KEY POINTS K Dyslipidemia is common in children with CKD. K All children with CKD should be screened for dyslipide- mias at presentation.


K All children with CKD should be screened for dyslipide- mias at presentation. K Because growth and development as well as modality switches may influence lipid metabolism, lipids could be regularly evaluated during follow-up and when children initiate dialysis or receive a kidney transplant. RESEARCH RECOMMENDATION K Future studies should be conducted to determine the prevalence of dyslipidemias among children initiating dialysis or receiving a kidney transplant. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. Table 5 | Plasma lipid concentrations for children and Category Acceptable Borderline High (75%) High (95%) Abbreviations: LDL-C, low-density lipoprotein cholesterol; Non-HDL-C, non-high- density-lipoprotein cholesterol. Values given are in mmol/l (mg/dl). Values for plasma lipid and lipoprotein levels are from the National Cholesterol Education Program (NCEP) Expert Panel on Cholesterol Levels in Children.


Values for plasma lipid and lipoprotein levels are from the National Cholesterol Education Program (NCEP) Expert Panel on Cholesterol Levels in Children. Non-HDL C values from the Bogalusa Heart Study are equivalent to the NCEP Pediatric Panel cut points for LDL C. Chapter 4: Pharmacological cholesterol-lowering treatment in children 4.1: In children less than 18 years of age with CKD (including those treated with chronic dialysis or kidney transplantation), we suggest that statins or statin/ezetimibe combination not be initiated. (2C) RATIONALE Clinical trials of dyslipidemias are limited in the pediatric CKD population given the rapid transitions from CKD to dialysis and/or transplant, which complicates trial design, recruitment and analyses (Supplemental Table 32 online). Accurately predicting CVD risk is also not possible in the pediatric CKD population given the limited data available; scores commonly used in adults have not been validated in the pediatric population. Nonetheless, young adults ages 20 24 treated with dialysis or kidney transplantation have significantly lower expected survival compared to an age-matched group in the general Treatment for dyslipidemia in children should first include nutrition and dietary counseling, and address obesity with weight loss regimens if necessary. Recent studies in the general population have shown that dietary fat restriction is safe in children.67 70 In particular, there have been no adverse effects on growth and development, or nutrition.67 70 Diets, however, should be used judiciously, or not at all, in children who are malnourished. Secondary causes of dyslipidemias should also be treated first (Table 1). Therapeutic lifestyle changes (TLC) should be adopted among all children with CKD.


Therapeutic lifestyle changes (TLC) should be adopted among all children with CKD. Statin therapy has been shown to reduce LDL-C in children and adolescents ages 8 18 years with no adverse effects on growth, development or sexual maturation However, the follow-up time of the studies was quite variable and safety data in children with CKD are very limited. Data on the benefits of treating LDL-C in children aged o10 years are extremely limited, and chiefly include patients with severe familial hypercholesterolemia or cardiac allografts. In the US, statins are approved for use among adolescent boys and post-menarchal girls ages 10 18 years (age 8 and older for pravastatin) for treatment of elevated LDL-C among those with familial dyslipidemias, family history of premature heart disease and 2 or more cardio- vascular risk factors.7 Four randomized trials have examined drug treatment of dyslipidemia in children with CKD, primarily in children with nephrotic syndrome.71 74 The trials demonstrate that statins lower LDL-C over 7 months to 5 years. No randomized trials have studied clinically relevant outcomes such as cardiovascular events or mortality. There have been 13 statin trials in 1683 children with dyslipidemias and normal kidney function. These trials have demonstrated that statins lower LDL-C by 17-50% (depending on dose) and have modest effects on TGs or HDL-C.75 87 There were only two studies that studied statins in combination with a second drug such as colestipol or ezetimibe.81,85 This is a weak recommendation that reflects the lack of evidence for benefit and safety associated with long-term use. As for all weak recommendations, practitioners should consider the clinical circumstances and the patient s pre- ferences when considering an individual patient. The Work Group further suggests that the patient s age could also be considered when applying this recommendation.


The Work Group further suggests that the patient s age could also be considered when applying this recommendation. Due to the very limited available data, the Work Group does not recommend the use of statins in children with CKD aged o10 years. Patients (boys aged 410 years and post- menarchal girls, together with their parents) with severely elevated LDL-C who place a higher value on the potential for preventing cardiovascular events and are less concerned about adverse events from statin use might be candidates for statin use especially those with multiple additional risk factors such as family history of premature coronary disease, diabetes, hypertension, smoking and ESRD. If a statin is prescribed, the Work Group suggests the lowest dose available. There are no data on the appropriate target for LDL-C in children (with or without CKD), extremely limited long-term safety data in pediatric CKD populations, and no dose escalation studies in children with CKD to confirm the safety of higher statin doses even over the short term. Given the lack of evidence for the benefit and safety of combination therapy with bile acid resins, colestipol and ezetimibe in pediatric CKD populations, the Work Group does not recommend the use of such multi-drug regimens even in children with severely elevated LDL-C. Suggested Audit Criteria K Determine the number of children treated with statins (and statin type) and other lipid-lowering therapies by CKD severity. K Document the number of children with intolerance and/ or non-compliance to statins or other lipid-lowering treatment. K Document the number of children that receive statin therapy for primary prevention. chapter 4 http://www.kidney-international.org & 2013 KDIGO KEY POINTS K TLC should be recommended to all children with CKD and dyslipidemia. K Statins are not recommended for children with CKD and dyslipidemia.


K Statins are not recommended for children with CKD and dyslipidemia. RESEARCH RECOMMENDATIONS Future studies should be conducted to assess short- and long- term association between lipids and CVD, using surrogate outcomes such as carotid intima-media thickness and clinically relevant outcomes such as MI and stroke. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccu- rate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. SUPPLEMENTARY MATERIAL Supplemental Table 32: Summary table of RCTs of statins vs. placebo in children with CKD without DM [continuous outcomes] Supplementary material is linked to the online version of the paper at http://www.kdigo.org/home/guidelines/lipids Chapter 5: Triglyceride-lowering treatment in adults 5.1: In adults with CKD (including those treated with chronic dialysis or kidney transplantation) and hypertriglyceridemia, we suggest that therapeutic lifestyle changes be advised. (2D) RATIONALE Non-pharmacological treatment of high triglycerides TLC includes dietary modification, weight reduction, increased physical activity, reducing alcohol intake, and treatment of hyperglycemia (if present). Evidence that TLC will reduce serum TGs in patients with CKD is weak.


Evidence that TLC will reduce serum TGs in patients with CKD is weak. However, the elements of TLC are unlikely to lead to harm and may improve general health. In the opinion of the Work Group, it is reasonable to advise patients with high fasting levels of serum TGs (45.65 mmol/l [4500 mg/dl]) to adopt TLC. Dietary changes that may reduce serum TGs include a low-fat diet (o15% total calories), reduction of mono- saccharide and disaccharide intake, reducing the total amount of dietary carbohydrates, and use of fish oils to replace some long-chain TGs. Dietary modification should be used judiciously, if at all, in individuals who are malnourished. This is a weak recommendation that is based on very low quality evidence. Pharmacological treatment of high triglycerides: effects on risk of pancreatitis Although previous guidelines have suggested the use of fibric acid derivatives for preventing pancreatitis from severe the evidence supporting the safety and efficacy of this approach is extremely weak, especially in patients with CKD. Therefore, the Work Group no longer recommends this approach, especially since statins appear to prevent pancreatitis in people with normal or mildly Fibric acid derivatives could be considered for the rare patients with CKD and markedly elevated fasting levels of serum TG (411.3 mmol/l [41000 mg/dl]). If such therapy is prescribed, fibric acid derivatives must be dose-adjusted for kidney function. There is limited evidence to recommend one fibric acid derivative over another in the setting of CKD and therefore any of the alternatives may be used. As mentioned in Chapter 2, concomitant therapy with both a fibric acid derivative and a statin is not recommended in patients with CKD due to the potential for toxicity.


As mentioned in Chapter 2, concomitant therapy with both a fibric acid derivative and a statin is not recommended in patients with CKD due to the potential for toxicity. Nicotinic acid has not been well studied in advanced CKD and therefore is not recommended for treatment of severe hypertriglyceridemia, given the risk of toxicity (especially flushing and hyperglycemia). The Work Group considered a weak recommendation against the use of fibric acid derivatives in people with CKD. However, in the judgment of the Work Group, there is insufficient evidence to recommend for or against the use of fibric acid derivatives in this population. Treatment with fibric acid derivatives might be warranted in patients who place a relatively high value on preventing pancreatitis, and a relatively low value on the risks of polypharmacy and drug toxicity. Pharmacological treatment of high triglycerides: effects on cardiovascular risk A meta-analysis of data from 18 randomized trials involving 45,058 participants drawn from the general population (i.e., not specific to CKD) demonstrated a modest 10% RR reduction (95% CI 0 18; p 0.048) in major cardiovascular events and a 13% RR reduction in coronary events (95% CI 7 19; p o0.0001) for fibrate therapy. But such benefits are smaller than the 20% reduction in vascular events and 10% reduction in mortality demonstrated by statins per mmol/l reduction in LDL-C.14,89,90 As mentioned in Chapter 1, the dyslipidemia associated with CKD appear particularly suited to therapy with fibric acid derivatives, which alter triglyceride-rich lipoproteins more than LDL-C, the main target of statins. This observation has raised the hypothesis that fibrates might be especially effective for preventing vascular events in CKD populations. Randomized treatment trials that examined the effect of fibrates relative to placebo in patients with diabetes and CKD are summarized below.


Randomized treatment trials that examined the effect of fibrates relative to placebo in patients with diabetes and CKD are summarized below. The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) found evidence that gemfibrozil reduces risk of major cardiovascular events (i.e., fatal CHD, nonfatal MI, and stroke) by 42% compared with placebo (RR 0.58; 95% CI 0.38 0.89) in a post hoc analysis of ) The Diabetes Atherosclerosis Intervention Study (DAIS)92 and the FIELD study93 reported that fenofibrate treatment significantly lowered the risk of developing new-onset microalbuminuria compared with placebo (RR 0.87 in patients with type 2 diabetes; 95% CI 0.77-0.97). In a pooled analysis of these two trials, fenofibrate also promoted regression from microalbuminuria to normoalbuminuria (RR1.15; 95% CI 1.04 1.28; n 2260). None of the other trials of fibrate therapy in diabetes reported CVD or kidney disease outcomes for the subgroup of patients with CKD. The FIELD study was a large randomized double-blind trial in which 9795 participants aged 50 75 years with type 2 chapter 5 http://www.kidney-international.org & 2013 KDIGO diabetes were allocated to micronized fenofibrate 200 mg daily or matching placebo, and followed for a median of Patients were eligible if there was no clear indication for, or treatment with, lipid-modifying therapy at study entry, and patients with renal impairment, defined as a plasma creatinine 4130 mmol/l (41.47 mg/dl), were excluded. There was a significant difference in the proportion of participants with progression of albuminuria, analyzed categorically to/from normo-, micro-, and macro-albumin- the fenofibrate group vs. 539 [11.0%] progressing and 400 [8.2%] regressing in the placebo group; i.e., 2.6% more patients were regressing or not progressing in those allocated fenofibrate than placebo, p 0.002).


, 2.6% more patients were regressing or not progressing in those allocated fenofibrate than placebo, p 0.002). Importantly, only 5% (519 of 9795) of the randomized participants had a baseline , so only 117 cardiovascular events occurred in this subgroup. The significant treatment effects presented for those with eGFR below 60 ml/min/ (for the outcomes of coronary revascularization, cardiovascular mortality, and total cardiovascular events) were based on too few events to be reliable. Hence, there was not good evidence that the treatment effects on vascular outcomes differed between those with and without lower baseline eGFR. Ting and colleagues also considered whether allocation to fenofibrate affected renal function but were unable to conclusively address this issue due to lack of statistical Another paper, which provides more detailed renal analyses from FIELD, suggested that after excluding the 10 12 mmol/l (0.11 0.14 mg/dl) step-rise in creatinine on commencing fenofibrate, allocation to fenofibrate was in fact associated with a slower rate of change in eGFR (1.19 vs. per year; But the inaccuracy of eGFR above 60 ml/min/ and the use of surrogate outcomes such as rate of change in eGFR and albuminuria remain important caveats. Furthermore, allocation to fenofibrate was also associated with an increased risk of doubling of plasma creatinine be explained by the small step-rise in creatinine. ACCORD Lipid, the other large randomized trial which investigated the effect of fibrates in type 2 diabetic patients, assessed the addition of fenofibrate 160 mg daily to simvastatin 10 40 mg daily (dose modified over time in response to changing guidelines) in 5518 participants.96 Again, this study excluded patients with impaired kidney function, creatinine 4133 mmol/l (41.5 mg/dl), such that only 141 participants had baseline eGFR below 50 ml/min/ .


ACCORD Lipid, the other large randomized trial which investigated the effect of fibrates in type 2 diabetic patients, assessed the addition of fenofibrate 160 mg daily to simvastatin 10 40 mg daily (dose modified over time in response to changing guidelines) in 5518 participants.96 Again, this study excluded patients with impaired kidney function, creatinine 4133 mmol/l (41.5 mg/dl), such that only 141 participants had baseline eGFR below 50 ml/min/ . Ultimately too few participants with eGFR o60 ml/ were included in either FIELD or ACCORD Lipid to provide reliable information on either the safety or efficacy of fenofibrate in this group. A recent large observational study in patients aged Z66 years demonstrated a clear association between new prescriptions for fibric acid derivatives and increased SCr levels, as well as a small increase in the risk of hospitalization and nephrologist consultation.97 These findings contribute to the uncertainty that fibric acid derivatives would yield net clinical benefit in people with CKD. For these reasons, use of fibric acid derivatives to reduce cardiovascular risk is not recommended in patients with CKD. Suggested Audit Criteria Given the lack of evidence to support this recommendation, no audit criteria are suggested. KEY POINTS K TLC should be recommended to adults with CKD and hypertriglyceridemia. K Fibric acid derivatives are not recommended to prevent pancreatitis or reduce cardiovascular risk in adults with CKD and hypertriglyceridemia. RESEARCH RECOMMENDATIONS K There are currently no published randomized trials of fibric acid derivatives in CKD populations and too few participants with CKD were included in previous trials to provide reliable information. Other agents, such as niacin and the cholesteryl ester transfer protein inhibitor anacetrapib are currently being investigated in clinical trials in the general population and deserve investigation in CKD patients.


Other agents, such as niacin and the cholesteryl ester transfer protein inhibitor anacetrapib are currently being investigated in clinical trials in the general population and deserve investigation in CKD patients. K CKD registries should report hypertriglyceridemia-in- duced pancreatitis to identify true incidence. K Studies should be conducted to confirm that pancreatitis due to TG levels above 11.3 mmol/l (1000 mg/dl) is infrequent in HD patients. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contri- butor, copyright holder, or advertiser concerned. Accord- ingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. Chapter 6: Triglyceride-lowering treatment in children 6.1: In children with CKD (including those treated with chronic dialysis or kidney transplantation) and hyper- triglyceridemia, we suggest that therapeutic lifestyle changes be advised. (2D) RATIONALE Non-pharmacological treatment of high triglycerides TLC includes dietary modification, weight reduction, increased physical activity, reducing alcohol intake, and treatment of hyperglycemia (if present). As for adults, the evidence that TLC will reduce serum TG levels and/or improve clinical outcomes is weak.


As for adults, the evidence that TLC will reduce serum TG levels and/or improve clinical outcomes is weak. Nonetheless, in the opi- nion of the Work Group, it is reasonable to advise children with high fasting levels of serum TGs (45.65 mmol/l [4500 mg/dl]) to adopt TLC based on similar considerations as mentioned in Guideline 5.1. Dietary changes that may reduce serum TGs include a very low-fat diet (o15% total calories), medium-chain TGs, and fish oils to replace some long-chain TGs. Dietary modification should be used judi- ciously, if at all, in children who are malnourished. Input from a social worker may be helpful if there are concerns that the patient or his/her parents are unable to safely implement TLC. Pharmacological treatment of high triglycerides: effects on risk of pancreatitis Although previous guidelines have suggested the use of fibric acid derivatives for preventing pancreatitis from severe hypertriglyceridemia, the evidence supporting the safety and efficacy of this approach is extremely weak especially in children with CKD. Therefore, the Work Group no longer recommends this approach. Evidence that very high TGs can cause pancreatitis in children comes from case reports and small series of patients with familial dyslipidemias.98,99 The safety and efficacy of lowering TGs with fibrates and niacin have not been established in adolescents; studies have been of extremely short duration and with very small sample sizes.100 102 There have been 4 trials of fish oil completed in children with glomerular causes of CKD and one trial among children on dialysis; fish oil appears to lower serum TGs after as little as but the longer-term benefits, harms, and tolerability of such treatment is unclear. Therefore, pharmacological treatment of hypertriglycer- idemia is not recommended in children with CKD.


Therefore, pharmacological treatment of hypertriglycer- idemia is not recommended in children with CKD. This is a weak recommendation that reflects the lack of evidence on clinical benefit and safety. Treatment could be considered in children with very severely increased hypertriglyceridemia (411.3 mmol/l [41000 mg/dl]); such children should be referred to a pediatric lipid specialist for management and to rule out familial hypertriglyceridemia or rare, inherited disorders such as lipoprotein lipase deficiency or apolipo- protein C-II deficiency. Suggested Audit Criteria K Audit the number of pediatric CKD patients treated with TLC, diet, and weight loss for lowering TGs. K Audit the number of pediatric CKD patients treated with pharmacological TG-lowering therapy. K Record the number of pediatric CKD patients with drug intolerance and/or non-compliance. KEY POINTS K TLC should be recommended to children with CKD and hypertriglyceridemia. K Fibric acid derivatives are not recommended to prevent pancreatitis or reduce cardiovascular risk in children with CKD and hypertriglyceridemia. RESEARCH RECOMMENDATIONS Future studies should be conducted to: K Determine prevalence of hypertriglyceridemia in pediatric kidney transplant recipients. K Determine the effect of diet and weight loss in lowering TG among pediatric CKD patients. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement.


Accordingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. chapter 6 http://www.kidney-international.org & 2013 KDIGO Methods for guideline development AIM The overall aim of this project was to develop an evidence- based CPG for the management of dyslipidemia and CKD. The guideline consists of recommendation statements, ratio- nales, and a summary of systematically generated evidence on relevant pre-defined clinical topics. The general guideline development method is described at http://www.kdigo.org/ home/guidelines/development as well as below.


The general guideline development method is described at http://www.kdigo.org/ home/guidelines/development as well as below. OVERVIEW OF PROCESS The development process for the KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease included the following steps: K Appointing Work Group members and the evidence review team (ERT) K Discussing process, methods, and results K Developing and refining topics K Identifying populations, interventions or predictors, and outcomes of interest K Selecting topics for systematic evidence review K Standardizing quality assessment methodology K Developing and implementing literature search strategies K Screening abstracts and retrieving full-text articles on the basis of pre-defined eligibility criteria K Creating data extraction forms K Extracting data and performing critical appraisal of the literature K Grading the methodology and outcomes in individual studies K Tabulating data from individual studies into summary tables K Grading quality of evidence for each outcome across studies, and assessing the overall quality of evidence across outcomes with the aid of evidence profiles K Grading the strength of recommendations on the basis of the quality of evidence and other considerations K Finalizing guideline recommendations and supporting rationales K Sending the guideline draft for peer review to the KDIGO Board of Directors in August 2012 and for public review in November 2012 K Editing the guideline K Publishing the final version of the guideline The Work Group Co-Chairs, KDIGO Co-Chairs and ERT met for a two-day meeting to go over the guideline develop- ment process, evidence review topics, and systematic review findings. Following this, the Work Group, KDIGO Co-Chairs and KDIGO support staff met held a two-day meeting to revisit the available evidence, formulate recommendation statements, deliberate on rationale for recommendations, and to develop consensus.


Following this, the Work Group, KDIGO Co-Chairs and KDIGO support staff met held a two-day meeting to revisit the available evidence, formulate recommendation statements, deliberate on rationale for recommendations, and to develop consensus. Commissioning of Work Group and ERT The KDIGO Co-Chairs appointed the Work Group Co- Chairs, who then assembled the Work Group of domain experts, including individuals with expertise in internal medicine, adult and pediatric nephrology, cardiology, hypertension, pharmacology, epidemiology, and endocrino- logy. The Tufts Center for Kidney Disease Guideline Development and Implementation at Tufts Medical Center in Boston, Massachusetts, USA, was contracted to conduct systematic evidence review and provide expertise in guideline development methodology. The ERT consisted of physician - methodologists with expertise in nephrology and evidence- based clinical practice guideline development, a project coordinator, a research assistant, and a project manager/ medical writer. Defining Scope and Topics The Work Group Co-Chairs and the ERT defined the overall scope and goals of the guideline (including a list of critical and important outcomes) and then drafted a preliminary list of topics and key clinical questions. They also reviewed the topics in the KDOQI guideline,1 which the ERT also had helped to develop. The Work Group and ERT further developed and refined each topic and specified screening criteria, literature search strategies, and data extraction forms (Table 6). Establishing the Process for Guideline Development The ERT performed systematic literature searches and organized abstract and article screening. The ERT also coordinated the methodological and analytical processes, and defined and standardized the methodology for perform- ing literature searches, data extraction, and summarizing the evidence. The Work Group took the primary role of writing the recommendation statements and rationales and retained final responsibility for their content.


The Work Group took the primary role of writing the recommendation statements and rationales and retained final responsibility for their content. The Work Group Co-Chairs and the ERT prepared the first draft of the scope of work document as a series of open-ended questions to be considered by Work Group members. Formulating Questions of Interest Questions of interest were formulated according to the PICODD (Population, Intervention, Comparator, Outcome, study Design and Duration of follow-up) criteria. Details of the PICODD criteria are presented in Table 6. http://www.kidney-international.org methods for guideline development & 2013 KDIGO Table 6 | Systematic review topics and screening criteria Lipid-lowering agents Population Adults and children with CKD of any severity, with or without dyslipidemia and diabetes; kidney transplant recipients; CKD subgroups in large studies of the general population Intervention Z1 lipid-lowering agent (typically statin, niacin, colestipol, or cholestyramine). Excluded dietary supplements, phosphate binders, apheresis, stanols, and sterols.


Details of the PICODD criteria are presented in Table 6. http://www.kidney-international.org methods for guideline development & 2013 KDIGO Table 6 | Systematic review topics and screening criteria Lipid-lowering agents Population Adults and children with CKD of any severity, with or without dyslipidemia and diabetes; kidney transplant recipients; CKD subgroups in large studies of the general population Intervention Z1 lipid-lowering agent (typically statin, niacin, colestipol, or cholestyramine). Excluded dietary supplements, phosphate binders, apheresis, stanols, and sterols. Comparator Active or control Outcome Categorical: All-cause mortality, cardiovascular mortality, clinical cardiovascular events, ESRD, graft failure, doubling of SCr, halving of GFR Continuous: changes in TC, LDL-C, or HDL-C or TGs Study design RCTs with parallel-group design; systematic reviews, CKD-subgroup analyses of general population RCTs if no evidence of selection bias and of sufficient size Minimum duration of follow-up 4 weeks for continuous lipid outcomes; 1 year for clinical outcomes; if general population study, 1 year Minimum N of Subjects Z100 per arm for adults, Z25 per arm for children; if general population study, Z500 per arm for adults or Z100 per arm for children in full study Diet or lifestyle modification Population Adults and children with CKD of any severity, with or without dyslipidemia and diabetes; kidney transplant recipients; CKD subgroups in large studies of the general population Intervention Weight loss, special diet, or exercise; also structured care vs. usual care Comparator Different diet or lifestyle modification or agent or placebo Outcome Categorical: All-cause mortality, cardiovascular mortality, clinical cardiovascular events, ESRD, graft failure, doubling of SCr, halving of GFR Continuous: changes in TC, LDL-C, or HDL-C or TGs Design RCTs with parallel-group design; systematic reviews, CKD-subgroup analyses of general population RCTs if no evidence of selection bias and of sufficient size Minimum duration of follow-up 4 weeks for continuous lipid outcomes; 1 year for clinical outcomes; if general population study, 1 year Minimum N of subjects Z25 per arm Drug interactions (update of Tables 32-37 in KDOQI 2003 guideline) Population General population Intervention Any statin and any other drug Comparator NA Outcomes Change in bioavailability of statin Design Systematic reviews Minimum duration of follow-up NA Minimum N of subjects NA Change in LDL-C level by statin Population General population Intervention Any statin Comparator Other agent or placebo Outcomes Change in LDL-C Design Systematic review or meta-analysis, 2006-2011 Minimum duration of follow-up NA Minimum N of subjects NA Adverse events from statin+fibrate therapy Population General population (typically focused on familial hypercholesterolemia or mixed dyslipidemia) Intervention Any statin or statins + any fibrate or fibrates Comparator Statin or statins alone (also captured data vs. fibrate alone or placebo) Outcomes Any adverse event, any serious adverse event, discontinuation owing to drug, AKI, cancer, rhabdomyolysis, myalgia, increased creatine kinase, increased creatinine, increased ALT or AST, any other specified; in children, also measures of growth, development, cognitive function Design Any Minimum duration of follow-up Any Minimum N of Subjects Any Frequency of lipids testing Population Any Intervention Any regimen with variable timing of measurement: e.g.


, more vs. less testing, some vs. no testing Comparator Active or placebo Outcomes Measures of compliance, cardiovascular outcomes, mortality Design RCTs or systematic reviews Minimum duration of follow-up 6 months Minimum N of subjects Z50 per arm Abbreviations: AKI, acute kidney injury; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKD, chronic kidney disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NA, not applicable; RCT, randomized controlled trial; SCr, serum creatinine; TC, total cholesterol; TG, triglyceride. methods for guideline development Ranking of Outcomes The Work Group ranked outcomes of interest on the basis of their importance for informing clinical decision making (Table 7). Mortality, cardiovascular mortality, cardiovascular or cerebrovascular events, ESRD, and graft failure were considered to be of critical importance; doubling of SCr and halving of GFR, high importance; and change in TC, LDL-C, or HDL-C or TG, moderate importance. The importance of adverse events was considered to depend on the event severity. Literature Searches and Article Selection Systematic search strategies were developed by the ERT with input from the Work Group Co-Chairs. Modules were created for RCTs, kidney disease, dyslipidemia, and lipid- lowering agents. For the primary search, search terms were limited to the year 2000 and later to capture trials that would affect current clinical practice and because the KDOQI dyslipidemia guideline covered through 2000. Five new topics were added to the KDOQI systematic review for studies in the general population: effect of diet or lifestyle modification; an update of drug interactions with statins and fibrates; changes in LDL-C levels associated with various statins; adverse events from statin and fibrate use; and frequency of lipid-level testing. These searches were not restricted to 2000 and later.


Five new topics were added to the KDOQI systematic review for studies in the general population: effect of diet or lifestyle modification; an update of drug interactions with statins and fibrates; changes in LDL-C levels associated with various statins; adverse events from statin and fibrate use; and frequency of lipid-level testing. These searches were not restricted to 2000 and later. The text words or medical subject headings (MeSH) that were included are provided in the Supplemental Appendix 1. In addition, the ERT searched for existing relevant systematic reviews. The final searches were con- ducted in August 2011. The ERT searched MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The ERT also relied on Work Group members to identify large, general population RCTs reporting on CKD subgroups. The search yield was also supplemented by articles provided by Work Group members through June 2013. For selection of studies, all members of ERT indepen- dently and manually screened the abstracts using the computerized screening program Abstrackr. To establish relevance and consensus among reviewers, the entire team screened and achieved consensus on an initial batch of 500 abstracts. A total of 11,337 citations were initially screened. Journal articles reporting original data, meta-analyses, and systematic reviews were selected for evidence review, based on a priori criteria for eligible evidence. Editorials, letters, abstracts, unpublished reports, and articles published in non peer-reviewed journals were not included. The Work Group also decided to exclude publications from journal supplements because of potential differences in the process of how they are solicited, selected, reviewed, and edited compared to peer-reviewed publications. The overall search yield along with the number of abstracts identified and articles reviewed for each topic are presented in Table 8. Data Extraction Data extraction was done by an ERT member.


Data Extraction Data extraction was done by an ERT member. Although no duplicate extraction was independently performed, data from each study was examined by another reviewer to confirm accuracy. The ERT, in consultation with the Work Group Co-Chairs, designed forms to capture data on design, methodology, sample characteristics, interventions, compara- tors, outcomes, results, and limitations of individual studies. Methodology and outcomes were also systematically graded (see the section on grading below) and recorded during the data extraction process. Summary Tables Summary tables were developed for each comparison of interest. Summary tables contain outcomes of interest, relevant population characteristics, description of interven- tion and comparator, results, and quality grading for each outcome. Categorical outcomes and continuous lipid out- comes were tabulated separately. For studies not exclusively examining CKD populations, only those reporting analysis by CKD subgroups were tabulated. Work Group members proofed all summary table data and quality assessments. Summary tables are available at http://www.kdigo.org/home/guidelines/lipids. Table 7 | Hierarchy of outcomes Hierarchy Outcome Critical importance Mortality, cardiovascular mortality, cardiovascular or cerebrovascular events, ESRD, graft failure High importance Doubling of SCr or halving of GFR Moderate importance Change in TC, LDL-C, or HDL-C or TGs Importance dependent on severity Adverse events Abbreviations: ESRD, end-stage renal disease; GFR, glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SCr, serum creatinine; TC, total cholesterol; TG, triglyceride Table 8 | Literature yield for RCTs* Studies included in Summary Tables Intervention Abstracts identified Articles retrieved Studies with data extracted Statin vs. Placebo Atorvastatin vs. Placebo, kidney transplant recipients Statin vs. Lifestyle Statin vs. Placebo, ADPKD Atorvastatin 80 mg vs. Low vs. Moderate Protein Diet Ezetimibe vs. Placebo Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; CKD, chronic kidney disease; RCT, randomized controlled trial.


Placebo Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; CKD, chronic kidney disease; RCT, randomized controlled trial. *Counts not listed for the four other topics for various reasons: no RCTs were found for frequency of testing and existing systematic reviews were used for change in LDL-C by statin and drug interactions. methods for guideline development Evidence Profiles Evidence profiles were constructed to assess the quality and record quality grades and descriptions of effect for each outcome across studies, as well as the quality of overall evidence and description of net benefits or harms of the intervention or comparator across all outcomes. These profiles aim to make the evidence synthesis process trans- parent. Decisions in the evidence profiles were based on data from the primary studies listed in corresponding summary tables and on judgments of the ERT and Work Group. When the body of evidence for a particular comparison of interest consisted of only one study, the summary table provided the final level of synthesis and an evidence profile was not generated. Each evidence profile was initially constructed by the ERT and then reviewed, edited, and approved by the Work Group. The work products created by the ERT for summarizing the evidence base are listed in Table 9. Grading of Quality of Evidence for Outcomes of Individual Studies Methodological quality (internal validity) refers to the design, conduct, and reporting of outcomes of a clinical study. A previously devised three-level classification system for quality assessment was used to grade the overall study quality and quality of all relevant outcomes in the study (Table 10). Grading of individual studies was done by one of the reviewers, then confirmed by another, and finalized in a group meeting.


Grading of individual studies was done by one of the reviewers, then confirmed by another, and finalized in a group meeting. Variations of this system have been used in most KDOQI and all KDIGO guidelines and have been recommended by the US Agency for Healthcare Research and Quality Evidence-based Practice Center program.107 Each study was given an overall quality grade based on its design, methodology (randomization, allocation, blinding, definition of outcomes, appropriate use of statistical methods, etc.), conduct (dropout percentage, outcome assessment methodologies, etc.)


Variations of this system have been used in most KDOQI and all KDIGO guidelines and have been recommended by the US Agency for Healthcare Research and Quality Evidence-based Practice Center program.107 Each study was given an overall quality grade based on its design, methodology (randomization, allocation, blinding, definition of outcomes, appropriate use of statistical methods, etc.), conduct (dropout percentage, outcome assessment methodologies, etc.) and reporting (internal Table 9 | Work products for the guideline* Topic Summary table of RCTs Evidence profile Lipid-lowering agents or diet/lifestyle modification Atorvastatin vs. atorvastatin + (single study) Ezetimibe vs. placebo (simvastatin+ezetimibe vs. simvastatin) + (single study) Statin vs. placebo in ADPKD + (single study) Statin vs. placebo in CKD + + (8 studies) Statin vs. usual care + (single study) Low vs. moderate protein diet + (single study) Statin + ezetimibe vs. placebo + (single study) Statin vs. placebo in kidney transplant recipients + + (2 studies) Statin vs. lifestyle in kidney transplant recipients + + (2 studies) Statin vs. placebo in children + (single study) Statin vs. placebo in CKD with dialysis + + (2 studies) Exercise vs. control + (single study) Drug interactions (update of Tables 32 37 in KDOQI 2003 guideline) Drug interactions + (single pre-existing systematic review) Adverse events from statin+fibrate therapy Any adverse event + (no evidence profiles prepared re adverse events) Serious adverse event + (no evidence profiles prepared re adverse events) Treatment-related adverse event + (no evidence profiles prepared re adverse events) Discontinuation due to adverse event + (no evidence profiles prepared re adverse events) Increased ALT or AST + (no evidence profiles prepared re adverse events) Increased creatine kinase + (no evidence profiles prepared re adverse events) Increased SCr + (no evidence profiles prepared re adverse events) Rhabdomyolysis + (no evidence profiles prepared re adverse events) Other adverse event + (no evidence profiles prepared re adverse events) Frequency of lipids testing Frequency of lipids testing (0 studies) Change in LDL-C by statin Change in LDL-C by statin + (single pre-existing systematic review) Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKD, chronic kidney disease; LDL-C, low-density lipoprotein cholesterol; RCT, randomized controlled trial; SCr, serum creatinine.


Coding: +: work product is indicated for the topic of interest; : work product is not indicated for the topic of interest. General population studies with a CKD subgroup are included. Table 10 | Classification of study quality Good quality Low risk of bias and no obvious reporting errors; complete reporting of data. Must be prospective. If study of intervention, must be RCT. Fair quality Moderate risk of bias, but problems with study or paper are unlikely to cause major bias. If study of intervention, must be prospective. Poor quality High risk of bias or cannot rule out possible significant biases. Poor methods, incomplete data, reporting errors. Prospective or retrospective. Abbreviation: RCT, randomized controlled trial. methods for guideline development consistency, clarity, thoroughness and precision, etc.). Each reported outcome was then evaluated and given an individual grade depending on the quality of reporting and methodo- logical issues specific to that outcome. However, the quality grade of an individual outcome could not exceed the quality grade for the overall study. Grading the Quality of Evidence and the Strength of a Guideline Recommendation A structured approach, based on GRADE108 110 and facili- tated by the use of evidence profiles, was used to grade the quality of the overall evidence and the strength of recommendations. For each topic, the discussion on grading of the quality of the evidence was led by the ERT, and the discussion regarding the strength of the recom- mendations was led by the Work Group Co-Chairs. The strength of a recommendation indicates the extent to which one can be confident that adherence to the recommendation will do more good than harm.


The strength of a recommendation indicates the extent to which one can be confident that adherence to the recommendation will do more good than harm. The quality of a body of evidence refers to the extent to which our confidence in an estimate of effect is sufficient to support a Grading the quality of evidence for each outcome across studies. Following GRADE, the quality of a body of evidence pertaining to a particular outcome of interest was initially categorized on the basis of study design. For questions of interventions, the initial quality grade was High if the body of evidence consisted of RCTs, Low if it consisted of observational studies, and Very Low if it consisted of studies of other study designs. For questions of interventions, the Work Group decided to use only RCTs. The grade for the quality of evidence for each intervention outcome pair was then lowered if there were serious limitations to the methodological quality of the aggregate of studies, if there were important inconsistencies in the results across studies, if there was uncertainty about the directness of evidence including limited applicability of the findings to the population of interest, if the data were imprecise (a low event rate [0 or 1 event] in either arm or a CI spanning a range 41) or sparse (only 1 study or total N o500), or if there was thought to be a high likelihood of bias. Once consensus is reached in a group meeting, the final grade for the quality of the evidence for an intervention outcome pair could be one of the following four grades: High , Moderate , Low or Very Low (Table 11). CKD subgroup analyses.


Once consensus is reached in a group meeting, the final grade for the quality of the evidence for an intervention outcome pair could be one of the following four grades: High , Moderate , Low or Very Low (Table 11). CKD subgroup analyses. The following criteria were devised to grade the quality of CKD-subgroup analyses of RCTs that were not specifically designed for or limited to individuals with CKD. CKD subgroups were graded only if they were of an acceptable size for the topic of interest (e.g., 50 per arm with CKD for lipid guideline). These criteria will be considered along with the assessment of whether the putative subgroup effect is plausible with regard to direction and size of effect. For the complete set of subgroup grading criteria, see Figure 3.


For the complete set of subgroup grading criteria, see Figure 3. Briefly, the study quality was graded according to Table 11 | GRADE system for grading quality of evidence Step 1: Starting grade for quality of evidence based on study design Step 2: Reduce grade Step 3: Raise grade Final grade for quality of evidence and definition Randomized trials = High Observational study = Low Study quality 1 level if serious limitations 2 levels if very serious limitations Consistency 1 level if important inconsistency Directness 1 level if some uncertainty 2 levels if major uncertainty Strength of association +1 level if stronga , no plausible confounders +2 levels if very strongb , no major threats to validity Other +1 level if evidence of a dose response gradient +1 level if all residual plausible confounders would have reduced the observed effect High = Further research is unlikely to change confidence in the estimate of the effect Moderate = Further research is likely to have an important impact on confidence in the estimate of effect, and may change the estimate Low = Further research is very likely to have an important impact on confidence in the estimate, and may change the estimate Any other evidence = Very Low Other 1 level if sparse or imprecise datac 1 level if high probability of reporting bias Very Low = Any estimate of effect is very uncertain Abbreviation: GRADE, Grading of Recommendations Assessment, Development and Evaluation. a Strong evidence of association is defined as significant relative risk of 42 (o0.5) based on consistent evidence from two or more observational studies, with no plausible confounders. b Very strong evidence of association is defined as significant relative risk of 45 (o0.2) based on direct evidence with no major threats to validity.


b Very strong evidence of association is defined as significant relative risk of 45 (o0.2) based on direct evidence with no major threats to validity. c Sparse if there is only one study or if total N o500. Imprecise if there is a low event rate (0 or 1 event) in either arm or confidence interval spanning a range 41. Adapted by permission from Macmillan Publishers Ltd: Kidney International. Uhlig K, Macleod A, Craig J et al. Grading evidence and recommendations for clinical practice guidelines in nephrology. A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 70: 2058 2065;110 accessed http:// methods for guideline development whether the CKD subgroup defined by kidney function or proteinuria measured at baseline (rather than after the start of treatment), whether or not analyses of subgroups were pre-specified before randomization, whether or not intervention and comparator groups were balanced within the CKD subgroup. The directness of the CKD subgroup analysis was graded on the basis of whether or not the CKD subgroup results of trials that were not specifically designed for CKD were applicable to patients with CKD and also whether or not a test for interaction by baseline kidney function (or the level of proteinuria) was performed. Quality of the main study: A. Good B. Fair C. Poor Is CKD subgroup defined by kidney function or proteinuria measured at baseline? If yes, do not downgrade for subgroup. If no, reject or downgrade for subgroup by 1 or 2 levels based on the risk of bias. Is CKD subgroup pre-specified before secondary analysis? If no, is the standard definition of CKD , or the presence of proteinuria) used? If yes, do not downgrade for subgroup. If yes, do not downgrade for subgroup.


If yes, do not downgrade for subgroup. If yes, do not downgrade for subgroup. If no, downgrade the quality for subgroup by 1 level. Are baseline characteristics by intervention and comparator groups provided in CKD subgroup? If yes, are there differences between groups? If no, do not downgrade for subgroup. If yes, downgrade by one level if differences are likely to have influenced results. Do not downgrade, if, on the judgment of the reviewer, differences are unlikely to have influenced results, or are properly accounted for in the analysis. If no, downgrade the quality for subgroup by 1 level. Final study quality for sub-group: A. Good (not downgraded) B. Fair (downgraded by 1 level) C. Poor (downgraded by 2 levels) Figure 3 | Grading the quality of CKD subgroups of non-CKD trials. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate. methods for guideline development Grading the overall quality of evidence. The quality of the overall body of evidence was then determined on the basis of the quality grades for all outcomes of interest, taking into account explicit judgments about the relative importance of each outcome. The resulting four final categories for the quality of overall evidence were: A , B , C or D (Table 12). Assessment of the net health benefit across all important clinical outcomes. The net health benefit was determined on the basis of the anticipated balance of benefits and harms across all clinically important outcomes (Table 13). The assessment of net benefit also involved the judgment of the Work Group and the ERT. Developing the recommendations. Draft recommendation statements were developed by the Work Group Co-Chairs and Work Group members with input from all Work Group members.


Draft recommendation statements were developed by the Work Group Co-Chairs and Work Group members with input from all Work Group members. The health benefits, side effects, and risks associated with each recommendation were considered when formulating the guideline, as well as information on patient preferences when available. Recommendation statements were revised in a multi-step process during teleconferences and a face-to-face meeting, as well as in subsequent drafts by email. All Work Group members provided feedback on initial and final drafts of the recommendation. The final draft was sent for internal and external peer review, and was further revised by the Work Group Co-Chairs and members. All Work Group members approved the final version of the guideline. Grading the strength of the recommendations. The strength of a recommendation is graded as level 1 or level 2. Table 14 shows the KDIGO nomenclature for grading the strength of a recommendation and the implications of each level for patients, clinicians, and policy-makers. Recommendations can be for or against doing something. Each recommenda- tion includes an explicit link between the quality of the Table 12 | Final grade for overall quality of evidence Grade Quality of Evidence Meaning A High We are confident that the true effect lies close to that of the estimate of the effect. B Moderate The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. C Low The true effect may be substantially different from the estimate of the effect. D Very low The estimate of effect is very uncertain, and often will be far from the truth.