Essential points from Evidence-based Clinical Practice Guidelines for Chronic Kidney Disease 2018

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 the effect is very uncertain and might often be far from the true effect. None Grade of recommendation


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CQ5: Is it recommended to treat metabolic acidosis of CKD patients to prevent deterioration of renal function? Statement: We recommend treating metabolic acidosis with sodium bicarbonate and other such bases to prevent hypertension, proteinuria, and CVD. It is recommended to consider treatment when a patient's HCO 3 is below 21 mmol/L. (Level: B, Grade: 1) Chapter 4. Management of hypertension and cardiovascular disease CQ1: Could appropriate BP control prevent the incidence of CKD in hypertensive patients? Statement: There is substantial supportive evidence indicating a positive association between high BP and development of incident CKD. Management of hypertension is strongly recommended for the prevention of CKD. Treatment to control excessive BP variations, such as nocturnal hypertension or morning surge, might be more beneficial. (Level: C, Grade: 1) CQ2: Is a target BP < 130/80 mmHg recommended for CKD patients (< 75 years of age) associated with hypertension? Statement: <CKD stage G1, 2> A target BP < 130/80 mmHg is recommended for adults with hypertension and CKD associated with diabetes. (Level: B, Grade: 1) A target BP < 140/90 mmHg is recommended for adults with hypertension and CKD with A1 level proteinuria not associated with diabetes. (Level: A, Grade: 1) A target BP < 130/80 mmHg is recommended for adults with hypertension and CKD with A2 or A3 level proteinuria not associated with diabetes. (Level: C, Grade: 1) <CKD stage G3-5> A target BP < 130/80 mmHg is recommended for adults with hypertension and CKD associated with diabetes.
(Level: C, Grade: 2) A target BP < 140/90 mmHg is recommended for adults with hypertension and CKD with A1 level proteinuria not associated with diabetes. (Level: C, Grade: 2) A target BP < 130/80 mmHg is recommended for adults with hypertension and CKD with A2 or A3 level proteinuria not associated with diabetes. (Level: C, Grade: 2) A systolic BP suppression below 110 mmHg is not recommended for adults with hypertension and CKD, regardless of CKD stage. (Level: C, Grade: 2) CQ3: Is a target BP < 150/90 mmHg recommended for elderly CKD patients (aged ≥ 75 years old) associated with hypertension? Statement: <CKD stage G1, 2> A target BP < 150/90 mmHg is recommended for elderly patients with hypertension and CKD. (Level: C, Grade: 1) A target BP < 140/90 mmHg is recommended for elderly patients with hypertension and CKD who may tolerate treatment with antihypertensive agents without any adverse events. (Level: C, Grade: 1) <CKD stage 3-5> Recommendations are the same as those for CKD stage G1, 2. (Level: C, Grade: 2) Systolic BP suppression below 110 mmHg is not recommended for elderly patients with hypertension and CKD, regardless of the CKD stage. (Level: C, Grade: 2) CQ4: What is the appropriate antihypertensive agent for CKD patients associated with hypertension?

Statement:
In CKD patients with diabetes mellitus (A1-A3 category) and without diabetes mellitus (A2, 3 category), ACEIs or ARBs are recommended. (Level: B, Grade: 1) In CKD patients without diabetes (A1 category), ACEIs, ARBs, CCBs or thiazide diuretics are recommended. (Level: B, Grade: 1) In CKD stages G4, 5, CCBs are recommended if ACEIs or ARBs may not be tolerated, despite dose-reduction, due to worsening of renal function or hyperkalemia. (Level: C, Grade: 1) In CKD stages G4, 5 in elderly patients aged more than 75 years, initial therapy should be CCBs because RAS inhibitors could deteriorate renal function in elderly patients due to dehydration or ischemia. In CKD patients stage G3b-5 (without 5D and transplant), antihypertensive therapy with ACEIs or ARBs might be intolerable due to hyperkalemia or renal impairment. The initial dose of ACEIs or ARBs should be low and gradually titrated upward as needed. (Level: D, Grade: None) Chapter 5. Management of nephrosclerosis and renal artery stenosis CQ1: Is strict reduction of BP recommended for CKD caused by nephrosclerosis with hypertension? Statement: We do not suggest the strict reduction of BP to a systolic pressure of < 120 mmHg in CKD caused by nephrosclerosis with hypertension, especially in A1 category proteinuria due to the risk of AKI. We suggest a target level of < 140/90 mmHg. (Level: C, Grade: 2) CQ2: Which antihypertensive drugs are recommended for CKD with renal artery stenosis? Statement: We suggest the use of RAS inhibitor for CKD with unilateral renal artery stenosis because it is superior in reducing BP in such patients compared to other Table 1 In case of CKD with coronary artery disease Table 2 In case of CKD with heart failure (HFrEF) antihypertensive drugs and may suppress progression to mortality, onset of CVD and progression of renal dysfunction. However, to avoid the risk of AKI, it is necessary to adjust the dose carefully starting with a low dose and checking the serum Cr and K levels approximately 2 weeks after start. A RAS inhibitor is not used in principle when bilateral renal artery stenosis is suspected. (Level: C, Grade: 2) CQ3: Which imaging studies are recommended for CKD (Stage G1-3) with suspected renal artery stenosis? Statement: We suggest performing renal artery ultrasound as a screening test first, followed by plain MR angiography. When CT angiography and gadolinium-enhanced MR angiography are performed, the risk of contrast-induced nephropathy and nephrogenic systemic fibrosis must be considered carefully. When these tests do not lead to a diagnosis or when the indication of angioplasty is considered, we suggest performing renal artery angiography. (Level: C, Grade: 2) CQ4: Is revascularization recommended for CKD with arteriosclerotic renal artery stenosis? Statement: We do not suggest performing revascularization for CKD with arteriosclerotic renal artery stenosis in principle due to the risk of complications, because it does not suppress the progression of renal dysfunction or decrease the risk of developing CVD. (Level: B, Grade: 2) Chapter 6. Renal anemia CQ1: What is the target Hb range in prescribing ESA for renal anemia in CKD patients? Statement: We propose that the target Hb range for prescribing ESA to non-dialysis CKD patients is 11 g/dL or more and below 13 g/dL. In case of ESA hypo-responsiveness, determining the cause and correcting it are mandatory. Attention should be paid to avoiding over-dosage of ESA. For patients with a past history or complication of severe CVD or any other medical indications, one should consider reducing or terminating ESA use if Hb level exceeds 12 g/ dL (Level: B, Grade: 2). CQ2: Is iron treatment recommended in anemic CKD patients with iron deficiency? Statement: We propose iron treatment for anemic CKD patients with iron deficiency. (Level: B, Grade: 2) Chapter 7. Management of chronic kidney disease-mineral bone disease CQ1: Is administration of phosphate binders recommended in non-dialysis CKD patients with hyperphosphatemia? Statement: In non-dialysis CKD patients with hyperphosphatemia, the use of phosphate binders may be considered because phosphate binders have the possibility of reducing progression to mortality. (Level: C, Grade: 2) CQ2: Is the administration of non-calcium-containing phosphate binders recommended for the treatment of hyperphosphatemia in non-dialysis CKD patients? Statement: In non-dialysis CKD patients with hyperphosphatemia, the administration of non-calcium-containing phosphate binders may be considered because they are potentially more effective in preventing progression to mortality and vascular calcification progression compared to calcium-containing phosphate binders (Level: C, Grade: 2).

CQ3: Is administration of active vitamin D recommended in non-dialysis CKD patients?
Statement: In non-dialysis CKD patients, administration of active vitamin D may be considered because it lowers PTH levels and may reduce proteinuria. However, active vitamin D can cause hypercalcemia and it is unknown whether this therapy decreases the risk of CKD progression, fracture, cardiovascular events, or mortality. Thus, we suggest therapeutic decisions be made on a case-by-case basis and active vitamin D be started with small doses. We also suggest that, in the case of hypercalcemia or worsening renal function, active vitamin D should be reduced or stopped promptly.
(Level: C, Grade: 2) CQ4: Is administration of anti-osteoporotic agents recommended in non-dialysis CKD patients? Statement: In non-dialysis CKD patients, administration of anti-osteoporotic agents, such as active vitamin D, bisphosphonates, selective estrogen receptor modulators (SERMs), teriparatide, and denosumab may be considered because these may reduce fracture risk. Special attention, however, needs to be paid during treatment in CKD patients, because, depending on the agent, the expected beneficial and adverse effects may differ from those observed in the general population. (Level: D, Grade: 2) 1 3 Chapter 8. Management of hyperuricemia and dyslipidemia CQ1: Is uric acid-lowering therapy recommended in patients with CKD? Statement: Uric acid-lowering therapy is suggested for patients with CKD and hyperuricemia, because it may potentially slow the progression of renal dysfunction and reduce urinary protein excretion. (Level: C, Grade: 2) CQ2: Is lipid-lowering therapy recommended in patients with CKD? Statement: Lipid-lowering therapy with statins or statins plus ezetimibe is recommended for patients with CKD and dyslipidemia, because it may potentially inhibit the development and recurrence of CVD events, reduce urinary protein excretion, and slow progression of renal dysfunction (Level: B Grade: 2). Meanwhile, lipid-lowering therapy with fibrates also could be useful for preventing development and recurrence of CVD events in those patients; however, we should use them carefully because fibrates are contraindicated or necessitate to be administered carefully in patients with moderate to severe renal dysfunction (Level: D, Grade: None).
Chapter 9. Management of metabolic syndrome CQ1: Are obesity and metabolic syndrome risk factors of mortality, CVD, ESKD, and progression of CKD in patients with CKD? Statement: Metabolic syndrome is potentially associated with mortality, CVD, ESKD, and progression of CKD in patients with CKD, although obesity is not obviously associated with these outcomes. (Level: C, Grade: None) CQ2: Is exercise training recommended for CKD patients with obesity and/or metabolic syndrome? Statement: We suggest that CKD patients with obesity and/ or metabolic syndrome follow an aerobic exercise training program, which is effective for weight loss and improvement of peak oxygen consumption (VO 2 peak). Considering the clinical characteristics of each patient, the adequate load of aerobic exercise training should be estimated carefully. Chapter 11. Management of pediatric CKD CQ1: Is urinary screening recommended for children at 3 years of age and throughout the school age? Statement: In pediatric populations, urinary screening at 3 years of age and throughout school age is considered to contribute to the discovery of CKD at an early stage, thus, facilitating early management and improving the renal prognosis. (Level: D, Grade: 2) CQ2: Is CKD in pediatric patients a risk factor for CVD? Statement: CKD in pediatric patients is a risk factor for CVD. (Level: C, Grade: None) CQ3: Should low birth weight, preterm birth, and fetal growth retardation be treated as risk factors for CKD? Statement: Since low birth weight, preterm birth, and fetal growth retardation are associated with future onset of CKD, it is recommended that they should be treated as risk factors. (Level: B, Grade: 1) CQ4: Is exercise recommended for pediatric patients with CKD?

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Statement: We suggest that pediatric patients with CKD perform mild to moderate exercise to improve QOL, motor function, and respiratory function. (Level: C, Grade: 2) CQ5: Is protein intake restriction recommended for pediatric patients with CKD? Statement: As any preventive effects due to protein intake restriction against deterioration of renal function are still unclear, we suggest that this should not be implemented. CQ8: Is management and therapy for CKD-MBD recommended for pediatric patients with CKD? Statement: As management of CKD-MBD for pediatric patients with CKD may improve bone lesions and cardiovascular function, we recommend that it should be implemented. We suggest that the corrected serum levels of calcium and phosphorus should be maintained within normal ranges in accordance with patient age. (Level: C, Grade: 2) CQ9: Is administration of recombinant human growth hormone (rhGH) recommended for pediatric patients with CKD showing growth stunting? Statement: We suggest that rhGH administration should be considered for pediatric CKD patients with growth stunting as it can significantly increase the height of patients. (Level: A, Grade: 2) CQ10: Is preemptive kidney transplantation (PEKT) recommended for pediatric patients with CKD? Statement: We suggested that preemptive kidney transplantation should be considered for pediatric patients with CKD, as the likelihood of graft survival is higher than that after dialysis has been implemented. (Level: C, Grade: 2)

Chapter 12. Management of elderly CKD
Preamble: Renal replacement therapy (RRT) for elderly CKD patients aged more than 75 years In elderly CKD patients aged more than 75 years, an improvement in life prognosis by RRT can be expected. It is important to consult with nephrologists/special medical institutions when choosing RRT. The selection should be based on appropriate decision-making through discussion with the patients and their families by comprehensive consideration through the evaluation of renal function, medical history, multiple complications (CVD, malignant neoplasms, advanced dementia, severe frailty, and other), the patient's social situation, and anticipated life expectancy. In addition, understanding and practice of an appropriate preservation therapy and palliative care are required when the patients decide to forgo hemodialysis.

CQ1: Is treatment for CKD-MBD recommended for the elderly (≥ 75 years) CKD patients?
Statement: In elderly patients (aged 75 years or more) with non-dialysis CKD, we suggest limiting dietary phosphate intake and/or using phosphate binders to maintain serum phosphate levels within the normal range. In this population, close monitoring for adverse effects is required to prevent malnutrition since the phosphate-lowering therapies may cause loss of appetite. (Level: C, Grade: 2) In elderly non-dialysis CKD patients with secondary hyperparathyroidism, we suggest lowering parathyroid hormone levels within the normal range by treating abnormalities in serum phosphate and calcium levels before administering active vitamin D agents. Hypercalcemia must be avoided when using active vitamin D agents. (Level: C, Grade: 2) CQ2: Can intervention in elderly CKD patients aged more than 75 years, prevent or control the progression of frailty, improve life prognosis, prolong induction of renal replacement therapy? Statement: In elderly CKD patients aged more than 75 years, frailty is one of the indicators of renal and life prognoses and incidence of renal replacement therapy. The effectiveness of intervention, nutrition therapy and exercise, in frail individuals is still not known. (Level: D, Grade: None) 1 3 CQ3: Is lipid lowering therapy recommended for elderly CKD patients aged more than 75 years? Statement: For elderly CKD patients aged 65-71 years, we propose that lipid lowering therapy (statin alone or a statin and ezetimibe combination) should be performed in elderly CKD patients aged 75 years or more since statins are effective for decreasing all -cause mortality and for primary or secondary prevention of CVD. (Level: C, Grade: 2) CQ4: Is renal biopsy recommended for elderly people aged more than 75 years? Statement: There is no basis for contraindications of renal biopsy in elderly individuals aged > 75 years. There is also the possibility that the appropriate treatment can be determined based on renal biopsy. With respect to implementation, renal biopsy on elderly people should be introduced to experienced nephrologists and specialized medical institutions and their recommendations should be judged in consideration of renal function prognosis/life prognosis. (Level: D, Grade: None) CQ5: Could strict glycemic control (HbA1c < 7.0%) be recommended for CKD patients with DM aged more than 75 years? Statement: CKD patients with DM aged ≥ 75 years should be recognized as being at risk of severe hypoglycemia and falls with strict glycemic therapy. We suggest that the target for glycemic control for elderly CKD patients should be decided individually depending on the health condition (age, cognitive function, physical function, comorbidity, risk of hypoglycemia, and time to live). (Level: D, Grade: None) CQ6: What is the optimal hemoglobin target range for anemic elderly patients (≥75 years) CKD patients? Statement: In anemic elderly patients (aged ≥ 75 years) with non-dialysis CKD, we suggest maintaining hemoglobin levels within the target range of 11-13 g/dL using erythropoietin-stimulating agents (ESAs) and/or iron supplementation. With respect to the mortality risk, the lower limit of the target range could be lowered to 9 g/dL. During the ESA therapy, clinical factors associated with resistance to ESAs should be removed to avoid use of high-dose ESAs. (Level: C, Grade: 2) CQ7: Are there any drugs to be especially attentive on drug usage for elderly CKD patients aged more than 75 years in daily clinical practice? Statement: Metabolic and excretion rates decline in elderly CKD patients aged more than 75 years, and attention must be paid to the control of the doses of RAS inhibitors, diuretics, vitamin D, and other drugs, which are frequently administered. Moreover, to avoid polypharmacy, we propose to check the medication notebook. (Level: D, Grade: 2) Chapter 13. Dialysis initiation CQ1: When should CKD patients be introduced to nephrologists to appropriately prepare for dialysis initiation?
Statement: It has been reported that the nephrologist's care of CKD patients before their dialysis initiation affects their selection of kidney transplantation or dialysis, increases the probability of success of operation of vascular access, and decreases early mortality after their dialysis initiation. When patients are at least CKD Stage G4, their consultation with nephrologists is proposed. (Level: C, Grade: 2) CQ2: To prevent the progression of kidney injury and late dialysis initiation, is patient education by various medical staff members recommended for CKD patients at CKD stage G3b or later? Statement: Because interdisciplinary team management including doctors and nurses may prolong dialysis initiation, patient education by various medical staff members is recommended for CKD patients at CKD stage G3b or later.
(Level: C, Grade: 2) CQ3: Should we perform CVD screening at the initiation of dialysis? Statement: There is no evidence to suggest that universal CVD screening is beneficial. However, as CKD is a wellknown risk factor for CVD, we suggest treatable CVD should be identified at least before the initiation of dialysis. Chapter 15. Management of drug treatment CQ1: Is either an NSAID or acetaminophen recommended for patients with CKD suffering from pain? Statement: Acetaminophen may be safer than NSAIDs for the short-term administration to patients with CKD. In particular, for elderly patients with decreased renal blood flow and GFR, the use of acetaminophen is proposed. However, even for acetaminophen, the safety of the long-term administration is not certain. (Level: D, Grade: 2) CQ2: Is it recommended to treat patients with an oral spherical carbon adsorbent? Statement: Although the therapeutic effect of an oral spherical carbon adsorbent on end-stage kidney disease (ESKD) or death in CKD patients is unclear, its treatment may be considered because there is a possibility of delaying CKD progression. (Level: C, Grade: 2) CQ3: Is it recommended to reduce treatment with antiviral drugs based on renal function in CKD patients suffering from herpesvirus infection? Statement: When administering antiviral drugs to CKD patients suffering from herpes simplex/herpes zoster virus infection, we propose designing drug administration based on evaluation of the renal function. In many cases, it may be expected that there will be a decrease in the adverse event occurrence by a drug administration design based on renal function, but even if only the dose is adjusted, it is necessary to pay close attention to the occurrence of adverse events (Level: D, Grade: 2).
CQ4: How does CKD affect anticoagulant treatment of patients with non-valvular atrial fibrillation? Statement: Anticoagulant treatment for non-valvular atrial fibrillation associated with CKD patients may reduce the risk of total death and thromboembolism. Meanwhile, given the potential increased risk of developing severe bleeding complications, a decision for administration is made in considering the balance between benefits and disadvantages in each case. (Level: D, Grade: 2) CQ5: Does iodinated radiocontrast media worsen kidney function in people with CKD? Statement: All individuals with GFR < 60 mL/min/1.73 m 2 (GFR categories G3a-5) are at risk for contrast media induced nephropathy (CIN) by the intravascular administration of iodinated radiocontrast media. This risk may increase especially in people with GFR < 45 mL/min/1.73 m 2 (GFR categories G3b-5) or in cases in which large amount of iodinated radiocontrast media was used. (Level: B, Grade: 1) If the radiography with intravascular administration of iodinated radiocontrast media is required for patients with GFR < 60 mL/min/1.73 m 2 (GFR categories G3a-5), informed consent, sufficient hydration with saline before, during, and after the procedure, and use of lowest possible iodinated radiocontrast media dose are recommended. CQ3: Is glycemic control with a target HbA1c level of less than 7.0% recommended in diabetic patients with chronic kidney disease? Statement: Glycemic control aiming for an HbA1c level of less than 7.0% is recommended to prevent the progression of early stage diabetic nephropathy. There is not enough evidence supporting the benefits of intensive glycemic control on renal outcomes in patients with diabetes with macroalbuminuria or renal dysfunction. Caution is required for the risk of hypoglycemia when aiming for an HbA1c level of less than 7.0%. Statement: There is no direct evidence to demonstrate that screening for intracranial aneurysms is beneficial for lowering overall mortality or preventing rupture of aneurysms. Considering that prevalence of intracranial aneurysms in ADPKD patients is significantly higher than that in general population, however, their screening using MRI is suggested for ADPKD patients with a family history of intracranial aneurysms or subarachnoid hemorrhage. (Level: D, Grade: 2) CQ 2: Is tolvaptan recommended for ADPKD patients? 1 3 Statement: We recommend using tolvaptan for autosomal dominant ADPKD patients with a total kidney volume of ≥ 750 mL and with an estimated creatinine clearance of ≥ 60 mL/min. We also recommend using tolvaptan for later-stage ADPKD patients with an eGFR of 25-60 mL/ min/1.73 m 2 to slow the increase in total kidney volume and the decline in kidney function. Safety and efficacy of tolvaptan in children have not been established yet. (Level: B, Grade: 1) CQ3: Can RAS inhibitors be administered for hypertensive ADPKD patients? Statement: We suggest that ACEIs or ARBs should be administered for hypertensive ADPKD patients from the viewpoint of suppressing the development of ESKD. (Level: C, Grade: 2) 17-4: Management of Rapidly Progressive Glomerulonephritis (RPGN) CQ1: Is the use of "The guide for early diagnosis of rapidly progressive nephritic syndrome" recommended for detecting RPGN in patients with urinary abnormalities and renal dysfunction? Statement: We recommend the use of "The guide for early diagnosis of rapidly progressive nephritic syndrome" for detecting RPGN in patients with urinary abnormalities and renal dysfunction. (Level: D, Grade: 1) CQ2: Is testing serum MPO-ANCA, PR3-ANCA and anti-GBM antibody levels recommended for a differential diagnosis of RPGN in patients showing urinary abnormalities and worsening renal function within a few weeks or a few months?
Statement: Immediate testing of serum MPO-ANCA, PR3-ANCA and anti-GBM antibody levels is recommended for a differential diagnosis of RPGN in patients showing urinary abnormalities and worsening renal function. (Level: D, Grade: 1) CQ3. Is starting glucocorticoids alone useful for the initial treatment of patients with ANCA-associated RPGN? Statement: For the initial treatment of ANCA-associated RPGN, starting glucocorticoids alone is useful and is suggested for ameliorating patient prognosis. (Level: D, Grade: 2) However, we recommend that patients refractory to initial treatment or having organ-threatening or life-threatening involvement be referred to, or managed in close collaboration with, an expert center and combined use of immunosuppressive therapy should be considered. (Level: D, Grade: 1)