Clinical practice guidelines for the provision of renal service in Hong Kong: General Nephrology.

Abstract

About one-third of the acute kidney injury (AKI) burden occurs in the perioperative context, and the incidence of AKI continues to rise. While mortality rates in AKI have improved, the figures remain significant. Crucial factors that determine the prognosis include timing of onset, severity and duration of injury, recovery status and recurrence. AKI is associated with an increased hospital mortality, risk of hospital readmissions and risk of chronic kidney disease (CKD). 1.5–1.9 times baseline OR ≥26.5 μmol/L increase 3.0 times baseline OR Increase to ≥354 μmol/L OR Initiation of dialysis OR In patients <18 years, decrease in estimated glomerular filtration rate (eGFR) to <35 mL/min per 1.73 m2 (Schwartz formula) <0.3 mL/kg/h for ≥24 h OR Anuria for ≥12 h The cause of AKI should try to be determined. (Not Graded) Generally, discontinuation of nephrotoxic agents whenever possible, maintenance of volume status and perfusion pressure, functional haemodynamic monitoring and that of SCr and urine output, avoiding hyperglycaemia and resort to alternatives avoiding radio-contrast procedures should all be considered for patients at high risk of or have developed AKI. Patients with AKI require diagnostic workup, and stage 2/3 patients require change in drug dosing as renal impairment advances and consideration for RRT. It is recommended that patients be stratified for risk of AKI according to their susceptibilities and exposures (R), and managed accordingly in order to reduce such risk. (Not Graded) Exposures that may cause AKI include sepsis, critical illness, circulatory shock, burns, trauma, cardiac surgery (especially with cardiopulmonary bypass), major non-cardiac surgery, nephrotoxic drugs, radio-contrast media, poisonous plants and animals. Even with these exposures, the risk of AKI would vary between different patient groups and in different clinical context. For patients at increased risk for AKI, monitor their SCr and urine output to detect (and stage severity) AKI, at individualized frequency and duration based on patient risk and clinical course. (Not Graded) The use of SCr and urine output would be meaningful when these are monitored regularly at a defined fashion, but clinical practice would usually be dictated by clinical judgment based on the clinical setting and indication, with a tendency for high-risk and critically ill patients being monitored more frequently. The availability of time-dependent biomarkers would be helpful. Evaluate patients 2 months after AKI to look for return to baseline, or development of new CKD or worsening of pre-existing CKD. (R) There is strong association of AKI with subsequent development of CKD and end-stage renal disease (ESRD).10, 11 Prediction tools have been tested to help identify patients with AKI who are at high risks of CKD.10, 12-14 For initial fluid replacement in hypovolemic (not haemorrhagic) patients at risk for, or with, AKI, isotonic crystalloids rather than albumin or starches are recommended. (R) Recent data from multi-centre, open-label trial continues to support this recommendation.15-17 The Acute Dialysis Quality Initiative group recently concluded on the evidence for harm with hetastarch (hydoxyethyl starch) or albumin administration in traumatic brain injury cases.18 While 0.9% saline may result in a chloride-induced tubule-glomerular feedback–mediated vasoconstriction and metabolic acidosis compared with more physiologically balanced and buffered crystalloids, supporting evidence is mainly derived from post hoc analyses of large patient data sets, rather than prospective, controlled trials.19 Vasopressors are recommended in volume-resuscitated patients with vasomotor shock at risk for, or with, AKI. (R) Current clinical data are insufficient to conclude on the best vasoactive agent in preventing AKI.20-23 Protocoled therapies with specific physiological goals (haemodynamic and tissue oxygenation targets) are suggested to reduce perioperative AKI in high-risk patients. (D) The results from few multi-centre trials that looked at protocoled resuscitation with or without an oximetric central venous oxygen saturation monitoring (early goal-directed therapy) failed to suggest survival benefit in patients with septic shock who have received timely antibiotics and usual fluid resuscitation.24-26 In high-risk patients in the perioperative setting, while studies using different protocoled therapies with specific physiological goals (haemodynamic and tissue oxygenation targets)27 have been shown to significantly reduce post-operative AKI, there is no evidence to support the identification of the best regime. In patients with stress hyperglycaemia, the target plasma glucose for insulin therapy is suggested to be 6.1–8.3 mmol/L, and to avoid hypoglycaemia. (D) It is important to avoid the danger of potentially serious hypoglycaemia. While the target blood glucose between 6.1 and 8.3 mmol/L have not been directly studied in randomized controlled trial (RCT), they are interpolated from the comparisons tested in the trials.28, 29 An energy intake of 20–30 kcal/kg per day is suggested, and enteral feeding is preferred. (D) Though the optimal energy intake has not been well determined, data from both retrospective and randomized trials in AKI patients support a total energy intake of at least 20, but not to exceed 25–30 kcal/kg per day.30, 31 Studies have suggested that enteral feeding is associated with improved outcome and survival in ICU patients.32-34 Protein intake is suggested to be 0.8–1.0 g/kg per day in non-catabolic patients not on dialysis, 1.0–1.5 g/kg per day in dialysis patients and up to 1.7 g/kg per day in hypercatabolic patients or patients on continuous renal replacement therapy (CRRT). (D) Since malnutrition is associated with increased mortality in critically ill patients, nutritional protein administration is not recommended to be restricted as a means to attenuate the rise in serum urea level when renal function declines. On the other hand, there is little evidence that hypercatabolism can be overcome by increasing protein intake to higher than physiological levels.35, 36 During RRT, nutritional support should include replacement for the losses during the procedures, especially with modalities associated with high filtration rates, including CRRT, sustained low efficiency dialysis (SLED) or peritoneal dialysis (PD).37 The use of diuretics to prevent (R) or treat (D) AKI is not recommended, except in the presence of volume overload or acute decompensated heart failure (ADHF). Though diuretics theoretically may reduce renal tubular oxygen consumption and attenuate intra-tubular obstruction, the benefits of its use has remained contentious in AKI prevention. In the setting of cardiac surgery, a double-blind RCT has demonstrated a higher rate of AKI being associated with the use of furosemide.38, 39 Studies have suggested that diuretics given to treat post-operative AKI is best avoided.40, 41 This also applies to patients on CRRT.42, 43 In patients with ADHF, there were no significant differences in symptom relief or renal safety when diuretic therapy was administered by bolus compared with continuous infusion.44 Although high-dose therapy (2.5 times the usual oral dose given intravenously) improved diuresis, with a trend towards improved symptom relief, there was associated increase in renal adverse events compared with low-dose therapy (usual oral dose given intravenously).45 Individual careful clinical judgment is needed. The use of low-dose dopamine to prevent or treat AKI is not recommended. (R) The early positive results in the use of dopamine for renal protection in the critically ill have been opposed by quality RCT trial and meta-analysis.45-47 The use of either dopamine or synthetic natriuretic peptide on top of standard therapy in ADHF is also not associated with enhanced pulmonary decongestion or improved renal function.48 This is also true in the setting of AKI after cardiac surgery.49, 50 The use of fenoldopam to prevent or treat AKI is not suggested. (D) Fenoldopam mesylate is a dopamine type-1 receptor agonist with similar haemodynamic renal effects as low-dose dopamine, without systemic α- or β-adrenergic stimulation. While early data suggests a lower incidence of AKI was associated with the use of fenoldopam, data from adequately powered multi-centre trials with clinically significant endpoints do not support recommending fenoldopam to either prevent or treat AKI,51, 52 noting in particular the concern of the associated hypotension. The use of atrial natriuretic peptide to prevent or treat AKI is not suggested. (D) Studies demonstrating benefits of recombinant human atrial natriuretic peptide in reduced need for dialysis and improved dialysis-free survival after cardiac surgery53 or solid organ transplantation tend to be underpowered, its routine use for the prevention or treatment of AKI cannot be recommended, the concern of hypotension aside.53-56 The use of off-pump coronary artery bypass graft in order to prevent post-operative AKI is not suggested. (D) While the conclusion from systematic review and meta-analysis of studies looking at off-pump surgery compared with on-pump surgery in cardiopulmonary bypass suggest a 43% reduction in the risk of post-operative AKI, it has been cautioned that the definitions of AKI were variable and that the RCT included were associated with lower than normal event rates.57-60 More data is thus awaited to reach a recommendation. Use traditional indications for RRT that include fluid status, electrolyte and acid–base balance, clinical context. (Not Graded) The optimal timing of initiation of RRT has yet to be determined, and is largely a clinical decision. In recent prospective studies, conflicting results have been obtained, with different definitions of early versus conventional initiation of dialysis being used.61-64 Thus, while traditional indications for RRT used for patients with CKD may not necessarily be valid for AKI, the best timing for RRT may only be confirmed through prospective RCT when there are candidate biomarkers, enabling the selection of the right target patients and the offer of therapy at the right time. There is a general trend to commence RRT earlier in the more critically ill.65, 66 The use of diuretics to enhance kidney function recovery is not suggested. (D) One RCT has evaluated the role of furosemide by continuous infusion at a rate of 0.5 mg/kg/h on top of continuous veno-venous hemofiltration (CVVH). While treated patients had a significantly increased urinary volume and greater sodium excretion compared to the controls, there were no differences in the need for repeated CVVH, or renal recovery during ICU or hospital stay.42 The use of anti-coagulation during RRT, except those with bleeding risk, is recommended: (R) Studies have shown that frequent clotting affected RRT treatment efficacy, increased circuit ‘down time’, and increased transfusion requirements and cost.67 The advantages of unfractionated heparin include low cost, wide availability, easy administration and monitoring and availability of antidote. Its disadvantages include unpredictable and complex pharmacokinetics, risk of heparin-induced thrombocytopenia, heparin resistance from low circulating anti-thrombin III levels and increased risk of haemorrhage. Data from studies in chronic haemodialysis (HD) comparing unfractionated with low-molecular-weight heparin concluded that both are equally safe in terms of bleeding complications and effectiveness in maintaining circuit patency.68 Recent meta-analyses concluded that regional citrate anticoagulation (RCA) decreased the risk of bleeding compared with heparin anti-coagulation, improved circuit patency, especially in patients with increased bleeding risk, provided that appropriate protocols for monitoring are in place to eliminate the risk of citrate toxicity.69 Unexpectedly, there are studies showing improved renal recovery and hospital survival associated with the use of RCA, awaiting further confirmation.70 Patients with severe liver failure may have difficulty metabolizing the calcium–citrate complex, resulting in citrate accumulation, characterized by low ionized calcium levels, and high anion gap metabolic acidosis. Both continuous and intermittent RRT are complementary therapies in AKI patients. (Not Graded) Both intermittent HD and CRRT should be regarded as complementary modalities of RRT, as supported by the absence of definitive data favouring either one, in terms of hospital or ICU mortality, length of hospitalization and renal recovery in survivors.71, 72 Also, availability, expertise, resources, cost and physician preference would influence the clinical choice. Transitions between both modalities would be based on the changing clinical status of the patient, technical considerations such as circuit ‘down time’, and clinical needs of the patients such as rescheduling of diagnostic or therapeutic procedures. CRRT instead of intermittent HD, is the suggested modality for both haemodynamically unstable patients and patients with raised intracranial pressure. (D) CRRT, rather than intermittent HD, resulted in a significantly higher mean arterial pressure and a lower requirement of vasopressor therapy.71 SLED is generally well tolerated in the settings where CRRT is commonly used and may have a role when other forms of CRRT are not available, but data from comparative studies are limited. Intermittent HD in patients with raised intracranial pressure (acute brain injury or brain oedema) may compromise cerebral perfusion pressure as a result of HD-associated hypotension or by aggravating cerebral oedema and intracranial pressure through rapid intracellular volume and solute shifts.73-76 A Kt/V of 3.9 per week for intermittent HD is recommended (R), and the actual delivery should be closely monitored (R). Two well-conducted RCT looking at the dialytic dose of intermittent HD in AKI failed to demonstrate improvement in mortality or renal recovery when the dialysis dose was increased, either by a higher Kt/V above 3.9 weekly or by maintaining a serum urea level <15 mmol/L.77, 78 It is thus recommended to offer thrice-weekly Kt/V of 1.3 for intermittent HD in AKI. More frequent dialysis treatments may, however, be required in order to optimize fluid control, in hypercatabolic individuals or in the presence of severe hyperkalaemia or acidaemia. Positive fluid balance has been shown to be an independent risk factor for mortality in AKI patients.79 An effluent volume of 20–25 mL/kg/h for CRRT is recommended. (R) The two large, multi-centre RCT, the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study77 and the Randomized Evaluation of Normal versus Augmented Level Renal Replacement Therapy (RENAL) trial80 did not confirm that a more intensive therapy (CVVHDF with effluent flow exceeding 20–25 mL/kg/h) was associated with improved patient survival or recovery of renal function. However, studies in CRRT have shown that delivery usually falls substantially short of the prescribed dose81 as a result of technical problems such as poor blood flows, reduced haemofilter efficiency with time or filter clotting. It is thus generally recommended to prescribe a higher dose at 25–30 mL/kg/h, in order to achieve the recommended target. In patients suspected to have contrast-induced (CI)-AKI, look out for other possible causes of AKI too. (Not Graded) The incidence may be as high as 25% in patients with pre-existing renal impairment or together with other risk factors such as diabetes, congestive heart failure, advanced age and concurrent administration of nephrotoxic drugs.82-84 Patients who develop CI-AKI have a greater risk for death or prolonged hospitalization.85, 86 Monitoring of SCr following contrast exposure is essential, looking for new-onset CKD.87 Assess the risk for CI-AKI and always screen for renal impairment in patients planned for a procedure that involves intravascular (i.v. or i.a.) administration of iodinated contrast medium, and consider alternative examinations in patients at increased risk. (Not Graded) While the CI-AKI Consensus Working Panel suggested that the risk of CI-AKI becomes clinically important when the baseline SCr concentration is ≥115 mmol/L in men and ≥ 88.4 mmol/L in women, equivalent to an eGFR <60 mL/min per 1.73 m2, there are recent data suggesting that patients with SCr concentration >159 mmol/L are the group at risk.88 When a recent SCr is not available, a simple questionnaire or a dipstick testing for urine protein may be useful for identifying pre-existing kidney disease.89, 90 The risk of CI-AKI appears to be greater after arterial compared to venous administration of contrast media, with an overall CI-AKI incidence of about 5% after procedures that involve intravenous low-osmolar contrast media.91 Controversial risk factors include diabetes, hypertension, congestive heart failure, advanced age, volume depletion (including the use of loop diuretics), haemodynamic instability, concurrent use of nephrotoxic drugs, metabolic syndrome, multiple myeloma, female gender, cirrhosis and large volume or high osmolality of the contrast media. The use of either iso-osmolar or low-osmolar iodinated contrast media, but not high-osmolar iodinated contrast media (R), at the lowest possible dose (Not Graded) in patients at increased risk is recommended. Repeated exposure should preferably be delayed for 48 h in patients without risk factors for CI-AKI, and for 72 h in those with risk factors. If AKI develops after contrast-media administration, repeat exposure should be postponed until the SCr level has returned to baseline.92 Intravenous fluid (unless clinically contraindicated), either isotonic sodium chloride or sodium bicarbonate, is recommended for patients at increased risk. (R) Despite the absence of RCT that directly evaluate the role of intravenous fluids versus placebo in the prevention of AKI, comparisons observed in trials looking at different fluids, when matched with historical untreated control subjects suggest a large benefit from fluids.100 The possible exception would be patients with fluid overload. Even though there is no clear evidence from the literature to guide the choice of the optimal rate and duration of fluid administration in CI-AKI prevention, a ‘good’ urine output (>150 mL/h) in the 6 h after the radiological procedure has been associated with reduced rates of AKI.101 As crystalloids given intravenously would not be retained in the vascular space for long, this target urine flow rate requires an infusion rate of around 1.0–1.5 mL/kg/h for 3–12 h before and 6–12 h after the contrast exposure. Isotonic 0.9% saline solution has been proven to be superior to 0.45% saline solution102, 103 in CI-AKI prevention. For the comparison between sodium bicarbonate and saline, meta-regression suggests that small studies tend to demonstrate the superiority of bicarbonate, even though there were no consistent effects in terms of the risk for dialysis, heart failure and total mortality.104 The additional burden and potential harm from errors in preparing the bicarbonate solutions at the bedside or by local pharmacy, may further argue against the use of this fluid at present. The on-going, large, multi-centre, randomized, double-blind controlled trial comparing isotonic sodium bicarbonate with isotonic saline, along with N-acetylcysteine (NAC) versus placebo, for CI-AKI prevention, the PRESERVE study, has scheduled to enrol 8000 participants. The fluid prescription personalized to the volume status of individual patients represents a promising approach when compared with the usual weight-based fluid prescriptions of specified duration pre-contrast and post-contrast exposure. One such trial utilized the invasively measured left ventricular end diastolic pressure in high-risk patients undergoing cardiac catheterization.105 The other approaches tested include device-assisted fluid administration matched with urine output106 or inferior vena cava volume measurement. We suggest using oral NAC, together with intravenous fluid, in patients at increased risk. (D) The effect of NAC on the incidence of CI-AKI is quite variable, with most of the published studies being relatively small in size. With marked heterogeneity in the studies recruited, it is not surprising that many but not all meta-analyses revealed a net benefit.107 There is at present no evidence that either oral or intravenous NAC can alter hard outcomes including mortality and need for RRT after contrast-media administration to patients at risk for CI-AKI. The overall benefit of NAC is not consistent or overwhelming.108 However, oral NAC has a good safety profile and is inexpensive. Also, studies of NAC combined with bicarbonate administration have shown substantially reduced overall incidence of CI-AKI, but not that of dialysis-dependent renal failure, when compared to the combination of NAC with saline.109, 110 The use of statins as an alternative to volume expansion is not suggested. (Not Graded) Although recent RCT are associated with significant study limitations including the focus on relatively low-risk populations, they consistently demonstrate the efficacy of rosuvastatin for prevention of CI-AKI, including among the subgroups of CKD patients, echoing the results from previous meta-analyses. Studies devoted to patients with stage 3–4 CKD, however, would be crucial to support a definitive conclusion.111, 112 The use of prophylactic HD or haemofiltration for contrast-media removal in patients at increased risk is not suggested. (D) While there are conflicting data on the use of prophylactic intermittent HD in the incidence of CI-AKI, leading to either increased harm113 or tendency towards being useful,114, 115 a recent meta-analysis of studies using peri-procedural extracorporeal blood purification techniques concluded that such treatments did not decrease the incidence of CI-AKI.116 HRS type 1 represents a severe form of AKI in chronic liver disease characterized by systemic and splanchnic haemodynamic abnormalities without concomitant structural kidney injury. The diagnosis requires demonstration of a recent rise in SCr and exclusion of other causes of AKI such as hypovolaemia, drugs and parenchymal renal disease. There are data showing that early initiation of treatment with vasoconstrictor therapy coupled with albumin infusion might improve patient survival and renal outcomes.117, 118 The National Kidney Foundation defined CKD as either kidney damage or GFR <60 mL/min per 1.73 m2 for ≥3 months.119 Kidney damage is defined as pathological abnormalities or the presence of markers of damage, including abnormalities in blood or urine tests or imaging studies. Damage to the kidney can be within the parenchyma, large blood vessels or collecting systems. The markers of kidney damage often provide a clue to the probable site of damage within the kidney and in association with other clinical findings, the aetiology of kidney disease. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) re-defined CKD as abnormalities of kidney structure or function, present for more than 3 months, with implications for health. CKD is classified based on Cause, GFR category and Albuminuria category (CGA).120 The stages of CKD were arbitrarily classified as follows: G3a G3b 45–59 30–44 Mild-to-moderate ↓ GFR Moderate-to-severe ↓ GFR The albuminuria categories in CKD were classified as follows: The classification was also expanded by KDOQI (2012) to reveal treatment status, as follows: CKD of any stage,119-123 with or without a kidney transplant, including both non–dialysis dependent CKD (CKD 1–5ND) and dialysis-dependent CKD (CKD 5D) Non–dialysis-dependent CKD of any stage,119-123 with or without a kidney transplant (i.e. CKD excluding CKD 5D) Non–dialysis-dependent CKD of any stage119-123 with a kidney transplant Specific examples and meanings: All of the above are known risk factors with the exception that recent observations showed that are Associations with and prognostic impact of CKD in heart failure, with CKD being more common in preserved than in mid-range and reduced ejection fraction.121 Reporting of eGFRcreat in addition to SCr in adults is preferred and the equation used should be specified. (R) The original Modification of Diet in Renal Disease (MDRD) study equation122 required more variables (including blood urea nitrogen and serum albumin) than was thought to be practicable for routine clinical practice, and an abbreviated four-variable version was eventually adopted and widely used in clinical practice.123 The MDRD study equation was limited to only estimating GFR in CKD patients, as GFR is underestimated when applied to patients with kidney function better than 60 mL/min per 1.73 m2. Subsequently, KDIGO recommended the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation124 designed to overcome the shortcomings of the MDRD study equation. CKD-EPI was derived from an ethnically broader population and included both healthy participants and subjects with CKD. Even then, it must be borne in mind that the validity of the CKD-EPI equation in non-European and non-African ethnicities remains uncertain. Other methods of improving the accuracy of the estimating equations include the use of an alternative or additional serum biomarker, and also muscle mass quantification to adjust for variations in SCr. Thus, the CKD-EPI collaboration group further developed an equation that used both SCr and cystatin C.125 Several investigators in Asia (including China, Japan, Korea, Taiwan and Thailand) assessed the performance of the various GFR estimating equations, in particular, the MDRD study equation, the CKD-EPI equation (creatinine only), and the CKD-EPI equations (creatinine and cystatin C). Since cystatin C measurement is not widely available in Hong Kong, we will adopt the most current KDIGO guideline that recommended using the CKD-EPI SCr-based GFR estimating equation. Screening for CKD be targeted and performed in individuals at increased risk of developing CKD, including those with diabetes mellitus, hypertension and established cardiovascular disease (see item 2 above). (D) The screening tools should include history taking, blood pressure (BP) recording, urine dipstick testing for protein and red cells, and measurement of SCr. Other screening tests should be included for specific at-risk groups, for example urine microalbumin in diabetic subjects, or urinary albumin:creatinine ratio in dipstick-positive individuals.126, 127 Patients with CKD should be referred to a specialist for consultation and co-management if the clinical action plan cannot be prepared, the prescribed evaluation of the patient cannot be carried out, or the recommended treatment cannot be instituted. (R) The criteria for specialist referral vary with individual practice and available resources. In general, the following scenarios deserve consideration of referral: The management of progression of CKD is aimed at tackling a myriad of factors known to be associated with progression. These measures have been shown to modify cardiovascular health and CKD concomitantly or separately. Addressing CV risk factors may indirectly and directly impact CKD progression, and vice-versa. Strategies include general lifestyle measures, salt restriction, BP control and blockade of the renin-angiotensin-aldosterone system. In addition, control of other metabolic parameters such as blood sugar, lipid, anaemia, bone metabolism, uric acid and acidosis are also important.120 For diabetic and non-diabetic patients with AER less than 30 mg/24 h (or equivalent), the suggested BP target is ≤140/90 mmHg. For diabetic and non-diabetic patients with UAE ≥30 mg/24 h (or equivalent), the suggested BP target is ≤130/80 mmHg. (D) Available evidence is inconclusive but does not prove that a blood pressure target of less than 130/80 mmHg improves clinical outcomes more than a target of less than 140/90 mmHg in adults with CKD.128 Adults over 50 years old with CKD G3a–G5 ND could be treated with a statin or statin/ezetimibe combination. (D) Recent studies have shed light on lipid management in patients with CKD. Although definitive evidence is still lacking, these studies suggest that lipid lowering could only confer tangible cardiovascular protection during early rather than late CKD.130 For renoprotection, lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD in a large randomized study using simvastatin/ezetimibe combination. (ungraded) Exploratory analyses of the SHARP study, however, showed no significant effect of lipid lowering on the rate of change in eGFR.131 A more recent study (PLANET I)* found atorvastatin to have more renoprotective effects than high-dose rosuvastatin in patients with diabetes who have progressive renal disease.132 Dietary phosphate reduction should be implemented during CKD 3–4 when plasma intact parathyroid hormone (iPTH) levels exceed 70 pg/mL (7.7 pmol/L) (stage 3) or >110 pg/mL (12.1 pmol/L) (stage 4). (D) The major disorders can be classified into those associated with high bone turnover and high PTH levels (including osteitis fibrosa, the hallmark lesion of secondary hyperparathyroidism and mixed lesion) and low bone turnover and low or normal PTH levels (osteomalacia and adynamic bone disease). The abnormalities that lead to bone disease begin to occur at earlier stages of CKD. Elevated levels of PTH and phosphorus, reduced levels of calcium and reduced urinary phosphate excretion have been described among patients with GFR <70 mL/min or lower.119 Vitamin D or analogues are useful in treating secondary hyper