Chronic Kidney Disease and its Management

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Chronic kidney disease represents the gradual, substantial, and irreversible reduction in the excretory and homeostatic functions of the kidneys. It is characterised by progressive destruction of renal tissue over a period of at least months to many years, depending on the underlying aetiology. Glomerular filtration rate (GFR) progressively decreases with loss of functioning nephrons. Until recently, the emphasis has been on patients needing dialysis or transplantation. It is now realised that less severe CKD is quite common, and monitoring in primary care will enable the minority of patients who go on to develop a more severe form to be detected at any earlier stage.1 This important because the earlier the intervention, the greater the impact. Patients with chronic conditions such as heart disease and diabetes may already undergo structured review in primary care but the full extent of reduced kidney function may not be recognised. 2

Classification of chronic kidney disease3 Kidney function should be assessed by estimated GFR (eGFR) and chronic kidney disease (CKD) is classified on this basis. The GFR should be estimated from serum creatinine using the 4-variable Modification of Diet in Renal Disease (MDRD) equation (see under investigations below). 4 Patients with a GFR of >60 ml/min/1.73 m2 without evidence of chronic kidney damage should NOT be considered to h necessarily need further investigation.

Stage 1: normal; eGFR >90 ml/min/1.73 m2 with other evidence of chronic kidney damage (see below) Stage 2: mild impairment; eGFR 60-89 ml/min/1.73 m2 with other evidence of chronic kidney damage Stage 3a: moderate impairment; eGFR 45-59 ml/min/1.73 m2 Stage 3b: moderate impairment; eGFR 30-44 ml/min/1.73 m2 Stage 4: severe impairment; eGFR 15-29 ml/min/1.73 m2 Stage 5: established renal failure (ERF); eGFR less than 15 ml/min/1.73 m2 or on dialysis

Use the suffix (p) to denote the presence of proteinuria when staging CKD. The other evidence of chronic kidney damage may be one of the following: Persistent microalbuminuria Persistent proteinuria Persistent haematuria (after exclusion of other causes, e.g. urological disease) Structural abnormalities of the kidneys demonstrated on ultrasound scanning or other radiological tests, e.g. polycystic kidney disease, reflux nephropathy Biopsy-proven chronic glomerulonephritis Epidemiology The incidence of chronic kidney disease requiring dialysis varies worldwide: the number of patients per million population starting dialysis each year is 110 in the UK.3 The prevalence of end-stage renal failure also varies worldwide: the number of patients per million population in the UK is 498.3 Causes The most important causes of chronic kidney disease are diabetes, glomerulonephritis, hypertension and other vascular disease. Arteriopathic renal disease and hypertension Glomerulonephritis Diabetes Infective, obstructive and reflux nephropathies Familial or hereditary kidney disease, e.g. polycystic kidneys Hypercalcaemia Connective tissue diseases Neoplasms Myeloma

Risk factors Factors other than the underlying disease process that may cause progressive renal injury include the following: Hypertension Acute insults from nephrotoxins or decreased perfusion Proteinuria Increased renal ammonia formation with interstitial injury Hyperlipidaemia Hyperphosphataemia with calcium phosphate deposition Presentation Symptoms Usually presents with non-specific symptoms caused by renal failure, complications (e.g. anaemia in chronic renal failure) and the underlying disease. May be discovered by chance following a routine blood or urine test. Specific symptoms usually develop only in severe renal failure, and include anorexia, nausea, vomiting, fatigue, weakness, pruritus, lethargy, peripheral oedema, dyspnoea, insomnia, muscle cramps, pulmonary oedema, nocturia, polyuria and headache. Sexual dysfunction is common. Hiccups, pericarditis, coma and seizures are only seen in very severe renal failure. Signs The physical examination is often not very helpful but may reveal findings characteristic of the underlying cause (e.g. SLE, severe arteriosclerosis, hypertension) or complications of CRF (e.g. anaemia, bleeding diathesis, pericarditis). Signs of CKD include increased skin pigmentation or excoriation, pallor, hypertension, postural hypotension, peripheral oedema, left ventricular hypertrophy, peripheral vascular disease, pleural effusions, peripheral neuropathy and restless legs syndrome. Differential diagnosis Acute renal failure: Making the distinction between acute renal failure and chronic renal failure can be very difficult. A history of chronic symptoms of fatigue, weight loss, anorexia, nocturia, and pruritus all suggest chronic kidney disease. The history and examination will provide clues, but renal ultrasound will provide the most important information. Renal abnormalities on ultrasound, such as small kidneys in chronic glomerulonephritis or large cystic kidneys in adult polycystic kidney disease, will almost always be present in patients with chronic kidney disease. Acute on chronic renal failure: may have features indicating chronic kidney disease but also features suggesting a cause of an acute deterioration of renal function, e.g. infection. Investigations Investigations are focused on assessment of renal function and therefore stage of CKD, identification of the underlying cause and assessment of complications of CKD. Assessment of renal function: Serum urea is a poor marker of renal function, because it varies significantly with hydration and diet, is not produced constantly and is reabsorbed by the kidney. Serum creatinine also has significant limitations. The level can remain within the normal range despite the loss of over 50% of renal function. A gold-standard measurement is an isotopic GFR, but this is expensive and not widely available. For most purposes in primary care, the best assessment or screening tool is the estimated glomerular filtration rate (eGFR).5 This uses the 4-variable Modification of Diet in Renal Disease (MDRD) equation3 - see the record Assessing Kidney Function and the Estimated Glomerular Filtration Rate Calculator based on this equation. Most laboratories now provide an estimated GFR (eGFR) when requesting serum creatinine which should be used in preference to calculator above. Biochemistry: Plasma glucose: to detect undiagnosed diabetes or assess diabetes control Serum sodium: usually normal, but may be low Serum potassium: raised Serum bicarbonate: low Serum albumin: hypoalbuminaemia in patients who are nephrotic and/or malnourished (low levels at the start of dialysis are associated with a poor prognosis) Serum calcium: may be normal, low or high Serum phosphate: usually high Serum alkaline phosphatase: raised when bone disease develops Serum parathyroid hormone: rises progressively with declining renal function

 Serum cholesterol and triglycerides: dyslipidaemia is common Haematology: Normochromic normocytic anaemia; haemoglobin falls with progressive renal failure. White cells and platelets are usually normal. Serology: Autoantibodies, particularly antinuclear antibodies, C-ANCA, P-ANCA, anti-glomerular basement membrane antibodies (very suggestive of underlying Goodpasture's syndrome) and serum complement. Hepatitis serology: ensure not infected and vaccinate against hepatitis B. HIV serology: performed before dialysis or transplantation. Urine: Urinalysis: dipstick proteinuria may suggest glomerular or tubulointerstitial disease. Urine sediment with red blood cells and red blood cell casts suggests proliferative glomerulonephritis. Pyuria and/or white cell casts suggest interstitial nephritis (especially if eosinophils are present in the urine) or urinary tract infection. Spot urine collection for total protein:creatinine ratio allows reliable estimation of total 24-hour urinary protein excretion. The degree of proteinuria correlates with the rate of progression of the underlying kidney disease and is the most reliable prognostic factor in chronic renal failure. Twenty-four-hour urine collection for total protein and creatinine clearance. Serum and urine protein electrophoresis: to screen for a monoclonal protein possibly representing multiple myeloma. ECG and echocardiography: to detect left ventricular hypertrophy and ischaemia, and to assess cardiac function. Imaging of the renal tract: Plain abdominal x-ray: may show radio-opaque stones or nephrocalcinosis. Intravenous pyelogram: not often used because of potential for contrast nephropathy. Renal ultrasound: Small echogenic kidneys are seen in advanced renal failure. Kidneys are usually initially large and then become normal in size in advanced diabetic nephropathy. Structural abnormalities may be seen, e.g. polycystic kidneys. Also used to screen for hydronephrosis caused by urinary tract obstruction, or involvement of the retroperitoneum with fibrosis, tumour or diffuse adenopathy. Retrograde pyelogram: may be indicated if clinical suspicion of obstruction despite a negative ultrasound study finding. Renal radionuclide scan: Useful to screen for renal artery stenosis when performed with captopril administration but is unreliable for GFR of less than 30 ml/minute. Also quantifies differential renal contribution to total glomerular filtration rate. CT scan: to better define renal masses and cysts seen on ultrasound; is the most sensitive test for identifying renal stones. MRI: For patients who require a CT scan but who cannot receive intravenous contrast. Like CT scan and renal venography, it is reliable in the diagnosis of renal vein thrombosis. Magnetic resonance angiography is also useful for diagnosis of renal artery stenosis, although renal arteriography remains the investigation of choice. Micturating cystourethrogram: for diagnosis of vesicoureteric reflux. Renal biopsy Criteria for referral to specialist services3 Estimated GFR less than 15 ml/min/1.73 m2: immediate referral Estimated GFR 15-29 ml/min/1.73 m2: urgent referral (routine referral if known to be stable) Estimated GFR 30-59 ml/min/1.73 m2: routine referral if: Progressive fall in GFR/increase in serum creatinine Microscopic haematuria present Urinary protein to creatinine ratio greater than 45 mg/mmol Unexplained anaemia (Hb below 11 g/dl); abnormal potassium, calcium or phosphate Suspected systemic illness, eg SLE Uncontrolled BP (above 150/90 mmHg on 3 antihypertensive medications) Estimated GFR 60-89 ml/min/1.73 m2: referral not required unless other problems present Renal problems irrespective of GFR Immediate referral for:

 Malignant hypertension Hyperkalaemia (potassium >7.0 mmol/l) Urgent referral for: Proteinuria with oedema and low serum albumin (nephrotic syndrome) Routine referral for: Dipstick proteinuria present and urine protein:creatinine ratio above 100 mg/mmol Dipstick proteinuria and microscopic haematuria present Macroscopic haematuria but urological tests negative Management Issues that should be discussed with the patient6 Many patients equate kidney disease with renal dialysis. It is important to explain that CKD a spectrum of disease. Mild CKD is common and rarely progresses to a more severe form later. Explain eGFR and that this will need to be monitored on a regular basis to ensure that the condition is not deteriorating. If relevant discuss the link between hypertension and CKD and that maintaining tight blood pressure control can limit the damage to the kidneys. Discuss the link between CKD and an increased risk of developing cardiovascular disease. In newly diagnosed with eGFR less than 60 ml/min/1.73 m2 Review all previous measurements of serum creatinine to estimate GFR and assess rate of deterioration. Review all medication including over the counter drugs; particularly consider recent additions (e.g. diuretics, NSAIDs, or any drug capable of causing interstitial nephritis, such as penicillins, cephalosporins, mesalazine, diuretics). Urinalysis: haematuria and proteinuria suggest glomerulonephritis, which may progress rapidly. Clinical assessment: e.g. look for sepsis, heart failure, hypovolaemia, palpable bladder. Repeat serum creatinine measurement within 5 days to exclude rapid progression. Check criteria for referral (above). If referral not indicated, ensure entry into a chronic disease management register and programme. All stages of CKD3 Regular measurements of kidney function and other laboratory tests depending on the severity of kidney impairment. General health advice: smoking cessation, weight loss, aerobic exercise, limiting alcohol intake, limiting sodium intake. Avoidance of nephrotoxins, e.g. IV radiocontrast agents, NSAIDs, aminoglycosides. Cardiovascular prophylaxis: For patients with 10 year risk of cardiovascular disease of greater than 20%, consider aspirin treatment (if BP is below 150/90 mmHg) and lipid-lowering drug therapy. Blood pressure monitoring: blood pressure should be measured at least annually. Control of hypertension: hypertension should be tightly controlled. The threshold for initiation of anti-hypertensive medication: If urine protein/creatinine ratio (PCR) is below 100 mg/mmol: threshold 140/90 mmHg, target 130/80 mmHg. If urine PCR is above 100 mg/mmol: threshold 130/80 mmHg, target 125/75 mmHg. ACE inhibitor or angiotensin receptor blocker to be started: If urine PCR is above 100 mg/mmol. In diabetic patients with micro-albuminuria. Serum creatinine and potassium should be checked before starting medication, two weeks after starting, and after subsequent increases in dose. If creatinine increases by more than 20% or fall in GFR of more than 15%, repeat creatinine, check potassium and refer for specialist opinion on whether to stop treatment or to investigate for renal artery stenosis. If hyperkalaemia is present (serum K above 6 mmol/l): stop relevant drugs, eg. NSAIDs and potassium-retaining diuretics; check diet and proprietary treatments, e.g. LoSalt. If hyperkalaemia persists the ACE or ARB should be stopped. Additional management for CKD stage 3 includes3 Annual measurement of haemoglobin, potassium, calcium and phosphate. If Hb below 11 g/dl and other causes excluded, treat with erythropoiesis stimulating agents to maintain Hb 11-12 g/dl depending on the patient's functional needs. Request renal ultrasound in patients with lower urinary tract symptoms, refractory hypertension, unexpected progressive fall in GFR. Immunise against influenza and pneumococcus. Review all prescribed medication regularly to ensure appropriate doses. Avoid nephrotoxic drugs including NSAIDs wherever possible. Check parathyroid hormone concentration when Stage 3 is first diagnosed: if raised, check serum 25hydroxyvitamin D and if low, treat with ergocalciferol or cholecalciferol with calcium supplement (not calcium phosphate). Repeat PTH after 3 months and refer if still raised.

Additional management for CKD Stages 4-5 includes3 Care of all patients with stage 4 or 5 CKD should be discussed formally with a nephrologist even if it is not anticipated that renal replacement therapy will be appropriate. Exceptions may include: Patients with another terminal illness. Patients with stable function in whom all the appropriate investigations and management interventions have been performed and who have an agreed and understood care pathway. Patients in whom further investigation and management is clearly inappropriate. 3-monthly tests: serum creatinine (for eGFR), Hb, calcium, phosphate, bicarbonate, parathyroid hormone. Dietary assessment. Immunisation against hepatitis B. Investigation and treatment of phosphate retention and hyperparathyroidism. Correction of acidosis. Timely provision of dialysis access depending on treatment choice. Renal replacement therapy Indications for renal replacement therapy (haemodialysis, peritoneal dialysis, chronic ambulatory peritoneal dialysis or renal transplantation) include: Serum creatinine greater than 500 mmol/l. Symptoms: pericarditis, encephalopathy, peripheral neuropathy, intractable gastrointestinal symptoms, failure to thrive and malnutrition. Severe metabolic acidosis: bicarbonate less than 12 mmol/L. Complications Anaemia: left ventricular hypertrophy, fatigue, impaired cognitive functioning Coagulopathy Hypertension: left ventricular hypertrophy, heart failure, stroke, cardiovascular disease Calcium phosphate loading: cardiovascular and cerebrovascular disease, arthropathy, soft tissue calcification Renal osteodystrophy: disorders of calcium, phosphorus and bone, most commonly osteitis fibrosa cystica Bone changes of secondary hyperparathyroidism: bone pain and fractures Neurological: uraemic encephalopathy, neuropathy including peripheral neuropathy Dialysis amyloid: bone pain, arthropathy, carpal tunnel syndrome Fluid overload: pulmonary oedema, hypertension Malnutrition: increased morbidity and mortality, infections, poor wound healing Glucose intolerance due to peripheral insulin resistance Management of complications Water and electrolyte balance: Patients with chronic kidney disease pass normal volumes of urine. Precise restriction of fluid intake is only required for patients with oliguric end-stage renal failure. The usual recommendation is for a daily intake of daily urinary output plus 500 ml (for insensible losses). Patients should avoid binge drinking and be vigilant in replacing extra fluid losses in hot weather and during episodes of diarrhoea or vomiting. Severe acute volume overload may require high dose loop diuretics or dialysis. Dietary restriction to 60 mmol/day each of sodium and potassium is appropriate but compliance is greatly improved with sensible and flexible dietary advice. Loop diuretics (with the addition of a thiazide diuretic if resistant) improve sodium balance and blood pressure. Hyperkalaemia is treated with dialysis if the potassium level rises above 7 mmol/L. Otherwise treatment is directed towards the cause, e.g. excess fruit, chocolate or coffee, gastrointestinal haemorrhage, acidosis or tissue necrosis. Hyperkalaemia with the GFR still above 10 ml/min may be due to hyporeninaemic hypoaldosteronism in patients with diabetes, hypoadrenalism or as a result of treatment with ACE inhibitors. Anaemia: Erythropoietin is given with iron. The serum ferritin is monitored throughout treatment and iron is stopped if the ferritin level becomes too high, e.g. above 500 mcg/L. Early erythropoietin therapy may prevent left ventricular hypertrophy. The timing for initiation of treatment remains uncertain. The haemoglobin level is usually maintained at or above 11 g/dl. Acidosis: Chronic acidosis aggravates hyperkalaemia, inhibits protein synthesis and accelerates calcium loss from bone. Treated with sodium bicarbonate as long as the patient can tolerate the increased sodium load as additional sodium may cause fluid overload and worsen hypertension. Hyperphosphatemia:

 Occurs late in chronic kidney disease. Treated with dietary restriction, dietary phosphate binders and calcium carbonate. Hypocalcaemia: Prescribe calcium supplements, with or without calcitriol. Hyperparathyroidism: Reduce hyperphosphataemia by diet and phosphate binders. Prescribe 1,25-dihydroxycholecalciferol and maintain a normal calcium level. Secondary hyperparathyroidism starts early in chronic renal failure and is difficult to treat when it becomes established. Secondary hyperparathyroidism may lead to tertiary hyperparathyroidism if not treated effectively. Malnutrition: Must be avoided, although protein restriction can slow progression of renal failure. Restriction of dietary protein slows the progress of glomerulosclerosis in residual nephrons in animal experimental models. There remains controversy as to the benefits of protein restriction for treatment. Although patients are advised against high-protein diets, low-protein diets are not usually recommended and the emphasis is to maintain good nutrition. Prognosis Much of the damage caused by chronic kidney disease occurs early, when interventions may be much more effective. Patients with chronic kidney disease usually progress to end-stage renal disease. The rate of progression depends on the underlying diagnosis, on the successful implementation of secondary preventative measures, and on the individual patient. Patients on chronic dialysis have a high incidence of morbidity and mortality. Patients with ESRD (endstage renal disease) who undergo renal transplantation survive longer than those on chronic dialysis. Cardiovascular disease is the most common cause of death in patients with chronic kidney disease. Cardiovascular mortality is doubled in patients with a GFR below 70 ml/minute. Prevention Early diagnosis and good control of potential causes, e.g. diabetes, hypertension and urinary tract obstruction. Quality and Outcome Framework Chronic kidney disease was included in the Quality and Outcome Framework of the GP Contract in April 2006. The following indicators were added: Records CKD1: The practice can produce a register of patients aged 18 years and over with CKD (US National Kidney Foundation: Stage 3 to 5 CKD). Initial Management CKD2: The percentage of patients on the CKD register whose notes have a record of blood pressure in the previous 15 months. Ongoing Management CKD3: The percentage of patients on the CKD register in whom the last blood pressure reading, measured in the previous 15 months, is 140/85 mmHg or less CKD4: The percentage of patients on the CKD register with hypertension who are treated with an angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) (unless a contraindication or side effects are recorded). Much of the rational for these indicators is enshrined in Part Two of the National Service Framework for Renal Services - Chronic Kidney Disease, Acute Renal Failure and End of Life Care.2