Dana Lecture 2 Chronic Kidney Disease

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1 Medicine Dr. Dana Lecture 2 Chronic Kidney Disease Chronic Kidney Disease Assessment of renal function Classification of CKD Why Chronic renal failure tends to progress Risk factors for progression Management of CKD Complications of CKD the Kidney Each kidney has: a renal artery, a renal vein, a ureter which enter the kidney at the hilum. The kidney has: an outer cortex layer, an inner medullary pyramid layer, fine branches of the ureter which form the calyx The NEPHRON is the functional unit of the kidney. Each kidney has nearly a million of nephrons. Each nephron: is supplied with an afferent arteriole, and produces urine which drains into a collecting duct. The collecting ducts fuse together to make larger and larger tubes until they join together as the ureter Each nephron consists of: a glomerulus & Bowman s capsule, a proximal convoluted tubule, a loop of Henle, a distal convoluted tubule Chronic Kidney Disease Longstanding and irreversible decline in renal function Injured nephrons replaced by extensive fibrosis Normal nephrons gradually fail due to hyperfilteration Is mainly TUBULAR scarring, so urine output usually normal, though urine quality reduced Any cause of AKI can eventually lead to CKD Assessment of renal function 60 years old woman - Creatinine 1.1 ( mg/dl) - Wt 48 Kg 20 years old man - Creatinine 1.4 ( mg/dl) - Wt 98 Kg 1

2 How do we assess renal function? Serum urea and creatinine - Small molecules - Filtered by glomerulus measure of GFR - But creatinine also depends on: + Muscle mass + Body size + Sex and race Measurement of GFR - Direct measurement - Estimation of GFR (egfr) Serum Creatinine Familiar But confounding factors: - Muscle mass - Nutrition - Race - Sex Not a linear relationship with GFR Staging of chronic kidney disease - K/DOQI guideline Stage GFR (ml/min) Description 1* 90 Normal kidney function but other evidence of kidney damage 2* Mild reduction in kidney function with other evidence of kidney damage Moderate kidney damage Severe kidney damage 5 <15 Established renal failure or end stage renal failure *Only considered to be CKD stage 1 or 2 if proteinuria and/or haematuria or structural renal disease are present. 2

3 CKD prevalence Stage 1: 3.3% Stage 2: 3.0% Stage 3: 4.3% Stage 4: 0.2% Stage 5: 0.2% Why is it important to identify patients with CKD? CKD predispose to increased cardiovascular risk (modify risk factors such as Hypertension) Some patient may benefit from other investigations ( such as renal biopsy) It may be possible to slow down the progression Complications of CKD can be identified and treated early Preparation for dialysis or transplantation once they reach end-stage.?acute or Chronic kidney impairment History and duration of symptoms Previous urinalysis or measurement of renal function Rapid changes in renal function Normocytic, normochromic anaemia( but haemorrhage, haemolysis) Ultrasound: small kidneys and increased echogenicity Evidence of renal osteodystrophy ( ie digital subperiosteal erosions) Who is at risk? Known CKD Hypertension Diabetes Unexplained oedema Congestive cardiac failure Atherosclerotic disease ( coronary, cerebral, peripheral) Multi systemic disease ( myeloma, SLE) Bladder outflow obstruction, neurogenic bladder, renal stone disease, recurrent UTI Chronic nephrotoxic use ( NSAID, ACEI, ARBII, ciclosporin, lithium) Urologically unexplained haematuria Why chronic renal failure tends to progress? Once CKD established, inexorable progression is likely While only 10% of those with CKD stage 3 may progress, all are at risk Therefore life-long follow up is desirable Mechanism of progression Raised intraglomerular pressure Glomerular damage Proteinuria Tubulo-intestitial scarring 3

4 Importance of proteinuria Normal glomeruli do not leak protein Proteinuria is a sign of glomerular dysfunction Proteinuria is also risk factor for progression of CKD Importance of proteinuria Normal glomeruli do not leak protein Proteinuria is a sign of glomerular dysfunction Proteinuria is also risk factor for progression of CKD Measures which reduce proteinuria slow down the progression of CKD* Albuminuria is a marker of cardiovascualr risk** Causes of End Stage Renal Disease* Case 1 Diabetes Glomerulonephritis Reflux nephropathy Renovascular disease Hypertension Polycystic kidney disease 55 years old male History of diabetes for 15 years He has CKD with egfr 35ml/min( checked 6 months ago). His BP was 140/90 and his doctor started him on Ramipril 2.5 mg two weeks ago. Lab results: egfr of 25ml/min otherwise well, HbA1c 6.0%, urinary protein excretion of 0.5g/24hrs ( no changes from previous results). What is the most likely cause of his renal deterioration? 1- Progression of his diabetic nephropathy 2- Uncontrolled hypertension 3- Infection 4- Drug induced 4

5 Reversible causes of deteriorating renal function Blood pressure control Diabetes control Obstruction Drug, contrast agent Intercurrent illness Exacerbation of underlying kidney disease (sarcoidosis, lupus) Preventing progression Blood pressure and diabetes - Uncontrolled Hypertension and diabetes makes proteinuria worse - Controlling hypertension and diabetes is vital ACE inhibitors and ARBs have antiproteinuric effects over and above their effects via blood pressure - Agents of choice in proteinuric renal disease - Even if blood pressure normal Blood pressure targets* CKD with no proteinuria: <140/90 mmhg CKD with proteinuria: <130/80 mmhg Diabetic nephropathy: <130/80mmHg (aim for 125/75 mmhg). Managing CKD 1- General advice: Smoking cessation Weight reduction if obese Encourage aerobic exercise Aspirin 75mg od ( if 10 years cardiovascular risk>20%) Treat hyperlipidaemia Avoid NSAID and other nephrotoxic drugs Limit alcohol intake( <21units/wk in male, <14units/wk in female Vaccination against influenza and pneumococcus 2- CKD stages 1-3: Monitor egfr, urinalysis and protein creatinine ratio Meticulous BP and diabetes control If Hb < 11g/dl check ferritin, B12 and folate( if ferritin <100mg/dl start on oral or IV iron) Annual check of PTH, Calcium and phosphate 5

6 3- CKD stages 4-5: Refer to nephrologist Full dietary assessment Optimize PTH, Calcium and phosphate Correct acidosis Hepatitis B immunization Discuss future treatment (dialysis, transplant or conservative/palliative) Complications of CKD/ESKD Uraemia Anaemia Renal bone disease Salt and water retention Electrolyte imbalance Acidosis Cardiovascular disease and lipids Salt and water retention Dietary salt restriction ( aim <5g/day) Fluid intake restriction Diuretics such as furosemide, titrate up Add thiazide ( metolazone) Those with fluid overload and on diuretics monitor: - Weight ( loss of 1kg/day) - BP control - Monitor electrolyte - if Ur > 70mg/dl consider reducing diuretics - Refractory volume overload = dialysis Hyperkalaemia Common and potentially fatal Rapid rise of K+ is more dangerous than gradual ones, as cell membrane stability is more vulnerable to acute changes K+ depolarization of the membrane resting potential Na+ channel inactivation membrane excitability neuromuscular depression and cardiac dysrhythmias. When to treat: K+: mmol/l: recheck routinely. Review medications and arrange dietary advice. K+: mmol/l: recheck urgently, review med, stop ACEI/ARB2 and arrange dietary advice. K+: >6.5 mmol/l: admit for emergency management 6

7 Measures to prevent K+ Dietary restriction: dairy products, potatoes and some fruits (such as banana, grapes, pineapple), fresh fruit juice, tomatoes, sweet corn, mushrooms, chocolate and coffee. Loop diuretics: promote urinary K+ excretion. Drug withdrawal or dose reduction (ACEI, ARB2), review other contributory drugs (spironolactone, NSAID and B-blockers) Correct acidosis. Dialysis ( especially in refractory K+) Acidosis Leads to: Bone: increase bone resorption and impaired mineralization, contributing to renal osteodystrophy. Over ventilation (compensatory mechanism) Hyperkalaemia Increased ionized Calcium (acidosis lead to reduced albumin bound fraction) Malnutrition: acidosis promotes catabolism How to correct acidosis? Treat when venous HCO3- is <21 mmol/l Give NaHCO3 tablet g/tds Refractory acidosis: dialysis Uraemia Clinical syndrome caused by substantial fall in GFR Failure to eliminate potentially toxic small and middle size molecules. NOT a result of high blood urea concentration. Ur and Cr are not directly toxic. Leads to: - Chronic inflammation and oxida ve stress - Accumulation of metabolic end products - Accelerated atherogenesis - Disruption of immune system - phosphate is retained: leads to PTH, arteriosclerosis and vascular Calcifica on - Nausea/ vomiting - Anorexia and weight loss - Malaise, fatigue - Confusion, fits and coma - Pericarditis 7

8 Anaemia Erythropoietin (EPO) is essential for the terminal maturation of erythrocyte EPO produced by the peritubular interstitial fibroblasts in the outer renal medulla and deep cortex in the kidney EPO deficiency occur in most advanced CKD (egfr < 35ml/min) with exception: Adult polycystic kidney disease Benign renal cysts Renal cell carcinoma Differential diagnosis of anaemia in CKD Case 2 EPO deficiency Iron deficiency anaemia Blood loss (GI tract, Haemodialysis) Folate deficiency B12 deficiency Haemolysis Myelodyplasia Myeloma 54 years old male with CKD stage 4 History or recurrent chest infection for the last 3months On oral co-amoxiclav, Erythropoietin injection 6000 iu sc weekly (increased recently) Lab results: Hb 8.5g/dl (no changes), WBC: 14, egfr: 16, CRP: 75, ferritin: 600 What is the most likely cause of EPO non-responsiveness 1. Non-compliance 2. Inadequate dose of EPO 3. High CRP 4. Iron deficiency anaemia EPO non-response Iron deficiency Chronic blood loss Infection/inflammation Severe hyperparathyroidism (causes bone marrow fibrosis) B 12 and folate deficiency Haemolysis Malnutrition Inadequate dosing Poor compliance 8

9 Renal bone disease (Osteodystrophy) Heterogeneous disorder leading to diminished bone strength Is a function of bone turnover, density, mineralization and architecture Mostly occur beyond CKD stage 3 High turnover (PTH > 450ng/L*): caused by secondary hyperparathyroidism leads to increased bone resorption and formation. Haphazardly organized (osteitis fibrosa cystica) Low turnover (Adynamic bone disease) (PTH < 100ng/L): paucity of cells with decreased bone resorption and formation. Pathophysiology poorly understood Osteomalacia: defect in mineralization, deficiency of 1,25(OH)2D Osteoporosis: reduced bone density Clinical features 1. Secondary hyperparathyroidism: Usually asymptomatic Bone pain and arthralgia Muscle weakness Pruritis (cutaneous calcium phosphate deposition) Bone deformity Increased fracture risks (hip fracture x5 in Dialysis) Marrow fibrosis contribute to anaemia 2. Adynamic bone disorder: asymptomatic and may have twice increase in fracture risk than dynamic bone disease. 3. Increased cardiovascular risk Treatment Measures to reduce serum phosphate: o Dietary PO 4 restriction (meat, egg, milk, cereals) o Dialysis o Oral phosphate binders (prevent absorption) such as Ca +2 and non-ca +2 containing phosphate binder Measures to increase serum calcium and suppress PTH: o Ca +2 salts (also act as PO 4 binder) o Vit D analogues (calciterol, alfacalcidol) Measures to suppress PTH directly: o Calcimimetic agents (cinacalcet) o Parathyroidectomy (tertiary PTH = PTH, Ca 2, PO 4 and ALP) Malnutrition Causes: Anorexic uraemic toxins ( leptin) Chronic low grade inflammation and oxidative stress. Dietary restriction (low protein diet) Medications (iron, PO4 binders) Acidosis Dialysis itself (protein loss during dialysis) Biochemical indicators: s. albumin, transferrin and cholesterol 9