CHRONIC KIDNEY DISEASE

Chinwuba Ijoma FMCP

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Definition of chronic kidney disease1

1 Kidney damage for 3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifest by either: Pathological abnormalities or Markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests. 2 GFR <60 ml/min/1.73m2 for 3 months, with or without kidney damage
1 National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney diseases: evaluation, classification, and stratification. Am J Kid Dis, 2002; 39(Suppl 1):S1-S266
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Classification of chronic kidney disease

stage description At increased risk 1 Kidney damage with normal or GFR Kidney damage with mild GFR Moderate Severe GFR GFR (ml/min/1.73m2) 90 (with CKD risk factors) 90 *Action Screening. CKD risk reduction Diagnosis and treatment of co morbid conditions, slowing progression, CVD risk reduction Estimating progression Evaluating and treating complications Prepare for kidney replacement therapy Replacement (if ureamic)

2 3 4 5

60-89 30-59 15-29 <15 (or dialysis)

GFR

Kidney failure

* includes actions from preceding stages GFR, glomerular filtration rate; CKD, chronic kidney disease; CVD, cardiovascular disease Chronic kidney disease defined as either kidney damage or GFR < 60 ml/min/1.73m2 for 3 months. Kidney damage defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies 05/08/2011 Lecture, Med Students 3

Global picture of

1 CKD

1.5 million patients on dialysis in yr 2000 Projection for 2010 is 2.5 million 7% increase each year
1 Lysaght MJ: Maintenance dialysis population dynamics: current trends and long term implications. J Am Soc Nephrol. 13: S37-40, 2002
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Epidemiology
Worldwide increase in incidence of CKD since the 1980s In the UK incidence of ESRD 45-85 new patients per million population (pmp) In the USA 268 pmp in 1996 Prevalence of pts on RRT in Europe 462 pmp in 1996 In USA prevalence of pts on RRT 1041 pmp in 1996 In general incidence of ESRD increases with age, reaching around 1000 pmp per yr in pts >65 yr
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Common causes of end stage renal disease

Percentage of patients starting renal replacement therapy Causes Glomerulonephritis Diabetes Cystic disease Hypertension Pyelonephritis Analgesic nephropathy Unknown or Missing Miscellaneous - Data not given
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England and wales 1995 12.4 13.8 5.9 7.8 9.1 17 15.7 18.1

USA 1991-1995 11.0 37.4 3.5 28.7 4.5 4.4 4.4 6.2

Australia 1996 34 18 7 12 4 7 7 11

Japan 1994 39.8 31.2 2.6 6.2

Less common causes of end stage renal disease

group metabolic Causes Cystinosis Oxalosis Nephrocalcinosis Cystinuria Hyperuricaemia Ischaemic renal disease Scleroderma Haemolytic uraemic syndrome Post partum renal failure Amyloid Myeloma Cryoglobulinaemia Light chain deposition disease
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vascular

dysproteinaemias

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Less common causes of end stage renal disease (2)

Group hereditary Causes Alport syndrome Fabrys disease Tuberous sclerosis Sickle cell disease Wegeners granulomatosis Microscopic polyangiitis Polyarteritis nodosa Lupus Renal cell carcinoma Lymphoma Cystic kidney disease other than adult onset Congenital and acquired abnormalities of the urinary btract

vasculitis

malignancy

structural

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Causes of chronic kidney disease in Nigeria

Causes. % of cases Number of cases studied CGN HTN DM Obst uropathy Unknown
CGN, chronic glomerulonephritis; HTN, hypertension; DM, diabetic nephropathy; obst uropathy, obstructive uropathy 1 Ulasi II, Ijoma CK. Prevalence of end stage renal disease secondary to diabetic nephropathy, J coll Med. 2 Ojogeu LI. The pathological basis of end stage renal disease in Nigerians 3 Akinsola W, Adesanmi WO, et al. Diseases causing chronic renal failure in Nigeria: A prospectiv study of 100 cases
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Enugu 19981 358 22 15 13.2

Benin 19902 1980 18 43 33

Ile-Ife 19983 100

Ibadan

Lagos

Mechanisms of progression of chronic kidney disease Evidence from experimental models Subtotal nephrectomy in rat leads to progressive renal insufficiency associated with hypertension, proteinuria, and progressive scarring. Representative of late changes of CKD Exp CGN (anti GBM antibodies) in rats produce acute proliferative GN followed by chronic membranoproliferative and sclerotic glom changes Models of nephrotic syndrome and glomerulosclerosis are induced in rat by inj of aminonucleoside (puromycin and adriamycin) Exp diabetic nephropathy induced in rats by inj of streptozotocin

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Glomerulosclerosis
Progression of CKD is associated with progressive sclerosis of glomeruli regardless of underlying nephropathy Numerous hypothesis to explain progressive sclerosis and fibrosis of glomeruli Similarity between pathogenesis of glomerulosclerosis and large vessel atherosclerosis Resolution of glomerular injury depends on apoptosis of infiltrating inflammatory cells or their efflux from glomeruli Apoptosis of glomerular cells may lead to their depletion
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Pathogenesis of glomerulosclerosis
Hypothesis Glomerular hyperfiltration/hyperperfusion Glomerular hypertension Nephrotoxicity of lipids Similarities with atherosclerosis Glomerular hypertrophy Nephotoxicity of proteinuria Growth factors platelet derived growth factor transforming growth factor Mesangial/myofibroblast differentiation Podocyte injury
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Authors(s) Hostetter and Brenner 1981 Anderson and Brenner 1985 Moorhead at al. 1982 El Nahas 1988 Diamond and Karnovsky 1988 Fogo and Ichikawa 1991 Remuzzi and Bertani 1990

Johnson et al 1994 Border et al 1993 Johnson et al 1994 Kriz 1996

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Pathogenesis of tubulointerstitial fibrosis

Hypothesis Adaptive tubular hypermetabolism Adaptive tubular ammoniagenesis Nephrotoxicity of lipids Nephrotoxicity of proteinuria Author(s) Harris and Schrier 1988 Nath and Hostetter 1985 Moorhead et al 1982 Remuzzi and Bertani 1990

Nephrotoxicity of calcium and phosphate Alfrey 1988 Nephrotoxicity of iron Nephrotoxicity of oxygen free radicals Tubular cells and fibrosis Tubular transdifferentiation Harris and Alfrey 1994 Nath et al 1994 Kuncio and Neilson 1991 Okada, Strutz, and Neilson 1994
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Glomerulosclerosis
Evolves in stages Initial stage of glomerular endothelial injury and inflammation Stage of mesangial proliferation Stage of glomerular sclerosis
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Inflammation

Proliferation

fibrosis

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Glomerular endothelial injury and inflammation Damage to endothelial cells induced by Immune insults Nonimmune insults 1. Haemodynamic (hypertension) 2. metabolic

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Damaged endothelium: Loses its anticoagulant, antiinflammatory, and antiproliferative properties Acquires new procoagulant, proinflammatory, and mitogenic characteristics

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New characteristics mediated through: Release of procoagulant factors 1. Platelet activating factor (PAF) 2. Thromboxane 3. others

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 1. 2. 3. 4. 5. 6.

Release of proinflammatory and mitogenic cytokines and growth factors: Platelet derived growth factor (PDGF) Interleukins Tumour necrosis factor alpha Chemokines Monocyte chemoatractant protein 1 (MCP-1) Macrophage inflammatory protein-2 (MIP2)
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 Damaged endothelium also express cell adhesion molecules Changes lead to attraction of platelets, and inflammatory cells (neutrophils, and monocytes) to the glomerular capillaries Infiltrating monocytes interact with mesangial cells and stimulate their proliferation (through cell-cell interaction or through release of mitogens eg PDGF)
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 Proliferating and activated mesangial cells have capacity to revert to a messenchymal phenotype expressing markers such as smooth muscle actin ( -SMA) and synthesis of a range of extracellular matrix (ECM) components

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Resolution of glomerular injury depends on: 1. Apoptosis (programmed cell death) of infiltrating inflammatory cells 2. Efflux of infiltrating inflammatory cells from glomerular capillaries

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Epithelial cells involved in glomerulosclerosis 1. Unable to replicate in response to injury 2. Leeds to stretching along the GBM exposing areas of denuded GBM 3. Exposed GBM attract and interact with parietal epithelial cells leading to formation of adhesion 4. Stretched epithelial cells favour proteinuria and increased traffic of inflammatory, mitogenic, and fibrogenic mediators 5. Infiltrating cells stimulate glom cells (through fibrogenic factors (TGF ) to produce ECM
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Clinical features of CKD

Stages 1 and 2: asymptomatic Stages 3 and 4: anaemia weakness anorexia metabolic bone disease electrolyte, water and acid-base abnormality
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Clinical features of CKD (2)

Stage 5: azotaemia, uraemia Fluid, electrolyte, acid-base disorder Bone disease and disorders of calcium and phosphate metabolism Cardiovascular abnormalities Haematological abnormalities Neuromuscular abnormalities Gastrointestinal and nutritional abnormalities Endocrine-metabolic disorders
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Diagnosis of CKD
1. 2. 3. Symptoms Signs Laboratory investigation: FBC SEUC, Calcium, phosphate Urinalysis Blood glucose Imaging Kidney biopsy GFR
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Treatment of CKD (1)

Stage 1 CKD. Diagnosis and treatment of co morbid conditions. Slowing progression CVD risk reduction
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Measures to prevent the progression of chronic kidney disease

Lifestyle modification Blood pressure control Glycaemic control Reduction of proteinuria Protein restriction Lipid lowering Avoidance of nephrotoxic agents Early referral to nephrologist Other measures (eg., correction of anaemia)
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Lifestyle modification Recommended to all patients with CKD

weight reduction if overweight healthy eating habits dietary salt restriction cessation of smoking moderation of alcohol consumption

increase physical activity

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Blood pressure control Blood pressure goal: <130/80 mm Hg ACEI and ARB preferred antihypertensive agents especially in patients with proteinuria Adjunctive dietary salt restriction Diuretics and multiple medications in addition to ACEI/ARB may be needed to achieve BP target
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Glycaemic control
Glycaemic control in diabetic patients with CKD optimized fasting plasma glucose <7.2 mmol/L HbA1c < 7% Optimal BP <130/80 mm Hg Hypertensive diabetics and those with microalbuminuria or macroalbuminuria, whether hypertensive or not should be treated with ACEI or ARB
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Reduction of proteinuria Patients with CKD and proteinuria (with and without hypertension) 1. Treated with ACEI or ARB to reduce proteinuria 2. ? combined ACEI and ARB

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Dietary restriction Manipulation of diet prevents complications of kidney failure:

metabolic acidosis, abnomalities of calcium and phosphate metabolism, uraemic symptoms, degree of proteinuria

Daily allowance of 0.8g protein/kg/day

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Lipid lowering
Unclear if lipid lowering per se can slow progression of CKD BUT Patients with CKD at increased risk for cardiovascular disease LDL cholesterol lowered to <2.6 mmol/L (100 mg/dL)
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Avoidance of nephrotoxic agents

Nonsteroidal anti-inflamatory drugs Aminoglycosides Radiocontrast media Certain herbs

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Early referral to nephrologists

Patients should be referred for evaluation when creatinine clearance <30 ml/min/1.73m2 or earlier in patients at risk of rapid progression Identify reversible causes of renal function deterioration Implement renal protective measures

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Other measures
Correction of anaemia with EPO Optimization of serum calcium x phosphate product (below 4.5 mmol2/L2 or 55 mg2 /dL2 ) Optimize parathyroid hormone levels (2 to 3 times upper limit of normal) Maintenance of fluid balance
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CVD risk reduction

Screen for risk factors for CVD
Smoking history, BP measurement, body wt, BMI, fasting plasma glucose, fasting lipid profile, serum uric acid, 12-lead ECG In adults with GFR <60 ml/min/1.73m2 look for evidence of complications of CKD: Hb, s albumin, calcium, phosphate Determine rate of GFR decline
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Treatment of CKD (2)

Stage 2 CKD Estimating progression Determine underlying diagnosis Presence of comorbid conditions Severity of renal impairment (GFR) Risk for loss of kidney function Presence of complications related to level of kidney function Renal imaging (ultrasound) Serum electrolytes
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Treatment of CKD (3)

Stage 3 CKD Evaluating and treating complications

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Treatment of CKD (4)

Stage 4 CKD Prepare for kidney replacement therapy Patient education and adjustment and counselling Decide on mode of RRT Establish permanent vascular access Peritoneal dialysis catheter placement Evaluate patient and prospective kidney donor
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Treatment of CKD (5)

Stage 5 CKD Replacement (if ureamic) Dialysis 1. Haemodialysis 2. Peritoneal dialysis Kidney transplantation
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Global cost implication of treating ESRD1

Dialysis cost: Decade 1991-2001=US$500 billion Decade 2001-2010=US$1.1 trillion
1 Lysaght MJ: Maintenance dialysis population dynamics: current trends and long term implications. J Am Soc Nephrol. 13: S37-40, 2002

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