Chronic Kidney Disease - Dr Ijoma

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05/08/2011 Lecture, Med Students 1

CHRONIC KIDNEY DISEASE

Chinwuba Ijoma FMCP




Definition of chronic kidney disease1

1 Kidney damage for � 3 months, as defined bystructural 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 kidneydiseases: evaluation, classification, and stratification. Am J Kid Dis, 2002; 39(Suppl1):S1-S266




Classification of chronic kidney diseaseClassification of chronic kidney disease

�� * includes actions from preceding stages* includes actions from preceding stages

�� GFR, glomerular filtration rate; CKD, chronic kidney disease; CVD, cardiovascular diseaseGFR, 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 � 3Chronic kidney disease defined as either kidney damage or GFR < 60 ml/min/1.73m2 for � 3months. Kidney damage defined as pathologic abnormalities or markers of damage,months. Kidney damage defined as pathologic abnormalities or markers of damage,including abnormalities in blood or urine tests or imaging studiesincluding abnormalities in blood or urine tests or imaging studies

stage description GFR (ml/min/1.73m2) *Action

At increased risk �90 (with CKD riskfactors)

Screening. CKD risk reduction

1 Kidney damage withnormal or GFR

�90 Diagnosis and treatment of comorbid conditions, slowingprogression, CVD risk reduction

2 Kidney damage withmild GFR

60-89 Estimating progression

3 Moderate GFR 30-59 Evaluating and treatingcomplications

4 Severe GFR 15-29 Prepare for kidney replacementtherapy

5 Kidney failure <15 (or dialysis) Replacement (if ureamic)




Global picture of CKD1

� 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 andlong term implications. J Am Soc Nephrol. 13: S37-40, 2002




Epidemiology� Worldwide increase in incidence of CKD sincethe 1980s

� In the UK incidence of ESRD 45-85 new patientsper 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




Common causes of end stage renal disease

Causes

Percentage of patients starting renal replacement therapy

England and

wales 1995

USA

1991-1995

Australia

1996

Japan 1994

Glomerulonephritis 12.4 11.0 34 39.8

Diabetes 13.8 37.4 18 31.2

Cystic disease 5.9 3.5 7 2.6

Hypertension 7.8 28.7 12 6.2

Pyelonephritis 9.1 4.5 4

Analgesic

nephropathy

- - 7

Unknown or 17 4.4 7

Missing 15.7 4.4

Miscellaneous 18.1 6.2 11

- Data not given




Less common causes of end stage renal disease

group Causes

metabolic Cystinosis

Oxalosis

Nephrocalcinosis

CystinuriaHyperuricaemia

vascular Ischaemic renal disease

Scleroderma

Haemolytic uraemic syndrome

Post partum renal failuredysproteinaemias Amyloid

Myeloma

Cryoglobulinaemia

Light chain deposition disease




Less common causes of end stage renal disease (2)

Group Causes

hereditary Alport syndrome

Fabry¶s disease

Tuberous sclerosis

Sickle cell disease

vasculitis Wegener¶s granulomatosis

Microscopic polyangiitis

Polyarteritis nodosa

Lupus

malignancy Renal cell carcinoma

Lymphoma

structural Cystic kidney disease other than adult onset

Congenital and acquired abnormalities of the urinary btract




Causes of chronic kidney disease in Nigeria

� CGN, chronic glomerulonephritis; HTN, hypertension; DM, diabetic nephropathy; obst

uropathy, obstructive uropathy1 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: Aprospectiv study of 100 cases

Causes. % of

cases

Enugu

19981

Benin

19902

Ile-Ife

19983

Ibadan Lagos

Number of cases

studied

358 1980 100

CGN 22 18

HTN 15 43DM 13.2

Obst uropathy 33

Unknown




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 latechanges of CKD

� Exp CGN (anti GBM antibodies) in rats produce acuteproliferative GN followed by chronicmembranoproliferative and sclerotic glom changes

� Models of nephrotic syndrome and glomerulosclerosisare induced in rat by inj of aminonucleoside (puromycin

and adriamycin)� Exp diabetic nephropathy induced in rats by inj of streptozotocin




Glomerulosclerosis

� Progression of CKD is associated with progressivesclerosis of glomeruli regardless of underlyingnephropathy

� Numerous hypothesis to explain progressive sclerosisand fibrosis of glomeruli

� Similarity between pathogenesis of glomerulosclerosisand 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




Pathogenesis of glomerulosclerosis

Hypothesis Authors(s)

Glomerular hyperfiltration/hyperperfusion Hostetter and Brenner 1981

Glomerular hypertension Anderson and Brenner 1985

Nephrotoxicity of lipids Moorhead at al. 1982

Similarities with atherosclerosis El Nahas 1988Diamond and Karnovsky 1988

Glomerular hypertrophy Fogo and Ichikawa 1991

Nephotoxicity of proteinuria Remuzzi and Bertani 1990

Growth factors

platelet derived growth factor

transforming growth factor

Johnson et al 1994

Border et al 1993

Mesangial/myofibroblast differentiation Johnson et al 1994

Podocyte injury Kriz 1996




Pathogenesis of tubulointerstitial fibrosis

Hypothesis Author(s)

Adaptive tubular hypermetabolism Harris and Schrier 1988

Adaptive tubular ammoniagenesis Nath and Hostetter 1985

Nephrotoxicity of lipids Moorhead et al 1982

Nephrotoxicity of proteinuria Remuzzi and Bertani 1990

Nephrotoxicity of calcium and phosphate Alfrey 1988

Nephrotoxicity of iron Harris and Alfrey 1994

Nephrotoxicity of oxygen free radicals Nath et al 1994

Tubular cells and fibrosis Kuncio and Neilson 1991

Tubular transdifferentiation Okada, Strutz, and Neilson1994




Glomerulosclerosis

Evolves in stages

� Initial stage of glomerular endothelial

injury andinflammation

� Stage of mesangialproliferation

� Stage of glomerular sclerosis

Inflammation

Proliferation

fibrosis




Glomerular endothelial injury and

inflammation

Damage to endothelial cells induced by

� Immune insults

� Nonimmune insults1. Haemodynamic (hypertension)

2. metabolic




Damaged endothelium:

� Loses its anticoagulant, antiinflammatory,

and antiproliferative properties� Acquires new procoagulant,

proinflammatory, and mitogeniccharacteristics




New characteristics mediated through:

� Release of procoagulant factors

1. Platelet activating factor (PAF)2. Thromboxane

3. others




� Release of proinflammatory and mitogeniccytokines and growth factors:

1. Platelet derived growth factor (PDGF)

2. Interleukins

3. Tumour necrosis factor alpha

4. Chemokines

5. Monocyte chemoatractant protein 1 (MCP-1)6. Macrophage inflammatory protein-2 (MIP2)




� Damaged endothelium also express celladhesion molecules

� Changes lead to attraction of platelets,and inflammatory cells (neutrophils, andmonocytes) 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)




� Proliferating and activated mesangial cellshave capacity to revert to a messenchymalphenotype expressing markers such as -smooth muscle actin (-SMA) andsynthesis of a range of extracellular matrix(ECM) components




Resolution of glomerular injury depends on:

1. Apoptosis (programmed cell death) of

infiltrating inflammatory cells2. Efflux of infiltrating inflammatory cells

from glomerular capillaries




Epithelial cells involved in glomerulosclerosis1. Unable to replicate in response to injury2. Leeds to stretching along the GBM exposing

areas of denuded GBM3. Exposed GBM attract and interact with parietalepithelial cells leading to formation of adhesion

4. Stretched epithelial cells favour proteinuria andincreased traffic of inflammatory, mitogenic,

and fibrogenic mediators5. Infiltrating cells stimulate glom cells (through

fibrogenic factors (TGF) to produce ECM




Clinical features of CKD

� Stages 1 and 2: asymptomatic

� Stages 3 and 4:

anaemiaweakness

anorexia

metabolic bone disease

electrolyte, water and acid-baseabnormality




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




Diagnosis of CKD

1. Symptoms2. Signs3. Laboratory investigation:

� FBC� SEUC, Calcium, phosphate� Urinalysis� Blood glucose

� Imaging� Kidney biopsy� GFR




Treatment of CKD (1)

Stage 1 CKD.

� Diagnosis and treatment of co morbid

conditions.

� Slowing progression

� CVD risk reduction




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)




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




Blood pressure control

� Blood pressure goal: <130/80 mm Hg

� ACEI and ARB preferred antihypertensiveagents especially in patients withproteinuria

� Adjunctive dietary salt restriction

� Diuretics and multiple medications in

addition to ACEI/ARB may be needed toachieve BP target




Glycaemic control

� Glycaemic control in diabetic patients with CKDoptimizedfasting plasma glucose <7.2 mmol/L

HbA1c < 7%

� Optimal BP <130/80 mm Hg

�Hypertensive diabetics and those withmicroalbuminuria or macroalbuminuria, whether hypertensive or not should be treated with ACEIor ARB




Reduction of proteinuria

Patients with CKD and proteinuria (with andwithout hypertension)

1. Treated with ACEI or ARB to reduceproteinuria

2. ? combined ACEI and ARB




Dietary restriction

� Manipulation of diet preventscomplications of kidney failure:

metabolic acidosis, abnomalities of calciumand phosphate metabolism, uraemic

symptoms, degree of proteinuria

� Daily allowance of 0.8g protein/kg/day




Lipid lowering

� Unclear if lipid lowering per se can slowprogression of CKD

BUT� Patients with CKD at increased risk for

cardiovascular disease

� LDL cholesterol lowered to <2.6 mmol/L(100 mg/dL)




Avoidance of nephrotoxic agents

� Nonsteroidal anti-inflamatory drugs

� Aminoglycosides

� Radiocontrast media� Certain herbs




Early referral to nephrologists

� Patients should be referred for evaluationwhen creatinine clearance <30ml/min/1.73m2 or earlier in patients at riskof rapid progression

� Identify reversible causes of renal functiondeterioration

� Implement renal protective measures




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 to3 times upper limit of normal)

� Maintenance of fluid balance




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





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





Stage 3 CKD

� Evaluating and treating complications





Stage 4 CKD

Prepare for kidney replacement therapy

� Patient education and adjustment andcounselling

� Decide on mode of RRT

� Establish permanent vascular access

� Peritoneal dialysis catheter placement� Evaluate patient and prospective kidney donor





Stage 5 CKD

Replacement (if ureamic)

� Dialysis1. Haemodialysis

2. Peritoneal dialysis

� Kidney transplantation




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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Chronic Kidney Disease - Dr Ijoma