10 Chronic Renal DiseaseDefinition: Chronic renal disease (CRD) is a pathophysiologic process with multiple etiologies, resulting in the inexorable attrition of nephron number and function, and frequently leading to end-stage renal disease (ESRD).Irreversible deterioration in renal function (C.R.W.Edwards et al, 1998, pg.631)Ref: Harrison 15th Ed.
11 Azotemia There is azotemia in chronic renal failure. Azotemia is the biochemical state in which there is an elevation of:Blood urea nitrogen (BUN) andCreatinine levels when there is a decreased glomerular filtration rate (GFR).Persistent azotemia gives rise to signs, symptoms and biochemical abnormalities, which is referred to as uremia.
12 Types of azotemia Type Feature Pre-renal azotemia Due to hypoperfusion of kidneys.For e.g. in congestive heart failure, shock, hemorrhage, and dehydration.Post-renal azotemiaDue to any obstruction to the urinary flow below the level of kidneys.[Note azotemia is not specific for chronic renal failure.]
13 UremiaDefinition:Uremia is the clinical and laboratory syndrome, reflecting dysfunction of all organ systems as a result of untreated or under-treated acute or chronic renal failure. (CD-ROM 15th Harrison)
14 PathogenesisDue to disturbances in water, electrolytes & acid-base balance.Accumulation of substances such as phosphate, parathyroid hormone, urea, creatinine, guanidine, phenols,& idoles.
18 End Stage Renal Disease (ESRD) In ESRD there is a degree of irreversible damage to the kidney and its function.The patient usually becomes dependent on renal replacement therapy (dialysis or transplantation) in order to avoid life-threatening uremia.
21 Clinical Features of Uraemia AnaemiaMetabolic bone diseases(renal osteodystrophy)NeuropathyMyopathyEndocrine abnormalitiesHypertension & atherosclerosisAcidosisSusceptibility to infection
22 Signs & Symptoms of Uraemia Vague-ill healthGeneralized weakness & lack of energyBreathlessness on exertionAnorexiaNausea & vomiting particularly in morningsDisordered intestinal motilityHeadachesVisual disturbancesPruritisPallorPigmentationsLoss of libido
23 Laboratory Investigation Aim - Diagnosis and disease monitoringFBC - anaemiaUEC – electrolyte imbalances, urea and nitrogen abnormalitiesRenal biopsyOthers – Ca, phosphate, EPO, etc.Genetic & immunological studies - transplant
24 Chronic Renal Diseases - Causes The causes of chronic renal failure can be due to any disease process affecting the following structures:Glomeruli (glomerulonephritis)Tubules (reflex nephropathy)Interstitium (pyelonephritis, reflux nephropathy)Blood vessels (Hypertension)
26 Immune mediated Glomerular Diseases Immune mechanism can be of antibody-associated injury. Two forms are known:Immune response resulting in injury due to deposition of soluble circulating antigen-antibody complexes in the glomeruli. Referred to as Circulating Immune complex injury.Immune response resulting injury due to antibodies reacting in situ within the glomerulus. Referred to as Cell Mediated Injury.Others may be due to cytotoxic antibodies directed against the glomerular cells.
27 Non-immune Mediated Glomerular Diseases 1. Metabolic glomerular injury.Diabetic nephropathy: the glomerular lesion is glomerulosclerosis whereby there is thickening of the glomeular basement membrane.2. Hemodynamic glomerular injury.This is due to the high intra-glomerular pressure caused by systemic hypertension or local change in glomerular hemodynamics (glomerular hypertension).3. Toxic glomerulopathies.The toxic verotoxic from the E.Coli is directly toxic to renal endothelium and induces hemolytic-uremic syndrome in patients with infective diarrhea caused by E.Coli.Verotoxic interacts with specific cell membrane receptor inducing thrombotic microangiopathy.
28 Non-immune Mediated Glomerular Diseases 4. Deposition disease.There is deposition of abnormal proteins in the glomeruli inducing inflammatory reaction or glomerulosclerosis. For e.g. amyloidosis, cryoglobulins, light and heavy chain deposition disease.5. Infectious glomerulopathies.Infectious microorganisms can cause injury by:Direct infection of renal cellElaboration of nephrotoxic e.g. E.ColiIntraglomerular deposition of immune complexes e.g. post-infectious glomerulonephritis.Providing chronic stimulus for amyloidosis.6. Inherited glomerular diseases.A common e.g. is:Alport’s disease: Transmitted, as X-linked dominant trait. There is mutation in COL4A5 gene that encodes -5 chain of type IV collagen located on X-chromosome. The glomerular basement membrane (GBM) is affected.
29 The determinants of the severity of glomerular damage are The nature of primary insult and secondary mediator system that evoke it.The site of injury within the glomerulus.The speed of onset, extend and intensity of disease.
38 Histological Types of GN Post-streptococcal GNRapidly Progressive GlomerulonephritisMembranous GNFocal glomerulosclerosisMembranoproliferative GN
39 Post-streptococcal GN Normal glomerulusAcute proliferate GNHypercellularity due to intercapillary leucocytes & proliferation of glomerular cellsRef: Robins Pathological Basis of Diseases, 6th Ed. Fig 21.16
41 Crescent GN Collapsed glomerular tufts Mass of crescent shaped proliferating cells & leucocytesRef: Robins Pathological Basis of Diseases, 6th Ed. Fig 21.17
42 Membranous GNDiffuse thickening of capillary wall without increase in number of cellsDiagrammatic representationRef: Robins Pathological basis of Diseases, 6th Ed. Fig
43 Minimal Change Disease (Lipoid Nephrosis) Visceral epithelial cells show uniform and diffuse effacement of foot processThin BN. No proliferation
44 Minimal Change Disease Normal glomerular tuft. No hypercellularity. Thin BM.Ref:
45 Focal Glomerular Sclerosis Sclerotic segment shows deposition of hyaline massesLipid in sclerotic area (small vacuoles)Foam cellsRef:www.med.niigata-u.ac.jp
46 Membranoproliferative GN Differentiation based on electron microscopyRef: Robins Pathological Basis of Diseases, 6th Ed. Fig 21.24
47 Membranoproliferative GN Thickened in BMProliferation of mesangial cells (glomerular cells)Leukocyte infiltrationRef: Robins Pathological Basis of Diseases, 6th Ed. Fig 21.23
48 IgA Nephropathy (Berger Disease) IgA deposited within mesangium increasing its cellularityImmunofluorescence demonstrating positivity with antibody to IgA.Ref:
49 Focal Proliferative & Necrotising GN (Focal GN) Main differential diagnosis for Focal glomerulosclerosis as histological features very similar.Main lesions are predominantly proliferative.Focal necrosis & fibrin deposition often occur within lesions.Occur as part of a systemic disease (e.g. SLE), component of known glomerular disease (e.g. IgA nephropathy) or primary (cause unknown).
50 Blood Vessel Injury - Hypertension Atherosclerosis:MultifactorialThe vascular injury is due to cholesterol- containing micro-emboli (atheroemboli) dislodged from atheromatous plaque in larger arteries. The micro-emboli occlude the small vessels in the kidney.Direct injury to blood vessel wall.It may result in renal artery stenosis and ischemic renal diseases.
51 Pathogenesis Of Disease Involving Blood Vessels Hypertension:The persistent exposure of renal circulation to intraluminal hypertension results in hyaline arteriosclerosis of the afferent arterioles and finally loss of function (nephrosclerosis). That is,Benign arteriolar nephrosclerosis: found in patients who are hypertensive for sometime with BP > 150/90 mmHg. Hypertension has not progressed to malignant form.Malignant arteriolar nephrosclerosis: found in patients who have long-standing benign hypertension and not known hypertensive. There is sudden elevation in BP (diastolic 130mmHg). There is accompanied papilledema, cardiac decompensation, CNS involvement, and progressive renal deterioration.
53 Others Reflux nephropathy – renal scaring and loss of glomeruli. Polycystic kidney diseases – multiple dilated cysts. Genetic.Kidney infections & obstructions – acute to chronic inflammation. Renal scaring and loss of glomeruli.Focal GN/Focal proliferative & nectrotising GN. Main differential diagnosis of Focal sclerosis GN.