1. Chronic renal failure Dr.H.N.Sarker FCPS(Medicine),MACP(USA), MRCP(UK),FRCP(GLASGO) Associate Professor. Medicine

2. Introduction Chronic renal failure (CRF) refers to an irreversible deterioration in renal function which classically develops over a period of years.

3. Introducttion Initially, it is manifested only as a biochemical abnormality. Eventually, loss of the excretory, metabolic and endocrine functions of the kidney leads to the development of the clinical symptoms and signs of renal failure, which are referred to as uraemia. Initially, it is manifested only as a biochemical abnormality. Eventually, loss of the excretory, metabolic and endocrine functions of the kidney leads to the development of the clinical symptoms and signs of renal failure, which are referred to as uraemia.

4. Introducttion When death is likely without renal replacement therapy, it is called end-stage renal failure (ESRF).

5. Introducttion The Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) defines chronic kidney disease as either kidney damage or a decreased kidney glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for 3 or more months.

6. Introducttion Whatever the underlying etiology, the destruction of renal mass with irreversible sclerosis and loss of nephrons leads to a progressive decline in GFR. The different stages of chronic kidney disease form a continuum in time; prior to February 2002, no uniform classification of the stages of chronic kidney disease existed. Whatever the underlying etiology, the destruction of renal mass with irreversible sclerosis and loss of nephrons leads to a progressive decline in GFR. The different stages of chronic kidney disease form a continuum in time; prior to February 2002, no uniform classification of the stages of chronic kidney disease existed.

7. Introducttion At that time, K/DOQI published a classification of the stages of chronic kidney disease, as follows: Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2) Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2)

8. Introducttion Stage 3: Moderate reduction in GFR (30- 59 mL/min/1.73 m2) Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2) Stage 5: Kidney failure (GFR <15 mL/min/1.73 m2 or dialysis)

9. Introducttion In stage 1 and stage 2 chronic kidney disease, GFR alone does not clinch the diagnosis. Other markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities in imaging tests, should also be present in establishing a diagnosis of stage 1 and stage 2 chronic kidney disease.

10. Pathophysiology Pathophysiology Approximately 1 million nephrons are present in each kidney, each contributing to the total GFR. Regardless of the etiology of renal injury, with progressive destruction of nephrons, the kidney has an innate ability to maintain GFR by hyperfiltration and compensatory hypertrophy of the remaining healthy nephrons.

11. Pathophysiology Pathophysiology This nephron adaptability allows for continued normal clearance of plasma solutes so that substances such as urea and creatinine start to show significant increases in plasma levels only after total GFR has decreased to 50%, when the renal reserve has been exhausted. The plasma creatinine value will approximately double with a 50% reduction in GFR.

12. Pathophysiology Pathophysiology A rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient, although still within the reference range, actually represents a loss of 50% of functioning nephron mass. A rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient, although still within the reference range, actually represents a loss of 50% of functioning nephron mass.

13. Types and causes Chronic renal failure (CRF) can be classified by the site (location) of primary damage: Chronic renal failure (CRF) can be classified by the site (location) of primary damage: Pre-renal CRF Renal CRF Post-renal CRF (obstructive uropathy)

14. Pre-Renal CRF Some medical conditions cause continuous hypoperfusion (low blood flow) of the kidneys, leading to kidney atrophy (shrinking), loss of nephron function, and chronic renal failure (CRF).

15. Pre-Renal CRF These conditions include poor cardiac function, poor cardiac function, chronic liver failure, chronic liver failure,and atherosclerosis ("hardening") of the renal arteries. Each of these conditions can induce ischemic nephropathy

16. Renal CRF Renal CRF Chronic renal failure caused by changes within the kidneys, is called renal CRF, and is broadly categorized as follows: Diabetic nephropathy- kidney disease associated with diabetes; the most common cause of CRF

17. Renal CRF Renal CRF Hypertensive nephrosclerosis- the second leading cause of CRF Chronic glomerulonephritis, a condition caused by diseases that affect the glomeruli and bring about progressive dysfunction – Membranous nephropathy, immunoglobulin A (IgA) nephropathy, immunoglobulin A (IgA) nephropathy,

18. Renal CRF focal and segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis, membranoproliferative glomerulonephritis, rapidly progressive (crescentic) glomerulonephritis

19. Renal CRF Chronic interstitial nephritis- a condition caused by disorders that ultimately lead to progressive scarring of the interstitium Renal vascular CRF- large vessel abnormalities such as renal artery stenosis (narrowing of the large arteries that supply the kidneys)

20. Renal CRF Vasculitis, inflammation of the small blood vessels- –systemic lupus erythematosus – scleroderma – Goodpasture syndrome –Wegener granulomatosis –mixed cryoglobulinemia – Henoch-Schönlein purpura,

21. Renal CRF Cystic kidney disease, kidney disease distinguished by multiple cysts (Polycystic kidney disease ) Hereditary diseases of the kidney, such as Alport's syndrome

22. Post-Renal CRF Interference with the normal flow of urine can produce backpressure within the kidneys, can damage nephrons, and lead to obstructive uropathy, a disease of the urinary tract. Abnormalities that may hamper urine flow and cause post-renal CRF include the following: Abnormalities that may hamper urine flow and cause post-renal CRF include the following:

23. Post-Renal CRF Bladder outlet obstruction due to an enlarged prostate gland or bladder stone Neurogenic bladder, an overdistended bladder caused by impaired communicator nerve fibers from the bladder to the spinal cord

24. Post-Renal CRF Kidney stones in both ureters. Retroperitoneal fibrosis. Vesicoureteral reflux (VUR), the backward flow of urine from the bladder into a ureter Vesicoureteral reflux (VUR), the backward flow of urine from the bladder into a ureter

25. Pathogenesis Disturbances in water, electrolyte and acid- base balance contribute to the clinical picture in patients with CRF, but the exact pathogenesis of the clinical syndrome of uraemia is unknown.

26. Pathogenesis Many substances present in abnormal concentration in the plasma have been suspected as being 'uraemic toxins', and uraemia is probably caused by the accumulation of various intermediary products of metabolism.

27. Clinical Feature Clinical Feature Patients with chronic kidney disease stages 1-3 (GFR >30 mL/min) are generally asymptomatic and do not experience clinically evident disturbances in water or electrolyte balance or endocrine/metabolic derangements. Patients with chronic kidney disease stages 1-3 (GFR >30 mL/min) are generally asymptomatic and do not experience clinically evident disturbances in water or electrolyte balance or endocrine/metabolic derangements.

28. Clinical Feature Generally, these disturbances clinically manifest with chronic kidney disease stages 4-5 (GFR <30 mL/min). Uremic manifestations in patients with chronic kidney disease stage 5 are believed to be primarily secondary to an accumulation of uraemic toxins. Generally, these disturbances clinically manifest with chronic kidney disease stages 4-5 (GFR <30 mL/min). Uremic manifestations in patients with chronic kidney disease stage 5 are believed to be primarily secondary to an accumulation of uraemic toxins.

29. Clinical Feature Patient usually presents with features of hyperkalemia, metabolic acidosis and uremia.

30. Clinical Feature Uraemic symptoms can affect every organ system, most noticeably the following: Gastrointestinal system– anorexia,nausea, vomiting, food distaste (often described as bland, metallic, "like cardboard"), hiccup.

31. Clinical Feature Neurological system–cognitive impairment, personality change, asterixis (motor disturbance that affects groups of muscles), muscular twitching, fits, drowsiness and coma.

32. Clinical Feature Blood-forming system–anemia due to relative deficiency of erythropoietin relative deficiency of erythropoietin diminished erythropoiesis due to toxic effects of uraemia on marrow precursor cells reduced red cell survival increased blood loss due to capillary fragility and poor platelet function reduced dietary intake and absorption of iron and other haematinics –easy bruising and bleeding due to abnormal platelets

33. Clinical Feature Pulmonary system–fluid in the lungs, with breathing difficulties Cardiovascular system –chest pain due to inflammation of the sac surrounding the heart (pericarditis) and pericardial effusion (fluid accumulation around the heart) Skin –generalized itching, pruritus. Myopathy.

34. Clinical Feature Renal osteodystrophy -This metabolic bone disease which accompanies CRF consists of a mixture of osteomalacia, hyperparathyroid bone disease (osteitis fibrosa), osteoporosis and osteosclerosis.

35. Clinical Feature Osteomalacia results from diminished activity of the renal 1α-hydroxylase enzyme, with failure to convert cholecalciferol to its active metabolite, 1,25-dihydroxycholecalciferol. A deficiency of the latter leads to diminished intestinal absorption of calcium, hypocalcaemia and reduction in the calcification of osteoid in bone.

36. Clinical Feature The physical examination often is not very helpful but may reveal findings characteristic of the condition underlying chronic kidney disease (eg, hypertension,diabetis, severe arteriosclerosis, lupus)or complications of chronic kidney disease (eg, anemia, bleeding diathesis, pericarditis).

37. Investigations Investigations Haematology Haematology Full blood count Urinanalysis- Dipstick proteinuria may suggest a glomerular or tubulointerstitial problem. The urine sediment finding of RBCs, RBC casts, suggests proliferative glomerulonephritis.

38. Investigations Urinanalysis- Pyuria and/or WBC casts are suggestive of interstitial nephritis (particularly if eosinophiluria is present) or urinary tract infection. Twenty-four–hour urine collection for total protein and CrCl Twenty-four–hour urine collection for total protein and CrCl

39. Investigations Biochemistry Biochemistry Urea, electrolytes and creatinine Calcium, phosphate and albumin Parathyroid hormone Lipids, glucose ± HbA1c

40. Investigations Imaging- Renal ultrasound- Small echogenic kidneys are observed in advanced renal failure. Structural abnormalities, such as polycystic kidneys, also may be observed. This is a useful test to screen for hydronephrosis.

41. Investigations Chest X-ray: heart size, pulmonary oedema ECG: if > 40 years or there are risk factors for cardiac disease Renal artery imaging: if renovascular disease is suspected

42. Investigations Histology- Renal biopsy. Microbiology-Hepatitis and HIV serology: if dialysis is needed (vaccination against hepatitis B if no previous infection; isolation of dialysis machine if positive)

43. Investigations Immunology -Group and save Tissue typing Cytomegalovirus,Epstein-Barr virus, varicella zoster virus

44. Investigations if transplantation is considered If diagnosis is not known- Immunoglobulins and protein electrophoresis Immunoglobulins and protein electrophoresis Urinary Bence Jones protein Urinary Bence Jones protein Complement Complement

45. Investigations ANA: and dsDNA if ANA is positive ANA: and dsDNA if ANA is positive ENA: if a connective tissue disorder is suspected ENA: if a connective tissue disorder is suspected Rheumatoid factor ANCA: in all possible inflammatory renal disease Rheumatoid factor ANCA: in all possible inflammatory renal disease Anti-GBM: in all possible inflammatory renal disease Anti-GBM: in all possible inflammatory renal disease

46. Management Once CRF has been diagnosed, the physician attempts to determine the cause and, if possible, plan a specific treatment. Once CRF has been diagnosed, the physician attempts to determine the cause and, if possible, plan a specific treatment. Nonspecific treatments are implemented to delay or possibly arrest the progressive loss of kidney function. Nonspecific treatments are implemented to delay or possibly arrest the progressive loss of kidney function.

47. Management There are several aspects to the management of CRF: Identify the underlying renal disease. Look for reversible factors which are making renal function worse Attempt to prevent further renal damage. Attempt to limit the adverse effects of the loss of renal function. Institute renal replacement therapy (dialysis, transplantation) when appropriate.

48. Management Treatment of the underlying cause- some causes of CRF are amenable to treatment eg. Glomerulonephritis with immunosuppressive therapy.

49. Management Retarding the progression of CRF- Control of blood pressure -control of blood pressure may retard deterioration of GFR. Various target blood pressures have been suggested: for example, 130/85 mmHg for CRF alone, lowered to 125/75 mmHg for those with proteinuria > 1 g/day.

50. Management ACE inhibitors have been shown to be more effective at retarding the progression of renal failure than other therapies which lower systemic blood pressure to a similar degree. This may be because they reduce glomerular perfusion pressure by dilating the efferent arteriole. Angiotensin II receptor antagonists also reduce glomerular perfusion pressure and can be used.

51. Management Diet -Restrict dietary protein,Moderate restriction for a CRF patient is about 0.6 to 0.8 gm/kg/day(to 60 g protein per day) and this should be accompanied by an adequate intake of calories to prevent malnutrition.

52. Management Limiting the adverse effects of CRF – Anaemia -Anaemia is common; it usually correlates with the severity of renal failure and contributes to many of the non- specific symptoms of CRF. Recombinant human erythropoietin is effective in correcting the anaemia of CRF. The target haemoglobin is usually between 100 and 120 g

53. Management Fluid and electrolyte balance - Due to the reduced ability of the failing kidney to concentrate the urine, a relatively high urine volume is needed to excrete products of metabolism and a fluid intake of around 3 litres/day is desirable.

54. Management Some patients with so-called 'salt-wasting' disease may require a high sodium and water intake, including supplements of sodium salts, to prevent fluid depletion and worsening of renal function. This is most often seen in patients with renal cystic disease, obstructive uropathy, reflux nephropathy or other tubulo-interstitial diseases, and is not seen in patients with glomerular disease. These patients benefit from taking 5-10 g/day (85-170 mmol/day) of sodium chloride by mouth.

55. Management Acidosis- The plasma bicarbonate should be maintained above 22 mmol/l by giving sodium bicarbonate supplements (starting dose of 1 g 8-hourly, increasing as required). The increased sodium intake may induce hypertension or oedema; calcium carbonate (up to 3 g daily) is an alternative that is also used to bind dietary phosphate.

56. Management Infection - they must be recognised and treated promptly. Renal osteodystrophy- plasma calcium and phosphate should be kept as near to normal as possible. Hypocalcaemia is corrected by giving 1α- hydroxylated synthetic analogues of vitamin D. The dose is adjusted to avoid hypercalcaemia.

57. Management Hyperphosphataemia is controlled by dietary restriction of foods with high phosphate content (milk, cheese, eggs) and the use of phosphate- binding drugs administered with food (e.g. calcium carbonate and aluminium hydroxide). Secondary hyperparathyroidism is usually prevented or controlled by these measures but, in severe bone disease with autonomous parathyroid function, parathyroidectomy may become necessary.

58. Management Renal replacement therapy (RRT) Early preparation is important. The health care team educates the patient about the different procedures involved in RRT, which include the following: Hemodialysis—removal of toxic elements from the blood, which is filtered through a membrane while circulated outside of the body Early preparation is important. The health care team educates the patient about the different procedures involved in RRT, which include the following: Hemodialysis—removal of toxic elements from the blood, which is filtered through a membrane while circulated outside of the body

59. Management Peritoneal dialysis—filtration through the lining membrane of the abdominal cavity; fluid is instilled into the peritoneal space, then drained kidney transplantation.