Pathophysiology of Brain & Body - USSJJQ-20-3

1. Pathophysiology of Brain & Body - USSJJQ-20-3 Renal Failure

2. What is it? • Kidneys unable to maintain homeostasis leading to… • a buildup of nitrogenous wastes • azotemia (high nitrogenous compounds in blood) • retention of fluid & electrolytes  • hypertension • acidosis (H+ retention) • retention of K+ • muscle cramps, paraesthesia, dysrhythmia

3. How is it caused? • Normal kidney function needs… • normal blood flow • functioning glomeruli and tubules to separate and process the ultrafiltrate • drainage/elimination of urine from the body • 75% of function can be lost before noticeable • ie it can be ‘silent’, progressive problem

4. Classification: Time Course • Acute (Acute Renal Failure, ARF) • sudden onset • rapid reduction in GFR/urine output • usually reversible • tubular cell death and regeneration • Chronic Renal Failure (arising from Chronic Kidney Disease, CKD) • progressive • gradual reduction in GFR • irreversible • nephron loss

5. Classification: Location • Pre-renal • functional (ie kidney could still ‘work’) • though can be structural – eg renal artery stenosis • ~55% of ARF • Post-renal • obstructive (ie problem with ‘drainage’) • ~10% of ARF • Renal (Intrinsic, Parenchymal) • structural (ie something wrong with renal ‘structure’) • ~35% of ARF • can be glomerular and/or tubular

6. Causes of Prerenal ARF • hypovolemia, hypotension, reduced renal perfusion • blood loss • sodium depletion • diarrhoea, diuresis • ascites • hepatic cirrhosis • reduced effective blood volume • heart failure, vasodilatory shock • renal artery stenosis (bilateral) • drugs affecting renal arteriolar resistance • eg ACE inhibitors • All affect ability to generate sufficient RBF/GFR

7. RAP ~ RBF Raff + Reff Prerenal ARF • Determinants of RBF (and GFR)… Raff Reff PGC RAP

8. Responses to Reduced Blood Vol • Increased sympathetic tone, angiotensin II, aldosterone, ADH  • increased efferent arteriolar tone (Ang II) to try to maintain SNGFR • decreased afferent arteriolar tone (NO and PG) to try to maintain SNGFR • increased tubular Na+ reabsorption (Ang II, Aldo) • increased tubular H2O reabsorption (ADH) • increased urea reabsorption (along with Na+ & H2O) •  effects on urine… • reduced urinary sodium (< 20 mEq/L) (vs 40-220) • reduced urinary volume • high urine osmolarity (> 600 mOsm)

9. Postrenal ARF • Obstruction of urinary flow • anywhere from the renal pelvis to the urethra • must be bilateral obstruction  renal insufficiency • Causes • prostatic hypertrophy • prostate, bladder or cervical cancer • neurogenic bladder • bilateral renal calculi • coagulated blood

10. Renal (Intrinsic) ARF • Causes reflect types of tissue/structure involved • Vascular • malignant hypertension • Acute Glomerulonephritis (AGN) • damage to filtering mechanisms • Acute Interstitial Nephritis (AIN) • often an allergic response • Acute Tubular Necrosis (ATN) • ischaemicor due to toxins • Tubular Obstruction • uric acid crystals

11. Intrinsic ARF: AGN, AIN • Acute Glomerulonephritis • abnormal immune reaction  damage to glomeruli • deposition of antibody-antigen complex on basement membrane of glomeruli • eg several weeks after streptococcal infection •  inflammation  blocked or leaky glomeruli • usually recover but can progress to chronic failure • Acute Interstitial Nephritis • Allergic Interstitial Nephritis • drugs (eg furosemide, antibiotics) • Infections • eg legionella • Sarcoidosis

12. Intrinsic ARF: ATN • Acute Tubular Necrosis (tubular epithelium) • Ischaemic ATN • Hypotension, prolonged pre-renal state • Nephrotoxic ATN • EndogenousToxins • eg from crush injuries; haempigments (Rhabdomyolysis) • ExogenousToxins • medications (eg tetracycline) • radiocontrastagents • heavy metals (eg mercury) • poisons (eg ethylene glycol)

13. Chronic Kidney Disease/Renal Failure • Kidney damage markers for three months • imaging, or blood or urine abnormalities • GFR <60 mL/min/1.73 m2 • Progressive, staged reduction in renal function • irreversible loss of functioning nephrons • can lose 75% without exhibiting overt symptoms • early stages ‘normal’, so diagnosis often by chance • >20 million Americans with CKD? • Last stage is End Stage Renal Disease (ESRD) • GFR < 15 ml/min or on dialysis • 571,000 in US (2009) • costs $42.5b • annual mortality ~ 15%

14. GFR and Risk of Death • Large study of 1.12m users within US hospital system N Engl J Med 2004; 351:1296-1305

15. 160 100 57 41 30 Lung Cancer Colo-rectal Cancer Prostate Cancer Kidney Failure Breast Cancer ESRD Compared to Cancer Deaths (US in 2000)(in Thousands) Seer, 2004

16. Prevalence of CKD and Estimated Adults with CKD in the US (NHANES 88-94) *Stages 1-4 from NHANES III (1988-1994). Population of 177 million with age 20. Stage 5 from USRDS (1998), includes approximately 230,000 patients treated by dialysis, and assuming 70,000 additional patients not on dialysis. GFR estimated from serum creatinine using MDRD Study equation based on age, gender, race and calibration for serum creatinine. For Stage 1 and 2, kidney damage estimated by spot albumin-to-creatinine ratio 17 mg/g in men or 25 mg/g in women in two measurements.

17. CKD is a Progressive Disease

18. Diseases Causing CKD/ESRD • Chronic Kidney Disease/End Stage Renal Disease • Diabetic Nephropathy (44%) • Hypertension (26%) • Glomerulonephritis (8%) • Polycystic kidney disease (2%) • HIV nephropathy • Reflux nephropathy in children • Kidney infections & obstructions

19. Pathophysiology of CKD/ESRD • Injury to Renal Vasculature • atherosclerosis of larger arteries  ischaemia • sclerotic lesions of arterioles/glomeruli (nephrosclerosis) • Benign changes occur with ageing • accelerated by hypertension & diabetes

20. Pathophysiology of CKD/ESRD • Injury to Glomeruli (Glomerulonephritis) • inflammation of capillary loops • slow, progressive • accumulation of immune complexes •  fibrosis •  thickening of filtration membrane, fewer loops •  reduced filtration •  CKD •  ESRD

21. Pathophysiology of CKD/ESRD • Injury to Interstitium • eg pyelonephritis • from ascending UTI (eg E Coli) • cystitis •  bladder inflammation •  vesicouretral reflux (retrogade urine flow when peeing) •  medullary inflammation ( poor conc ability) •  progressive damage to other areas •  CKD •  ESRD

22. Pathophysiology of CKD/ESRD • Nephroticsyndrome… • increased permeability of the glomerular membrane •  loss of protein in urine • Normal albumin excretion is… • <30 mg/24 hours • Microalbuminuria… • 30-300 mg/24 hours • Nephroticrange proteinuria • >3 g/24 hours • caused by chronic glomerulonephritis, • amyloidosis (abnormal protein deposition in vessels) • loss of –ve charge on BM (usually helps stop protein crossing; like charges repel)

23. Treatment of CKD • Manage hypertension (eg ACE inhibitors) • Manage protein (eg low protein diet) • Manage glucose(underlying diabetes)

24. Nephron Function in CKD • Remaining nephrons excrete more H2O/solutes • person can be in fairly good H2O/solute balance; ‘independent’ of GFR • other compounds more dependent on GFR • egcreatinine/urea • Excreted ~ GFR x PCr • balance achieved at higher [plasma] • this offsets effect of reduced GFR • some compounds intermediate • eg phosphate

25. Nephron Function in CKD • A) creatinine, urea • B) phosphate • C) sodium, chloride • Not shown… • Urine concentrating ability impaired

26. Renal Failure  Uremia • Generalisedoedema (salt/water retention) • Acidosis (failure to excrete non-volatile acids) • High conc of non-protein nitrogen (NPN, azotemia) and others (eg guanidine bases, K+)

27. Dialysis • Dialysis, 4-6 hours, 3 times a week • ~ ½ of patients with CKD eventually require dialysis • diffuses harmful waste out of body • controls BP (by controlling volume) • maintains safe level of electrolytes • 2 types : both exchange components across a semipermeable membrane, between blood and dialysate • haemodialysis • pass blood across artificial membrane (cellophane) • peritoneal dialysis • pass dialysate across natural membrane (peritoneal mesentery)

28. Dialysis

29. CV Mortality in the General Population and in ESRD Treated by Dialysis Annual mortality (%) 100 Dialysis 10 General population 1 0.1 Male Female 0.01 Black White 25–34 35–44 45–54 55–64 65–74 75–84 85 Age (years)