Syndromology in nephrology

1. Syndromology in nephrology Martina Peiskerová 1.LF UK Praha Klinika nefrologie 9/2007

2. Haematuria Proteinuria Leucocyturia Polyuria, oliguria, anuria Nephrotic syndrome Nephritic syndrome Acute glomerulonephritis Rapidly progressive glomerulonephritis Pulmonary-renal syndromes Chronic glomerulonephritis ?? Acute renal failure Chronic kidney disease (Chronic renal failure) Uraemia Tubular syndromes Hypertension Pain Obstruction Syndromology in nephrology - outline

3. Haematuria • Definition > 2 red cells / hpf , • Hamburger’s sediment (3 hours)>2000/min. • microscopic x macroscopic • persitent x transient (exercise, menstruation, trauma, infection) • glomerular x non-glomerular x uncertain origin (exercise, over-anticoagulation, factitious) • Source:kidney x urinary tract • Renalglomerular haematuria (IgA GN, thin basement memrane disease, Alport, other GN) • Renalnon-glomerular haematuria (tumours, cysts, calculs, pyelonephritis, papillary necrosis, renal vein thrombosis) • Urinary tract bleeding (cystitis, prostate, tumours, stricture, Schistosoma haematobium)

4. Clinical importance of haematuria • Cause dependent • The most frequent causes: - inflammation or infection of the prostate or urinary bladder • urinary calculi • malignant neoplasms • glomerular disorders • Risk of malignity: age >40, smoking, NSA, pelvic irradiation, CFA treatment) • Glomerular disorder more likely if: • proteinuria >0.5 g/24h • dysmorphic erythrocytes present and red blood cells casts on phase-contrast microscopy • ↑BP

5. Diagnosis of haematuria - history and physical examination • Pyuria or dysuria  urinary tract infection • Respiratory tract infection  postinfectiousGN, IgA nephropathy • Family history  polycystic kidney disease, hereditary nephritides • Low back pain  ureteral obstruction • Physical exercise, injury  post-exercise/post-traumatic hematuria • Micturition disorders in older men  prostatic obstruction • History of bleeding from multiple sources  coagulation disorder

6. A-dysmorphic erythrocytes B-isomorphic erythrocytes C-acanthocytes (spur / spiny / star cells) D- neutrophils E-lymphocytes F-eosinophils (arrow), Phase-contrast microscopy

7. Diagnosis + Treatment of haematuria • Urinalysis • Urine microscopy (sediment, phase-contrast) • PSA • Imaging (US, IVU,CT, angiography) • Cystoscopy • Urine cytology • Renal biopsy (in glomerular hematuria) • Early diagnosis is essential • Treatment of the causing disorder

8. Proteinuria • benign (<1g/day, age < 30, fever, cold, exercise, CCF, seizures, postural), vs. pathological • importance of abnormal proteinuria: marker of intrinsic renal disease, prognostic factor for progression of renal insufficiency, risk factor for CV mortality, treatment target in CKD • normally < 150 mg/day (albumine < 30 mg/ day) • microalbuminuria 30-300 mg/day

9. Proteinuria 2 Pathophysiology • glomerular (mostly albumin), • tubular (beta2microglobulin), • overflow (light chains in myeloma), • secretory (tumour, inflammation) Quantity • Mild < 1,0 g/day • Significant 1,0 – 3,5 g/day (probably glomerular) • Nephrotic range > 3,5 g/day (probably glomerular)

10. Leucocyturia • neutrophiles – infection, GN, TIN • sterile pyuria (treated UTI, Chlamydia, calculi, prostatitis, bladder tumor, papillary necrosis, TIN, TB) • lymphocytes – TIN Active urinary sediment • red blood cells, proteinuria, white blood cells, and "casts" of cells

11. Urinary sediment abnormalities„Mixed urinary findings“ • isolated haematuria or haematuria + mild proteinuria (<1g/day) … good prognosis • isolated proteinuria (<3,5g/day) .. worse prognosis • nephrotic proteinuria + haematuria … the worst prognosis

12. Nephrotic syndrome= clinical complex consisting of: • Proteinuria of >3.5g / 1.73m2 / 24 hours • Hypoalbuminaemia • Oedema • Hyperlipidaemia • Lipiduria • Hypercoagulability

13. Patophysiology of the nephrotic syndrome. Primary insult- increased glomerular permeability, causing plasma protein leakage into urine. Hypoalbuminemia is the cause of the main clinical features.

14. Metabolic albumin turnover in healthy subjects vs. subjects with nephrotic syndrome.

15. ?? The“underfill” mechanismof edema formation. In this theory, hypovolemia (caused by hypoalbuminemia and decreased oncotic plasma pressure) is the main cause of renal Na+ a H20 retention.

16. ?? The“overfill” mechanismof edema formation.In this theory, abnormal renal Na+ and H20 retentionis the main cause of Starling forces alteration at local tissue level.

17. (Possible) consequences of proteinuria and lipid spectrum abnormalities.

18. Diagram showing pathogenetic factors leading to hypercoagulability, tromboembolism and renal vein thrombosis.

19. Causes of nephrotic syndrome

20. Symptomatic NaCl, H20 restriction diuretic therapy ultrafiltration nephrectomy Specific (depending on the causative disease) immunosuppressive therapy in amyloidosis, treatment of the causative process Treatment of nephrotic syndrome • Treatment and prevention of complications • thromboembolism • lipid metabolism disturbances • immunoglobulin deficiency • Ineffective: high protein diets, albumin supplementation.

21. Nephritic syndrome Glomerular inflammatory changes leading to • ↓ GFR • moderate proteinuria • oedema • hypertension • haematuria (red cell casts). Typical example: Poststreptococcal glomerulonephritis in children

22. Differences between nephrotic and nephritic syndromes

23. Histology (light microscopy) of acute poststreptococcal GN (marked invasion of polymorphonuclear cells)

24. Histology of acute poststreptococcal GN(subepithelial hump-like deposits (strait arrows), subendothelial (arched arrows)and mesangial deposits). Endocapillary hypercellularity caused by neutrophil infiltration, endothelial and mesangial proliferation.

25. Immunological findings in poststreptococcal GN 1. The serial estimation of complement - • Early in the acute phase, the levels of hemolytic complement activity(CH50 and C3) reduced. • Within 8 weeks return to normal 2. Serial ASO titer measurements - twofold or greater rise in titer are highly indicative of a recent infection.

26. Continuous alterations of structural changes caused by glomerular inflammation (upper part), clinical syndromes (middle part) and specific nosologic units (lower part).

27. Rapidly progressive GN (RPGN) • Severe glomerular disorder → ↓ glomerular filtration in days or weeks. • Clinical features: acute uremic or nephritic syndrome with renal insufficiency rapidly→ renal failure • Histology: negative IF (pauci-immune), crescentic GN(crescent = half-moon-shaped lesion in Bowman’s space composed of proliferating parietal epithelial cells and infiltrating monocytes). Crescentic GN: >70% glomeruli are involved. • Typical diseases : WG, GP and SLE. • + Extrarenal symptoms: pulmonary, skin, ORL, CNS..

28. Large cellular crescent filling the Bowman’s space and compressing the glomerular tuft in WG.

29. Acute renal failure 1 • due to rapid ↓ GFR (hours, days) • retention of urea, creatinine, disorders in electrolytes, acid-base, fluid homeostasis • oliguric x non-oliguric • anuria < 100 ml/day, oliguria < 400 ml/day, polyuria > 3l/day • RIFLE classification Risk.. Injury…Failure.. Loss…End-stage) • Acute kidney injury classification : 1. s-creat to 1,5-2x baseline / oliguria > 6 hours 2. s-creat to 2-3x baseline / oliguria > 12 hours 3. s-creat above 3x baseline / anuria * the highest risk – pulmonary edema, hyperkalemia

30. Acute renal failure 2 - causes • Prerenal (from ↓ BP → ↓ GFR, or arterial stenosis or NSA, ACEI) • Intrinsic - ATN (ischemic – e.g.myoglobinuria, myeloma casts, nephrotoxic – radiocontrast, drugs – gentamicin, vancocin, cisplatin) - vascular - acute GN - acute TIN • Postrenal (obstructive) • Patients at risk of developping ARF: ↑age, DM, pre-existing renal disease, surgery, volume depletion, cardiac disease, cirrhosis, drugs – NSA, ACEI, ARB), myeloma

31. Chronic kidney disease → Renal insufficiency → Renal failure * exocrine dysfunction(ions – K, Na, P, H.., fluid, and other catabolites– uremic toxins retention) • endocrine dysfunction (erythropoietin, 1,25 vitamin D metabolism, renin-angiotensin system) → laboratory: GF < 1,0 ml/s, hyperkalemia, hypocalcemia, hyperphosphatemia, metabolic acidosis, anemia

32. Stages of kidney disease NKF/ KDOQI • Asymptomatic urinary abnormalities: GFR > 90 ml/min (> 1,5 ml/s) • Mild CRF: GFR60-89 ml/min (1-1,5 ml/s) • Moderate CRF: GFR 30-59 ml/min (0,5-1 ml/s) • Severe CRF: GFR15-29% (0,25-0,5 ml/s) 5Approaching ESRD: GFR <15 ml/min (< 0,25 ml/s)

33. Uremic syndrome - clinical features 1 • Gastrointestinal • Anorexia, nausea, vomiting • Neurological • Central:uremic encefalopathy (daytime drowsiness, disorientation, myoclonus, coma) • Peripheral:uremic polyneuropathy (restless legs syndrome) • Respiratory • pulmonary edema

34. Uremic syndrome - clinical features2 • Cardiac • uremic pericarditis • Dermatological • pruritus • Hematological • fatigue due to anemia • Endocrinological • secondary hyperparathyreoidism (bone pain), dysmenorrhea

35. Uremia * in 3 different clinical situations →different clinical features • acute renal failure –exocrine dysfunction, no time for endocrine dysfunction development • chronic renal failure –endocrine and exocrine renal dysfunction (fluid excretion usually preserved until late stages) • dialysis treated CRF –caused by insufficient dialysis treatment and/or insufficient substitution of thedecreased renal endocrine production (EPO, vitamin D, etc.).

36. Treatment of uremia • Conservative: • diet: Na, K, PO3 and protein restriction • control of hypertension • NaHC03 treatment to reduce metabolic acidosis • anemia management (erythropoietin) • secondary hyperparathyroidism management (vitamin D, phosphate binders) • Renal replacement therapy:hemodialysis, peritoneal dialysis, renal transplantation

37. Pulmonary-renal syndromes • Acute kidney disease (ARF or RPGN) + Pulmonary haemmorhage • Features:cough, anaemia, dyspnoea, haemoptysis, hypoxaemia, alveolar shadowing on CXR (df.dg. pulmonary oedema) + features of systemic disease: skin rush, sinusitis, artritis, fever, fatigue • Main causes:ANCA vasculitis, antiGBM nephritis, SLE, Henoch-Schonlein purpura • Other causes: pulmonary oedema, infection (pneumonia – Pneumocystis, viruses..), hantavirus, pulmonary emboli, acute respiratory distress syndrome

38. Hypertension • Primary hypertension – kidney is victim – - vascular nephrosclerosis.. • Secondary hypertension – kidney is vilain - glomerular and vascular diseases • Control of hypertension is crucial in slowing progression of kidney disease → aim BP 120/75 mm Hg

39. Tubular syndromes Tubular dysfunction may occur in any renal injury Tubular syndromes in the context of normal GFR: • Generalised – Fanconi syndrome : multiple tubular defects caus in variable degree → phosphaturia → rickets, osteomalacia, osteoporosis → aminoaciduria – no clinical sequelae → glycosuria – rarely hypoglycemia → defective bicarbonate reabsorption – renal tubular acidosis → Na loss → rarely ↓BP or metabolic alcalosis → K loss → hypokalaemia → muscle weakness, constipation, arrhytmias → proteinuria – LMW, no clinical sequelae → polyuria – dehydration → hypercalciuria → rarely nephrolitihiasis/calcinosis • Isolated – genetic mechanisms involved - glycosuria - to distinguish from DM - aminoaciduria - e.g. cystinuria → recurrent cystin stone formation (AR inheritance) - phosphaturia – e.g. vitamin D resistant rickets(XR inheritance)

40. Pain An agressive and destructive renal disease may be painless !! Loin pain - constant dull ache, may irradiate to abdomen, genitalia • cause: distension of the renal capsule • differential: nerve root irritation (T10-12) Ureteric colic - sudden onset, extremely sever, pale, distressed patient • localisation: loin, iliac fossa, genitalia, upper thigh • cause: passage of the stone, blood clot or necrotic papillae Suprapubic pain • causes: over-distension of the bladder, cystitis, bladder cancer Bladder irritability - dysuria, frequency, urgency • causes: over-distension of the bladder, cystitis

41. Bladder outflow obstruction Symptoms • Obstructive – voiding: hesitancy, impaired force of stream, incomplete emptying • Storage – filling : frequency, dysuria, urgency Causes • Structural – prostatic hyperplasia, carcinoma, urethral stricture • Functional – bladder neck dyssynergia, DM, multiple sclerosis, spinal corde lesions, drugs - antidepressants