Syndromology in nephrology Martina Peiskerov 1 LF UK

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

Syndromology in nephrology outline • 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

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 – Renal glomerular haematuria (Ig. A GN, thin basement memrane disease, Alport, other GN) – Renal non-glomerular haematuria (tumours, cysts, calculs, pyelonephritis, papillary necrosis, renal vein thrombosis) – Urinary tract bleeding (cystitis, prostate, tumours, stricture, Schistosoma haematobium)

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/24 h – dysmorphic erythrocytes present and red blood cells casts on phase-contrast microscopy – ↑BP

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

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

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

Proteinuria • benign (<1 g/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

Proteinuria 2 Pathophysiology • glomerular (mostly albumin), • tubular (beta 2 microglobulin), • 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)

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

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

Nephrotic syndrome = clinical complex consisting of: • • • Proteinuria of >3. 5 g / 1. 73 m 2 / 24 hours Hypoalbuminaemia Oedema Hyperlipidaemia Lipiduria Hypercoagulability

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

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

? ? The “underfill” mechanism of edema formation. In this theory, hypovolemia (caused by hypoalbumine mia and decreased oncotic plasma pressure) is the main cause of renal Na+ a H 20 retention.

? ? The “overfill” mechanism of edema formation. In this theory, abnormal renal Na+ and H 20 retention is the main cause of Starling forces alteration at local tissue level.

(Possible) consequences of proteinuria and lipid spectrum abnormalities.

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

Causes of nephrotic syndrome

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

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

Differences between nephrotic and nephritic syndromes Typical features Nephrotic syndrome Nephritic syndrome onset slow acute swelling ++++ ++ arterial blood pressure normal increased central venous pressure normal/low increased proteinuria ++++ ++ hematuria present/not present +++ red cell casts not present glomerular filtration normal/low serum albumin low normal/slightly decreased

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

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

Immunological findings in poststreptococcal GN 1. The serial estimation of complement • Early in the acute phase, the levels of hemolytic complement activity (CH 50 and C 3) 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.

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

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. .

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

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 > 3 l/day • RIFLE classification Risk. . Injury…Failure. . Loss…End-stage) • Acute kidney injury classification : 1. s-creat to 1, 5 -2 x baseline / oliguria > 6 hours 2. s-creat to 2 -3 x baseline / oliguria > 12 hours 3. s-creat above 3 x baseline / anuria * the highest risk – pulmonary edema, hyperkalemia

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, preexisting renal disease, surgery, volume depletion, cardiac disease, cirrhosis, drugs – NSA, ACEI, ARB), myeloma

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

Stages of kidney disease NKF/ KDOQI 1. Asymptomatic urinary abnormalities: GFR > 90 ml/min (> 1, 5 ml/s) 2 Mild CRF: GFR 60 -89 ml/min (1 -1, 5 ml/s) 3 Moderate CRF: GFR 30 -59 ml/min (0, 5 -1 ml/s) 4 Severe CRF: GFR 15 -29% (0, 25 -0, 5 ml/s) 5 Approaching ESRD: GFR < 15 ml/min (< 0, 25 ml/s)

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

Uremic syndrome - clinical features 2 • Cardiac – uremic pericarditis • Dermatological – pruritus • Hematological – fatigue due to anemia • Endocrinological – secondary hyperparathyreoidism (bone pain), dysmenorrhea

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 the decreased renal endocrine production (EPO, vitamin D, etc. ).

Treatment of uremia • - Conservative: diet: Na, K, PO 3 and protein restriction control of hypertension Na. HC 03 treatment to reduce metabolic acidosis anemia management (erythropoietin) secondary hyperparathyroidism management (vitamin D, phosphate binders) • Renal replacement therapy: hemodialysis, peritoneal dialysis, renal transplantation

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, anti. GBM nephritis, SLE, Henoch-Schonlein purpura • Other causes: pulmonary oedema, infection (pneumonia – Pneumocystis, viruses. . ), hantavirus, pulmonary emboli, acute respiratory distress syndrome

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

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)

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 (T 10 -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

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