Outline of Session

Physiology AKI CKD Glomerular RRT Aetiology Presentation Diagnosis Treatment Outcome Outline of Session Core Medical Training Curriculum, updated August 2011

7extra Which is incorrect concerning dipstick testing of urine for protein? • A A positive test can be found in patients with normal kidneys • B If positive only after several hours spent in the upright posture, it may be of no significance • C A positive test will result from lower urinary tract infection • D A positive test will result from increased light chain excretion • E 2+ proteinuria represents approximately 1gm/litre

Dipstick urinalysis for protein • Proteinuria can occur with urinary infection and after exercise or fever in people who have normal kidneys • Orthostatic proteinuria (literally on standing) disappears after lying in bed and is of no significance • Bence-Jones proteins don’t register on a dipstix (which only detects albumin) • Semiquantitative only eg 2 plus protein ~ 1g/l

Proteinuria Equivalents ACR PCR 24hour mg/mmol mg/mmol protein 30 50 0.5g 70 100 1.0g Many labs do ACR first because more accurate at low levels proteinuria but switch to PCR if ACR>30 because PCR cheaper and as accurate at higher levels proteinuria

Classification of CKD StageeGFR (ml/min) 1+2 60 plus other evidence CKD 3A 45-59 3B 30-44 4 15-29 5 <15 Sometimes add suffix P to indicate PCR>100mg/mmol, T to indicate transplant and D if on dialysis

21. Macroscopic haematuria is commonly associated with which of the following? • A Reflux nephropathy • B Diabetic glomerulosclerosis • C Membranous glomerulonephritis • D Light-chain nephropathy • E Henoch Schönlein disease

Common causes Haematuria Urological Nephrological • Cancers of kidney, • bladder or prostate • Stones • Urinary infection • Benign tumours • eg bladder papilloma • Trauma • IgA nephropathy • Henoch Schonlein Purpura • Alports Syndrome • Other glomerular disease • (usually with proteinuria) • Polycystic kidney • Medullary sponge

Microscopic haematuria • Persistent microscopic haematuria +/- proteinuria should prompt investigation for urinary tract malignancy if >50 years • Most common renal abnormality on biopsy is IgA nephropathy though biopsy not usually necessary • Persistent microscopic haematuria in absence of proteinura should be followed annually with BP, urine ACR, U&E for as long as haematuria persists NICE guideline on CKD, 2008

1 .Which of the following is most accurate regarding tubular function? • A 90% of sodium has been reabsorbed by the start of the distal convoluted tubule • B Over 25% of urinary creatinine derives from proximal tubular secretion • C Aldosterone acts on collecting duct cells only • D Distal tubular lesions lead to amino aciduria • E Tubular reabsorption of phosphate can be increased by PTH

Sodium & the Kidney Na 5% 100% Filtered Na 4% Na 25-30% Na 60-65% Day to day control of Na excretion takes place in CCD by aldo and ADH Nearly all filtered Na is reabsorbed in PCT, TAL and DCT

Sodium & the Kidney Na 5% 100% Filtered Na 4% Na 25-30% Na 60-65% Day to day control of Na excretion takes place in CCD by aldosterone Nearly all filtered Na is reabsorbed in PCT, TAL and DCT

PCT - most aminoacids, Ca and PO4 reabsorbed; creatinine secreted (accounting for up to 15% urinary creatinine) • proximal tubular secretion of creatinine does not account for more than 25% urinary creatinine (except in advanced renal failure) • distal tubular lesions do not lead to aminoaciduria • tubular reabsorption PO4 not increased by PTH (PTH acts to raise serum calcium and to lower serum PO4) • Aldosterone acts on connecting segment and CCD

3. With metabolic acidosis, a normal anion gap would be most suggestive of: • A Alcohol excess • B Lactic acidosis • C Diarrhoea • D Salicylate poisoning • E Diabetic ketosis

How do you know if acidosis is due to diarrhoea or to some other cause?

Normal because when bicarb is lost kidneys retain chloride to maintain electroneutrality Raised due to presence of unmeasured anions Measure anion gap = [Na+ + K+] - [Cl- + HCO3-] Raised >18 DKA Renal Failure Salicylate Methanol, ethylene glycol Normal 12 -18 Diarrhoea RTA Urinary diversion

Acidosis with raised chloride suggests diarrhoea, RTA or urinary diversion

5A 62-year-old man develops oliguria 48 hours after a laparotomy for bowel obstruction. Which of the following would be most suggestive of acute tubular necrosis rather than pre-renal uraemia • A Urinary sodium less than 10mmol/L • B Blood pressure 95/60 • C Red cell casts • D Urinary osmolality of less than 350 mosm/Kg • E Increased skin pigmentation

Incipient (tubules still function) >1.5 <20mmol/l 350-1000mOsm/kg Established (tubules don’t function) <1.1 >40mmol/l <350mOsm/kg Incipient v established ATN U/P osmolality Urine Na Urine Osm NB - red cell casts are a feature of active GN not ATN - BP 95/60mmHg reflects volume depletion or shock not necessarily ATN - skin pigmentation is a feature of CRF not ATN Nephrologists don’t use these criteria at all!

10.A 44-year-old man has a serum creatinine of 476 mol/l and urea 38 mmol/l. Which of the following would be most helpful in differentiating chronic from acute renal failure? • A Haemoglobin 9.8 g/dl • B Blood pressure 165/100 • C Kidneys 7.8 cm bipolar length at ultrasound scan • D 1.2 gm proteinuria/24-hours • E PTH 92 pg/ml(normal range 10-55)

Chronic usually anaemic but not ADPKD HT if glomerular usually small* none to heavy if glomerular usually low Ca with high PO4 variable - high in 2y hyperpara Acute may become anaemic quickly HT if RPGN normal none to heavy if RPGN usually low Ca with high PO4 variable - can be high Chronic v acute renal failure Haemoglobin Blood pressure Renal size Proteinuria Calcium and PO4 PTH *Normal kidney length >10cms on sonar, borderline 9-10cms, small <9cms, unequal if >1.5cms difference, but patients with CRF can have normal size kidneys

6.Which of following is not associated with an increased risk of contrast nephropathy? • A Pre-existing renal failure • B Hyperuricaemia • C Non-insulin dependent diabetes mellitus • D Concomitant therapy with theophyllines • E Sodium depletion

Contrast Nephropathy • Risk increases with: • - high doses of contrast • - pre existing renal failure • - diabetes • - volume depletion • - hyperuricaemia • - advanced age NB adenosine, a renal vasoconstrictor, is thought to be involved in pathogenesis of CN, but trials of adenosine antagonists, theophylline and amitryptiline, have given conflicting results. Current advice is to give 500ml saline before and after procedure +/- N-acetyl cysteine.

7. Which of the following statements concerning HUS is correct ? • A Infective diarrhoea is invariably associated • B Platelet counts are usually higher than in thrombotic thrombocytopaenic purpura • C It is usually fatal in children • D Steroids are of proven benefit • E Surviving patients are likely to require long term dialysis

7. Which of the following statements concerning HUS is correct ? • A Infective diarrhoea is invariably associated • B Platelet counts are usually higher than in thrombotic thrombocytopenic purpura • C It is usually fatal in children • D Steroids are of proven benefit • E Surviving patients are likely to require long term dialysis

Thrombotic Microangiopathy MAHA with red cell fragments, raised LDH, low haptoglobin. Thrombocytopenia (may be less severe in HUS) AKI which may require RRT Neurological features eg confusion, TIA, stroke, seizures, coma More likely HUS More likely TTP

HUS/TTP • Aetiology • D+ verotoxin producing strain of E coli 0157 esp in children • D- sporadic form more commonly seen in adults. May be idiopathic or assoc with drugs, HIV and malignancy (infective diarrhoea not invariably associated) • Pathogenesis • ADAMTS13 is a metalloproteinase which cleaves VWF to smaller subunits. Absence of or antibodies to this enzyme leads to build up of VWF multimers which promote platelet aggregation triggering MAHA • Presentation • Triad of ARF with MAHA and thrombocytopenia (HUS)

Healthy Endothelial cells Mature vWF molecules Shear stress Large unfolded vWF molecules ADAMTS13 Cleaved plasma VWF which supports platelet adhesion

HUS/TTP Endothelial cells Mature vWF molecules Shear stress Large unfolded vWF molecules Deficiency of ADAMTS13 Platelet aggregation in microcirculation

HUS/TTP • Differential diagnosis • HUS, MHT, scleroderma renal crisis and DIC can all cause same triad but clotting will be normal in first three and abnormal in DIC • Treatment • D+ supportive care only in children; PE with FFP in adults • D- daily PE and FFP in adults until no further haemolysis • Steroids may help idiopathic adult HUS/TTP if platelets do not increase after several days PE (steroids not of proven value) • Outcome • D+ usually make complete recovery (not usually fatal in kids) • D- up to 25% left with some renal impairment but long term dialysis not usually necessary. MI and heart failure are common

6E Which of the following is correct concerning hyperkalaemia? • A It may be caused by beta blockers • B It may be caused by paracetamol • C It may be caused by liquorice excess • D It can be corrected by IV calcium gluconate • E Causes ventricular tachycardia and fibrillation

Hyperkalaemia • Aetiology • Main causes begin with A - ARF, Addisons, Acidosis, Artefact, ACEI, ARBs, Aldosterone antagonists, anti-inflammatories eg NSAIDs, also beta blockers but not paracetamol (no effect) or liquorice (hypokalaemic alkalosis) • Presentation • Peaked T waves followed by loss of P wave, broadening of QRS complex (may mimic LBBB) then bradycardia leading to asystoleor VF (but not VT) • Management • Depends on level of K, likelihood it will rise further (always more dangerous in ARF than CRF) and ECG changes

Treatment of hyperkalaemia in acute renal failure Reduce risk of asystole Drive K+ into cells Remove K+ from body Insulin/dextrose Beta agonists Sodium bicarbonate Calcium Chloride/ Gluconate Dialysis Resonium

14 Concerning diabetic nephropathy • A It is unusual in patients with type 2 diabetes mellitus of < 5 years duration • B It is unlikely to occur in a patient free of proteinuria after 40 years of diabetes • C It is usually associated with urinary ACR 3-30mg/mmol • D Renal functional decline can be halted by angiotensin receptor blockers • E It can be reversed by meticulous control of blood glucose

14 Concerning diabetic nephropathy: • A It is unusual in patients with type 2 diabetes mellitus of < 5 years duration • B It is unlikely to occur in a patient free of proteinuria after 40 years of diabetes • C It is usually associated with urinary ACR 3-30mg/mmol • D Renal functional decline can be halted by angiotensin receptor blockers • E It can be reversed by meticulous control of blood glucose

Diabetic nephropathy • Aetiology • - occurs after diabetic 15-20 years (rare in type 2 <5yrs) • - risk to individual is greater in type 1 because have disease for longer • - increased incidence among asians, blacks and pima indians • - unlikely if patient free of proteinuria for 40 years • Presentation • - DN present when Urine ACR >30mg/mmol • Diagnosis • - triad of diabetes + retinopathy + proteinuria = DN • - most don’t need biopsy or arteriogram but consider other diagnoses if no proteinuria (renovascular) or abnormal serology (eg lupus)

Diabetic nephropathy • Treatment • - good evidence that tight BP control will slow but not halt rate of progression, and that ACEI/ARB have benefits that extend beyond their BP lowering effects. Optimal BP 130/80mmHg • - likely that tight glucose control will prevent DN but no evidence that this will reverse established disease • - some evidence smoking and lipids influence renal outcome in DN • - stop metformin when SC>200umol/l because risk of acidosis • Outcome - commonest cause of ESRD requiring dialysis - most patients have type 2 because this accounts for 90% of all diabetes - rate of decline of renal function is 10ml/min/year (untreated) - death rate from vascular disease exceeds that from renal failure

13.Which of the following is most likely to be true in a patient with autosomal dominant polycystic kidney disease? • A The gene mutation is on chrome 16 or 4 • B Pancreatic cysts occur in > 25% of patients • C Mitral stenosis is a recognised association • D Liver failure may develop • E End stage renal failure occurs in 90% of patients by age 50 years

Polycystic kidneys • Aetiology • - PKD1 gene on chrome 16 in 85%, PKD2 gene on chrome 4 in 15% • - Incidence is 1 in 1000 with “genetic anticipation” • Presentation • - often asymptomatic but also loin pain, haematuria, UTI, stones, HT or CRF • Diagnosis • - usually by ultrasound – but can’t definitely exclude till 30 years • Extrarenal manifestations • - liver cysts 40-90% but liver failure rare, pancreatic cysts 5-10% (not >25%) • - berry aneurysms 3-5%. Screening by MRA recommended if FH of SAH or has unexplained headache, but not routinely. Intervene if aneurysm >10mm • - MVP, AR (not Mitral Stenosis) and colonic diverticulae • - erythrocytosis • Treatment • - tight control of BP may slow rate of decline of renal function • Outcome • - 50% PKD1 and 2 develop ESRD by 55 and 70 years accounting for ~10% patients on RRT

29. A 68-year-old man has backache and hypercalcaemia, plasma globulins are elevated at 52 g/l and he has a normocytic anaemia. 24 hour urinary protein excretion is 0.5 grams. He develops diarrhoea and vomiting and presents with acute renal failure. A renal biopsy is performed. What is the most likely diagnosis? • A Acute tubular necrosis • B Amyloidosis • C Interstitial nephritis • D Intra-glomerular thrombi • E Light chain nephropathy

Outline of Session