Membership of the Royal College of Physicians (MRCP UK) Nephrology Syllabus

What is the principle of peritoneal dialysis (PD) and what acts as the membrane?

The patient's own peritoneal membrane is the dialysing surface. Hypertonic (glucose-based) dialysate is instilled into the peritoneal cavity; solutes diffuse from blood across the peritoneum and water is removed by osmotic ultrafiltration. Modes: CAPD (manual exchanges) and APD (overnight machine).

Compare key complications of haemodialysis versus peritoneal dialysis.

Haemodialysis: access problems (fistula thrombosis/stenosis, line infection), intradialytic hypotension, disequilibrium syndrome, bleeding. Peritoneal dialysis: PD peritonitis (turbid effluent, abdominal pain), exit-site infection, catheter malfunction, hernias, encapsulating peritoneal sclerosis, hyperglycaemia/weight gain.

What organism most commonly causes PD-associated peritonitis and how is the diagnosis made?

Coagulase-negative staphylococci (e.g. Staphylococcus epidermidis), often skin contamination. Diagnosis: cloudy PD effluent with WCC $>100\ cells/\mu L$ and $>50\%$ neutrophils. Treat with intraperitoneal antibiotics.

What HLA loci are matched in renal transplantation, and which donor type gives best graft survival?

HLA-A, HLA-B and HLA-DR are matched (DR most important). Living-donor (especially HLA-identical) transplants give the best graft survival; pre-transplant crossmatch must exclude preformed donor-specific antibodies.

Distinguish hyperacute, acute and chronic renal allograft rejection.

Hyperacute: minutes–hours, preformed antibodies, immediate graft thrombosis (now rare with crossmatching). Acute: days–months, T-cell mediated (cellular) or antibody-mediated; rising creatinine, treat with steroids/antibody therapy. Chronic: months–years, interstitial fibrosis/tubular atrophy and transplant glomerulopathy, poorly reversible.

Outline a standard maintenance immunosuppression regimen after renal transplant and its major drug toxicities.

Triple therapy: a calcineurin inhibitor (tacrolimus/ciclosporin) + an antiproliferative (mycophenolate or azathioprine) + corticosteroid. Tacrolimus: nephrotoxicity, tremor, diabetes. Ciclosporin: nephrotoxicity, gum hypertrophy, hirsutism. Mycophenolate: GI upset, marrow suppression. Long-term: infection (CMV, BK) and malignancy (skin, PTLD).

Define nephrotic syndrome by its diagnostic criteria.

Triad of: heavy proteinuria $>3.5\ g/24h$ (or PCR $>350\ mg/mmol$); hypoalbuminaemia ($<30\ g/L$); and peripheral oedema. Usually accompanied by hyperlipidaemia and lipiduria. Reflects podocyte/glomerular basement membrane injury with preserved nephritic features absent.

List the major complications of nephrotic syndrome.

Venous thromboembolism (loss of antithrombin III, renal vein thrombosis); infection (urinary loss of immunoglobulins, e.g. pneumococcal); hyperlipidaemia and accelerated atherosclerosis; acute kidney injury; vitamin D deficiency; protein malnutrition.

What is the commonest cause of nephrotic syndrome in children and its key features?

Minimal change disease. Light microscopy normal; electron microscopy shows podocyte foot process effacement. Selective proteinuria, highly steroid-responsive ($>90\%$ remit with corticosteroids), associated with NSAIDs and Hodgkin lymphoma.

Name the commonest cause of primary nephrotic syndrome in adults and key associations.

Membranous nephropathy. Subepithelial immune deposits ('spike and dome' on silver stain); anti-phospholipase A2 receptor (anti-PLA2R) antibodies in primary disease. Secondary causes: malignancy, hepatitis B, SLE, gold/penicillamine. Follows the 'rule of thirds' for outcome.

What is focal segmental glomerulosclerosis (FSGS) and its associations?

FSGS shows segmental sclerosis of some glomeruli; commonest cause of nephrotic syndrome in adults of African descent. Secondary causes: HIV, heroin, obesity, reflux nephropathy, sickle cell. Often steroid-resistant with risk of progression to ESRD.

Define nephritic syndrome and list its characteristic features.

Glomerular inflammation causing: haematuria (often with dysmorphic red cells and red-cell casts); proteinuria (usually $<3.5\ g/day$); hypertension; oliguria; and varying degrees of renal impairment/fluid overload. Reflects an inflammatory, proliferative glomerular lesion.

What is rapidly progressive glomerulonephritis (RPGN) and its pathological hallmark?

RPGN is a nephritic syndrome with rapid loss of renal function over days–weeks. Histological hallmark: crescents (extracapillary proliferation) in Bowman's space on biopsy. Requires urgent diagnosis and immunosuppression.

Classify crescentic/RPGN into its three immunological types with examples.

Type 1 – Anti-GBM disease (linear IgG; Goodpasture's). Type 2 – Immune complex (granular deposits; post-infectious GN, IgA, lupus, cryoglobulinaemia). Type 3 – Pauci-immune (ANCA-associated vasculitis: GPA, MPA, EGPA).

What are the ANCA serology patterns and their associated vasculitides?

c-ANCA / anti-PR3: granulomatosis with polyangiitis (GPA). p-ANCA / anti-MPO: microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA, Churg–Strauss). These cause pauci-immune crescentic GN; treat with steroids plus cyclophosphamide or rituximab.

What is anti-GBM (Goodpasture) disease and its target antigen?

Autoantibodies against the $\alpha_{3}$ chain of type IV collagen in the glomerular and alveolar basement membranes, causing crescentic GN with pulmonary haemorrhage. Linear IgG on immunofluorescence. Treat with plasma exchange, corticosteroids and cyclophosphamide.

What is IgA nephropathy (Berger disease) and its classic presentation?

Commonest primary glomerulonephritis worldwide; mesangial IgA deposition. Classically presents as visible (macroscopic) haematuria within 1–2 days of an upper respiratory tract infection ('synpharyngitic'), or as asymptomatic microscopic haematuria. Contrast with post-streptococcal GN which lags 1–2 weeks.

How is lupus nephritis classified and which class is most severe?

ISN/RPS classes I–VI: I minimal mesangial, II mesangial proliferative, III focal, IV diffuse, V membranous, VI advanced sclerosing. Class IV (diffuse proliferative) is the most common and most severe, requiring aggressive immunosuppression (steroids + mycophenolate or cyclophosphamide).

What immunological/serological findings support active lupus nephritis?

Positive ANA and anti-double-stranded DNA antibodies; low complement (C3 and C4 consumed); 'full house' immunofluorescence (IgG, IgA, IgM, C3, C1q). Anti-dsDNA titres and complement levels track disease activity.

Describe the natural history and stages of diabetic nephropathy.

Stage 1: glomerular hyperfiltration (raised GFR, renal hypertrophy). Stage 2: silent, basement membrane thickening. Stage 3: incipient nephropathy (microalbuminuria, ACR $3–30$). Stage 4: overt nephropathy (macroalbuminuria, declining GFR, hypertension). Stage 5: ESRD. Histology: Kimmelstiel–Wilson nodules and GBM thickening.

How is diabetic nephropathy treated to slow progression?

Tight glycaemic control; ACE inhibitor or ARB (reduce intraglomerular pressure and proteinuria, even if normotensive once microalbuminuria present); SGLT2 inhibitors; strict BP control $<130/80$; and a non-steroidal mineralocorticoid antagonist (finerenone) in selected patients.

What are the renal features of hypertensive nephrosclerosis?

Chronic hypertension causes hyaline arteriolosclerosis and fibrointimal thickening, leading to ischaemic glomerular damage, modest proteinuria and slowly progressive CKD with small, smooth kidneys. Malignant hypertension causes fibrinoid necrosis ('onion-skin') and acute AKI.

How do you classify hyponatraemia by volume status with examples?

Hypovolaemic (Na and water loss: diuretics, GI losses, Addison's). Euvolaemic (SIADH, hypothyroidism, glucocorticoid deficiency, primary polydipsia). Hypervolaemic (oedematous: heart failure, cirrhosis, nephrotic syndrome, renal failure). Assess serum and urine osmolality and urine sodium to refine.

State the diagnostic criteria for SIADH.

Euvolaemic hyponatraemia with: low serum osmolality ($<275\ mOsm/kg$); inappropriately concentrated urine (osmolality $>100\ mOsm/kg$); urine $Na^{+} >30\ mmol/L$; normal thyroid, adrenal and renal function; and no diuretic use. Patient is clinically euvolaemic.

Why must severe hyponatraemia be corrected slowly, and what is the safe correction limit?

Over-rapid correction risks osmotic demyelination syndrome (central pontine myelinolysis). Limit correction to $\leq 10\ mmol/L$ in the first 24 hours (some advise $\leq 8\ mmol/L$). Conversely, chronic hypernatraemia must also be corrected slowly to avoid cerebral oedema.

Compare cranial and nephrogenic diabetes insipidus, including the water deprivation/desmopressin test result.

Cranial DI: deficient ADH secretion; urine concentrates after desmopressin (osmolality rises $>50\%$). Nephrogenic DI: renal ADH resistance (lithium, hypercalcaemia, hypokalaemia); urine fails to concentrate after desmopressin. Both: dilute high-volume urine despite plasma hyperosmolality after water deprivation.

List causes and ECG changes of hyperkalaemia, and outline emergency management.

Causes: renal failure, ACEi/ARB, potassium-sparing diuretics, Addison's, rhabdomyolysis, acidosis. ECG: tall tented T waves, small/absent P waves, broad QRS, sine wave. Emergency treatment: IV calcium gluconate (cardioprotection), insulin + dextrose and nebulised salbutamol (shift $K^{+}$ intracellularly), then remove $K^{+}$ (diuresis, dialysis, binders).

Classify hypokalaemia by associated acid-base status with examples.

Hypokalaemia with metabolic alkalosis: vomiting, diuretics, Conn's (hyperaldosteronism), Cushing's, Bartter/Gitelman. Hypokalaemia with metabolic acidosis: diarrhoea, renal tubular acidosis (types 1 and 2). ECG: U waves, flat T waves, ST depression, long QT.

How do you calculate and interpret the anion gap in metabolic acidosis?

$$\text{Anion gap} = [Na^{+}] - ([Cl^{-}] + [HCO_3^{-}])$$ Normal $\approx 8–12\ mmol/L$. Raised anion gap acidosis (mnemonic MUDPILES: methanol, uraemia, DKA, propylene glycol, isoniazid, lactate, ethylene glycol, salicylates). Normal anion gap (hyperchloraemic): diarrhoea, renal tubular acidosis, acetazolamide.

Compare the three main types of renal tubular acidosis (RTA).

Type 1 (distal): cannot excrete $H^{+}$, urine pH $>5.5$, hypokalaemia, risk of stones/nephrocalcinosis. Type 2 (proximal): impaired $HCO_3^{-}$ reabsorption, urine pH variable, hypokalaemia, associated with Fanconi syndrome. Type 4: aldosterone deficiency/resistance, hyperkalaemic, urine pH $<5.5$ (e.g. diabetic hyporeninaemic hypoaldosteronism). All cause normal-anion-gap metabolic acidosis.

List common causes of hypomagnesaemia and its key clinical/biochemical consequence.

Causes: diuretics, PPIs, alcohol, diarrhoea, aminoglycosides, ciclosporin, Gitelman syndrome. Hypomagnesaemia causes refractory hypokalaemia and hypocalcaemia (Mg required for PTH release/action), tremor, tetany, and arrhythmias (long QT, torsades). Correct magnesium to fix the others.

Give the main causes of hyperphosphataemia and hypophosphataemia.

Hyperphosphataemia: CKD/renal failure (commonest), tumour lysis, rhabdomyolysis, hypoparathyroidism. Hypophosphataemia: refeeding syndrome, DKA treatment, hyperparathyroidism, Fanconi syndrome, alcohol, respiratory alkalosis. Severe hypophosphataemia causes muscle weakness, rhabdomyolysis and respiratory failure.

Contrast Bartter syndrome and Gitelman syndrome (inherited tubular disorders).

Bartter: defect in the thick ascending loop of Henle ($Na^{+}/K^{+}/2Cl^{-}$ transporter), mimics loop diuretics; presents in childhood, hypokalaemic metabolic alkalosis with hypercalciuria and normal/low magnesium. Gitelman: defect in distal convoluted tubule $Na^{+}/Cl^{-}$ cotransporter, mimics thiazides; milder, later onset, with hypomagnesaemia and hypocalciuria.

What is Fanconi syndrome and its biochemical hallmarks?

Generalised dysfunction of the proximal tubule causing impaired reabsorption of glucose, amino acids, phosphate, bicarbonate and uric acid. Results in glycosuria (with normal blood glucose), aminoaciduria, phosphaturia (hypophosphataemia), type 2 RTA and polyuria. Causes: cystinosis, Wilson's, myeloma, tenofovir, heavy metals.

What is Liddle syndrome and how does it present?

Autosomal dominant gain-of-function mutation of the epithelial sodium channel (ENaC) in the distal nephron causing excess sodium reabsorption. Presents with early hypertension, hypokalaemia and metabolic alkalosis but LOW renin and LOW aldosterone (mimics hyperaldosteronism). Responds to amiloride/triamterene, not spironolactone.