14.4 Tubulointerstitial & Inherited Renal Diseases
Key Takeaways
- Acute interstitial nephritis (AIN) is driven by drug-induced hypersensitivity (>75% of cases; NSAIDs, penicillins, cephalosporins, ciprofloxacin, PPIs, allopurinol); the classical triad of fever, rash, and arthralgia is present in only 10–30%, while sterile pyuria and white cell casts are hallmark urinary findings.
- Management of AIN requires immediate withdrawal of the offending drug; if serum creatinine fails to improve within 5–7 days, a prompt course of oral corticosteroids should be initiated to avert permanent chronic interstitial fibrosis.
- Renal tubular acidosis (RTA) presents as normal anion gap (hyperchloraemic) metabolic acidosis: Type 1 (distal defect in intercalated cell H+ secretion, urine pH >5.5 despite acidaemia, hypokalaemia, nephrocalcinosis/stones), Type 2 (proximal bicarbonate wasting, urine pH <5.5 when bicarb low, hypokalaemia, Fanconi syndrome), and Type 4 (hypoaldosteronism, hyperkalaemia, urine pH <5.5).
- Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 (chromosome 16, 85%, earlier ESRD) or PKD2 (chromosome 4, 15%); extra-renal features include hepatic cysts (70–80%), intracranial berry aneurysms (screening MRA if positive family history of SAH), mitral valve prolapse, and diverticulosis; tolvaptan (vasopressin V2 antagonist) slows cyst growth.
- Alport syndrome is an X-linked defect in the alpha-5 chain of type IV collagen (COL4A5) presenting with microscopic haematuria, high-frequency sensorineural deafness, anterior lenticonus, and 'basket-weave' lamina densa on electron microscopy; ~3–5% develop de novo anti-GBM disease post-renal transplant.
Tubulointerstitial nephropathies and inherited nephrogenetic disorders constitute a significant source of diagnostic and management questions in MRCP(UK) Part 1. A firm grasp of drug-induced hypersensitivity mechanisms, acid-base physiology across the collecting duct, genetic loci, and targeted therapies is critical.
1. Acute Interstitial Nephritis (AIN)
Acute interstitial nephritis is an immunologically mediated inflammatory condition characterized by interstitial oedema and inflammatory cellular infiltration of the renal interstitium with secondary tubular damage (tubulitis). Over 75–85% of cases are secondary to adverse drug hypersensitivity reactions.
Culprit Medications
- Antibiotics: Penicillins (amoxicillin, ampicillin, flucloxacillin), cephalosporins, fluoroquinolones (ciprofloxacin), sulfonamides (co-trimoxazole), and rifampicin.
- Proton Pump Inhibitors (PPIs): Omeprazole, lansoprazole, pantoprazole. Key exam pearl: PPI-induced AIN characteristically exhibits an insidious, delayed onset, frequently developing weeks to months after starting the drug, often without any systemic hypersensitivity symptoms.
- Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Ibuprofen, naproxen, celecoxib. Uniquely, NSAIDs can cause concurrent podocyte foot process effacement, presenting as combined AIN and full-blown nephrotic-range proteinuria (minimal change-like picture).
- Other Common Culprits: Allopurinol, thiazide and loop diuretics, immune checkpoint inhibitors (anti-PD-1 / PD-L1 monoclonal antibodies: nivolumab, pembrolizumab).
- Non-Drug Aetiologies: Autoimmune systemic diseases (sarcoidosis with non-caseating granulomas, Sjögren's syndrome, systemic lupus erythematosus), infections (Legionella, leptospirosis, CMV, EBV), and Tubulointerstitial Nephritis with Uveitis (TINU syndrome, seen primarily in adolescents and young women).
Clinical Presentation & Diagnostic Evaluation
- Classical Triad: Fever, maculopapular cutaneous rash, and arthralgia. Crucially, this complete triad is present in only 10–30% of biopsy-proven cases. Its absence must never rule out AIN!
- Urinalysis & Microscopy:
- Sterile Pyuria: Leukocyturia without bacterial bacteriuria on standard culture.
- White Blood Cell (WBC) Casts: Highly specific for acute interstitial inflammation in the absence of active pyelonephritis.
- Proteinuria: Typically mild to moderate (sub-nephrotic, < 1 g/24 hours), except in NSAID-induced AIN.
- Microscopic Haematuria: Present in up to 80% of cases.
- Urinary Eosinophils: Stained via Hansel or Wright stain. While historically tested, urinary eosinophil testing has poor sensitivity and specificity and is no longer recommended by international guidelines to confirm or exclude AIN.
- Definitive Diagnosis: Renal Biopsy is the diagnostic gold standard, demonstrating diffuse interstitial oedema, interstitial infiltration by T-lymphocytes, monocytes, macrophages, plasma cells, and eosinophils, accompanied by invasion of the tubular basement membrane (tubulitis).
Therapeutic Management
- Immediate Drug Withdrawal: Prompt cessation of the offending medication is the single most critical therapeutic intervention.
- Corticosteroid Therapy: If serum creatinine fails to show objective improvement within 5–7 days following drug withdrawal, initiate oral corticosteroids (oral prednisolone 1 mg/kg/day, typically 40–60 mg daily for 2–3 weeks, followed by a taper over 4–6 weeks). Early initiation of steroids significantly reduces the risk of irreversible chronic interstitial fibrosis and permanent loss of GFR.
2. Renal Tubular Acidosis (RTA)
Renal tubular acidosis comprises a clinical group of transport defects that cause normal anion gap (hyperchloraemic) metabolic acidosis ([Na⁺] - [Cl⁻ + HCO₃⁻] = 8–12 mmol/L) in the presence of relatively preserved glomerular filtration.
Comparative Physiology of RTA Types 1, 2, and 4
| Feature | Type 1 (Distal RTA) | Type 2 (Proximal RTA) | Type 4 (Hyperkalaemic RTA) |
|---|---|---|---|
| Primary Defect | Impaired H⁺ secretion by α-intercalated cells in medullary collecting duct | Impaired HCO₃⁻ reabsorption in proximal convoluted tubule | Aldosterone deficiency or resistance at cortical collecting duct |
| Minimum Urine pH | Fundamentally > 5.5 (cannot acidify urine even during severe acidaemia) | < 5.5 when plasma HCO₃⁻ is low (distal acidification intact) | < 5.5 (distal H⁺ pumps work, but NH₄⁺ buffer is deficient) |
| Serum Potassium | Hypokalaemia (distal K⁺ wasting) | Hypokalaemia (distal delivery of Na⁺ and HCO₃⁻ wastes K⁺) | Hyperkalaemia (pathognomonic hallmark) |
| Nephrocalcinosis & Stones | Frequent (bilateral calcium phosphate stones due to high urine pH, hypercalciuria, hypocitraturia) | Absent (urine can be acidified, urinary citrate excretion is normal) | Absent |
| Associated Features | Systemic osteomalacia / rickets, sensorineural deafness (genetic forms) | Fanconi Syndrome (glucosuria with normal blood sugar, phosphaturia, aminoaciduria, hypouricaemia) | Mild acidosis; hyperkalaemia out of proportion to GFR reduction |
| Common Aetiologies | Autoimmune: Sjögren's syndrome, SLE, rheumatoid arthritis; Amphotericin B, lithium | Multiple myeloma (light chains), Wilson's disease, cystinosis, tenofovir, expired tetracyclines | Diabetic nephropathy (hyporeninaemic hypoaldosteronism), Addison's, ACEi/ARBs, spironolactone, trimethoprim |
| Diagnostic Test | Ammonium chloride (NH₄Cl) challenge test: urine pH remains > 5.3 | Sodium bicarbonate infusion test: fractional excretion of HCO₃⁻ > 15% | Positive urinary net charge ([Na⁺ + K⁺] - Cl⁻ > 0) with hyperkalaemia |
| Treatment | Oral sodium bicarbonate or potassium citrate (corrects both acidosis and hypokalaemia) | High-dose oral bicarbonate (large doses required due to urinary wasting), thiazides | Low-potassium diet, loop diuretics (furosemide), oral fludrocortisone in primary deficiency |
Urine Net Charge (Anion Gap): In normal anion gap metabolic acidosis, the kidney should increase ammonium (NH₄⁺) excretion paired with chloride (Cl⁻). The urinary net charge ([Na⁺ + K⁺] - Cl⁻) estimates urinary ammonium. In GI bicarbonate loss (diarrhoea), the urinary net charge is negative (normal renal response). In distal RTA (Type 1 and Type 4), ammonium excretion is impaired, resulting in a positive urinary net charge.
3. Autosomal Dominant Polycystic Kidney Disease (ADPKD)
ADPKD is the most common monogenic cause of end-stage renal disease worldwide, affecting approximately 1 in 400 to 1 in 1,000 live births.
Molecular Genetics
- PKD1 Gene Mutation (~85% of cases): Located on chromosome 16p13.3. Encodes polycystin-1, a high-molecular-weight integral membrane glycoprotein localized to primary cilia that acts as a mechanoreceptor. Patients with PKD1 mutations exhibit more severe disease, earlier onset of hypertension, larger kidney volumes, and earlier ESRD (median age ~53–58 years).
- PKD2 Gene Mutation (~15% of cases): Located on chromosome 4q21. Encodes polycystin-2, a calcium-permeable transient receptor potential (TRPP2) cation channel. Clinically milder phenotype, with later onset of hypertension and deferred ESRD (median age ~74 years).
- Pathophysiological Cascade: Disrupted ciliary polycystin signalling reduces intracellular calcium and paradoxically upregulates intracellular cyclic adenosine monophosphate (cAMP). High cAMP activates protein kinase A, driving aberrant tubular epithelial proliferation and CFTR-mediated transepithelial fluid secretion, producing progressively expanding, fluid-filled cysts.
Clinical Manifestations
- Renal: Bilateral massive nephromegaly; early hypertension (intra-renal vascular stretching stimulates local RAAS hyperactivation before eGFR declines); bilateral flank/loin pain; macroscopic haematuria (cyst rupture into collecting system); recurrent cyst infections / pyelonephritis (requires lipid-soluble antibiotics that penetrate cyst walls, such as ciprofloxacin or co-trimoxazole); and nephrolithiasis (uric acid and calcium oxalate stones in 20%).
- Extra-Renal Manifestations:
- Polycystic Liver Disease (Hepatic Cysts): The most common extra-renal feature, found in > 70–80% of patients by age 40. Hepatic synthetic function remains completely normal; symptoms arise purely from massive hepatomegaly (abdominal distension, early satiety).
- Intracranial Berry Aneurysms: Located within the Circle of Willis. Present in 8–12% of all ADPKD patients, rising to 20–25% in those with a positive family history of intracranial aneurysm or subarachnoid haemorrhage (SAH). Rupture causes catastrophic SAH.
- Screening Guidelines: Routine unselected screening is not recommended. Targeted screening with non-contrast Magnetic Resonance Angiography (MRA) is strictly indicated for: (a) family history of intracranial aneurysm or SAH; (b) prior intracranial aneurysm rupture; (c) high-risk professions (e.g. airline pilots, commercial divers); or (d) prior to major elective surgery.
- Cardiovascular: Mitral valve prolapse (present in up to 25%), aortic root dilatation, tricuspid regurgitation, and thoracic/abdominal aortic aneurysms.
- Gastrointestinal: Colonic diverticular disease (significantly increased risk of diverticulitis and colonic perforation, especially post-transplant) and abdominal wall/inguinal hernias.
Diagnosis: Pei-Ravine Ultrasound Criteria
In individuals with a positive family history of ADPKD, ultrasound diagnostic criteria (Ravine criteria, modified by Pei) are stratified by age:
- Age 15–39 years: At least 3 unilateral or bilateral cysts.
- Age 40–59 years: At least 2 cysts in each kidney (bilateral).
- Age >= 60 years: At least 4 cysts in each kidney (bilateral).
- Exclusion of Disease: The complete absence of cysts on high-resolution ultrasound at age >= 30 years has a negative predictive value of > 99%, effectively excluding the diagnosis.
Disease-Modifying Therapy: Tolvaptan
- Mechanism of Action: Tolvaptan is a selective oral vasopressin V2 receptor antagonist. In the collecting duct, endogenous arginine vasopressin (AVP) binds to basolateral V2 receptors, activating adenylyl cyclase and boosting intracellular cAMP. Tolvaptan competitively inhibits V2 receptors, lowering intracellular cAMP and thereby decelerating tubular epithelial cellular proliferation and fluid secretion.
- Clinical Evidence & Indications (NICE TA578): In the TEMPO 3:4 and REPRISE randomized trials, tolvaptan significantly slowed the rate of total kidney volume (TKV) growth and attenuated the annual decline in eGFR. Indicated for adults with CKD stages 1–3 at baseline who demonstrate evidence of rapidly progressive disease (e.g. eGFR decline >= 3 mL/min/1.73 m² per year, or Mayo imaging classification 1C, 1D, or 1E).
- Adverse Effects & Monitoring: Profound aquaresis (polyuria, polydipsia, nocturia, thirst) due to drug-induced nephrogenic diabetes insipidus. Idiosyncratic drug-induced liver injury mandates monthly liver function test (LFT) monitoring for the first 18 months of therapy, then every 3 months thereafter.
4. Alport Syndrome
Alport syndrome is an inherited disorder of type IV collagen basement membrane biosynthesis, characterized by progressive hereditary nephritis, high-frequency sensorineural deafness, and specific ocular lesions.
Molecular Genetics & Pathogenesis
- Inheritance Patterns:
- X-Linked Alport Syndrome (~85% of cases): Mutations in the COL4A5 gene on chromosome Xq22, encoding the alpha-5 chain of type IV collagen. Hemizygous males develop full phenotypic expression with inevitable progression to ESRD by the second to fourth decade. Heterozygous females display variable phenotypes ranging from lifelong isolated microscopic haematuria to overt renal failure (due to random X-chromosome inactivation/lyonization).
- Autosomal Recessive (~15%): Mutations in COL4A3 or COL4A4 on chromosome 2.
- Type IV collagen heterotrimers (specifically the alpha-3-alpha-4-alpha-5(IV) network) form the fundamental structural backbone of mature basement membranes in the glomerulus, cochlea, and anterior eye. Failure of normal heterotrimer assembly leaves the thinner, developmentally primitive alpha-1-alpha-1-alpha-2(IV) network, which is mechanically fragile and vulnerable to proteolytic degradation.
Clinical Triad
- Progressive Nephropathy: Microscopic haematuria from early childhood; intermittent macroscopic haematuria precipitated by viral infections; progressive proteinuria; hypertension; and progressive decline to ESRD in early adult life in affected males.
- Sensorineural Hearing Loss: Bilateral, symmetrical, progressive high-frequency sensorineural deafness. Typically absent in infancy; manifests in late childhood or early adolescence.
- Ocular Abnormalities: Pathognomonic anterior lenticonus (bilateral conical protrusion of the central anterior lens capsule into the anterior chamber, causing progressive axial myopia; virtually specific to Alport syndrome), central perimacular flecks (yellow-white punctate dots surrounding the fovea), and corneal endothelial vesicles.
Histopathology
- Light Microscopy: Segmental glomerulosclerosis, tubular atrophy, and prominent interstitial lipid-laden foam cells.
- Electron Microscopy (Pathognomonic): Irregular thickening, thinning, and longitudinal splitting/lamellation of the lamina densa of the glomerular basement membrane, producing a classic "basket-weave" appearance.
Management & Post-Transplant Complication
- Renoprotection: Early initiation of ACE inhibitors or ARBs at the first sign of microalbuminuria substantially delays progression to ESRD.
- Renal Allograft Transplantation & De Novo Anti-GBM Disease: Kidney transplantation is the definitive treatment for ESRD. However, approximately 3–5% of transplanted Alport males develop de novo anti-GBM crescentic glomerulonephritis in the donor allograft. Because the recipient's native immune system was never exposed to the normal alpha-3-alpha-4-alpha-5(IV) collagen chains, it mounts a vigorous humoral immune response against the donor kidney's normal basement membrane.
A 62-year-old woman with a history of hypertension, type 2 diabetes, and gastro-oesophageal reflux disease is referred to the nephrology acute clinic. She has been taking omeprazole 20 mg daily for the past 4 months, amlodipine 5 mg daily for 3 years, and metformin 500 mg twice daily. Routine biochemical screening reveals a serum creatinine of 230 umol/L; her baseline creatinine was 70 umol/L 6 months ago. She feels mildly fatigued but denies fever, skin rash, flank pain, or joint stiffness. Physical examination reveals a blood pressure of 134/78 mmHg, clear chest, and no peripheral oedema. Urinalysis demonstrates pH 6.0, 1+ protein, 2+ blood, leukocyte esterase positive, and nitrites negative. Automated urine microscopy reveals 45 white blood cells per high-power field and white blood cell casts, with no red blood cell casts. Urine bacterial culture is sterile. Full blood count shows a mild peripheral eosinophilia of 0.65 x 10^9/L (normal <0.4 x 10^9/L). Renal ultrasound shows normal-sized kidneys with preserved corticomedullary differentiation and no hydronephrosis. What is the most appropriate initial management step?
A 38-year-old woman with a 5-year history of primary Sjögren's syndrome presents to the emergency department complaining of progressive, severe muscle weakness in her legs, generalised muscle cramps, and paresthesias. Physical examination reveals symmetrical proximal lower limb weakness (power 3/5) and depressed deep tendon reflexes. Blood investigations demonstrate: Sodium 141 mmol/L, Potassium 2.3 mmol/L, Chloride 115 mmol/L, Bicarbonate 13 mmol/L, Urea 5.1 mmol/L, Creatinine 78 umol/L. Arterial blood gas on room air shows: pH 7.27, PaCO2 3.8 kPa, PaO2 12.8 kPa, Bicarbonate 12.8 mmol/L, Base excess -12 mmol/L. The calculated serum anion gap is 13.2 mmol/L. Simultaneous spot urine biochemistry reveals: Urine pH 6.8, Urine sodium 42 mmol/L, Urine potassium 38 mmol/L, Urine chloride 24 mmol/L. The calculated urinary net charge ([Na+ + K+] - Cl-) is +56 mmol/L. Renal ultrasound reveals bilateral medullary nephrocalcinosis. What is the fundamental cellular mechanism responsible for this patient's disorder?
A 32-year-old man with autosomal dominant polycystic kidney disease (ADPKD) attends the specialized inherited kidney disease clinic. His father developed end-stage renal disease at age 52 and died of a subarachnoid haemorrhage at age 56. Genetic analysis confirmed a pathogenic mutation in the PKD1 gene on chromosome 16. The patient's blood pressure is well controlled at 122/76 mmHg on losartan 100 mg once daily. His serum creatinine is 108 umol/L, corresponding to an eGFR of 76 mL/min/1.73 m² (CKD stage G2A1). Over the past 2 years, serial volumetric MRI imaging has demonstrated rapid total kidney volume (TKV) expansion of 8.2% per year, placing him in Mayo risk class 1E. The supervising nephrologist recommends initiating disease-modifying therapy with tolvaptan to slow the rate of renal function decline. By what cellular mechanism does tolvaptan exert its therapeutic effect in ADPKD?