Tubular and Interstitial Diseasex

Tubular and Interstitial Disease The Tubulointerstitium • 5-7% of cortex volume • 30% of medulla volume • Components o Fibroblasts  secrete EPO o Dendritic cells: have MHC II  develop peripheral immunity in kidney • Tubulointerstitial disease o Tubular obstruction from interstitial inflammation and fibrosis  obstruct urine flow  AKI o Alteration in TG feedback mechanism o Glomerulartubular disconnection: atrophic tubules and glomeruli no longer connected to each other Diseases due to Tubular or Interstitial Problems • AKI • Renal tubular acidosis (RTA) and Fanconi syndrome • Diabetes insipidus • ATN • Acute interstitial nephritis • Chronic interstitial nephritis RTA • Disorders characterized by a normal anion gap (hyperchloremic) metabolic acidosis despite a well-preserved GFR with either hypokalaemia (types 1 and 2) or hyperkalaemia (type 4) • Defect in distal tubules H secretion leads to distal (type 1) RTA • Defect in HCO3- reabsorption in proximal tubule leads to proximal (type 2) RTA • Type 4 RTA (most common) is characterised by ↓aldosterone or ↓responsiveness of CCD to aldosterone Hypokalaemia Distal RTA – Type 1 Proximal RTA – Type 2 Unable to secrete H Unable to reabsorb HCO3- Urine pH >5.5 Urine pH <5.5 (DCT compensate by excreting H) Nephrolithiasis, nephrocalcinosis No renal stones No Fanconi syndrome Fanconi syndrome: glucosuria, phosphaturia, uricaciduria and aminoacidu Sjogren’s, SLE, PBC, autoimmune hep. Myeloma, Wilson’s disease, drugs: tenofovir, acetazolamide Treat with alkali K replacement Same treatment as type 1 but needs more alkali Hyperkalaemia • Type 4 RTA • ↓Production or responsiveness to aldosterone • Associated with DM, NSAIDs, ACEIs, calcineurin inhibitors (cyclosporine, tacrolimus), K-sparing diuretics, high dose heparin • Treatment: synthetic mineralcorticoid such as fludrocortisone Diabetes Insipidus or Polyuria • Polyuria: urine output >3L/day in adults, >2L/m 2 in children • Causes: (in the absence of DM) o Hyponatraemia: due to primary polydipsia o Hypernatraemia: due to:  Central diabetes insipidus  Nephrogenic diabetes insipidus • Primary polydipsia o Primary increase in water intake o Psychiatric illness, including patients on phenothiazine  dry mouth o Hyponatraemia due to dilutional effect of increased water intake • Diabetes insipidus (DI) o Central: posterior pituitary trauma/surgery, brain tumours  deficient ADH production o Nephrogenic: tubular resistance to ADH  Causes: hereditary, lithium, hypercalcaemia, hypokalaemia sickle cell disease or trait • Measure plasma NA and Osmolality o Primary polydipsia: ↓plasma Na with low urine osmolality (<50% of plasma osmolality) o DI: high or normal plasma Na with urine osmolality < plasma osmolality o Urine osmolality >600mOsm/kg excludes DI diagnosis Water Restriction Test • Restrict water intake and measure urine osmolality and volume hourly and plasma Na concentration and osmolarity 2 hourly • If urine osmolarity reaches normal value (>600mOsm/kg) then ADH is sufficient and DI can be ruled out • Once urine osmolality has stabilised on 2 subsequent samples or plasma osmolality reaches 295mOsm/kg then exogenous ADH (desmopressin) administered • Interpretation after desmopressin administration: o Central DI: ↑urine osmolarity, ↓urine volume o Nephrogenic DI: no elevation in urine osmolality o Primary polydipsia: ↑urine osmolarity, >500mOSm/kg after water restriction and no response to desmopressin since endogenous release is intact • Treatment of DI o Mild volume restriction, low Na diet, thiazide diuretic o Desmopressin o Drugs that ↑ADH secretion: clofibrate, carbamazepine or NSAIDs Acute Interstitial Nephritis • Acute, reversible AKI characterised by inflammatory interstitial infiltrates  Causes: o Drugs: usually antibiotics (70-75% of cases) o Infections: 4-10% o Tubulointerstitial nephritis and uveitis (TINU) syndrome o Systemic diseases: sarcoidosis, Sjogren’s, SLE – 10-20% Clinical Presentation of AIN • Previously, methicillin-induced AIN presented classically with fever, rash, arthralgia, eosinophilia • Now, <10% of AIN presents as this because less AIN is caused by methicillin • Usual presentation is with acute or semi-acute loss of renal function within 7-10 days of starting offending drug and absence of significant proteinuria or haematuria and eosinophilia AIN • Eosinophilia is not a very specific or sensitive feature of AIN • Urine shows WBC casts • Cessation of offending drug  renal function does not improve  renal biopsy  definitive diagnosis • Treatment o Offending drug withdrawal o If renal function doesn’t improve in 3-7 days  biopsy o Prednisolone at 1mg/kg/ day for 2 weeks then tapering off over 2-3 months o Treat underlying condition if not drug-induced Chronic Interstitial Nephritis • Progressive scarring and fibrosis of tubulointerstitium, tubular atrophy, macrophage and/or lymphocyte infiltration • All glomerular diseases lead to secondary tubulointerstitial disease due to proteinuria and ischaemia • Presents with o Gradual loss of renal function o Minimal or no proteinuria o Urinary concentration defects o Acidification defects o Anaemia out of proportion to degree of renal dysfunction • Causes o Metabolic disorders: chronic urate nephropathy, hypokalaemia, hypercalcaemia o Drugs: lithium, analgesics, tacrolimus and cyclosporine, cisplatin, indinavir o Heavy metals/toxins: lead, cadmium, aristolochic acid (Balkan nephropathy) o Connective tissue disorders: Sjogren’s, sarcoidosis, SLE Chronic Urate Nephropathy • Before allopurinol, >50% patients with gout had CKD • Most patients had coexisting HTN/metabolic syndrome so difficult to differentiate between urate and HTN contributions to CKD • Uricosuria leads to intratubular sodium urate crystal deposition • Urate crystals can block tubules, rupture into interstitum, granulomatous interstitial nephritis Hypokalaemic Nephropathy • Hypokalaemia for >1month  vacuolar lesions in epithelial tubular cells • Prolonged hypokalaemia  irreversible cystic changes in medulla accompanied by tubular atrophy and interstitial fibrosis • Chronic hypokalaemia causes milk nephrogenic DI by decreasing expression of aquaporin-2 in CD Hypercalcaemic Nephropathy • Hypercalcaemia (>3mmol/L) can lead to AKI by causing transient, reversible renal vasoconstriction • Chronic hypercalcaemia leads to nephrogenic DI by downregulating aquaporin-2 • Long-standing hypercalcaemia and hypercalciuria may lead to tubular cell degeneration  tubular atrophy  interstitial fibrosis • Macroscopic nephrocalcinosis is often defecting on imaging Lithium Nephropathy • Lithium enters principal cells of CD via epithelial Na channels in luminal membrane • Intracellular lithium decreases ability of ADH to reabsorb water thus causing nephrogenic DI • Lithium induced DI treated with amiloride and NOT thiazides • Chronic lithium use  chronic tubulointerstitial disease accompanied by nephrogenic DI Analgesia-Induced Nephropathy • In the past, patients consumed analgesic mixtures often containing phenacetin (metabolised to acetaminophen) and codeine, aspirin and caffeine • Incidence declined after phenacetin • Papillary necrosis and papillary calcification, bumpy contour of the kidney and associated with urothelial malignancy Lead Nephropathy • Rarely seen now as paint, gasoline, etc. are all now unleaded • Lead stored in bones has half-life of 20-30 years and can reenter the circulation during periods of bone recycling • Causes renal, haematological, musculoskeletal, ocular, immunological, neurological, reproductive and developmental abnormalities • Anaemia due to toxic effect of lead on mitochondrial enzyme ACAS (aminolevunilic acid synthetase) which catalyses the first and rate limiting step in haeme synthesis • Acute lead exposure  PCT injury  type 2 RTA and Fanconi syndrome • The classic effect of lead on kidneys is chronic interstitial nephritis • Treatment is chelating regime of repeated injections of EDTA salts Aristolochic Acid Nephropathy and Balkan Endemic Nephropathy • Balkan: contamination of wheat with aristolochic acid from aristolochia clematitis in Balkan region • Brussels: Chinese herb aristolochia fangchi • Disease characterised by severe interstitial fibrosis, progressive renal failure and very high risk of urothelial malignancy • No known treatment Sjogren’s Syndrome • Chronic interstitial nephritis occurs in 25% of patients with Sjogren’s • Sjogren’s leads to proximal (type 2) RTA and less commonly nephrogenic DI • Treatment: steroids, sometimes cytotoxic agents Sarcoidosis • Hyperabsorption of dietary Ca  hypercalciuria in 40% of patients • Common renal manifestations o Nephrolithiasis o Nephrocalcinosis • Non-caseating granulomatous interstitial nephritis can be seen but rarely leads to clinically significant disease • When it occurs in ESRD, is most often due to hypercalcaemia nephropathy rather than interstitial nephritis Steroids are often used for both hypercalcaemia and interstitial nephritis in sarcoidosis