Tubulointerstitial Chronic Kidney Disease

Tubulointerstitial chronic kidney disease is progressive loss of kidney function in which the dominant lesion is interstitial fibrosis, tubular atrophy and a mononuclear cell infiltrate, with glomeruli relatively spared until late. It accounts for a substantial minority of chronic kidney disease worldwide and is frequently under recognised because the urinalysis is bland and proteinuria is modest.

Because tubular function fails before glomerular filtration, patients often present with polyuria, nocturia, anaemia out of proportion to the glomerular filtration rate, and metabolic acidosis, before the creatinine rises.

Main causes

• Reflux nephropathy and chronic pyelonephritis with scarring, and chronic obstruction.
• Drugs and toxins: analgesic combinations, long term NSAIDs, lithium, calcineurin inhibitors, aristolochic acid (herbal remedies, Balkan endemic nephropathy), lead, cadmium, proton pump inhibitor related interstitial nephritis that has become chronic.
• Metabolic: chronic hypercalcaemia and nephrocalcinosis, chronic hypokalaemia, hyperuricaemia, hyperoxaluria.
• Immune and systemic: sarcoidosis, Sjögren syndrome, IgG4-related disease, tubulointerstitial nephritis with uveitis, systemic lupus erythematosus, granulomatosis with polyangiitis.
• Haematological: sickle cell disease, myeloma cast nephropathy, light chain proximal tubulopathy.
• Radiation nephritis and chronic kidney disease of uncertain aetiology in agricultural workers (heat stress, dehydration, agrochemicals).

Pathophysiology. Initial tubular injury, hypoxia and inflammation lead to activation of fibroblasts and myofibroblasts, peritubular capillary rarefaction and irreversible nephron loss. Interstitial fibrosis correlates more closely with eventual kidney function than does the glomerular lesion.

• Often asymptomatic until stage G3b to G4. Polyuria and nocturia (impaired concentrating ability), salt craving, and recurrent dehydration in salt wasting forms.
• Blood pressure is normal early, in contrast to glomerular disease, and rises later.
• Early anaemia (loss of erythropoietin producing peritubular fibroblasts), non-anion gap acidosis (type 1 or type 4 renal tubular acidosis), hyperkalaemia out of proportion to eGFR, and hyperchloraemia.
• Low grade proteinuria, typically albumin:creatinine ratio under 70 mg/mmol and protein excretion under 1.5 g daily; nephrotic range proteinuria suggests secondary focal segmental glomerulosclerosis.
• Specific features: flank pain and haematuria with papillary necrosis (analgesic, sickle cell, diabetes); stones and urinary tract infections in reflux or obstruction; dry eyes and mouth in Sjögren syndrome; uveitis, arthralgia and rash in sarcoidosis; pancreatitis, sialadenitis and retroperitoneal fibrosis in IgG4-related disease; renal colic with passage of sloughed papillae.

Red flags

• Rapid decline in eGFR (more than 5 mL/min/1.73 m² within a year) in a patient with presumed chronic interstitial disease: look for acute interstitial nephritis, obstruction or myeloma.
• Serum calcium above 2.6 mmol/L, anaemia with raised globulin gap, or monoclonal band.
• Painless macroscopic haematuria in a long term analgesic or aristolochic acid user: urothelial carcinoma risk is raised and needs cystoscopy.
• Hypokalaemia below 3.0 mmol/L or severe polyuria above 3 litres daily.

Initial tests

• Creatinine based eGFR with cystatin C for confirmation, urea, electrolytes, bicarbonate, calcium, phosphate, magnesium, urate, parathyroid hormone, full blood count, ferritin and transferrin saturation.
• Urinalysis: usually bland, sterile pyuria, white cell casts in active disease, low grade protein. Urine albumin:creatinine and protein:creatinine ratios; a protein:creatinine ratio much greater than the albumin:creatinine ratio indicates tubular proteinuria.
• Tubular markers: urinary beta-2 microglobulin, alpha-1 microglobulin or retinol binding protein (raised), urinary pH (fixed above 5.5 in distal acidosis despite acidaemia), urinary osmolality after overnight water restriction (under 500 mOsm/kg indicates concentrating defect), fractional excretion of sodium.

Imaging

• Ultrasound: small kidneys with irregular cortical scars (reflux, pyelonephritis) or small smooth kidneys with increased echogenicity; nephrocalcinosis; papillary calcification; hydronephrosis. Isotope DMSA scan defines scarring and differential function.

Causal workup (targeted)

• Serum and urine protein electrophoresis with serum free light chains, angiotensin converting enzyme level and chest imaging, antinuclear antibodies, anti-Ro and anti-La, serum IgG subclasses (IgG4 above 1.35 g/L), HLA typing where relevant, blood lead, urinary heavy metals, drug and herbal history.

Biopsy

• Indicated when the cause is uncertain, the eGFR is falling faster than expected, or immunosuppression is being considered. Diffuse interstitial fibrosis above 50% of cortex with tubular atrophy indicates limited reversibility. Granulomas suggest sarcoidosis; storiform fibrosis and IgG4-positive plasma cells suggest IgG4-related disease; lymphoplasmacytic infiltrate with tubulitis suggests ongoing immune injury.

Differential diagnosis

• Glomerular disease with secondary tubulointerstitial fibrosis (distinguished by heavy albuminuria, haematuria, red cell casts).
• Hypertensive nephrosclerosis and ischaemic nephropathy (hypertension, atherosclerosis, bruits).
• Polycystic kidney disease and nephronophthisis (cysts, family history).
• Myeloma and light chain tubulopathy.
• Obstructive uropathy.

First line: remove the cause

• Stop all NSAIDs and combined analgesics, aristolochic acid products, and unnecessary proton pump inhibitors. Avoid nephrotoxins and iodinated contrast where possible.
• Treat obstruction and reflux complications: relieve obstruction, treat infection promptly, correct stones. Refer urology for surgery in recurrent infection with scarring.
• Correct hypercalcaemia (stop calcium and vitamin D supplements, thiazides), treat hypokalaemia, and treat hyperuricaemia only if gout or urate stones (allopurinol 100 mg daily, increase by 100 mg every 2 to 4 weeks to a maximum of 600 mg daily, with lower starting dose when eGFR is under 30).
• Lithium: involve psychiatry before changing. Aim for the lowest effective level (0.4 to 0.8 mmol/L), measure levels every 3 to 6 months and eGFR every 3 to 6 months. If polyuric nephrogenic diabetes insipidus is troublesome, amiloride 5 to 10 mg daily (monitor potassium, hold if above 5.5 mmol/L) can be added. Consider an alternative mood stabiliser if eGFR falls by 25% or more.

Immune mediated disease

• Sarcoid, Sjögren syndrome, tubulointerstitial nephritis with uveitis: prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) for 2 to 4 weeks, then taper over 8 to 12 weeks according to creatinine and the underlying disease. Maintain on 5 to 10 mg daily for at least 6 months if relapses occur.
• IgG4-related disease: prednisolone 30 to 40 mg daily for 2 to 4 weeks, reduced by 5 mg every 1 to 2 weeks to 5 mg daily, then continue for 3 to 6 months. For relapse or steroid dependence, rituximab 1 g intravenously on days 1 and 15.
• Biopsy with more than 50% fibrosis usually gains little from immunosuppression; weigh the risk of infection and diabetes.

Slow progression

• Blood pressure target below 130/80 mmHg. If albuminuria is present, an ACE inhibitor or angiotensin receptor blocker (for example ramipril 2.5 mg daily increased to 10 mg daily), checking creatinine and potassium at 1 to 2 weeks; accept a creatinine rise up to 30%, and stop if potassium exceeds 6.0 mmol/L.
• SGLT2 inhibitor: dapagliflozin 10 mg daily when eGFR is at least 25, or empagliflozin 10 mg daily when eGFR is at least 20. Hold on days of vomiting or dehydration, because tubular patients are especially volume sensitive.
• Sodium bicarbonate 500 mg to 1 g orally two to three times daily to keep serum bicarbonate at least 22 mmol/L.
• Salt wasting phenotype: do not restrict sodium; sodium chloride supplements 2 to 6 g daily in divided doses, adjusted to postural blood pressure and weight. Maintain generous fluid intake (2 to 3 litres daily, more in hot weather).

Complication care. Treat anaemia, mineral and bone disorder and acidosis at the usual thresholds. Screen for urothelial cancer if analgesic or aristolochic exposure.

Referral and escalation. Refer to nephrology for any unexplained progressive tubulointerstitial disease, eGFR under 30 mL/min/1.73 m², suspected immune mediated disease or biopsy need. Plan renal replacement therapy when eGFR is falling toward 10 to 15.

Special groups

• Children: reflux and dysplasia dominate; early referral to paediatric nephrology.
• Pregnancy: chronic tubulointerstitial disease with eGFR above 60 usually tolerates pregnancy; monitor blood pressure and urinary infection monthly; stop ACE inhibitors before conception.