Chronic Tubulointerstitial Nephritis & Papillary Necrosis
Quiet urine, failing tubules: find the drug, toxin, or disease
Recognizing chronic tubulointerstitial disease
The urine. Chronic tubulointerstitial nephritis (TIN) leaves a quiet urinalysis. The sediment is bland or shows sterile pyuria with WBC casts, and proteinuria stays under 1–2 g/day. The protein is mostly low-molecular-weight tubular protein such as β2-microglobulin, which the albumin dipstick underestimates, so measure it with a urine protein-to-creatinine ratio.
The tubules fail first. Other findings appear early, before GFR falls much:
- a concentrating defect with polyuria, nocturia, and isosthenuria
- salt wasting
- a non-gap metabolic acidosis with hyperkalemia out of proportion to GFR
- anemia, because the peritubular interstitial cells that make erythropoietin are destroyed
Imaging shows small, scarred kidneys. Hypertension and edema are less prominent than in glomerular disease.
| Feature | Tubulointerstitial | Glomerular |
|---|---|---|
| Proteinuria | <1–2 g/day, tubular proteins | Often heavy, albumin-rich (>3.5 g/day if nephrotic) |
| Sediment | Bland, sterile pyuria, WBC casts | RBC casts, dysmorphic RBCs |
| Tubular function | Polyuria, non-gap acidosis, hyperkalemia | Usually preserved early |
| Other | Early anemia; milder hypertension | Edema, hypertension |
Drugs and toxins
Analgesic nephropathy. This follows years of daily combination analgesics: historically phenacetin, and more recently aspirin–acetaminophen mixtures with caffeine or codeine. The classic patient is a woman with chronic headache or back pain. It causes papillary necrosis and chronic TIN, and CT shows small kidneys with bumpy contours and papillary calcifications. The risk of urothelial carcinoma rises, so hematuria needs evaluation with imaging and cystoscopy.
Lithium. Lithium enters collecting duct principal cells through ENaC, inhibits GSK-3β, and reduces aquaporin-2 insertion. The result is nephrogenic DI with polyuria, thirst, and hypernatremia if water access is limited. Amiloride blocks lithium entry and reduces polyuria. Years of use cause chronic TIN with distal tubular microcysts and a slowly falling GFR. Monitor creatinine, lithium levels, TSH, and calcium; lithium also causes hypothyroidism and hyperparathyroidism. Thiazides, NSAIDs, and ACE inhibitors raise lithium levels. If eGFR keeps falling, decide with psychiatry whether to switch mood stabilizers.
Lead. Chronic exposure comes from battery manufacturing and smelting, renovation of old painted surfaces, and moonshine from lead-soldered stills. It produces chronic TIN with hypertension and saturnine gout, because lead impairs urate excretion. Blood lead reflects recent exposure. The EDTA mobilization test, which measures urine lead after an EDTA dose, reflects the body burden stored in bone. Chelation may slow CKD progression.
Aristolochic acid. Aristolochia plants in some herbal remedies, including slimming preparations, and contaminated grain in Balkan endemic nephropathy cause progressive interstitial fibrosis with small kidneys. Aristolochic acid forms DNA adducts that drive upper tract urothelial carcinoma, so exposed patients need lifelong surveillance.
Systemic and structural causes
Sjögren syndrome. Lymphocytes infiltrate the interstitium and cause distal (type 1) RTA with hypokalemia and an inappropriately alkaline urine, nephrogenic DI, and sometimes nephrocalcinosis or stones. Treat with alkali and potassium, and add glucocorticoids for active TIN.
Sarcoidosis. Sarcoidosis causes granulomatous interstitial nephritis. In addition, macrophage 1α-hydroxylase produces calcitriol, causing hypercalcemia, hypercalciuria, nephrocalcinosis, and stones. Glucocorticoids treat both mechanisms and usually improve kidney function.
Reflux nephropathy. Vesicoureteral reflux with childhood UTIs scars the renal poles, leaving focal cortical scars over clubbed calyces. Adults present with hypertension, proteinuria from secondary FSGS as the remaining nephrons hyperfilter, and progressive CKD. Treatment is ACE inhibition or ARB therapy and blood pressure control. Pregnant women with reflux nephropathy face higher risks of preeclampsia and UTI.
Papillary necrosis
Why the papilla dies. The papillary tip is supplied by a sparse, hypoxic vasa recta circulation. Anything that lowers medullary flow or adds inflammation can infarct it:
- diabetes (the most common cause, often with pyelonephritis)
- analgesic abuse
- sickle cell disease or trait
- pyelonephritis and urinary obstruction
- tuberculosis and cirrhosis
- renal transplant rejection and systemic vasculitis
The mnemonic POSTCARDS covers the causes: Pyelonephritis, Obstruction, Sickle cell, TB, Cirrhosis, Analgesics, Rejection, Diabetes, Systemic vasculitis.
Presentation and imaging. A detached papilla causes gross hematuria. If it lodges in the ureter it causes renal colic, obstruction, infection, or AKI, and tissue fragments may be passed in the urine. CT urography shows contrast encircling a sloughed papilla within its calyx (the "ring sign"), or clubbed and cavitated calyces.
Management. Treat the cause: antibiotics for pyelonephritis, stopping analgesics, controlling diabetes, sickle cell care, and hydration. Relieve obstruction from a lodged papilla with a ureteral stent or nephrostomy, urgently if the obstructed system is infected. Send passed tissue for pathology to confirm the diagnosis and exclude tumor.