Chronic interstitial nephritis (CIN), also referred to as chronic tubulointerstitial nephritis (CTIN), is a group of diseases or clinical syndromes characterized primarily by dysfunction of the renal tubules and interstitium, caused by a variety of etiologies. Unlike acute interstitial nephritis (AIN), CIN has a prolonged course, an insidious onset, and often progresses slowly to chronic renal failure. Pathologically, it is characterized by chronic changes, with prominent findings of tubular atrophy and interstitial fibrosis.
Etiology
Hereditary Diseases
Examples include mitochondrial gene mutations.
Metabolic Disorders
These include hypercalcemia, nephrocalcinosis, hyperoxaluria, hypokalemia, hyperuricemia, cystinosis, and methylmalonic acidemia.
Nephrotoxic Drugs or Toxins
These include:
- Analgesics and Anti-inflammatory Drugs: Such as NSAIDs.
- Heavy Metals: Including cadmium, lead, lithium, and mercury.
- Herbal Medicines: Especially those containing aristolochic acid.
- Immunosuppressants: Such as cyclosporine and tacrolimus.
- Antineoplastic Agents: Including platinum-based drugs, methotrexate, and nitrosourea alkylating agents.
Autoimmune Diseases
Examples include granulomatosis with polyangiitis, IgG4-related diseases, Sjögren's syndrome, systemic lupus erythematosus, TINU syndrome, and sarcoidosis.
Hematologic Diseases
Examples include multiple myeloma, light chain deposition disease, lymphoma, and sickle cell anemia.
Infections
These include complicated pyelonephritis, renal tuberculosis, HIV infection, Epstein-Barr virus infection, and xanthogranulomatous pyelonephritis.
Obstructive Nephropathy
This is caused by tumors, stones, urethral obstruction, or vesicoureteral reflux.
Cystic Kidney Diseases
Examples include juvenile nephronophthisis-medullary cystic disease and polycystic kidney disease.
Other Causes
These include vascular diseases, hypertension, ischemia, and radiation-induced kidney injury.
Pathology
Grossly, the kidneys may appear irregularly shaped and atrophic. In light microscopy, the main findings include interstitial fibrosis and patchy infiltration of chronic inflammatory cells within the interstitium. Tubular lumens may be dilated, with epithelial cell detachment, thickening or destruction of the tubular basement membrane, and tubular atrophy. In the early stages, the glomeruli may appear normal or show minimal changes, surrounded by fibrotic tissue in the later stages, leading to segmental or global glomerulosclerosis. Chronic vascular wall thickening may also develop as the disease progresses.
Pathological features vary depending on the underlying cause:
In chronic pyelonephritis with urinary obstruction, the kidneys may be asymmetrical in size, with uneven surfaces, partial adhesion to the capsule, and varying degrees of renal pelvis and calyceal dilation.
In analgesic nephropathy, characteristic changes include medullary damage, with yellow-brown lipofuscin-like pigments observed in tubular cells. Granular hypertrophy of medullary rays extending through the atrophic cortex, medullary interstitial cell loss, and extracellular matrix accumulation can also be observed. Early renal papillary necrosis may present with microvascular sclerosis around the tubules and patchy tubular necrosis, while late-stage necrotic areas may form calcifications.
Calcineurin inhibitor (e.g., cyclosporine, tacrolimus)-related nephropathy is characterized by vascular proliferative and sclerotic lesions, such as hyaline arteriopathy, thickened vessel walls, and even vascular occlusion, accompanied by tubular atrophy and interstitial fibrosis in a striped pattern with ischemic glomerulosclerosis.
Chronic urate nephropathy is often associated with arteriolosclerosis and glomerulosclerosis. Urate crystals may be observed in the tubules or interstitium, especially in the medulla, in polarized light microscopy in frozen or alcohol-fixed specimens.
In hypokalemic nephropathy, severe vacuolar degeneration of tubules is commonly observed in the renal medulla.
In hypercalcemic nephropathy, tubular calcification and multiple interstitial calcifications are seen.
Clinical Manifestations
The primary clinical features include elevated serum creatinine levels and symptoms or signs resulting from tubulointerstitial damage, which progress slowly and insidiously. These manifestations include persistent low specific gravity of urine, increased nocturnal urination, fatigue, and nausea.
The clinical presentations vary depending on the underlying cause. Analgesic nephropathy may lead to renal papillary necrosis, presenting as renal colic and gross hematuria. IgG4-related kidney disease may be accompanied by retroperitoneal fibrosis, resulting in obstructive nephropathy. Herbal medicine-related kidney damage may manifest as acquired Fanconi syndrome.
Urinalysis may reveal fixed specific gravity urine, renal glycosuria, and non-nephrotic range proteinuria (usually <1.5 g/day), along with red blood cells, white blood cells, and granular casts. Sterile pyuria is often observed.
As glomerular filtration function declines, varying degrees of metabolic acidosis and hyperphosphatemia are commonly seen. Renal tubular acidosis is frequently associated. Between 60% and 90% of patients present with anemia in the early stages, which does not correlate with the degree of glomerular filtration impairment.
Typical imaging findings include reduced kidney size, atrophic scarring, and irregular renal cortical contours. Renal papillary necrosis may occasionally be observed.
Diagnosis
A detailed patient history is essential, including a history of analgesic abuse or other specific drug use, exposure to heavy metals or toxins, chronic pyelonephritis, and systemic diseases. The disease often has an insidious onset, with notable features such as polyuria and increased nocturnal urination.
Routine laboratory tests should evaluate renal function, electrolytes (potassium, calcium, phosphorus), and uric acid. Urinalysis may indicate fixed low specific gravity urine (around 1.010), occasional renal glycosuria, proteinuria (usually <1.5 g/day, with increased low-molecular-weight proteins), red blood cells, white blood cells, and granular casts.
Screening for specific etiologies may require additional tests, such as serum and urine protein electrophoresis, autoimmune disease-related markers (e.g., antinuclear antibodies, antineutrophil cytoplasmic antibodies, IgG4), and infection-related tests (e.g., urinary acid-fast bacilli).
Definitive diagnosis primarily relies on pathological examination. Renal biopsy should be performed promptly when clinical suspicion arises.
Differential Diagnosis
Conditions such as hypertensive nephropathy and atherosclerotic kidney damage, as well as incomplete obstructive nephropathy, also primarily involve tubulointerstitial damage. These conditions should be differentiated based on the patient’s medical history and medication history.
Treatment
Efforts should focus on eliminating causative factors, such as discontinuing implicated drugs or treating infections. However, because CIN often has an insidious onset and is frequently detected at a stage where chronic, irreversible fibrosis dominates, removing the causative factors may not reverse the disease progression. At this stage, treatment is primarily supportive and symptomatic:
- Early use of ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs).
- Blood pressure control.
- Correction of electrolyte imbalances and acid-base disturbances.
- Management of renal anemia using erythropoiesis-stimulating agents or hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs).