# Lecture 11: Tubulointerstitial Diseases ## Unit 2.1: Renal System --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Differentiate tubulointerstitial diseases from glomerular diseases 2. Describe the pathophysiology and causes of acute interstitial nephritis 3. Explain the causes and features of chronic tubulointerstitial nephritis 4. Describe the clinical features of inherited tubular disorders 5. Explain the manifestations of toxic nephropathies 6. Apply diagnostic and management principles to tubulointerstitial diseases --- ## Overview of Tubulointerstitial Diseases Tubulointerstitial diseases affect the tubules and surrounding interstitial tissue while largely sparing the glomeruli, at least initially. This anatomical distinction produces a clinical pattern markedly different from glomerular diseases and allows differentiation based on history, physical examination, and simple laboratory tests. Recognition of these patterns guides appropriate evaluation and management. The clinical features of tubulointerstitial disease contrast sharply with glomerular presentations. Proteinuria remains mild, typically below 1-2 grams per day, because tubular protein reabsorption is impaired while glomerular filtration remains relatively intact. Hematuria occurs rarely, and when present, red blood cell casts—the hallmark of glomerular disease—are absent. Instead, white blood cell casts may appear, reflecting interstitial inflammation. Hypertension develops late in tubulointerstitial disease if at all, whereas glomerular diseases often present with early and prominent hypertension. Tubular dysfunction produces characteristic abnormalities that precede significant GFR decline. Concentrating ability fails early, causing polyuria, nocturia, and isosthenuria (urine osmolality fixed near plasma osmolality). Acidification defects produce renal tubular acidosis before generalized acidemia develops. Sodium wasting may require salt supplementation despite normal volume intake. These functional abnormalities reflect the primary tubular injury and often provide the first clinical clues to diagnosis. Tubulointerstitial diseases divide into acute and chronic forms based on temporal course and histologic findings. Acute interstitial nephritis (AIN) develops over days to weeks, typically in response to drugs or infections. Chronic tubulointerstitial nephritis evolves over months to years from diverse causes including reflux, analgesics, and obstruction. Panel A: Tubulointerstitial disease histology showing inflammatory infiltrate around tubules with normal-appearing glomerulus preserved. Panel B: Glomerular disease histology showing damaged glomerulus with protein leaking through the filtration barrier. Panel C: Clinical features comparison with tubulointerstitial disease showing mild proteinuria, no RBC casts, WBC casts possible, late hypertension, early concentrating defect, and early RTA versus glomerular disease showing heavy proteinuria, hematuria with RBC casts, and early hypertension. Panel D: Urinalysis microscopy showing WBC cast characteristic of tubulointerstitial disease versus RBC cast characteristic of glomerular disease. --- ## Acute Interstitial Nephritis: Causes and Pathogenesis Acute interstitial nephritis accounts for 10-15% of cases of acute kidney injury, making it an important consideration in the differential diagnosis of rising creatinine. Drug-induced AIN predominates, causing 70-75% of cases, while infections, autoimmune conditions, and idiopathic cases comprise the remainder. The list of drugs implicated in AIN is extensive and continues to grow. Beta-lactam antibiotics represent the classic cause, with penicillins, cephalosporins, and carbapenems all capable of triggering the reaction typically 1-3 weeks after initiating therapy. NSAIDs cause AIN through a somewhat different mechanism and may be accompanied by nephrotic-range proteinuria from an associated minimal change-like lesion. Proton pump inhibitors have emerged as increasingly recognized causes, often with insidious onset weeks to months after starting therapy. Other common culprits include sulfonamides, fluoroquinolones, rifampin, and allopurinol. Infectious causes include acute pyelonephritis with extension to the interstitium, viral infections (Epstein-Barr virus, cytomegalovirus), and atypical bacteria such as Legionella. Autoimmune conditions associated with AIN include sarcoidosis, Sjögren syndrome, systemic lupus erythematosus, and IgG4-related disease. Tubulointerstitial nephritis with uveitis (TINU syndrome) represents a specific entity primarily affecting adolescents and young adults. The pathogenesis of drug-induced AIN involves type IV (delayed-type) hypersensitivity mediated by T lymphocytes. The offending drug acts as a hapten, binding to tubular proteins and creating a neoantigen that triggers immune recognition. This mechanism explains why AIN is not dose-dependent—even small amounts of the offending drug can trigger a reaction in sensitized individuals. T cells infiltrate the interstitium, releasing cytokines that recruit additional inflammatory cells and damage tubular epithelium. Panel A: Drug causes in descending frequency showing beta-lactam antibiotics (penicillins, cephalosporins, carbapenems), NSAIDs, proton pump inhibitors, quinolones, sulfonamides, and rifampin, with typical onset 1-3 weeks after exposure (longer for PPIs). Panel B: Type IV hypersensitivity pathogenesis showing drug acting as hapten binding to tubular protein, creating neoantigen triggering T-cell recognition, T-cell infiltration of interstitium, cytokine release, and tubular damage. Panel C: Infectious causes including acute pyelonephritis extension, viral infections (EBV, CMV), and atypical bacteria (Legionella). Panel D: Autoimmune causes including sarcoidosis, Sjogren syndrome, systemic lupus erythematosus, IgG4-related disease, and TINU syndrome affecting eyes and kidneys in adolescents and young adults. --- ## Acute Interstitial Nephritis: Clinical Features and Diagnosis The classic triad of drug-induced AIN consists of fever, rash, and peripheral eosinophilia. However, this complete triad appears in fewer than 10% of cases, and each individual component occurs in only a minority of patients. Fever affects 27-50%, rash 15-50%, and eosinophilia 35-50%. The absence of these features should not dissuade the clinician from considering AIN in the appropriate clinical context. Clinical presentation typically includes acute kidney injury of variable severity, from mild creatinine elevation to dialysis-requiring renal failure. Flank pain may be present, reflecting renal capsular stretching from inflammation. Onset generally occurs 1-3 weeks after initiating the offending medication, though proton pump inhibitor-induced AIN may develop months later. NSAID-associated AIN may be accompanied by nephrotic-range proteinuria and edema from a concurrent minimal change-like podocyte injury. Laboratory findings supporting AIN include sterile pyuria and white blood cell casts on urinalysis. Urine eosinophils, once considered a useful diagnostic marker, have limited sensitivity (40-60%) and specificity, making them suggestive but not definitive when present and unhelpful when absent. Peripheral eosinophilia provides additional supportive evidence. Fractional excretion of sodium is variable and does not reliably distinguish AIN from other causes of AKI. Definitive diagnosis requires kidney biopsy, though this is not always performed when clinical suspicion is high and the patient improves after discontinuing the suspected drug. Biopsy reveals interstitial edema (in acute cases), cellular infiltrate composed of T lymphocytes, eosinophils, and plasma cells, and tubulitis (lymphocytes invading tubular epithelium). Granulomas may be present in drug-induced AIN and sarcoidosis. Gallium scanning may show increased uptake but has largely been replaced by clinical assessment and biopsy when needed. Panel A: Classic triad with individual frequencies showing fever (27-50%), rash (15-50%), and eosinophilia (35-50%), with notation that the complete triad appears in fewer than 10% of cases. Panel B: Laboratory findings showing urinalysis with sterile pyuria and WBC casts on microscopy, urine eosinophils on Wright stain (limited sensitivity of 40-60%), and peripheral blood smear with eosinophilia. Panel C: Kidney biopsy histology showing interstitial edema, lymphocytic infiltrate with T lymphocytes and plasma cells, and eosinophils scattered among the infiltrate. Panel D: Tubulitis detail showing lymphocytes invading tubular epithelium as a hallmark finding, with possible granulomas in drug-induced AIN and sarcoidosis. --- ## Acute Interstitial Nephritis: Management The cornerstone of AIN management is identification and removal of the offending agent. Drug discontinuation alone leads to recovery in many patients, particularly when the diagnosis is made early and the drug is promptly stopped. Supportive care includes monitoring renal function, managing fluid and electrolyte abnormalities, and avoiding additional nephrotoxic exposures. The role of corticosteroids in AIN remains controversial. No randomized controlled trials have definitively established their benefit, and available evidence comes from observational studies with inherent limitations. However, these studies suggest that corticosteroids may improve outcomes, particularly when renal function fails to improve within one week of drug discontinuation or when AKI is severe. The typical regimen involves prednisone at 1 mg/kg daily for 2-4 weeks followed by a gradual taper. Prognosis depends on several factors. Early diagnosis and prompt drug discontinuation favor complete recovery. Prolonged duration of AKI before treatment correlates with greater interstitial fibrosis and worse long-term outcomes. Some patients develop chronic kidney disease despite appropriate management, particularly when diagnosis is delayed or the offending agent continues to be administered. NSAID-associated AIN deserves special mention because its pathogenesis may differ from other drug-induced forms, involving both immune-mediated interstitial inflammation and podocyte injury. The accompanying nephrotic syndrome typically resolves with NSAID discontinuation, though corticosteroids may be needed for the interstitial component. Panel A: First step showing removal of the offending agent as the most important intervention, highlighted as the cornerstone of management. Panel B: Decision point at one week assessing for renal function improvement, with continued observation if improving and consideration of corticosteroids (prednisone 1 mg/kg for 2-4 weeks then taper) if no improvement or severe AKI. Panel C: Prognosis factors showing early diagnosis and prompt drug discontinuation favoring complete recovery versus prolonged AKI duration correlating with interstitial fibrosis and CKD risk. Panel D: NSAID-associated AIN as a special case showing dual pathology with interstitial inflammation plus minimal change-like podocyte injury causing nephrotic syndrome, both resolving with NSAID discontinuation. --- ## Chronic Tubulointerstitial Nephritis Chronic tubulointerstitial nephritis develops insidiously over months to years, eventually progressing to end-stage kidney disease if the underlying cause is not addressed. Diverse etiologies share a common final pathway of tubular atrophy, interstitial fibrosis, and ultimately secondary glomerulosclerosis that eventually involves the entire nephron. Chronic obstruction from kidney stones, benign prostatic hyperplasia, or other causes produces back-pressure that damages tubules and triggers fibrosis. Vesicoureteral reflux, particularly when complicated by recurrent urinary tract infections in childhood, causes reflux nephropathy with characteristic polar scarring. Drug and toxin exposure, including chronic analgesic use, lithium, and heavy metals, produces cumulative tubular injury. Metabolic abnormalities such as chronic hyperuricemia and hypercalcemia deposit crystals or calcium in the interstitium. Chronic infections including tuberculosis and chronic pyelonephritis directly damage renal tissue. Inherited conditions including autosomal dominant polycystic kidney disease and medullary cystic disease cause progressive tubulointerstitial damage. Clinical features develop gradually and often remain subtle until significant renal impairment has occurred. Slow progression over months to years is typical. Proteinuria remains mild, usually below 2 grams per day. Concentrating defects produce polyuria and nocturia early in the disease course, often before creatinine elevation becomes apparent. Salt wasting may require sodium supplementation. Type 4 renal tubular acidosis is common. Anemia develops out of proportion to the degree of GFR reduction, reflecting erythropoietin deficiency from destroyed peritubular interstitial cells. Panel A: Categories of causes showing obstruction (stones, BPH), reflux (vesicoureteral reflux), drugs and toxins (analgesics, lithium), metabolic (hyperuricemia, hypercalcemia), infection (TB, chronic pyelonephritis), and inherited conditions (polycystic kidney disease). Panel B: Histology progression from normal tubules and interstitium through inflammatory infiltrate to tubular atrophy and interstitial fibrosis to secondary glomerulosclerosis. Panel C: Early clinical features including concentrating defect with nocturia and polyuria, salt wasting requiring sodium supplementation, and type 4 renal tubular acidosis. Panel D: Late clinical features showing rising creatinine, anemia disproportionate to GFR reduction from erythropoietin deficiency in destroyed peritubular cells, and mild proteinuria typically below 2 g/day. --- ## Specific Chronic Tubulointerstitial Diseases Analgesic nephropathy results from chronic consumption of analgesic combinations, historically phenacetin-containing compounds and now primarily NSAIDs combined with acetaminophen or aspirin. The medullary location of injury reflects high analgesic concentrations achieved through the countercurrent mechanism. Papillary ischemia and direct tubular toxicity produce papillary necrosis, eventually progressing to chronic tubulointerstitial damage. Imaging reveals small kidneys with papillary calcifications. Treatment requires complete cessation of analgesic use and supportive care for CKD. Lithium nephropathy affects a significant proportion of patients on long-term lithium therapy for bipolar disorder. Acute effects include nephrogenic diabetes insipidus, occurring commonly and often early in treatment. Chronic effects include progressive tubulointerstitial nephritis with characteristic tubular cysts and interstitial fibrosis on biopsy. Lithium enters collecting duct cells through ENaC and accumulates, interfering with aquaporin-2 trafficking and causing the concentrating defect. Management includes lithium level monitoring, amiloride for diabetes insipidus (blocks lithium entry), and consideration of alternative mood stabilizers if significant CKD develops. Reflux nephropathy results from vesicoureteral reflux combined with urinary tract infection during childhood. Intrarenal reflux allows infected urine to reach the renal parenchyma, triggering inflammation and scarring. The polar regions (upper and lower poles) are preferentially affected because compound papillae in these areas allow intrarenal reflux more readily. Adults present with hypertension, proteinuria, and chronic kidney disease. Imaging shows atrophic, scarred kidneys. Prevention through early treatment of urinary tract infections and surgical reflux correction in appropriate cases can prevent this condition. Aristolochic acid nephropathy, formerly called Chinese herb nephropathy or Balkan endemic nephropathy, results from exposure to aristolochic acid found in certain herbal preparations and contaminated food. Direct tubular toxicity causes rapidly progressive chronic kidney disease. A unique association with urothelial carcinoma necessitates ongoing surveillance with urinalysis and cystoscopy in affected patients. Panel A: Analgesic nephropathy showing medullary concentration of analgesics leading to papillary ischemia and necrosis, imaging with ring sign, and treatment requiring complete analgesic cessation. Panel B: Lithium nephropathy showing lithium entry into collecting duct cells via ENaC, nephrogenic diabetes insipidus (acute), characteristic tubular cysts and interstitial fibrosis (chronic), and amiloride blocking lithium entry as treatment. Panel C: Reflux nephropathy showing vesicoureteral reflux mechanism with grade III-V reflux, polar scarring pattern on DMSA scan due to compound papillae allowing intrarenal reflux, and adults presenting with hypertension and CKD. Panel D: Aristolochic acid nephropathy showing herbal preparation source, direct tubular toxicity causing rapidly progressive CKD, and unique urothelial carcinoma association requiring lifelong surveillance with cystoscopy and urine cytology. --- ## Inherited Tubular Disorders: Fanconi Syndrome Fanconi syndrome represents generalized dysfunction of the proximal tubule, affecting the reabsorption of essentially all substances normally reclaimed by this nephron segment. The clinical consequences reflect loss of glucose, amino acids, phosphate, uric acid, bicarbonate, and low-molecular-weight proteins into the urine. Glucosuria occurs at normal blood glucose levels because proximal tubular glucose reabsorption is impaired. Generalized aminoaciduria involves all amino acid classes. Phosphaturia causes hypophosphatemia that can produce rickets in children and osteomalacia in adults. Uricosuria leads to hypouricemia, the opposite of what occurs in gout. Bicarbonaturia produces type 2 (proximal) renal tubular acidosis with a low threshold for bicarbonate reabsorption. Low-molecular-weight proteinuria, including beta-2-microglobulin, reflects failure to reabsorb normally filtered small proteins. Inherited causes include cystinosis, the most common genetic cause in children, as well as Wilson disease, galactosemia, hereditary fructose intolerance, and glycogen storage diseases. Acquired causes include multiple myeloma (light chain toxicity), heavy metal poisoning (lead, cadmium, mercury), and medications (tenofovir, outdated tetracyclines). Cystinosis deserves particular attention as the most common inherited cause of Fanconi syndrome. This autosomal recessive disorder results from mutations in the CTNS gene encoding cystinosin, a lysosomal cystine transporter. Without functional cystinosin, cystine accumulates within lysosomes throughout the body. Renal manifestations include Fanconi syndrome in infancy and progressive chronic kidney disease leading to end-stage renal disease by late childhood or adolescence if untreated. Corneal cystine crystals, visible on slit-lamp examination, provide a diagnostic clue. Treatment with cysteamine, which depletes intracellular cystine, slows disease progression when started early. Panel A: Proximal tubule schematic with multiple failing transporters showing SGLT2 (glucosuria at normal blood glucose), amino acid transporters (generalized aminoaciduria), NaPi-IIa (phosphaturia causing hypophosphatemia), and URAT1 (uricosuria causing hypouricemia). Panel B: Additional transport defects showing NHE3/NBC failure (bicarbonaturia causing Type 2 proximal RTA) and megalin/cubilin failure (low-molecular-weight proteinuria including beta-2-microglobulin). Panel C: Causes listed as inherited (cystinosis, Wilson disease, galactosemia, hereditary fructose intolerance) and acquired (multiple myeloma with light chain toxicity, heavy metals including lead, cadmium, mercury, and medications including tenofovir). Panel D: Cystinosis detail showing CTNS gene defect, lysosomal cystine accumulation, corneal cystine crystals on slit-lamp examination, progression to ESRD by late childhood if untreated, and cysteamine treatment depleting intracellular cystine. --- ## Inherited Tubular Disorders: Salt-Wasting Syndromes Bartter syndrome encompasses a group of genetic disorders affecting transport in the thick ascending limb of the loop of Henle. Various mutations in NKCC2, ROMK, ClC-Kb, barttin, or the calcium-sensing receptor produce a phenotype that mimics chronic loop diuretic administration. Impaired sodium chloride reabsorption in the TAL leads to volume depletion that activates the renin-angiotensin-aldosterone system, causing potassium wasting at the collecting duct. The resulting biochemical profile includes hypokalemia, metabolic alkalosis, and hypercalciuria. Clinical presentation typically occurs in infancy or childhood with polyuria, polydipsia, failure to thrive, and sometimes nephrocalcinosis from the hypercalciuria. Treatment involves potassium and magnesium supplementation, and NSAIDs (which reduce prostaglandin-mediated renin release) can improve the phenotype. Gitelman syndrome results from loss-of-function mutations in SLC12A3, encoding the thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule. The phenotype mimics chronic thiazide diuretic administration. Like Bartter syndrome, volume depletion activates RAAS and causes hypokalemia and metabolic alkalosis. However, two key features distinguish Gitelman from Bartter: hypocalciuria (rather than hypercalciuria) and hypomagnesemia. These differences reflect the distinct tubular segments involved—impaired NCC function enhances calcium reabsorption through compensatory mechanisms. Clinical presentation is typically milder than Bartter syndrome and often does not manifest until adolescence or adulthood. Patients may present with muscle cramps, fatigue, or salt craving. Treatment involves potassium and magnesium supplementation; the prognosis is generally good. The comparison between Bartter and Gitelman syndromes illustrates how different tubular segments produce distinct clinical phenotypes despite similar overall patterns of salt wasting. Bartter affects the TAL (loop diuretic effect) with hypercalciuria, while Gitelman affects the DCT (thiazide effect) with hypocalciuria. Age of onset tends to be earlier and disease more severe in Bartter syndrome. Panel A: Bartter syndrome showing thick ascending limb with NKCC2 blocked (or ROMK, ClC-Kb mutations), mimicking chronic loop diuretic use, leading to Na/Cl loss, volume depletion, RAAS activation, and K wasting with hypercalciuria. Panel B: Gitelman syndrome showing distal convoluted tubule with NCC blocked, mimicking chronic thiazide use, leading to K wasting but with hypocalciuria and hypomagnesemia as distinguishing features. Panel C: Comparison table showing site (TAL vs DCT), diuretic mimic (loop vs thiazide), urine calcium (high vs low), magnesium (normal-low vs low), age of onset (childhood vs adolescence/adulthood), and severity (more vs less severe). Panel D: Treatment for both syndromes showing potassium and magnesium supplementation, with NSAIDs reducing prostaglandin-mediated renin release for Bartter syndrome specifically. --- ## Inherited Tubular Disorders: Collecting Duct Liddle syndrome results from gain-of-function mutations in the epithelial sodium channel (ENaC) subunits, causing constitutive channel activation independent of aldosterone regulation. Unregulated sodium reabsorption in the collecting duct produces severe hypertension, typically presenting in childhood or adolescence. The biochemical profile shows hypokalemia and metabolic alkalosis from increased potassium secretion driven by the lumen-negative potential. Critically, aldosterone levels are suppressed rather than elevated, because volume expansion inhibits the renin-angiotensin-aldosterone system. This distinguishes Liddle syndrome from primary aldosteronism, which shares the hypertension and hypokalemia but has elevated aldosterone. Treatment with amiloride, which directly blocks ENaC, is highly effective, while mineralocorticoid receptor antagonists (spironolactone) are ineffective because the channel is constitutively active regardless of aldosterone signaling. Dietary sodium restriction complements pharmacologic therapy. Pseudohypoaldosteronism type 1 represents the opposite defect: loss-of-function mutations in ENaC or the mineralocorticoid receptor cause aldosterone resistance. Despite elevated aldosterone levels, the collecting duct cannot respond, resulting in sodium wasting, hyperkalemia, and metabolic acidosis. Hypotension occurs from volume depletion. Treatment requires generous salt supplementation and potassium restriction; fludrocortisone is ineffective in the ENaC mutation form but may help in milder mineralocorticoid receptor mutations. Nephrogenic diabetes insipidus results from collecting duct resistance to vasopressin (ADH). X-linked forms result from mutations in the V2 vasopressin receptor, while autosomal forms involve aquaporin-2 mutations. Without functional vasopressin signaling, aquaporin-2 water channels are not inserted into the apical membrane, and the collecting duct remains impermeable to water. Patients excrete large volumes of dilute urine despite elevated ADH levels and develop hypernatremia if fluid intake is inadequate. Treatment includes maintaining adequate free water intake, thiazide diuretics (which paradoxically reduce urine volume by inducing mild volume depletion and enhancing proximal reabsorption), amiloride, and a low-sodium, low-protein diet. Panel A: Liddle syndrome showing ENaC gain-of-function stuck in the on position, with increased Na reabsorption creating lumen-negative voltage and increased K secretion, producing severe hypertension, hypokalemia, and suppressed aldosterone, treated with amiloride. Panel B: Pseudohypoaldosteronism type 1 showing ENaC or mineralocorticoid receptor loss-of-function, elevated aldosterone that is ineffective, producing hypotension, hyperkalemia, and metabolic acidosis, treated with generous salt supplementation. Panel C: Nephrogenic diabetes insipidus showing V2 vasopressin receptor or aquaporin-2 defect, vasopressin present but collecting duct impermeable to water, producing massive dilute polyuria and hypernatremia risk. Panel D: Nephrogenic DI treatment showing thiazide diuretics (paradoxical volume contraction enhancing proximal reabsorption), amiloride, and low-sodium low-protein diet to reduce urine volume. --- ## Toxic Nephropathies Heavy metals cause characteristic patterns of tubular injury depending on the specific metal and chronicity of exposure. Lead primarily affects the proximal tubule, producing Fanconi syndrome with acute exposure and chronic tubulointerstitial nephritis with prolonged exposure. The association between lead exposure and "saturnine gout" reflects impaired uric acid excretion. Hypertension commonly accompanies chronic lead nephropathy. Diagnosis relies on blood lead levels and EDTA mobilization testing, which demonstrates increased lead excretion after chelation. Treatment involves chelation therapy and elimination of ongoing exposure. Cadmium similarly targets the proximal tubule, causing Fanconi syndrome and eventually chronic kidney disease. Occupational exposure (battery manufacturing, electroplating) and environmental contamination (contaminated rice, seafood) represent common sources. Unlike lead, cadmium nephropathy may progress even after exposure ceases because cadmium accumulates in renal tissue with a biological half-life of decades. Osteomalacia from phosphate wasting can be severe ("itai-itai disease" in Japan). Mercury affects proximal tubules and may cause proteinuria, acute tubular necrosis, or membranous nephropathy depending on the mercury compound and exposure pattern. Arsenic primarily causes acute tubular necrosis. Aristolochic acid nephropathy produces direct tubular toxicity and rapidly progressive chronic kidney disease. The unique association with urothelial carcinoma (bladder, ureter, renal pelvis) reflects the carcinogenic properties of aristolochic acid-DNA adducts. Lifelong surveillance with urine cytology and periodic cystoscopy is recommended for affected patients. Contrast nephropathy prevention in patients with CKD involves adequate hydration with intravenous normal saline before and after contrast exposure, use of the lowest effective contrast dose, and avoidance of concurrent nephrotoxic medications. The benefit of N-acetylcysteine and sodium bicarbonate remains unproven in modern studies. Panel A: Lead nephropathy showing sources (paint, pipes), proximal tubule injury causing Fanconi syndrome, saturnine gout from impaired uric acid excretion, hypertension, diagnosis with EDTA mobilization testing, and chelation therapy. Panel B: Cadmium nephropathy showing sources (batteries, contaminated rice), proximal tubule damage causing Fanconi syndrome, decades-long renal half-life with progression even after exposure cessation, and osteomalacia from phosphate wasting. Panel C: Mercury causing proximal tubular damage, ATN, or membranous nephropathy depending on compound and exposure pattern, and arsenic causing acute tubular necrosis. Panel D: Contrast nephropathy prevention protocol showing risk identification (GFR below 45), IV normal saline hydration before and after, minimizing contrast dose, and holding concurrent nephrotoxic medications. --- ## Summary Tubulointerstitial diseases affect tubules and interstitium, producing mild proteinuria, absent RBC casts, early concentrating defects, and early renal tubular acidosis—a pattern distinct from glomerular diseases. Acute interstitial nephritis is drug-induced in 70-75% of cases, with beta-lactams, NSAIDs, and proton pump inhibitors among the most common culprits. The classic triad of fever, rash, and eosinophilia occurs completely in fewer than 10% of patients. Treatment involves removing the offending agent and considering corticosteroids if improvement does not occur within one week. Chronic tubulointerstitial nephritis results from obstruction, reflux, analgesics, lithium, and other causes, producing progressive chronic kidney disease. Fanconi syndrome represents generalized proximal tubular dysfunction with glucosuria, aminoaciduria, phosphaturia, and type 2 RTA; cystinosis is the most common inherited cause in children. Bartter syndrome affects the thick ascending limb and mimics loop diuretic use with hypokalemia, alkalosis, and hypercalciuria. Gitelman syndrome affects the distal convoluted tubule and mimics thiazide use with hypokalemia, alkalosis, and hypocalciuria. Liddle syndrome results from ENaC gain-of-function causing hypertension and hypokalemia, treated with amiloride. Toxic nephropathies from lead, cadmium, and aristolochic acid cause proximal tubular damage or chronic tubulointerstitial disease, with aristolochic acid uniquely associated with urothelial carcinoma. --- ## Key Terms | Term | Definition | |------|------------| | Acute interstitial nephritis | Inflammation of tubules and interstitium, most commonly drug-induced | | Chronic tubulointerstitial nephritis | Progressive fibrosis of tubules and interstitium from diverse causes | | Tubulitis | Lymphocyte infiltration of tubular epithelium, a hallmark of AIN | | Fanconi syndrome | Generalized proximal tubular dysfunction affecting multiple transport processes | | Bartter syndrome | Genetic defect in TAL causing salt wasting and mimicking loop diuretic effect | | Gitelman syndrome | Genetic defect in DCT causing salt wasting and mimicking thiazide diuretic effect | | Liddle syndrome | ENaC gain-of-function mutation causing hypertension and hypokalemia | | Reflux nephropathy | Renal scarring from vesicoureteral reflux combined with infection | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*