R12 Tubulointerstitial Diseases

• Low Grade Proteinuria (vs GN)
• -may have elevated protein, but not nephrotic range
• -Tubular dysfunction prevents PT reabsorption of filtered proteins

• Urinary Casts
• -don't typically see red cell casts
• -may see white cell casts

• Tubular Dysfunction
• -RTA, Fanconi Syndrome problems (NDI)
• -acid secretion and urine concentration

• Elevated serum Cr
• -usually the reason the condition is identified

• -Urine RBCs
• -abdominal pain
• -positive FHx

• -Urine RBCs and WBCs
• -eosinophils in urine and blood
• -rash
• -hx of drug exposure

• -Urine RBCs and WBCs
• -bacteria in urine
• -flank pain
• -fever

• -Urine WBCs
• -bacteria in urine
• -age < 6 yrs

• -Exposure to low BP or tubular toxins
• -Granular casts

• -Proteinuria (sometimes > 3.5 g/dL)
• -Hx of exposure to known offending agent

• 1. Primary
• -initiating renal injury occurs in the interstitial compartment of the kidney
• -may also have secondary abnormalities of the glomeruli (non-specific scarring) with chronic damage

• 2. Secondary
• -occurs secondary to some initiating injury in the glomerular compartment

• -progression of disease correlated with fall in GFR
• -interstitial disease correlates with GFR more than glomerular disease

• Abnormally filtered proteins and lipids activate tubular epithelial cells
• -produce chemokines/proteases
• -cause breaks in the BM and
• -migration of tubular cells into interstitium
• -present Ags/secrete cytokines --> inflammation

Sloughing of epithelial cells can lead to obstructing casts

• 1. Proximal tubules
• -filtered proteins end up in the tubular lumen

• 2. Efferent Arteriole
• -proteins added to the efferent arteriole due to inflammation din the glomerulus
• -in contact with the interstitium

3. Bowan's Capusle Breaks

• 4. Misdirected Filtration
• -normal interdigitations in bowman's capsule
• 

-implicated in the pathogenesis of tubulointerstitial damage and progressive renal disease

-secrete many products that are involved in injury (TGFb)

• 1. Obstruction of tubules
• -diminish downstream flow

• 2. Increased intratubular pressure
• -due to inflammation and swelling
• -backpressure decreases GFR

• 3. Fibrosis
• -decreases blood flow --> ischemia --> more fibrosis

• 4. Atubular glomeruli
• -due to fibrosis
• -glomeruli not connected to tubule

-cause 5-15% of AKI

• Etiology:
• 1. Hypersensitivity reaction to a drug (particularly β-Lactam antibiotics)
• -most common cause
• -Drugs: Abx, NSAIDs, PPIs, diuretics
• 2. Infection
• -not due to direct infection of kidney (vs pyelonephritis)
• -due to hypersensitivity reaction to the microbe
• 3. Autoimmune diseases
• -Sarcoidosis, SLE

• Clinical Presentation:
• -Maculopapular skin rash
• -fever
• -eosinophilia/eosinophiluria
• *triad only present in 30%
• -flank pain (swelling of kidney stretches capsule)
• -less commonly edema and HTN
• -always have an increased serum Cr
• 

• Natural History:
• 1. Classic Time Course
• -onset 10-15 days after drug tx
• 2. Challenge responses
• -AKI within days (ie: took the med 1 year ago with no problems --> rechallenge leads to more rapid response)
• *IMPORTANT: document as an adverse drug reaction

• Lab Findings:
• 1. Urine WBCs, WBC casts
• 
• 
• 2. Microscopic hematuria
• 3. Proteinuria (non-nephrotic range)
• 4. Tubular Function defects
• -elevated FeNa+
• -urine concentrating defects
• -bicarbonaturia
• 5. Renal U/S (normal or symmetrically enlarged kidneys)

• Pathogenesis
• -drugs as haptens bind serum proteins and are processed and presented to T cells
• -molecular mimicry occurs --> cross reactive with BM components
• -immune mediated damage (mostly cell mediated: T cells and macrophages)
• -can get a robust response --> granuloma formation
• **Ab/immune complexes less important

• Pathology:
• 
• -diffuse immune infiltrate in interstitium
• 

IF and EM not typically helpful

• Clinical Presentation:
• -Proteinuria (nephrotic range!)
• -may have HTN, edema
• -lesion may appear after months of treatment
• -more common in elderly (vs MCD in children)
• -rare to have fever, rash or eosinophils

• Pathology:
• -AKI/interstitial nephritis with nil lesion by microscopy (looks like MCD)
• 

• Etiology:
• -immune response to microbial antigen that cross reacts with renal interstitium
• -no direct infection of kidney
• -Bacterial: Strep, E Coli, Legionella
• -Viral: EBV, HIV, CMV, Hantavirus
• -Parasites: Schistosoma

• Treatment:
• -tx infection
• -no specific tx
• -abnormalities may persist longer than infection itself

• Treatment:
• -discontinue possibly offending drugs
• -no controlled medication trials
• -short course of prednisone accelerates tempo of recovery but ultimately leads to same results in GFR and Cr

• Prognosis:
• -renal function typically recovers over 4-6 weeks (IF recognized within 2 weeks of onset)
• -may progress to CKD if initial diagnosis is missed (due to fibrosis)

• Etiology:
• -analgesics
• -uric acid
• -radiation
• -heavy metals (lead)
• -Li
• -urinary tract obstruction
• -advanced kidney disease of any kind
• **may be impossible to determine primary cause

• Clinical Presentation:
• -low grade proteinuria (non-nephrotic range)
• -gradual development (GFR loss over time) --> slower than GN and nephrotic range proteinuria
• -15-30% --> CKD
• -Hypertension is common (vs acute)
• -Tubular defects common

• Pathology:
• -small kidneys
• -bumpy contours (due to scarring)
• 
• -tubular atrophy, interstitial fibrosis, little inflammation

• -MPs and parenchymal cells make TGFb in response to injury
• -TGFb --> augmented interstitial matrix production/inhibition of matrix proteinases
• -TGFb leads to many of the steps involved in fibrosis

• Etiology:
• -long term ingestion of large quantities of analgesics associated with analgesic nephropathy
• -often due to combined use of codeine and/or caffeine with analgesics
• -synergy between aspirin and acetaminophen (aspirin depletes glutathione which is needed to detox an acetaminophen metabolite)

• Analgesic Nephropathy:
• -chronic interstitial nephritis
• -papillary necrosis
• 

• Treatment:
• -discontinuation of drugs can slow/arrest progression of CKD

• Prognosis/Complications:
• -associated with urothelial malignancies (anywhere from renal pelvis to bladder)
• -8-10% of patients

• Etiology:
• -UTIs in children
• -retrograde travel of urine from bladder to kidneys

• Pathophysiology:
• 
• -normal ureter enters bladder at a steep angle --> segment in wall is collapsed during voiding
• -if the segment is shorter there is an increased risk of reflux (usually in children)
• -hydronephrosis (dilation of ureter and calices)
• -chronic can --> renal scarring
• -occasional FSGS
• -can lead to thyroidization of the kidney (proteinacious casts filling the lumen)
• 

• Treatment:
• -conservative management
• -surgical correction in complicated cases

• Etiology:
• -calcineurin inhibitors (immunosuppression)
• -solid organ transplants

Can cause nephrotoxicity

• -Simple Renal Cysts
• -Acquired Renal Cystic Disease (dialysis)
• -Adult Polycystic Kidney Disease
• -Childhood Polycystic Kidney Disease
• -Medullary Sponge Kidney
• -Nephronophthisis (NPHP)
• -VHL disease
• -Tuberous Sclerosis Complex

• Etiology:
• -frequent incidental finding
• -increasing frequency with age

• Pathology:
• -solitary, multiple or bilateral
• -round, smooth with amber fluid

• Prognosis:
• -almost always benign (<1% progress to cancer)

• Etiology:
• -dialysis induced (7-10 years)
• -asymptomatic in 85%

• Pathology:
• -similar to simple cysts
• -calcium deposits

• Prognosis:
• -increased risk of renal cell carcinoma (5-10%)

• Etiology:
• -autosomal dominant
• -most common inherited cystic disease of the kidney

• Pathophysiology:
• -mutations in PC1 (PKD1, 85%) or PC2 (PKD2, 15%) (bothi involved in cilia)
• -bilateral enlarged kidney with cysts in cortex and medulla
• -cysts compress adjacent normal tissue --> scarring and renal failure

• Complications:
• -cysts in the liver, pancreas and spleen
• -ruptured intracerebral berry aneurysm
• -mitral valve prolapse

• Clinical Features:
• -may progress to ESRD
• -cystic bleeding or infection common
• -hematuria and kidney stones common

• Etiology:
• -autosomal recessive
• -rare genetic disorder
• -usually established by U/S at 30-36 weeks

• Pathophysiology:
• -mutations in PKHD1 gene (fibrocystin)
• -bilaterally enlarged sponge-like kidneys with relatively smooth surface
• -may present with oligohydramnios and Potter Sequence (lung hypoplasia, flat face, low set ears, defects of extremities)
• 

• Complications
• -progressive loss of renal function
• -hepatic fibrosis
• -NO increased risk of cancer

• Etiology:
• -relatively uncommon
• 
  Pathophysiology:
• -uniformly dilated collectin ducts

• Clinical Manifestations:
• -usually asymptomatic
• -hematuria, kidney stones
• -"brush like" appearance with IV pyelography

• Etiology:
• -rare
• -most common genetic cause of ESRD in patients <30
• -usually renal failure before age 15

• Pathophysiology:
• -nine affected genes total (all localize to cilia/centrosome complex)

• Pathology:
• -numerous corticomedullary cysts
• -severe atrophy and scarring of cortex
• -smaller kidneys

• Clinical Features:
• -Tubular dysfunction (Na wasting, DI, RTA)

• Etiology:
• -VHL (tumor suppressor gene)

• Pathology:
• -multiple, bilateral clear lined cysts

• Clinical Presentation:
• -linked to a broad range of cancers
• -60% risk of cancer

• Etiology:
• -mutations in TSC1 (hamartin) and TSC2 (tuberin)

• Pathology:
• -generally few cysts
• -angiomyolipomas in the skin, kidney, face and heart

-Cysts form when there is a second hit (somatic mutation) to a cell with a first hit (inherited mutation)



-ADH R antagonists can slow rate of cyst growth in AKD patients (have significant side effects)