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Clinical Features of Tubulointerstitial Disease
- 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
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Findings: Cystic renal disease
- -Urine RBCs
- -abdominal pain
- -positive FHx
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Findings: Acute Interstitial Nephritis
- -Urine RBCs and WBCs
- -eosinophils in urine and blood
- -rash
- -hx of drug exposure
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Findings: Acute Pyelonephritis
- -Urine RBCs and WBCs
- -bacteria in urine
- -flank pain
- -fever
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Findings: Vesicouteral Reflux
- -Urine WBCs
- -bacteria in urine
- -age < 6 yrs
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Findings: Acute Tubular Injury
- -Exposure to low BP or tubular toxins
- -Granular casts
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Findings: Chronic Interstitial Nephritis
- -Proteinuria (sometimes > 3.5 g/dL)
- -Hx of exposure to known offending agent
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Primary vs Secondary Interstitial Nephritis
- 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
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Interstitial Disease Correlated with GFR
- -progression of disease correlated with fall in GFR
- -interstitial disease correlates with GFR more than glomerular disease
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Effects of Urinary Proteins on Tubular Cells
- 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
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Points of direct communication between proteins and glomerular ultrafiltrate and the tubulointerstitium
- 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

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Macrophages and tubulointerstitial damage
-implicated in the pathogenesis of tubulointerstitial damage and progressive renal disease
-secrete many products that are involved in injury (TGFb)
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Mechanisms of reduced renal function in TIN
- 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
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Acute Interstitial Nephritis
-Etiology
-Clinical Presentation
-Natural History/Course
-Lab Findings
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Acute Interstitial Nephritis
-Pathogenesis
-Pathology
- 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
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Acute Interstitial Nephritis
-NSAIDs
- 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)

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Acute Interstitial Nephritis
-Infection-related
- 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
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Acute Interstitial Nephritis
-Treatment
-Prognosis
- 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)
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Chronic Interstitial Nephritis
- 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
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Role of Growth Factors in Fibrosis
- -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
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Analgesic Nephropathy: Chronic Drug-Induced Interstitial Nephritis
- 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
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Reflux Nephropathy
- 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
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Calcineurin Inhibitor Nephrotoxicity
- Etiology:
- -calcineurin inhibitors (immunosuppression)
- -solid organ transplants
Can cause nephrotoxicity
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Renal Cystic Diseases
- -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
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Simple Renal Cysts
- 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)
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Acquired Cystic Renal Disease
- 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%)
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Adult Polycystic Kidney Disease (ADPKD)
- 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
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Childhood Polycystic Kidney Disease (ARPKD)
- 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
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Medullary Sponge Kidney
- Etiology:
- -relatively uncommon
Pathophysiology:- -uniformly dilated collectin ducts
- Clinical Manifestations:
- -usually asymptomatic
- -hematuria, kidney stones
- -"brush like" appearance with IV pyelography
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Nephronophthisis (NPHP)
- 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)
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Von Hippel-Lindau Disease
- Etiology:
- -VHL (tumor suppressor gene)
- Pathology:
- -multiple, bilateral clear lined cysts
- Clinical Presentation:
- -linked to a broad range of cancers
- -60% risk of cancer
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Tuberous Sclerosis Complex
- Etiology:
- -mutations in TSC1 (hamartin) and TSC2 (tuberin)
- Pathology:
- -generally few cysts
- -angiomyolipomas in the skin, kidney, face and heart
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Two Hit Model of Cystic Disease
-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)
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