R12 Tubulointerstitial Diseases

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R12 Tubulointerstitial Diseases
2013-03-09 18:47:19
Renal II

Renal II
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  1. 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

  2. Findings: Cystic renal disease
    • -Urine RBCs
    • -abdominal pain
    • -positive FHx
  3. Findings: Acute Interstitial Nephritis
    • -Urine RBCs and WBCs
    • -eosinophils in urine and blood
    • -rash
    • -hx of drug exposure
  4. Findings: Acute Pyelonephritis
    • -Urine RBCs and WBCs
    • -bacteria in urine
    • -flank pain
    • -fever
  5. Findings: Vesicouteral Reflux
    • -Urine WBCs
    • -bacteria in urine
    • -age < 6 yrs
  6. Findings: Acute Tubular Injury
    • -Exposure to low BP or tubular toxins
    • -Granular casts
  7. Findings: Chronic Interstitial Nephritis
    • -Proteinuria (sometimes > 3.5 g/dL)
    • -Hx of exposure to known offending agent
  8. 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
  9. Interstitial Disease Correlated with GFR
    • -progression of disease correlated with fall in GFR
    • -interstitial disease correlates with GFR more than glomerular disease
  10. 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

  11. 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
  12. Macrophages and tubulointerstitial damage
    -implicated in the pathogenesis of tubulointerstitial damage and progressive renal disease

    -secrete many products that are involved in injury (TGFb)
  13. 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
  14. Acute Interstitial Nephritis
    -Clinical Presentation
    -Natural History/Course
    -Lab Findings
    -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)
  15. Acute Interstitial Nephritis
    • 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
  16. Acute Interstitial Nephritis
    • 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)
  17. Acute Interstitial Nephritis
    • 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
  18. Acute Interstitial Nephritis
    • 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)
  19. 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
  20. 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

  21. 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
  22. 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
  23. Calcineurin Inhibitor Nephrotoxicity
    • Etiology:
    • -calcineurin inhibitors (immunosuppression)
    • -solid organ transplants

    Can cause nephrotoxicity
  24. 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
  25. 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)
  26. 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%)
  27. 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
  28. 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
  29. Medullary Sponge Kidney
    • Etiology:
    • -relatively uncommon

    • Pathophysiology:
    • -uniformly dilated collectin ducts

    • Clinical Manifestations:
    • -usually asymptomatic
    • -hematuria, kidney stones
    • -"brush like" appearance with IV pyelography
  30. 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)
  31. 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
  32. Tuberous Sclerosis Complex
    • Etiology:
    • -mutations in TSC1 (hamartin) and TSC2 (tuberin)

    • Pathology:
    • -generally few cysts
    • -angiomyolipomas in the skin, kidney, face and heart
  33. 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)