Chronic Glomerulonephritis

 end-stage glomerular disease

 may result from specific types of glomerulonephritis
 Membranous nephropathy, MPGN, IgA nephropathy, and FSGS all may progress to chronic renal
failure
 develops insidiously and slowly

Morphology

 symmetrically contracted and have diffusely  granular cortical surfaces
 cortex is thinned
 increase in peripelvic fat
 obliteration of glomeruli
 acellular eosinophilic masses
 arterial and arteriolar sclerosis may be conspicuous
 Marked atrophy of associated tubules
 irregular  interstitial fibrosis
 mononuclear leukocytic infiltration of the  interstitium

Glomerular Lesions Associated with Systemic Diseases

 Lupus Nephritis
o recurrent microscopic or gross hematuria
o nephritic syndrome
o rapidly progressive glomerulonephritis
o nephrotic syndrome
o acute and chronic renal failure
o hypertension
 Henoch-Schönlein Purpura
o childhood syndrome
o purpuric skin lesions
 extensor surfaces of arms and legs and buttocks
o abdominal pain
o intestinal bleeding
o arthralgias
o renal abnormalities
o IgA is deposited in the glomerular mesangium
o Ig and C3 deposits in glomeruli
o mild    focal mesangial proliferation
o to diffuse mesangial proliferation  and/or  endocapillary proliferation
o to  crescentic  glomerulonephritis
o pathognomonic feature by fluorescence - deposits of IgA, IgG and C3 in the mesangial
region
 o sometimes extending to the capillary loops
o subepidermal hemorrhages in skin lesions
o necrotizing  vasculitis  involving  the  small  vessels  of  the  dermis
o Vasculitis also occurs in other organs but is rare in the kidney
o recurrences of hematuria may persist for many years
o excellent prognosis

Glomerulonephritis Associated with Bacterial Endocarditis and Other Systemic Infections

 occurring in the course of bacterial endocarditis or other systemic infections

 immune complex nephritis
 complexes of bacterial antigen and antibody
 Hematuria and proteinuria
 RPGN may occur
 may have a MPGN pattern

 Diabetic Nephropathy
o leading cause of chronic kidney failure in the United States
o end-stage kidney disease occurs in as many as 40% of both type
 Fibrillary Glomerulonephritis
o fibrillar deposits in the mesangium and glomerular capillary walls
o resemble amyloid fibrils superficially
o but differ ultrastructurally
o do not stain with Congo red
o membranoproliferative or mesangioproliferative patterns
o deposition of polyclonal IgG4, C3, and Igκ and Igλ light chains
o nephrotic syndrome
o hematuria
o progressive renal insufficiency
o recurs in kidney transplants
 Other Systemic Disorders
o Goodpasture syndrome
o microscopic polyangiitis
o granulomatosis with polyangiitis
 Essential mixed cryoglobulinemia
o deposits of cryoglobulins composed principally of IgG-IgM complexes
o cutaneous vasculitis
o synovitis
o proliferative glomerulonephritis, typically MPGN type 1
o associated with infection with hepatitis C virus
 Tubular and Interstitial Diseases

 Most forms of tubular injury involve the interstitium as well

 two major processes
o ischemic or toxic tubular injury
o tubulointerstitial nephritis

Acute Tubular Injury/Necrosis

 ATI is a clinicopathologic entity

 acute renal failure
 tubular injury; necrosis of tubular epithelial cells
 reversible process
 most common cause of acute kidney injury by 50%
 caused by a variety of conditions:
o Ischemia, due to decreased or interrupted blood flow
 malignant hypertension, HUS, TTP, DIC
o Direct toxic injury to the tubules by endogenous or exogenous agents
 Endogenous - myoglobin, hemoglobin, monoclonal light chains, bile/ bilirubin
 Exogenous - drugs, radiocontrast dyes, heavy metals, organic solvents
 Patterns of ATI
o Ischemic ATI
 severe trauma to acute pancreatitis
 marked hypotension and shock
o Nephrotoxic ATI
 caused by a multitude of drugs, such as gentamicin
o Combinations of ischemic and nephrotoxic ATI
 mismatched blood transfusions
 hemoglobinuria
 myoglobinuria
 Critical events in both ischemic and nephrotoxic ATI
o tubular injury
o persistent and severe disturbances in blood flow
 Ischemia causes numerous structural and functional alterations
o early reversible result of ischemia is loss of cell polarity
o increased sodium delivery to distal tubules
o vasoconstriction via tubuloglomerular feedback
o injured cells detach from the basement membranes and cause luminal obstruction
o increased intratubular pressure
o decreased GFR
o interstitial edema
o increased interstitial pressure
 Disturbances in blood flow
o intrarenal vasoconstriction
o increased distal sodium delivery via tubuloglomerular feedback
o sublethal endothelial injury
o increased release of the vasoconstrictor endothelin
o decreased production of the vasodilators nitric oxide and prostaglandin I2
o repair is dependent on the capacity of reversibly injured epithelial cells to proliferate
and differentiate
o Re-epithelialization is mediated by a variety of growth factors and cytokines produced
locally by the tubular cells
 ATI  is  characterized  by  focal tubular epithelial necrosis
 With tubulorrhexis - rupture  of  basement membrane
 occlusion of tubular lumens by casts
 straight portion of the proximal tubule and the ascending thick limb in the renal medulla are 
especially vulnerable
 focal lesions may also occur in the distal tubule
 Eosinophilic  hyaline  casts
 pigmented  granular  casts
 which are seen in  distal tubules and collecting  ducts
 Tamm-Horsfall protein - urinary glycoprotein secreted by the cells of ascending 
thick  limb  and  distal  tubules
 interstitial  edema and accumulations of leukocytes within dilated vasa  recta
 epithelial regeneration in the  form of flattened epithelial cells
 hyperchromatic nuclei and  mitotic figures
 Toxic ATI – in proximal convoluted tubules
 mercuric chloride - injured cells may contain large acidophilic  inclusions and later
desquamated and undergo calcification
 Carbon tetrachloride poisoning -  accumulation of neutral lipids
 Ethylene glycol - ballooning and hydropic or vacuolar degeneration of PCT
 Calcium oxalate crystals also found in ethylene glycol poisoning
 3 stage of ATI
o Initiation phase
 36 hours
 slight decline in urine output with a rise in BUN
o Maintenance phase
 decreases in urine output to between 40 and 400 mL/day
 salt and water overload, rising BUN concentrations
 hyperkalemia, metabolic acidosis
o Recovery phase
 steady increase in urine volume that may reach up to 3 L/day
 Hypokalemia
Tubulointerstitial Nephritis

 often insidious in onset

 manifest by azotemia
 Secondary tubulointerstitial nephritis is also present in a variety of vascular, cystic, and
metabolic renal disorders

Acute tubulointerstitial nephritis

 interstitial edema
 leukocytic infiltration of the interstitium and tubules
 tubular injury

Chronic interstitial nephritis

 mononuclear leukocytes
 prominent interstitial fibrosis
 tubular atrophy
 Absence of nephritic or nephrotic syndrome
 impaired ability to concentrate urine
 polyuria or nocturia
 salt wasting
 metabolic acidosis

Pyelonephritis and Urinary Tract Infection

 Acute pyelonephritis - bacterial infection

 Chronic pyelonephritis - bacterial infection plays a dominant role
 Pyelonephritis is a serious complication of urinary tract infections
 Cystitis
 Bacterial infections of the lower urinary tract may be asymptomatic
 and often remain localized to the bladder without the development of renal infection
 85% are gram-negative bacilli that are normal inhabitants of the intestinal tract
 Escherichia coli, followed by Proteus, Klebsiella, and Enterobacter
 Streptococcus faecalis, also of enteric origin, staphylococci, and virtually every other bacterial
and fungal agent
 Mycobacterial cause caseating granulomatous inflammation
 fungal organisms induce non-caseating granulomatous inflammation
 polyomavirus, cytomegalovirus, and adenovirus can also be a cause of renal infection especially
when immunocompromised
 two routes by which bacteria can reach the kidneys
o hematogenous infection
o ascending infection
 Ascending infection is the most common cause of clinical pyelonephritis
 Normal human bladder and bladder urine are sterile
 first step in ascending infection is the colonization of the distal urethra and introitus (in the
female) by coliform bacteria
o adhesins on the P-fimbriae (pili) of bacteria
o pap gene
o certain types of fimbriae promote renal tropism, persistence of infection, or an
enhanced inflammatory response
 from the urethra to the bladder
o during urethral catheterization
o In the absence of instrumentation, urinary infections are much more common in
females
 antibacterial properties found in prostatic fluid

Mechanisms by which microbes move from the bladder to the kidney

 Urinary tract obstruction and stasis of urine

 Vesicoureteral reflux
o incompetence of the vesicoureteral valve
o normal ureteral insertion into the bladder is a one-way valve
 Intrarenal reflux
o most common in the upper and lower poles of the kidney
o papillae tend to have flattened or concave tips
o reflux can be demonstrated radiographically by a voiding cystourethrogram

 Acute Pyelonephritis
o suppurative inflammation
o bacterial and sometimes viral
o Hallmarks of acute pyelonephritis
 patchy interstitial suppurative inflammation
 intratubular aggregates of neutrophils
 neutrophilic tubulitis
 tubular necrosis
o Early stages - neutrophilic infiltration is limited to the  tubules
o Glomeruli are relatively resistant  to the infection
o Three  complications
 Papillary necrosis
 usually bilateral but may be unilateral
 One or all  of the pyramids are involved
 tips or distal two thirds of the pyramids have  areas 
of gray-white to yellow necrosis
 coagulative necrosis
 with preservation of outlines  of tubules
 Pyonephrosis
 total or almost complete obstruction
 suppurative exudate is unable to drain
 fills the renal pelvis, calyces, and ureter with pus
 Perinephric abscess
 extension of suppurative inflammation
 renal capsule into the perinephric tissue
o Neutrophilic infiltrate is replaced by one that is predominantly 
composed of macrophages, plasma cells, and lymphocytes
o patchy, jigsaw pattern with intervening preserved  parenchyma
o pyelonephritic scar is almost always associated with
 inflammation
 fibrosis
 deformation of calyx and pelvis
o Acute pyelonephritis is often associated with:
 Urinary tract obstruction
 Instrumentation
 Vesicoureteral reflux
 Pregnancy
 Gender and age
 Preexisting renal lesions
 Diabetes mellitus
 Immunosuppression and immunodeficiency
o polyomavirus nephropathy
 infection of tubular epithelial cell nuclei
 leading to nuclear enlargement and intranuclear inclusions
 inclusions are composed of virions arrayed in distinctive crystal line-like lattices
 immunosuppression of the allograft recipient
 Latent infection with polyomavirus
 Treatment consists of a reduction in immunosuppression
 Chronic Pyelonephritis and Reflux Nephropathy
o chronic tubulointerstitial inflammation and scarring
o involve the calyces and pelvis
o only chronic pyelonephritis and analgesic nephropathy affect the calyces
o divided into two forms:
 Reflux nephropathy
 more common
 superimposition of a urinary infection
 early in childhood
 unilateral or bilateral
 may cause scarring and atrophy of one kidney or involve both
 Chronic obstructive pyelonephritis
 parenchymal atrophy
 can be bilateral - posterior urethral valves
 or unilateral – calculi
o kidneys  usually are irregularly scarred
o involvement is  asymmetric
o In contrast, both kidneys in chronic glomerulonephritis are diffusely 
and symmetrically scarred
o Hallmarks of  chronic pyelonephritis
 coarse, discrete, corticomedullary scars
 dilated, blunted, or deformed calyces
 flattening of the papillae
o Scare are most in the upper and lower poles
o involve predominantly tubules and  interstitium
o Dilated tubules with flattened  epithelium may be filled with casts 
resembling thyroid colloid  (thyroidization)
o inflammation and fibrosis in the cortex and medulla
o Arcuate  and interlobular vessels demonstrate obliterative intimal sclerosis
o In hypertension,  hyaline arteriolosclerosis is seen in the entire kidney
o Glomeruli may appear normal
o Xanthogranulomatous pyelonephritis
 rare  form of chronic pyelonephritis
 accumulation of  foamy macrophages intermingled with plasma 
cells, lymphocytes,  polymorphonuclear  leukocytes, and giant cells
 associated with Proteus infections and obstruction
 lesions sometimes produce large, yellowish orange nodules
o Clinical signs
 back pain, fever, pyuria, and bacteriuria
 gradual onset of renal insufficiency and hypertension
 Reflux nephropathy is often discovered in children
 Loss of tubular function—in particular of concentrating ability
  polyuria and nocturia
 asymmetrically contracted kidneys
 coarse scars and blunting and deformity of the calyceal system
 bacteriuria
 proteinuria is usually mild
 secondary focal segmental glomerulosclerosis with significant proteinuria
 FSGS has poor prognostic sign
 renal ablation nephropathy - pyelonephritic scarring

Tubulointerstitial Nephritis Induced by Drugs and Toxins

 second most common cause of acute kidney injury

 injure kidneys in at least three ways:
o trigger an interstitial immunologic reaction; methicillin
o acute tubular injury
o subclinical but cumulative injury to tubules - unrecognized until irreversible

Acute Drug-Induced Interstitial Nephritis

 after the use of sulfonamides

 most frequently occurs with synthetic penicillins (methicillin, ampicillin)
 other synthetic antibiotics (rifampin)
 diuretics (thiazides)
 NSAIDs
 allopurinol, cimetidine
 analgesic nephropathy - chronic tubulointerstitial nephritis caused by phenacetin-containing
analgesics
 begins about 15 days (range: 2-40) after drug exposure
 fever, eosinophilia, rash
 hematuria, mild proteinuria, and leukocyturia
 rising serum creatinine or acute kidney injury with oliguria
 late-phase reaction of an IgE-mediated (type I) hypersensitivity
 mononuclear or granulomatous reaction
 T cell-mediated (type IV) delayed hypersensitivity reaction
 drugs function as haptens and covalently bind to some plasma membrane or extracellular
component of tubular cells
 interstitium has edema and infiltration by mononuclear cells; lymphocytes  and 
macrophages
 smaller numbers of plasma  cells and mast cells
 may be more prominent in the medulla
 interstitial  nonnecrotizing  granulomas
 Tubulitis is common
 glomeruli are normal except in some cases caused  by NSAIDs
  papillae  can  show  various  stages  of  necrosis,  calcification, fragmentation, 
and sloughing
 irreversible damage can occur
 necrotic papillae are excreted
 gross hematuria or renal colic
 ureteric obstruction
 Papillary necrosis is not specific for analgesic nephropathy
 compression may be caused by interstitial edema or microvascular disease
 analgesic nephropathy develop urothelial carcinoma of the renal pelvis

Nephropathy Associated with NSAIDs

 Many NSAIDs are nonselective cyclooxygenase inhibitors

 adverse renal effects are related to their ability to inhibit cyclooxygenase-dependent
prostaglandin synthesis
 selective COX-2 inhibitors, while sparing the gastrointestinal tract, do affect the kidneys because
COX-2 is expressed in human kidneys
 NSAID-associated renal syndromes include:
o Acute kidney injury - decreased synthesis of vasodilatory prostaglandins and ischemia
o Acute hypersensitivity interstitial nephritis - renal failure
o Acute interstitial nephritis and minimal-change disease - nephrotic syndrome
o Membranous nephropathy - nephrotic syndrome

Other Tubulointerstitial Diseases

Urate Nephropathy

 hyperuricemic disorders:
o Acute uric acid nephropathy
 uric acid crystals in the renal tubules, principally in collecting ducts
 in with leukemias or lymphomas who are undergoing chemotherapy
 Precipitation of uric acid is favored by the acidic pH in collecting tubules
o Chronic urate nephropathy
 gouty nephropathy
 protracted forms of hyperuricemia
 monosodium urate crystals
 distal tubules and collecting ducts as well as in the interstitium
 birefringent needle-like crystals
 mononuclear response that contains foreign-body giant cells
 lesion is called a tophus
 cortical atrophy and scarring from obstruction
  chronic nephropathy have evidence of increased exposure to lead

o Nephrolithiasis
 uric acid stones
 secondary hyperuricemia

Hypercalcemia and Nephrocalcinosis

 hypercalcemia
o hyperparathyroidism
o multiple myeloma
o vitamin D intoxication
o metastatic cancer
o excess calcium intake (milk-alkali syndrome)
 formation of calcium stones and deposition of calcium in the kidney (nephrocalcinosis)
 earliest functional defect is an inability to concentrate the urine
 tubular acidosis
 salt-losing nephritis
 calcium stones with secondary pyelonephritis

Acute Phosphate Nephropathy

 accumulations of calcium phosphate crystals in tubules

 high doses of select oral phosphate solutions in colonoscopy
 not hypercalcemic
 excess phosphate load, perhaps complicated by dehydration, causes marked precipitation of
calcium phosphate
 renal insufficiency several weeks after the exposure
 reversible injury typically recover partial renal function

Light-Chain Cast Nephropathy (“Myeloma Kidney”)

 Overt renal insufficiency occurs in half of those with multiple myeloma

 Several factors contribute to renal damage:
o Bence-Jones proteinuria and cast nephropathy
 directly toxic to epithelial cells
 combine with Tamm-Horsfall protein under acidic condition - obstruction
o Amyloidosis of AL type - λ type
o Light-chain deposition disease
o Hypercalcemia and hyperuricemia
  Bence-Jones tubular casts appear as  pink  to  blue  amorphous  masses
 Concentrically laminated and fractured which fill and distend the tubular lumens
 Multinucleate giant cells from activated macrophages
 casts rupture  the tubules
 granulomatous inflammatory reaction
 Amyloidosis, light-chain deposition disease, nephrocalcinosis,  and infection may 
also be present
 Precipitating factors
o Dehydration
o Hypercalcemia
o acute infection
o treatment with nephrotoxic antibiotics
 Bence-Jones proteinuria occurs in 70% of individuals with multiple myeloma

Bile Cast Nephropathy

 Hepatorenal syndrome
 impairment of renal function in patients with acute or chronic liver disease
 serum bilirubin levels can be markedly elevated
 bile cast formation (cholemic nephrosis) in distal nephron segments
 casts can extend to proximal tubules
 tubular bile casts can range from yellowish-green to pink
 reversibility of the renal injury depends upon the severity and duration of the liver dysfunction
 Vascular Diseases of Kidney

Nephrosclerosis

 sclerosis of renal arterioles and small arteries

 strongly associated with hypertension
 hypertension can be both a cause and a consequence
 affected vessels have thickened walls
 narrowed lumens
 focal parenchymal ischemia
 Ischemia leads to glomerulosclerosis and chronic tubulointerstitial injury
 reduction in functional renal mass
 more frequent in blacks
 may be seen in the absence of hypertension
 Hypertension and diabetes mellitus, however, increase the incidence
 Two processes participate in the arterial lesions:
o Medial and intimal thickening - hemodynamic changes, aging, genetic defects
o Hyalinization of arteriolar walls - caused by extravasation of plasma proteins
 kidneys are either normal or moderately reduced in size
 cortical surfaces have a fine, even granularity that resembles grain leather
 loss of mass is due mainly to cortical scarring and shrinking
 narrowing of the lumens of  arterioles and small arteries
 caused by hyaline arteriolosclerosis
 subcapsular scars with sclerotic glomeruli and tubular dropout
 interlobular  and  arcuate  arteries  show  medial  hypertrophy
 replication of the internal elastic lamina
 increased myofibroblastic tissue in the intima
 fibroelastic hyperplasia
 patchy ischemic atrophy consist of
o foci of tubular atrophy and interstitial fibrosis
o variety  of  glomerular alterations
 collapse of the GBM
 deposition  of collagen within Bowman space
 periglomerular fibrosis
 total sclerosis of glomeruli
 wedge shaped infarcts
 three groups of hypertensive patients with nephrosclerosis are at increased risk of developing
renal failure:
o African descent
 o severe blood pressure elevations
o second underlying disease, especially diabetes

Malignant Nephrosclerosis

 renal vascular disorder

 with malignant or accelerated hyper tension
 develops suddenly in previously normotensive individuals
 more often is superimposed on preexisting essential hypertension
 frequent cause of renal failure in individuals with systemic sclerosis
 pure form usually affects younger individuals
 more often in men and in blacks
 fundamental lesion is vascular injury
 initial insult from longstanding hypertension or in combination
 initiating event injures endothelium
 results in increased permeability of the small vessels to fibrinogen
 fibrinoid necrosis of arterioles and small arteries
 activation of platelets and coagulation factors
 intravascular thrombosis
 Mitogenic factors from platelets (e.g., PDGF), plasma, and other cells cause hyperplasia of
intimal smooth muscle of vessels
 hyperplastic arteriolosclerosis
 kidneys become markedly ischemic
 severe involvement of the renal afferent arterioles
 renin-angiotensin system receives a powerful stimulus
 markedly elevated levels of plasma renin
 Small, pinpoint petechial hemorrhages on the cortical surface
 rupture of  arterioles or glomerular capillaries
 “flea-bitten” appearance
 Two  histologic  alterations  characterize  blood  vessels:
o Fibrinoid necrosis of arterioles
 Vessel wall takes on a smudgy eosinophilic appearance due to fibrin deposition
 Inflammation  is usually not seen
 glomeruli  become  necrotic  and  infiltrated  with  neutrophils
 glomerular capillaries may thrombose
o Hyperplastic arteriolitis
 interlobular arteries and arterioles
 intimal thickening
 elongated, concentrically  arranged smooth muscle cells
 collagen, proteoglycans, and plasma proteins
 onion-skinning
 intraluminal thrombosis
 infarction distal to the abnormal vessels
 systolic pressures greater than 200 mm Hg and diastolic pressures greater than 120 mm Hg
 papilledema
 retinal hemorrhages
 encephalopathy
 cardiovascular abnormalities
 renal failure
 early symptoms are related to increased intracranial pressure
 scotomas or spots before the eyes
 “Hypertensive crises” are sometimes encountered
 marked proteinuria and microscopic or macroscopic hematuria
 75% of patients survive 5 years
 50% survive with restoration of pre-crisis renal function