Malakoplakia and amayloidosis of kidney

1. Amyloidosis and
malakoplakia of
kidneys.
Dr. Prateek Laddha
DEPARTMENT of UROLOGY

2. DEFINITIONS:
 Amyloidosis comprises a diverse group of
systemic and local diseases
 Characterized by organ involvement by the
extracellular deposition of fibrils composed of
subunits of a variety of normal serum proteins.

4. Systemic Amyloidoses
 A amyloidosis (AA)
 Light chain amyloidosis (AL)
 Heavy chain amyloidosis (AH)
 Transthyretin amyloidosis
 Beta2-microglobulin amyloidosis ( Abeta2M)
 Cryopyrin-associated periodic syndrome (CAPS)-associated amyloidosis
 MWS

5. PHYSİCAL NATURE
 Amyloid fibril protein occurs in
tissue deposits as rigid, non-
branching fibrils 7-to 10 nm in
dm
 When analysed by X-ray
diffraction, the fibrils exhibit a
characteristic cross Beta
diffraction pattern

6. CHEMICAL NATURE
 Pentagonal molecule
 95% Protein Fibril
 5% Glycoprotein P component

7. Amyloid fibril protein nomenclature
 The established amyloid fibril nomenclature is based on the chemical
nature of the fibril protein
 Which is designated protein A and followed by a suffix that is an
abbreviated form of the parent or precursor protein name
 For example, when amyloid fibrils are derived from immunoglobulin light
chains, the amyloid fibril is AL and the disease is AL amyloidosis
Amyloid, 2010; 17(3–4): 101–104

8. Amyloid fibril protein nomenclature
 At least 25 different precursor proteins are known
 They are associated with variety of
 Inflammatory
 Immune
 Infectious
 Hereditary conditions

10. TYPING OF RENAL AMYLOIDOSIS
 Typing of amyloid deposits is important because of the difference in their
treatment strategies
 Typing of the amyloid deposits can be performed with various
techniques
 The most definitive method used is IF or IHC staining of tissue using
antibodies that are directed against known amyloid proteins

11.  The most common type of amyloidosis depends on the population studied
 In the USA and the Western World AL amyloidosis is the most prevelant, followed
by AA amyloidosis
 In Turkey AA amyloidosis with an underlying disease of FMF is the most common
type
 In developing countries AA amyloidosis is far more common than AL amyloidosis
(Tbc !)

12. AL Amyloidosis
 Derived from the immunoglobulin light chain
 Can occur alone or in association with
 M. Myeloma
 Malignant lymphomas
 Macroglobulinemia
Kyle RA et al N Engl J Med. 2006;354:1362

13. AL Amyloidosis
• Wide spectrum of organ system involvement
The kidneys are commonly affected
• Proteinuria
• Edema and hypoalbuminemia
• Mild renal dysfunction is frequent
• Rapidly progressing renal failure is rare

14. • Kidney is the most frequently affected target organ
• The primary clinical manifestation is proteinuria
• The underlying disease usually is longstanding
• Active inflammation typically is present when
amyloidosis becomes evident
AA Amyloidosis

15. RENAL AMYLOIDOSIS
 Clinically evident renal involvement occurs mainly in AA and AL
amyloidosis
 The deposition of Abeta2 M occurs in patients on prolonged dialysis
 But diagnosis on the kidney biopsy is unexpected
 Eight precursor fibrils are particularly important
for kidney

17. RENAL AMYLOIDOSIS
 The incidence of amyloid in patients with nephrotic syndrome or
proteinuria was found in 2% to 12% of native renal biopsies
 Amyloidosis without therapy usually progresses to endstage kidney
disease

18. Diagnosis of Amyloidosis
• Can be very difficult
• No blood test can diagnose or exclude amyloidosis
• Usually relies on clinical suspicion
• Possibility supported by
• Underlying chronic inflammatory state – AA
• Underlying plasma cell dyscrasia – AL
• Family history - hereditary
• Evidence of renal dysfunction

19. Detection of Renal Amyloid
H&E stained sections, amyloid is
recognized as amorphous hyaline and
eosinophilic material
Weakly PAS positive

20. Detection of Amyloid
Amyloid do not stain by silver staining
•Occasionally may stain with silver stains and
show spicules (Jones silver)

21. Detection of Amyloid
Congo red is the gold standard
• Slides must be examined under
polarized light
• Apple-green birefringent deposits
is diagnostic

22. Other stains, or techniques
 Fluorescence
 Thioflavin S and T
 Methyl violet
 Sulphonated Alcian blue
 They are less specific

23. Electron Microscopy
• Characterized by randomly disposed, rigid,
nonbranching, variably long, 7-to 10nm-dm fibrils
• Ultrastructural immunogold labelling can depict the
precursor protein in amyloid fibrils

24. • Rare cases exhibit massive aggregates of amyloid fibrils in
subendothelium
• They arranged in thightly packed, electron-dense structures and can be
easily confused with
• MPGN
• Cryoglobulinemic glomerulopathy
• These cases are usually associated with monoclonal kappa light cahins
Electron Microscopy

25. Gross Pathology of Renal Amyloidosis
• Enlarged kidneys
• Pale, waxy appearing cut surfaces
• Increase in the weight of kidney
Weight of the kidney did not correlate with
Renal function
The site of renal amyloid deposition
Inversely proportional to the amount of amyloid

26. Microscopy of Renal Amyloidosis
• Amyloid can be found in any of the
renal compartment
• The most common and the earliest
site of amyloid deposition in the
kidney is the glomeruli
• Glomerular amyloid formations
begins in the mesangium
• Extends into capillary walls

27. Microscopy of Renal Amyloidosis
• Amyloid deposition in glomeruli may occur
• Segmental
• Diffuse mesangial
• Nodular
• Pure basement membrane patterns

28. Renal amyloidosis was divided into 6 classes
Similar to the classification of SLE
A proposed histopathologic classification
Sen S. Arch Pathol Lab Med 2010: 134: 532

29. Microscopy of Renal Amyloidosis
• Early segmental deposits are small and confined to mesangium without
creating nodularity
• It is very easy to miss this early form

30. Microscopy of Renal Amyloidosis
• In the diffuse form
• The mesangium is uniformly expanded by
deposit

31. Microscopy of Renal Amyloidosis
• In the nodular form
• Mesangium is asymmetrically expanded by amyloid
• Distinguish from diabetic nephropathy
• Other forms of nodular glomerulosclerosis

32. Microscopy of Renal
Amyloidosis
• Subepithelial amyloid deposition
Associated with spikes
Can be seen at the periphery of mesangial areas

33. Microscopy of Renal Amyloidosis
• Interstitial amyloid are seen in
50% cases
• Generally begins in areas
adjacent to blood vessels
• Medullary amyloid deposits are
more frequent

34. Microscopy of Renal Amyloidosis
• Renal vessels are often involved
• Arteriolar deposits being most frequent
• Followed by deposits in arteries, PTCs and veins

35. RENAL AMYLOIDOSIS
• Therapies are not successful in patients diagnosed at advanced stages of
amyloidosis
• Supportive therapy is essential
• There are two choices for the therapy
• Hemodialysis
• Transplantation

36. • The survival of patients begining dialysis is poor
• Mean survival is only 33 months
• Worse than patients with other renal diseases
Hemodialysis in Renal Amyloidosis

37. • The European experience showed a 76% survival at
2 years for all patients compared with 53% among
amyloidosis patients
• Similarly in our center the 2-year survival was 50% among patients with
amyloidosis
• The mean survival of our patients on hemodialysis was 33 months
Hemodialysis in Renal Amyloidosis

38. Dialysis associated renal amyloidosis
 Beta-2 ̶ microglobulin (beta-2m) amyloidosis is a disabling condition that affects patients
undergoing long-term hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD).
 Doesn’t affect individuals with normal or mildly reduced renal function or patients with a
functioning renal transplant.
 Evolves predictably over time and is rare in the first few years of HD
 Beta-2m is a major constituent of amyloid fibrils.
 It has been shown that, through accumulation, it invades synovial membranes and
osteoarticular sites.
 Visceral involvement has been found in different organs, such as the gastrointestinal (GI) tract,
heart, and tongue, but overt manifestations are rare.

39.  In the normally functioning kidney, beta-2m is cleared by glomerular filtration and is catabolized in
the proximal tubules.
 Reference range serum levels are 1.5-3 mg/L.
 In renal failure, impaired renal catabolism causes an increase in synthesis and release of beta-2m,
and levels can rise 10- to 60-fold.
 Retention and accumulation of this type of amyloid protein is presumed to be the main pathogenic
process underlying beta-2m amyloidosis.
 The dialysis process itself may stimulate beta-2m synthesis, by activation of complements and
cytokine production. However, it is unlikely that this is a significant mechanism of dialysis-related
amyloidosis (DRA), since the disease is also seen in patients on CAPD and people who have never
been on dialysis.

40. Type of dialysis membrane
Cuprophan and cellulose acetate membranes cannot clear molecular
weights higher than 200 dalton.
This makes them impermeable to beta-2m, elevating the protein’s
serum levels.
Newer cellulose  triacetate dialyzers and the high-flux synthetic
dialyzers do a better removal of beta-2m.
High cut-off, high-flux dialysis and online hemodiafiltration have been
shown to be superior to previously used HD membranes in the
removal of beta-2m, possibly decreasing beta-2 amyloidosis.

41. Prolonged uremic state and/or decreased
diuresis
Chronic renal failure who have not yet started dialysis.
Inadequate diuresis and prolonged uremia are suggested
contributing factors.

42. Elevated levels of cytokines
Dialysis is an inflammatory stimulus, inducing cytokine
production and complement activation.
Interleukin 1 (IL-1),
tumor necrosis factor-alpha (TNF-alpha), and
interleukin 6 (IL-6),
Thought to stimulate the synthesis and release of beta-2m by
macrophages and/or augment the expression of HLA class I
antigens, increasing beta-2m expression.

43. Advanced glycation end products
 HD and peritoneal dialysis are ineffective in removing these low–molecular weight compounds
from circulation.
 As AGE-modified beta-2m accumulates, chemotaxis is enhanced, stimulating macrophages to
release proinflammatory cytokines, as well as interfering with collagen synthesis.
 This inflammatory response may ultimately lead to bone and joint destruction.
 Oxidation of beta-2m may enhance amyloid deposition. Studies suggest that increased
oxidative stress during HD and exposure of beta-2m to hydroxyl radicals stimulate the
autoxidation of unstable molecules, leading to augmented AGE production.

44. Dialysate
Acetate and/or bacterial lipopolysaccharide (endotoxin) may enter the blood via the dialyzer and
stimulate the release of cytokines, inducing beta-2m production.

45. Epidemiology
 Incidence of greater than 95% in patients who have been on dialysis for
more than 15 years.
 European studies have suggested that DRA can be seen in as many as
20% of patients after 2-4 years of HD and in 100% after 13 years of HD.
 There is some mention in the literature that the incidence and
prevalence of beta-2m amyloidosis are less in CAPD than in HD
(because of residual renal function).

46. Clinical manifestations of beta-2m amyloidosis almost never appear
before a patient has undergone 5 years of dialysis therapy. Unlike
other types of amyloids, beta-2m amyloid is confined largely to
osteoarticular sites.
Patients often present with a characteristic triad of
carpal tunnel syndrome,
shoulder pain, and
flexor tenosynovitis in the hands.
The rate of surgery for osteoarticular disorders, such as carpal tunnel
syndrome, destructive spondyloarthropathy (DSA), and joint
arthropathy, which may show the presence of DRA, is very high.
Visceral deposits are rare, occur after 10 or more years of dialysis, and
tend not to cause symptoms in most cases.

47. Osteoarticular manifestations
Osteoarticular manifestations can include the following:
 Carpal tunnel syndrome
 Flexor tenosynovitis
 Scapulohumeral arthropathy
 Spondyloarthropathy
 Lytic bone lesions
 Bone cysts
 Pathologic fractures - Caused by amyloid deposition within joints, intervertebral discs, and tendon
sheaths
 musculoskeletal deformities

48. Systemic manifestations
 Systemic manifestations are rare, and patients with systemic involvement generally
are asymptomatic. Most individuals with systemic manifestations have undergone
dialysis for longer than 10-15 years.
 If systemic involvement does occur, small, localized deposits are observed around
blood vessels and in the mucosa of the GI tract, heart, lungs, and genitourinary
tract. In rare cases, fatal GI hemorrhages, cardiac arrhythmias, and renal vein
thromboses have occurred.

49. GI involvement
 Macroglossia, dysphagia, small bowel ischemia, malabsorption, and pseudo-obstruction
 Can occur because of subepithelial, submucosal, and blood vessel amyloid deposits.

50. Cardiovascular involvement
 Myocardial, pericardial, and cardiac valves may be involved.
 Beta-2m amyloid deposits have also been identified in small pulmonary arteries and veins.

51. Genitourinary tract involvement
 Renal and bladder calculi containing beta-2m deposits and causing obstruction have been
described.
 Beta-2m amyloid has also been identified in the prostate and the female reproductive tract.

52. Diagnosis
 Clinical appearance on tissue or bone biopsy.
 Synovium biopsy, followed by routine hematoxylin and eosin staining, reveals homogeneous
eosinophilic material.
 Amyloid deposits are positive for Congo red staining, showing green birefringence of the amyloid
fibrils under polarized light.
 Immunostaining with Monoclonal anti ̶ beta-2m antibody confirms the diagnosis of beta-2m
amyloidosis.
 Antisera to amyloid beta-2m are taken up by the Congo red–positive areas, but are not taken up
in other types of amyloidosis.

53. Treatment Approaches and Impact on the
Kidney
 Ongoing amyloid deposition in the kidney is associated with progressive
deterioration in renal function.
 In a group of patients who had AL amyloidosis and kidney involvement
followed in the 1980s, progression to ESRD occurred at a median of only
14 months after diagnosis
 Most rapid in AL amyloidosis
 Hemodynamic alterations that result from severe nephrotic syndrome,
autonomic dysfunction, or heart failure often underlie abrupt changes in
kidney function and contribute to the fragility in renal function that
frequently is present in this disease.

54. AL Amyloidosis
The goal is to eradicate the clonal plasma cells that produce the
amyloidogenic light chain.
The prognosis of AL amyloidosis has improved in the past decade with
the increasing use of aggressive anti-plasma cell treatment.
High-dose intravenous melphalan followed by autologous stem cell
transplantation to support bone marrow recovery (HDM/SCT)  best
treatment option

55.  Experience from several treatment centers has suggested that 25 to 50%
of patients who undergo such treatment have complete hematologic
responses, meaning that there is no evidence of ongoing production of
the monoclonal light chain
 In contrast, complete hematologic responses are exceedingly rare with
oral melphalan and prednisone administered in repeated cycles, an
approach that was standard treatment until relatively recently

56. Survival after high-dose melphalan and autologous stem cell transplantation for AL amyloidosis.
Laura M. Dember JASN 2006;17:3458-3471
©2006 by American Society of Nephrology

57. AA Amyloidosis
 Treat the underlying inflammatory disease and thereby reduce production of SAA.
 FMF, life-long treatment with colchicine to inhibit FMF-associated inflammation
 The clinical manifestations of amyloidosis and improved survival
 Marked reductions in proteinuria have been reported in individuals with AA
amyloidosis–associated kidney disease from a variety of underlying inflammatory
conditions after treatment with cytotoxic agents or TNF antagonists

58. Hereditary amyloidosis
 OLT

59. Dialysis associated
 Renal transplantation is the treatment of choice for beta-2m amyloidosis. It lowers the blood
concentration of beta-2m to the reference range, halting the progression of the disease.
 Osteoarticular symptoms, such as joint pain, swelling, and stiffness, disappear within the first
week after transplantation.
 Cystic lesions usually remain unchanged, and regression of amyloid deposits probably does not
occur.
 Transplantation is not an option for all patients. Some patients on long-term dialysis will have
undergone unsuccessful renal transplantation before they first developed beta-2m amyloidosis;
in certain other cases, patients are not suitable candidates.

60. Treatment of A beta 2 Amyloidosis
Doxycycline
 A recent pilot study demonstrated reduction in arthralgia and increased range of motion with doxycycline treatment.
 Doxycycline inhibits β2-microglobulin fibrillogenesis and inhibits the accumulation in bone architecture.
 Long-term dialysis patients with severe amyloid arthropathy low dose of 100 mg of doxycycline daily
 pain reduction,
 increased range of motion, and
 no adverse effects at 5 months.
Beta-2m-adsorbing columns for dialysis
 β2-m–adsorbing columns have demonstrated some benefit in dialysis-related amyloidosis. This addition to long-
term dialysis may reduce inflammation and accumulation of fibrils without major adverse effects. [96]

61. Immunotherapy
 bapineuzumab and solanezumab
 Failed to provide meaningful cognitive changes in clinical trials. Further studies using this strategy are
ongoing.

62. Tocilizumab
 A subset of patients with amyloidosis (AA) in the setting of arthritis were monitored for benefits
from the IL-6 receptor antibody tocilizumab.
 After a year of therapy with the standard regimen for rheumatoid arthritis (RA) (8 mg/kg q4wk) a
significant reduction in renal dysfunction, serum AA concentration, and urinary protein secretion
was observed in conjunction with reduced disease activity.

63. Medications
 No medical treatment presently exists to reverse or alter the course of beta-2 amyloidosis. Low-
dose steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are symptomatic approaches to
ameliorating joint pain and inflammation. Medications used include the following:
 Prednisone - Immunosuppressive agent
 Triamcinolone - Immunosuppressive agent
 Capsaicin topical -Topical analgesic
 Ibuprofen -NSAID
 Sulindac – NSAID

64. MALAKOPLAKIA
 Malakoplakia is a rare granulomatous disease of infectious etiology.
 The name is derived from the Greek malakos (soft) and plakos (plaque), describing its usual
clinical presentation as friable yellow soft plaques.

65. HISTORY
 First described by von Hansemann in 1901
 1902 by Michaelis and Gutmann.
 Most frequently reported to occur in the genitourinary system.
 First case reported to occur outside the genitourinary system was in 1958.
 Since then, various organs have been reported to be affected.
 Cutaneous malakoplakia is rare. 50 CASES IN LITERATURE.
 First reported in 1972 by Leclerc and Bernier.

66.  Malakoplakia is usually reported in the setting of immunocompromise, although rare reports in
immunocompetent individuals have been documented.
 Malakoplakia presents clinically with a wide spectrum of findings, and the criterion standard for
diagnosis is pathological examination.

67. PATHOPHYSIOLOGY
 Believed to result from the inadequate killing of bacteria by macrophages or monocytes that
exhibit defective phagolysosomal activity.
 Partially digested bacteria accumulate in monocytes or macrophages and lead to the deposition
of calcium and iron on residual bacterial glycolipid.
 The presence of the resulting basophilic inclusion structure, the Michaelis-Gutmann body,
Pathognomonic for malakoplakia.

68.  Studies have suggested that a decreased intracellular cyclic guanosine monophosphate (cGMP)
level may interfere with adequate microtubular function and lysosomal activity, leading to an
incomplete elimination of bacteria from macrophages and monocytes.
 The incidence of malakoplakia in immunocompromised states, including post organ
transplantation, diabetes mellitus, AIDS, malignancy, and immunosuppressive therapy, suggests
that a disturbed function of T lymphocytes may play a role in the pathogenesis of malakoplakia in
patients in states of immunocompromise.

69. EPIDEMIOLOGY
Frequency
 The total number of patients Is fewer than 500.
 Most patients have genitourinary tract disease
 Cutaneous malakoplakia is rare, with fewer than 50 cases reported in the literature.
 Because this disease is often diagnosed after biopsy of nondescript lesions, the true incidence is most likely higher.
Race
 Cutaneous malakoplakia is more commonly reported in whites (39%) than in African Americans (19%) or Asians (12%), although the
patient's ethnic group is often not specified in case reports.
Sex
 Cutaneous malakoplakia occurs with a male-to-female ratio of 2.3:1.
Age
 Cutaneous malakoplakia presents in patients with a broad age range. The median age at the time of presentation is 53 years.
Occurrence of the disease is associated more with the presence of an immunocompromised state affecting monocyte and
macrophage function than with age.

70. HISTORY
 history of immunosuppression due to
 renal transplantation,
 diabetes mellitus, or
 lymphoma or
 a history of receiving long-term therapy with systemic corticosteroids.
 Close to one quarter of patients present with internal organ involvement, most commonly in the
retroperitoneal area, the kidney, the bladder, or the colon.
 Symptoms reflect the organ system involved, but patients can often present with draining
sinuses originating from deeper organ involvement.
 It rarely presents in patients with HIV infection and AIDS, which may be because of the
preservation of monocyte antimicrobial function in these patients.
 Can present with renal failure or a pyelonephritis like picture

71. CLINICAL PRESENTATION
Malakoplakia lesions may present as erythematous papules,
subcutaneous nodules, draining abscesses, ulcers, nonhealing
surgical wounds, or draining fistulas.

72. CAUSES
 Defective macrophage killing of bacteria, most commonly E coli, leads to malakoplakia.
 Defective macrophage killing results in an accumulation of bacterial degradation products and a
granulomatous reaction, which clinically manifests as the formation of a papule, a plaque, or an
ulceration.
 Although E coli is the most common gram-negative bacteria isolated, other enteric bacteria may
be found on culture. Staphylococcus aureus, Pseudomonas aeruginosa, and Rhodococcus equi
may also be cultured.
 Other rare associations that have been reported include papillary urothelial carcinoma and
abdominal malakoplakia following blunt trauma to the abdomen.

73. IMAGING STUDIES
 Positron emission tomography scanning diagnose malakoplakia renal disease  Intense uptake
of fluorodeoxyglucose was noted in the kidney.
 MRI of a patient with renal Malakoplakia: multiple nodules with low signal on T1-weighted, T2-
weighted, and early and late postgadolinium images.

74. HISTOPATHOLOGY
 Sheets of ovoid histiocytes with fine eosinophilic
cytoplasmic granules (von Hansemann cells) are
seen on routine staining. Histiocytes with 5- to
15-mm basophilic inclusions with concentric
laminations (Michaelis-Gutmann bodies) are
diagnostic.
 Michaelis-Gutmann bodies
 periodic acid–Schiff stain positive
 diastase resistant.
 von Kossa stain for calcium
 Perls Prussian blue stain for iron.

75.  Electron microscopy results show that Michaelis-Gutmann bodies consist of lysosomes filled with
partially digested bacteria.
 Gram stain may demonstrate gram-negative bacteria.
 Immunohistochemical studies
 positive results for CD68 antibodies, lysosomes, α -chymotrypsin.
 Immunostaining with polyclonal anti– Mycobacterium bovis antibody may demonstrate organisms in
patients with malakoplakia.

76. TREATMENT
 Antibiotics that concentrate in macrophages (eg, quinolone, trimethoprim-sulfamethoxazole) is
associated with a high cure rate.
 Antibiotic therapy directed against E coli in combination with surgery provides the best chance of
cure.
 Bethanechol, a choline agonist, has been used in combination with antibiotics and surgery.
Bethanechol may correct the decreased cGMP levels that are believed to interfere with complete
bacterial killing.

77.  Ascorbic acid has been used to increase the cGMP and cyclic adenosine monophosphate (cAMP)
levels in monocytes, which may represent an effective strategy for therapy.
 An insufficient number of patients have been treated with ascorbic acid to determine its overall effect.
 Discontinuation of immunosuppressive drug therapy is usually needed to effectively treat
malakoplakia .
 Sustained antimicrobial therapy together with reduction of immunosuppression may be
appropriate for treating malakoplakia with reduction of the risk of poor graft survival in patients
taking immunosuppression following renal transplantation.