pathology, cystic kidney diseases, kidneys, gross, cysts, ADPKD, ARPKD, cystic nephroma, tuberous sclerosis, VHL syndrome, cystic dysplastic kidney, glomerulocystic kidney, genetic

1. Cystic Diseases of the Kidney
Presentor : Dr. Pallavi Prasad
Senior Resident
SGPGIMS

2. Classification of cystic kidney diseases
 A. Polycystic kidney disease
 B. Renal medullary cysts
 C. Cysts in hereditary cancer syndromes
 D. Multilocular renal cyst and variants
 E. Localized cystic disease
 F. Simple cortical cysts
 G. Acquired (dialysis-induced) cysts
 H. Miscellaneous

3. A) Polycystic kidney disease
1. Autosomal dominant (ADPKD)
a. Classic ADPKD in adults
b. Early-onset ADPKD in children
2. Autosomal recessive (ARPKD)
a. Classic ARPKD in neonates and infants
b. Delayed-onset ARPKD in older children and adults
3. GCKD
a. Primary
b. Secondary

4. B. Renal medullary cysts
1. Nephronopthisis, autosomal recessive
2. Medullary cystic disease , autosomal dominant
a. MCKD 1
b. MCKD 2
c. UROM-associated hyperuricemia
d. Renin
e. HPRT1
f. SLC2A9
3. Medullary sponge kidney

5. C. Cysts in hereditary cancer syndromes
1. Von Hippel-Lindau disease
2. TSC
D. Multilocular renal cyst and variants
E. Localized cystic disease
F. Simple cortical cysts
G. Acquired (dialysis-induced) cysts

6. H. Miscellaneous
1. Pyelocalyceal diverticuli
2. Perinephric pseudocysts
3. Hygroma renalis-lymphangiomatosis

7. Renal Cystic Diseases
 Sporadic & genetically determined congenital, developmental
& acquired conditions
 Cysts in one or both kidneys
 Tubules cysts
 Different etiologies – similar
 Same etiologic entity - wide spectrum of renal abnormalities

8. Diagnostic work-up of cystic kidney disease

9. Autosomal Dominant Polycystic Kidney
Disease (ADPKD)
 M/c inherited kidney disease
 Women < severe disease
 Renal complications - stones, infections, flank pain, gross
hematuria
 Extrarenal manifestations - intracranial (arachnoid cysts) and
extracranial aneurysms (5% to 10%), colon diverticula, and
mitral valve prolapse
 Pancreatic cysts - rare

10. Autosomal Dominant Polycystic Kidney
Disease (ADPKD)
 PKD1 (80-85%); PKD2 (10-15%)
 PKD3 - isolated cases, not yet confirmed.
 PKD1 : earlier onset of symptoms
 PKD2 : delayed cyst formation, hypertension ,ESRD by 10 to
20 years.
 Allelic heterogeneity that correlates with variability in
clinical manifestations

11. Relative Frequency of Clinical Manifestations in
ADPKD and age at onset
Clinical Manifestations Frequency (%) Mean Age (Years)
Kidney cysts 100 15-29
Liver cysts 75 [>60 years] 45
Pancreatic cysts 10 47
Intracranial aneurysms 5-10 37
Hypertension 50-75 31
Cardiac valve defects 25 Later in life

12. ADPKD

13. ADPKD1 ADPKD2
16p13.3 4q13-q23
polycystin1 polycystin2
460-kDa 5.4kb
30 y >50 y
>1 kg 650 gm
More and earlier development Fewer cysts, same growth rate
50 y 70 y
Common, severe Less severe
~8% yes
Men have worse disease

14. Pathology of Classic ADPKD
 ~2.5 kg each and appear enormous (mean weight 0.150 kg).
 Reniform appearance is lost
 External surface is distorted by multiple cysts that may contain
clear, turbid, gelatinous, or hemorrhagic fluid

15. Pathology of Classic ADPKD
 Cysts vary in size from mm to several cms, randomly distributed
 Typically unilocular, oval or spherical
 Renal pelvis and calyces cannot be identified, and replacement of the
normal renal parenchyma is usually extensive
 Residual renal parenchyma is compressed and eventually becomes
atrophic by the enlarging cysts filled with eosinophilic fluid
 Interstitial fibrosis , globally sclerosed glomeruli ; cystic glomeruli
 The epithelium lining the cysts is denuded, flat, or hyperproliferative
 Micropolyps=90%

16. ADPKD

17. Advanced ADPKD

18. micropapillae within fluid filled cysts

19. Tubular epithelial cell proliferation,
apoptosis, fluid accumalation
Gradual luminal dilatation
cyst
Cysts seperate from parent
tubules
Sac-like structure
Lining epithelial cells-autonomous
proliferation
Loss of polarity
Mispolarisation of
proteins(Na-K-ATPase)
Electrolyte transport
proteins into cysts
EGFR

20. Malignancy in ADPKD
 > 10x increase of malignancy
 Intracystic RCCs -1 to 4 cm
 Renal cell carcinomas, clear cell, papillary, or chromophobe
type
 Multifocal and bilateral RCC
20% of ADPKD kidneys

22. Early-Onset ADPKD
 Develop in utero
 Intracystic epithelial micropolyps
 Relevant family history-U/L
 Genetic analysis may be necessary in ambiguous cases
Early-
Onset
ADPKD
glomerular
cysts
bilaterally
enlarged
kidneys
young

24. Differential Diagnosis of Early-Onset ADPKD
Early-
Onset
ADPKD
Classic
ARPKD
tuberous
sclerosis
bilateral
Wilms'
tumor
lymphoma
cystic
dysplasia.

25.  7-year-old boy
 Bilateral renal cysts
 Concurrent liver cysts
 No family history of ADPKD
 Biopsy
 ADPKD

26. Autosomal Recessive Polycystic Kidney Disease
(ARPKD)
 Antenatally/ neonatal period
 a/w hepatic fibrosis
 30% die of respiratory failure because of lung hypoplasia or
sepsis
 Older children - liver symptoms [acute cholangitis to cirrhosis]
Potter's
sequence
bilateral
massive kidney
enlargement
hepatic fibrosis

27. Autosomal Recessive Polycystic Kidney
Disease (ARPKD)
 Complications - chronic lung disease, growth retardation,
hyponatremia, UTI
 In ARPKD, neither parent has the disease; each child of
parents who are both carriers has a 1:4 chance of
inheriting the disease and 1:2 chance of being a carrier
 PKHD1 : 6p21 - fibrocystin/polyductin

28. ARPKD

29. Autosomal Recessive Polycystic Kidney
Disease (ARPKD)
 Diffuse microcysts sponge appearance
 diffuse replacement of the renal parenchyma
by cylindrical cysts

30. Autosomal Recessive Polycystic Kidney Disease
(ARPKD)
 M/F : cysts involve the collecting ducts and typically extent to
the cortex
 Collecting duct dilatation and renal cortical involvement
increase with gestational age
 Type of mutation also affects the
extent & time of cyst development

31. Autosomal Recessive Polycystic Kidney Disease
(ARPKD)
 Histologic variability prompted some authors to devise a
scoring system –
• extent of collecting duct dilation
• loss of proximal tubules
• cortical involvement
• loss of the nephrogenic zone
 grades 1 to 4 were proposed.

32. medullary duct ectasia uninvolved cortex
proliferation of bile ducts

33. Liver cirrhosis in neonatal ARPKD
Atypical, irregular, degenerating
cysts

34. Gross pathology of cystic liver disease

35. Glomerulocystic Kidney Disease
 GCKD is not one disease but a heterogeneous group
of entities with glomerular cysts as the common
histologic finding
Primary causes
ADPKD PKD1,2
ARPKD PKDH1
GCKD UROM, HNF1β
TSC2
NPHP Infantile
Other ?
Secondary causes
Renal dysplasia sporadic
obstructive
syndromic
Ischemic HUS/TTP
vasculitis
Vascular stenosis
Drug induced

36. Glomerulocystic Kidney Disease
>5% of
glomeruli
cystic
Dilated Bowman
space >=2x
normal
Kidneys
enlarged/N/
small

37. Glomerulocystic Kidney Disease
 Glomerular cysts involve the Bowman space and sometimes
the origin of the proximal tubule
 Focal or diffuse
 M/F : majority of glomeruli are cystic but interestingly orderly
arranged in rows
 No tubular cysts
 Intervening stroma is not fibrotic

38. Glomerulocystic Kidney Disease
 UROM mutations and hyperuricemia
 Hyperuricemic nephropathies have overlapping symptoms
with infantile or juvenile NPH.
 GCKD can also be a feature of NPH
EMA PAX-2

41. Multilocular Renal Cyst (Multilocular
Cystic Nephroma)
 <4, >30 yrs
 encapsulated and consists of noncommunicating multiloculated
lobules that are filled with gelatinous or clear fluid , single layer of
flat or “hobnail”-appearing cells

42.  partially differentiated nephroblastoma

43. Medullary nephronopthisis
 NPHP family of genes (1-9)- Nephrocystin-cilia/centrosomes
of renal epithelial cells (ciliopathies)
 Juvenile (m/c), infantile, adolescent
 AR
 C/F : polyuria, polydipsia, extrarenal manifestations

44. Meckel-Gruber syndrome

45. Medullary nephronopthisis
 Gross : bilateral, N/slightly smaller
 Multiple cysts <2mm, corticomedullary junction, medulla,
pyramids
 M/F : Cysts dervived from LOH, DCT, CD and lined by
flattened to squamous epithelium
 Diffuse interstitial fibrosis, tubular basement membrane
thickening, atrophic tubules, periglomerular fibrosis,
sclerotic glomeruli

46. Medullary cystic disease
 AD
 MCKD 1,2,3
 MCKD1 – 1q21-q23
 MCKD2 – 16p12 – protein thrombomodulin
 MCKD3 – 1q41
 C/F : polydipsia, polyuria-ESRD, a/w hyperuricemia
and gout

47. Medullary cystic disease
 Gross : N/slightly smaller
 Multiple cysts <2mm, corticomedullary junction, medulla
 M/F : similar to nephronopthisis

48. Medullary sponge kidney
 Unknown etiology
 GDNF gene
 a/w : marfan syndrome, ehler danlos syndrome, caroli
disease
 C/F : sporadic, asymptomatic, detected incidentally
 C/C : recurrent urolithiasis, pyelonephritis, septicemia
 Gross : n/slightly enlarged
 Cysts <5mm, localised to medullary pyramids and
papillary tips

50. Medullary sponge kidney
 Cysts derived from the collecting ducts, ectatic
ducts in the papillae
 Urothelial, columnar or squamous epithelium
 IF, II

51. Renal Cysts in Hereditary Syndromes

52. Von Hippel-Lindau Disease
 AD
 germ-line mutations of the VHL tumor suppressor gene [3p25-26]
 high degree of vascularization + clear cell component
 at a minimum, one characteristic tumor (CNS hemangioblastoma or clear
cell tumor in a visceral organ) suffices for diagnosis if definitive family
history exists
 In the absence of family history, two characteristic (clear cell) tumors are
required for diagnosis.
 Kidney cysts =70%
 Pancreatic cysts affect 26% of patients, but cysts in the liver are rare.

53. Von Hippel-Lindau Disease
 Gross : normal or slightly enlarged
 diffuse replacement of the renal parenchyma by multiple cysts
 Pancreas, spleen, lungs, bone, and skin
 VHL type 1
 VHL type 2

54. Von Hippel-Lindau Disease
 Gross : small, do not transform the kidneys into the giant organs as in ADPKD
 cysts are few in number
 Histologically, cysts may be denuded or lined by low epithelium.
 Intracystic tumor nodules are typically clear cell type RCC
 A lesion in the CNS / spinal cord = hemangioblastoma > RCC
 Distinguishing VHL from ADPKD and TSC as well as other hereditary cystic
diseases may at times be difficult ??
 For example, cysts primarily in the pancreas are characteristic of VHL. Solid
nodules within cysts are common in VHL and rare in ADPKD. Liver cysts are
rare in VHL in contrast to ADPKD
 Distinguishing VHL from adult TSC is easier based on the fact that the most
common tumor is angiomyolipoma, and extrarenal manifestations are distinct
from VHL

55. Pathogenesis
 VHL also regulates genes related to cell cycle,
epithelial cell differentiation, and fibronectin
assembly in the ECM
hypoxia-inducible
factor (HIF)-1
hypoxia-inducible
genes
PDGFB, Flik-1, Tie-
2, erythropoietin,
TGFα

56. Tuberous Sclerosis
 Systemic phacomatosis
 Hamartomatous proliferative lesions
 Brain, skin, retina, heart, endocrine glands, digestive system, lung,
and kidney.
 Angiomyolipomas, cysts and RCC
 Angiomyolipomas are present in approximately 85%, cysts in 45%

57. Cystic kidney from a child with tuberous sclerosis

58. TSC cysts

59. TSC cysts

60. Simple Cortical Cysts
 12% to 25%
 Common findings in autopsy of older men
 Oval or round with a smooth outline and are filled with clear
or yellow fluid
 Originate from the diverticula of the distal convoluted or
collecting tubules
 Divericula increase in number with age, probably as a result
of weakening of tubular basement membranes.

61. Simple Cortical Cysts
 M/F : empty space, often without lining
surrounded by compressed, fibrotic interstitium

62. Acquired Cystic Kidney Disease
 Native kidneys of patients with ESRD treated for uremia with
hemo- or peritoneal dialysis that did not have hereditary cystic
kidney disease prior to dialysis
 >= 3 cysts per kidney in a dialysis patient
 The number of cysts increases with time on dialysis
 >50% of patients develop cysts within 5 years of dialysis and
about 90% by 10 years.

63. Acquired Cystic Kidney Disease
 Risk of developing RCC = 40 to 100x (B/L, metastatic)
 Gross : >25% of the renal parenchyma
 Normal size/slightly smaller
 Lined by cuboidal or hobnail epithelial cells arranged in single
or multiple layers
 Flat epithelium and micropapillary proliferation forming small
adenomas (<5mm)
 Papillary RCC –m/c

65. Acquired Cystic Kidney Disease
 Oxalate crystals - cysts /interstitium
 sustained uremia
Oxalate
crystals
Genetic
changes
malignancy

66. Miscellaneous Renal Cysts
 Present diagnostic difficulty on radiologic examination
and sometimes clinically but rarely require the
pathologist's attention
Pyelocalyceal
diverticuli
perinephric
pseudocysts
hygroma renalis

67. Pyelocalyceal Diverticuli
 Circular or ovoid filling defects of the renal pelvis or the calyces
on intravenous pyelogram
 children ; solitary
 Found incidentally / severe acute flank pain and gross
hematuria or urinary infection
 Ureteric bud branches that failed to induce nephrons and/or to
be integrated into the normal tubulocalyceal system.
 A/w xanthogranulomatous pyelonephritis
 Histologically, the cavity is lined by flat epithelium surrounded
by a thin layer of smooth muscle
 Inflammation , squamous metaplasia , calcifications+

68. Perinephric Pseudocysts
 Urine accumulation within the perinephric fat
 Reactive variably inflamed fibrous tissue and fat without a
lining epithelium
 Localized
 Blunt trauma to the kidney or a surgical procedure that caused
damage to the renal capsule is the most frequent cause
 C/F : flank or abdominal pain or discovered incidentally

69. Hygroma Renalis
 Pericalyceal lymphangiomatosis - ectasia of the lymphatics in the
renal capsule
 Circumscribed cystic mass that consists of dilated lymphatics
containing eosinophilic fluid, encircles the renal pelvis or extends
to the renal capsule
 Kidney enlarged and diffusely cystic ~ polycystic kidneys
 Thin fibrous walls lined by endothelial cells
 C/F : asymptomatic or experience symptoms of urinary
obstruction

70. Hygroma Renalis

71. Multicystic renal dysplasia
 Etiology : urinary tract obstruction, urinary reflux during kidney
development
 Genetic disorders…….

72. Multicystic renal dysplasia
 Abnormal renal organisation with abnormal differentiation of
metanephric elements
 Urinary tract abnormality (ureteral atresia, urethral valves)
 Nonfunctional (reflux-focal, some function retained)
 Flank mass in newborns
 Gross : small, abnormally shaped, multiple communicating cysts
 M/F : lobar disorganisation, primitive ducts, metaplastic cartilage,
thick f/m collars surrounding collecting ducts, hyaline cartilage, renal
blastema

77. Thank you