Cystic kidney diseases dr.a.hassan end123

Cystic Diseases of the
Kidney CNE

Ahmed Hassan Mohamed MD
Lecturer of nephrology
National institute urology & nephrology
NIUN

ESNT-CNE 1st Course, Cairo, Sept 10-14, 2012

Kidney cysts
 Cysts are abnormal blisters that may contain fluid or other
matter. Many kinds of cysts can affect the kidney. Kidney
cysts are classified by:
 Cause – inherited, acquired kidney disease or advancing
age
 Features – like the number of cysts (one or more) and
whether the cysts are simple or complicated.
 Location – outer (cortex) or inner (medulla) part of the
kidney
ESNT-CNE 1st Course Cairo Sept 10-14, 2012

Categories
 Developmental: Multicystic dysplastic kidney disease
 Genetic:ARPKD, ADPKD, juvenile nephronophthisis
(JNPHP), medullary cystic kidney disease (MCKD),
glomerulocystic kidney disease (GCKD) .
 Cysts associated with systemic disease: Von Hippel-
Lindau syndrome, tuberous sclerosis complex.
 Acquired - Simple cysts, acquired cystic renal
disease, medullary sponge kidney.
 Malignancy: cystic renal cell carcinoma (RCC).


Bonsib (2009) classification of renal cystic
diseases & congenital anomalies of the kidney &
urinary tract.


Bosniak Classification of Renal Cysts
 Class I: Simple benign cysts with a well-defined
homogeneous mass, a thin wall. These lesions do not enhance.
 Class II: Minimally complicated cysts with smooth thin
internal deputations, thin peripheral rim of calcification in its
wall or septa. These lesions do not show enhancement
 Class IIF: Minimally complicated cysts, ?hyper dense,
contain more calcium in the wall & may have thicker internal
deputations. Follow up scanning is needed.
 Class III: More complicated cystic structures with irregular
thickened septa, wall thickening, solid non-enhancing mural
nodules, or irregular calcifications. Surgical exploration.
 Class IV: Malignant cyst, with non-uniform wall thickening,
have irregular margins, and/or contain solid components that
enhance on CT (total nephrectomy is warranted).

Pathophysiology
 Cysts develop from renal tubule segments and most
detach from the parent tubule after they grow to a few
millimeters in size.
 Cyst development is generally attributed to

 Increased proliferation of tubular epithelium

 Abnormalities in tubular cilia

 Excessive fluid secretion


Pathophysiology
 MCDK represents abnormal development 2ndry to
1-dysfunctional genetics
2-abnormal differentiation of the metanephros
 ADPKD is due to mutations in the genes
PKD1(Chromosome 16) & PKD2(chromosome 4)
that encode polycystin proteins.
 Mutated PKD1 and PKD2 genes cause the
production of polycystin-1 and polycystin-2
proteins respectively.


Polycystin 1 involved in cell-cell interaction, activates JAK-STAT
pathway, causing cell cycle arrest.
Polycystin 2 involves calcium signaling via G protein. Expressed in
.renal tubular epithelium, hepatic ducts & pancreatic ducts


Pathophysiology

ARPKD is due to mutations in PKHD1, a gene that

encodes fibrocystin / polyductin, which plays critical
roles in collecting-tubule and biliary development.
 JNPHP: (AR inheritance).

 MCKD: (AD), there are 2 types:
 MCKD1 due to mutations in the MCKD1 gene (average
age of ESRD 62YRS)
 MCKD2 is caused by mutations in the UMOD gene (on
chromosome 16 & encodes uromodulin. ((average age of
ESRD 32yrs).

Pathophysiology
 Medullary sponge kidney of unknown etiology (?
AD/ sporadic mutation). there is a cystic dilatation of
the collecting tubules in 1 or more renal pyramid.
 VHLS: due to mutations in the VHL gene on (ch. 3),

 TS: due to by mutations in the suppressor genes

TSC1 (ch. 9) & TSC2 (ch. 6), which encode hamartin
and tuberin, respectively.
 Acquired Cystic Kidney Disease d.t. an unidentified
waste product not removed through dialysis

Kidney cysts


Cut surface of a nephrectomy
specimen from a patient with a Medullary cysts in normal size
multicystic dysplastic kidney kidney in a case of
(MCDK). nephronophthisis


Nephrectomy specimen from External surface of a nephrectomy
a patient with a large benign specimen from a patient with
simple cyst. autosomal dominant polycystic
kidney disease (ADPKD).


Epidemiology
 MCDK 1:1000-4000 live births. (>male).
 ADPKD 1:400-1000 , has a bimodal distribution of
onset (more rapid in male).
 ARPKD 1:6000-55,000 live births, with a
heterozygous carrier frequency of 1 per 70
 JNPHP affects 1:5000 persons.
 JNPHP & MCKD 10-20% of children with CRF.
 TS 1:10,000-50,000 (25% of pts have renal cysts).
 VHLS 1:39,000, (M=F) & 2/3 pts develop renal
cysts, & presents in the 3rd or 4th decade of life


Epidemiology
 MSK 1:5000 (M: F 2:1), is found in 20% of pts with
nephrolithiasis.
 In acquired cystic renal disease (> in male) , cysts are
present in 8-13% of pts with CRF prior to dialysis,
40-60% > 5 yrs of dialysis & > 90% >10 yrs.
 Simple cysts (5% of the general population & rare in
children), are the most common cystic renal lesions,
account for 65-70% of renal masses & are present in
25-33% of pts > 50 yrs.
 Cystic RCC accounts for < 1% of RCC cases.

Clinically
 ADPKD presents flank pain ,hematuria, proteinuria,
UTI, HTN, calculus & renal insufficiency (it is intact
until the 4th decade & decline at a rate of 4-6ml
/min/yr). (faster in PKD1, proteinuria, HTN, male)
 Extra renal manifestations includes:
 cerebral aneurysms (4% based on F.H., age & SAH
increases risk).
 Hepatic cysts (80%), age (15-40 yrs), (>female) ,
multiple pregnancies (? Estrogen) & mostly a
symptomatic.


Clinically

Cardiac disease includes:


 MVP & AR 30%

 Coronary aneurysm not infrequent

 Asymptomatic pericardial effusion represents 30%.

 Colonic diverticula  abdominal pain
 Abdominal wall hernia (45% of pts).


ARPKD clinical presentation
 four presentations:
 Neonatal & infancy with a profound respiratory
compromising 2ndry to oligohydraminas.
 Childhood & adolescence with hepatic disease
predominant.
 Cholongitis

 ESRD


Clinically
 MCKD (insidious onset, > older pts associated with
hyperuricemia & gouty arthritis)
 JNPHP) young children, associated with retinitis
pigmentosa, hepatic fibrosis & situs inversus), both
presented by:
polyuria (the earliest sign), polydepsia from urinary

concentration defect.
 Nocturia, Weakness &? normal blood pressure in early
stages of renal dysfunction due to renal salt wasting.
 Late in the disease, manifestation of CRF may develop.


Clinically
 MSK, (3rd and 5th decades of life), usually
a symptomatic /incidental (0.5% in pts examined
with excretory urography).
 Recurrent ca phosphate , ca oxalate stones

 U.T.I / Haematuria

 VHLS: commonest systemic lesion is hemangio-
blastoma of eye & brain + pheochromocytoma (10-
20%) + renal involvement, multiple cysts, RCC
(bilateral, multicenteric & affect 2/3 Pts).

Clinically
 TSC, presented by:
 Triad of adenoma sebeceum, epilepsy & MR

 Formation of angiomyolipomas (50-70%) of skin,
kidneys, brain & other organs
 Benign cysts (30-50%) & RCC (2%).

 Condition ? asymptomatic or flank pain, hematuria
from mass effect of angiomyolipomas & cysts
together with HTN (renin dependant) manifestation.


Differential diagnosis of different types of
renal cysts
Disease Kidney size Cyst size Cyst location Liver

Nephronophthisis Small 1MM-2CM Medullary Normal

Acquired cyst Normal/small 0.5-3CM Any Normal

Medullary sponge Normal / MM Precalyceal Normal
Enlarged
ARPKD Enlarged MM Any Fibrosis

Multicystic Enlarged 1MM-10CM Any Normal
dysplastic
ADPKD Enlarged MM-10CM Any Cysts


Morbidity & Mortality
Cystic renal disease accounts for 10% of ESRD pts.
 ADPKD account for 5-10% of ESRD pts.
 ARPKD accounts for 5% of ESRD in children, with
neonatal mortality (25-35%)& > 50% of pts with
ARPKD require kidney transplant before age 20 yrs.
 JNPHP is the most common cause of genetic ESRD
in children.
 Patients with acquired cystic disease are more likely
to develop RCC (5-25%), which are commonly
bilateral & 15% are metastatic.

Diagnosis of cystic kidney disease
 Physical examination: to detect high blood pressure
or enlarged kidneys
 Urine tests: for hematuria &/or proteinuria /infection
 Blood tests: to assess kidney function/CBC
 Renal U/S: It is good at identifying even quite small
cysts
 Computed tomography (CT) and magnetic resonance
imaging (MRI) scans can detect very small cysts.
 Excretory urography.
 Genetic testing – not a routine test.

CT abdomen demonstrates
A prenatal sonogram of a fetus with bilateral atrophic kidneys with
a multicystic dysplastic kidney. multiple renal cysts in a dialysis
patient.


CT abdomen reveals the kidneys
CT abdomen demonstrates multiple are bilaterally enlarged with multiple
hepatic cysts in a case of ADPKD cysts in a case of ADPKD.


Axial non enhanced CT scan of a 1-day-old boy with ARPKD shows
massively enlarged, hypo attenuating kidneys (K) that occupy most of
the abdominal area.


Contrast urography shows normal Unenhanced CT scan of abdomen
collecting system and renal pelvis with medullary nephrocalcinosis
with striated and saccular collections in pt. with medullary sponge
of contrast in the renal papilla. kidney.


A right-sided abdominal mass, which Bilateral renal angiomyo-lipomas
is a renal cell carcinoma in a case of in a case of TS
TS.


Contrast-enhanced axial CT scan abdomen shows cysts within the
pancreas and the right kidney. Note also a solid 3 cm lesion (mid pole,
right kidney, posterior renal cortex [red arrow]). A further smaller lesion
is seen in the renal cortex more anteriorly, which is too small to
characterize (blue area) in a case of von Hippel-Lindau syndrome .


Treatment
 MCDK is not treatable.
 Regular follow up of infant for the first few years by
ultrasounds
 Nephrectomy of unhealthy kidney is indicated in:

 renal hypertension

 malignant transformation.

 Evaluation of contra lateral kidney to rule out
vesicoureteric reflux, about 25% (MCUG).


Treatment
 ADPKD, Treatment may include:
 Blood pressure control (ACEI,ARB).
 MTOR inhibitors show some benefit in limiting in
limiting the increase in kidney size but not the
decrease in GFR & increase proteinuria
 Vasopressin receptor antagonist have shown
promising result in mice & rat model (via
intracellular CAMP) phase 3 trial in progress),
 Diuretics & Low salt diet


Treatment
 Treatment of urinary UTI
 Cysts that are painful, infected, bleeding, or causing a
blockage may need to be drained.
 Surgery to remove one or both kidneys may be
needed.
 Treatments for ESRD (dialysis / kidney transplant).


HALT PKD is the first large multicenter randamized double blind
placebo control study that evaluate potential benefits of rigorous BP
control and inhibition of the renin-angiotensin-aldosterone system on
kidney disease progression in ADPKD.

Study A: change in the
(kidney volume (MRI

Study B: time to 50%
pts 548 pts 470
4 yrs 4-6 yrs reduction of GFR

HALT polycystic
kidney disease (PKD)
Boehringer ingelheim –Merck PKD
Foundation
Randomized, double blind, placebo-
controlled 2006-2011


Treatment

MCKD, there is no cure for this disease.


 Drinking plenty of fluids and take salt supplements to
avoid dehydration.
 Treatment of hyperuricaemia/gout (allopurinol).

 Treatment of CRF includes medications and diet
changes, (limiting foods containing phosphorus and
potassium).
 For those with ESRD need dialysis or a kidney
transplant.

Treatment
 MSK , to reduce the incidence of stones formation in
high risk patients. They can include the following:

 Thiazide diuretics for hypercalciuria
 Potassium citrate or allopurinol for hyperuricosuria
 Potassium citrate for hypocitraturia

 Initial dose of K citrate 20meq/d titrated to urinary
citrate 450mg/d.
 Increasing fluid, reducing salt and protein intake.


Treatment of VHL
 VEGF inhibitors, sorafenib and sunitinib FDA
approval.
 Rapamycin may also be an option.
 Bevacizumab, a monoclonal antibody targeting
VEGF, is under clinical trials
 Iron, 2-oxoglutarate and oxygen are necessary for the
inactivation of HIF, their deficiency reduce the ability
of hydroxlases in inactivating HIF.
 Vitamin C may be a potential treatment for HIF
induced tumors
ESNT-CNE 1 Course Cairo Sept 10-14, 2012

st

Treatment of TSC
 ? Rapamycin decrease the size of mass of
angiomyolipomas by 50% ( as it is associated with
phosphorylaton by MTORs).

 Bilateral nephrectomy before renal transplantation (as
there is increase risk of RCC by immunosupression.


References
1-Amoroso. Autosomal dominant medullary cystic kidney disease with or without
hyperuricemia. Orphanet. June 2006.
2-Avner ED, Sweeney WE. Renal cystic disease: new insights for the clinician. Pediatr
Clin North Am. Oct 2006;53(5):889-909,
3-Bisceglia M, Galliani CA, Senger C, Stallone C, Sessa A. Renal cystic diseases: a
review. Adv Anat Pathol. Jan 2006;13(1):26-56
4-Bonsib M.S.,2009 renal cystic disease & renal neoplasm journal: clinical journal of
the American society of nephrology, CLIN.J.AM.SOC. Vol.4.(12) pp 1998-2007.
5-Choyke PL. Acquired cystic kidney disease. Eur Radiol. 2000;10(11):MF, Meller J
2004. "von Hippel–Lindau tumor 1716-21.
Curry, Nancy SCochran, et al., 2000: cystic renal masses , accurate Bosniak
classification reqiure accurate CT Am. J. Roentgnol, 175-339-432.
6-Czyzyk-Krzeska suppressor: not only HIF's executioner". Trends in molecular
medicine (4): 146–9.
7-Gunay-Aygun M, Avner ED, Bacallao RL, Choyke PL, Flynn JT, Germino GG, et al.
Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis:
summary statement of a first National Institutes of Health/Office of Rare Diseases
conference. J Pediatr. Aug 2006;149(2):159-64.

References
8-Guay-Woodford LM. Renal cystic diseases: diverse phenotypes converge on the
cilium/centrosome complex. Pediatr Nephrol. Oct 2006;21(10):1369-76.
9-Kaelin, WG (2004). "The von Hippel–Lindau Tumor Suppressor Gene and Kidney
Cancer". Clinical Cancer Research 10 (18 Pt 2): 6290s–6295s
10-Kalyoussef E, Hwang J, Prasad V, Barone J. Segmental multicystic dysplastic
kidney in children. Urology. Nov 2006;68(5):1121.e9-11.
11-Knowles HJ, Raval RR, Harris AL, Ratcliffe, PJ. (2003). "Effect of ascorbate on the
activity of hypoxia-inducible factor in cancer cells". Cancer Research 63 (8):
1764–8.
12-Saunier S, Salomon R, Antignac C. Nephronophthisis. Curr Opin Genet Dev. Jun
2005;15(3):324-31
13-Thomsen HS, Levine E, Meilstrup JW, Van Slyke MA, Edgar KA, Barth JC, et al.
Renal cystic diseases. Eur Radiol. 1997;7(8):1267-75.


Important abbreviation
AC= adenyl cyclase
AMP= adenosine mono phosphate
ATP= adenosine triphosphate
CDK= Cyclin dependant kinase
CFTR= cystic fibrosis transmembrane conductor regulator
ER= endoplasmic reticulum
ErbB= epidermal growth factor receptor
JAK= Janus kinase
MTOR= Mammalian target of rapamycin
Rheb= Ras homolog enriched in brain
V2R= vasopressor 2 receptor
PC1= polycystin 1
PC2= polycystin 2
PDE=phosphodiesterase
PKA= protein kinase
STAT= Signals transducer & a Activator s of transcription
TSC1= tuberous sclerosis complex 1
TSC2= tuberous sclerosis complex 2

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