cystic kidney diseases dr.a.hassan end123

Cystic Diseases of the Kidney

Ahmed Hassan Mohamed MD Lecturer of nephrology

National institute urology & nephrology

NIUN

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

CNECNE

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

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

Kidney cysts


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


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.

Pathophysiology


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

multicystic dysplastic kidney (MCDK).

Cut surface of a nephrectomy specimen from a patient with a

multicystic dysplastic kidney (MCDK).

Medullary cysts in normal size kidney in a case of nephronophthisis

Medullary cysts in normal size kidney in a case of nephronophthisis


Nephrectomy specimen from a patient with a large benign simple cyst.

Nephrectomy specimen from a patient with a large benign simple cyst.

External surface of a nephrectomy specimen from a patient with autosomal dominant polycystic kidney disease (ADPKD).

External surface of a nephrectomy specimen from a patient with 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).


four presentations: Neonatal & infancy with a profound respiratory

compromising 2ndry to oligohydraminas. Childhood & adolescence with hepatic disease

predominant. Cholongitis ESRD

ARPKD clinical presentation


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.


Disease Kidney size Cyst size Cyst locationLiver

NephronophthisisSmall 1MM-2CMMedullary Normal

Acquired cystNormal/small0.5-3CMAny Normal

Medullary spongeNormal / Enlarged

MMPrecalyceal Normal

ARPKDEnlarged MMAny Fibrosis

Multicystic dysplastic

Enlarged 1MM-10CMAny Normal

ADPKDEnlarged MM-10CMAny Cysts

Differential diagnosis of different types of renal 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 bilateral atrophic kidneys with multiple renal cysts in a dialysis patient.

CT abdomen demonstrates bilateral atrophic kidneys with multiple renal cysts in a dialysis patient.

A prenatal sonogram of a fetus with a multicystic dysplastic kidney.A prenatal sonogram of a fetus with a multicystic dysplastic kidney.


CT abdomen demonstrates multiple hepatic cysts in a case of ADPKDCT abdomen demonstrates multiple hepatic cysts in a case of ADPKD

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

CT abdomen reveals the kidneys are bilaterally enlarged with multiple 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 collecting system and renal pelvis with striated and saccular collections of contrast in the renal papilla.

Contrast urography shows normal collecting system and renal pelvis with striated and saccular collections of contrast in the renal papilla.

Unenhanced CT scan of abdomen with medullary nephrocalcinosis in pt. with medullary sponge kidney.

Unenhanced CT scan of abdomen with medullary nephrocalcinosis in pt. with medullary sponge kidney.


Bilateral renal angiomyo-lipomas in a case of TS Bilateral renal angiomyo-lipomas in a case of TS

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

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

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 .


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


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.

548 ptsyrs 4

548 pts4 yrs

470 ptsyrs 4-6

470 pts4-6 yrs

Study A: change in the kidney volume (MRI)

Study B: time to 50% reduction of GFR

Study A: change in the kidney volume (MRI)

Study B: time to 50% reduction of GFR

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

HALT polycystic kidney disease (PKD)Boehringer ingelheim –Merck PKD FoundationRandomized, 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


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):26-564-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 cyclaseAMP= adenosine mono phosphateATP= adenosine triphosphateCDK= Cyclin dependant kinaseCFTR= cystic fibrosis transmembrane conductor regulator ER= endoplasmic reticulumErbB= epidermal growth factor receptorJAK= Janus kinaseMTOR= Mammalian target of rapamycinRheb= Ras homolog enriched in brainV2R= vasopressor 2 receptorPC1= polycystin 1PC2= polycystin 2PDE=phosphodiesterasePKA= protein kinaseSTAT= Signals transducer & a Activator s of transcriptionTSC1= tuberous sclerosis complex 1TSC2= tuberous sclerosis complex 2

cystic kidney diseases dr.a.hassan end123

Education