Definition

Pathophysiology

Classification (or lack thereof)

Diseases

Cyst: fluid-filled sac that grows on the surface of, or within the kidney

Generally arise from renal tubules

No good classification system – 9 proposed schema over past 120 years

Classification initially began with structural features, but has evolved to include advances in genetics

Ideal scheme would take into account morphological features, pathogenesis, and therapeutic potential

Genetic vs Non-genetic

Congenital vs Acquired

Isolated vs Systemic Disease

Malignant Potential

Disease Kidney Size Cyst Size Cyst Location Liver

Nephronophthisis Small 1MM-2CM Medullary Normal

Acquired Cysts Normal/Small 0.5-3CM Any Normal

Medullary Sponge Normal/Enlarged MM Precalyceal Normal

ARPKD Enlarged MM Any Fibrosis

Multicystic Dysplastic Enlarged 1MM-10CM Any Normal

ADPKD Enlarged MM-10CM Any Cysts

Prevalence 1:400 to 1:1000, but estimated ½ cases clinically silent and undiagnosed

Commonest defect is in PKD1 gene on chromosome 16 (85-95%), or PKD2 on chromosome 4

Cysts/ESRD occur later in PKD2 vs PKD1 (mean age of ESRD is 74 vs 54)

PKD1/2 encode genes for Polycystin 1/2

Polycystin1 involved in cell-cell interactions; activates JAK-STAT pathway, causing cell cycle arrest

Polycystin2 involves calcium signaling via G-proteins

Expressed in renal tubulular epithelium, hepatic bile ducts, and pancreatic ducts

Diagnosis/Screening Diagnosis generally relies on imaging

(usually U/S); sometimes genetic testing is required for definitive diagnosis

3 main criteria: family history, number/type of cysts, age of patient

Screening not recommended before age 18 (psychological)

Family History Positive - Genotype Unknown

Age 15-39: 3 or more unilateral or bilateral cysts (sensitivity 82-96%, specificity 100%)

Age 40-59: 2 or more cysts in each kidney (sensitivity 90%, specificity 100%)

Age 60 or more: 4 or more cysts in each kidney (sensitivity/specificity 100%)

Family History of PKD1 Genetic screening is often better

Age 15-30: At least two unilateral or bilateral cysts (sens 95%, spec 100%)

Age 30-59: At least 2 cysts in each kidney (sensitivity 97%, specificity 100%)

Age >60: 4 cysts in each kidney (sensitivity 97%, specificity 100%)

Family History of PKD2

Genetic testing recommended

Same ultrasound criteria as unknown genotype

Criteria for Exclusion of Disease (if family history

positive) Age <30: no criteria

Age 30-39: No cysts – false negative rate of 2%

Age >40: 0 or 1 cyst (NPV 100%)

Alternate Imaging

CT and MRI are more sensitive and may pick up smaller cysts

No studies have examined diagnostic criteria with these modalities

Current opinion – if no cysts detected in kidney or liver by age 20, may exclude disease; if results inconclusive, genetic testing should be pursued

Absence of Family History What about patients who meet criteria

but have no family history of disease?

25% of these patients have an undiagnosed relative (can screen family); 5% represent new mutation

In absence of FH, there is no definitive criteria – diagnosis suspected if >10 cysts in each kidney; other cystic disease should be considered

Genetic Testing

Linkage analysis: uses microsatellite DNA markers that flank the PKD genes

Requires at least 4 diagnosed family members; therefore useful in <1/2 of cases

Direct DNA Analysis Difficulty arises from large size of gene,

multitude of “PKD-like” genes, and heterogeneity of alleles

65-70% detection rates with liquid chromatography

85-90% detection with direct sequencing

Drawback: mutation of gene does not necessarily lead to pathology

Clinical Course

Symptoms may present as flank pain, hematuria, proteinuria, calculus, UTI, HTN, renal insufficiency

Renal function intact until 4th decade, and declines at rate of 4-6ml/min per year (faster with PKD1, proteinuria, HTN, male)

Cerebral Aneurysm

4-10% based on age; family history of aneurysm or SAH increases risk

Rupture occurs with larger aneurysms and with poorly controlled HTN

SAH presents as acute severe headache CT scan might miss small bleed – lumbar

puncture should be done 6-12 hrs later

Role of radiological screening studies in asymptomatic patients with ADPKD is controversial

Rate of interventional-related morbidity/mortality is 13.7%

Routine screening recommended for high-risk pts (previous rupture, FH, high-risk occupation)

Procedures of choice are CTA/MRA (but beware NSF with GFR<30 {?<60})

Suggested screening is yearly for 3 years, and if stable, every 2-5 years afterwards

Unknown if warfarin increases risk of bleeding; reasonable to screen these pts

Hepatic Cysts

Prevalence of ~80% in pts age 15-45

Massive cysts occur almost exclusively in women; multiple pregnancies accelerates growth (? Estrogen)

Most asymptomatic; some require pain control or antibiotics

Cardiac Disease

Valvular abnormalities in 30% (MVP, AR)

Coronary aneurysms not infrequent

Asymptomatic pericardial effusion seen in 35%, with 50% of these being moderate to severe in size

Other

Colonic Diverticula (abd pain may be misleading)

Abd wall hernia in up to 45% (consideration in PD patients)

No treatment has been proven to delay progression of disease

Control of HTN should be attained with ACE-I (increased RAS activity from focal ischemia due to cyst expansion)

Nephrectomy is sometimes necessary for transplant, recurrent UTI, RCC, chronic pain, chronic hematuria

Ideas for the future?

MTOR inhibitors: show some benefit in limiting the increase in kidney size, but do not limit the decrease in GFR (over 2 yrs) and cause more proteinuria

Vasopressin receptor antagonists have shown promising results in mice/rat models (via intracellular cAMP), phase 3 trials in progress

ARPKDARPKD Estimated incidence 1:10,000-40,000

Generally diagnosed in pediatric age; cases diagnosed in adulthood have mild renal impairment but more hepatic dysfunction

PKHD1 gene encodes fibrocystin, a cilial protein of cortical/medullary collecting ducts and hepatic bile duct

Features Kidneys enlarge due to microcysts

(<3mm)

Liver always has hepatic fibrosis (portal hypertension, ascites, esophageal varices)

Diagnostic criteria: imaging criteria plus one of following: absence of cysts in parents, sibling with disease, evidence of hepatic fibrosis

Nephronophthisis

Autosomal recessive, heterogenous disorder affecting proteins in cilia

Characteristic findings: reduced urinary concentrating ability; chronic tubulointerstitial nephritis resulting in ESRD by age of 20

Commonest extrarenal manifestation is retinitis pigmentosa (20%)

Manifestations

Presents as polyuria/polydipsia due to impaired concentration of urine

Hepatic Fibrosis

Situs Inversus

Diagnosis-Polyuria with bland urinalysis-Progressive CKD without HTN-Normal Size Kidneys

If above 3 are present, genetic testing should be undertaken

If genetic test negative, biopsy can be suggestive – tubulointerstitial nephritis with thickened basement membrane

Medullary cysts in normal-sized kidneys

Medullary Cystic Kidney Disease

A rare (~50 cases per year in USA) autosomal dominant disease

Two types, with variable clinical courses - ESRD at age 20-70

MCKD2MCKD2

Also called Familial Juvenile Hyperuricemia

Describes families with mutations in the uromodulin gene – a Tamm-Horsfall mucoprotein

Uromodulin is produced exclusively in thick ascending limb of Loop of Henle

It is a sticky insoluble protein which may assist with water-tight integrity

Mutant proteins cannot exit cell, and cause tubular atrophy/death

Hyperuricemia/Gout results from reduced urate excretion (mechanism not well understood)

Progressive decline in renal function secondary to tubular death

3 criteria:-Family history of renal disease in

autosomal dominant pattern-Family History of Gout-Bland Urinary sediment without little or no

proteinuria

Definitive Diagnosis through genetic test, which is cheaper and more specific than biopsy (IF with antibody to uromodulin shows deposition in tubules)

Gout is best controlled with allopurinol; uncertain whether this slows progression of kidney disease

MCKD1MCKD1 Gene within chromosome 1q21 has not

been identified, so pathophysiology unknown

HTN and Hyperuricemia are more prevalent as renal function declines, therefore late features (contrast to MCKD2)

Course within families in extremely variable (ESRD ranging from age 30-75)

Biopsy reveals tubular atrophy, interstitial fibrosis, splitting of basement membrane (which is thick and irregular)

No specific treatment

Transplant is preferred therapy – disease will not recur

A congenital dysplasia in which a mass of cysts and connective tissue forms, with no identifiable renal tissue

Usually unilateral, with compensatory hypertrophy of remaining kidney (but may have positional or structural defect)

Often detected on prenatal sonography, or palpable flank mass

Evaluation of contralateral kidney, including ultrasound and voiding cytourethrography to rule out vesicoureteral reflux (25%)

No indication for nephrectomy (no increased risk of Wilms tumor)

Characterized by malformation of terminal collecting ducts in pericalyceal region of pyramids

Generally clinically benign, but recurrent nephrolithiasis and UTI may lead to renal insufficiency

Sometimes autosomal dominant, but usually sporadic mutations

Prevalence unknown, but seen in 10-20% of patients who form calcium stones

Diagnosis usually incidental - made by IVP, with dilation of cystic ducts showing “brush” appearance radiating outward from calyces

U/S and CT less specific – show nephrocalcinosis

Usually asymptomatic - incidental

Recurrent calcium phosphate or calcium oxalate stones – concretions within cysts act as nidus for stone formation

UTI (secondary to stones, stasis)

Hematuria

Patients with stone risk factors (hypercalciuria, hyperuricosuria, hyperoxaluria, hypocitraturia) may benefit from potassium citrate

Initial dose 20meq/day titrated to urinary citrate level of 450mg/day

Tuberous Sclerosis

Autosomal dominant; 1/3 familial

Characterized by formation of angiomyolipomas of skin, brain, kidneys, other organs

2 genes – TSC1 (hamartin) and TSC2 (tuberin)

Commonest lesion is angiomyolipoma (50-70%), then benign cysts (30-50%)

Symptoms include flank pain, hematuria from mass effect of angiomyolipoma; cysts usually asymptomatic

Renin-dependent HTN from ischemia

Since TSC2 gene is adjacent to PKD1, some have both diseases

ESRD can occur from mass effect

RCC in 1-2% - U/S every 1-3 years

Intervention for pain, bleeding, malignancy – 1st line is arterial embolization, second line is partial or total nephrectomy

TreatmentTreatment Since angiomyolipoma is associated

with phosphorylation by MTOR, there is limited evidence that rapamycin decreases size of mass by 50%, but returns upon discontinuation of drug

Transplantation should be accompanied by bilateral nephrectomy due to increased risk of RCC by immunosuppresssion

Von-Hippel Lindau

Autosomal dominant syndrome with a variety of benign and malignant tumors

Commonest systemic lesion is hemangioblastoma of eye/brain; pheochromocytoma in 10-20%

Renal involvement includes multiple cysts and RCC (2/3 of pts)

RCC often multicentric and bilateral, therefore cysts are benign, but considered premalignant

Screening for RCC should begin in adolescence

No guidelines, but current opinion is annual ultrasound, plasma catecholamine, retinal exam, MRI brain and spine with gad at age 10

New tumors arise every 5 years in 30% of pts; every 10 years in 85%

Small lesions may be observed (<3cm), or undergo radiation ablation, cryotherapy, or partial nephrectomy

Transplantation feasible in setting of bilateral nephrectomy; minimal data available regarding RCC recurrence

HD and PD associated with development of multiple bilateral small cysts; usually less than 0.5cm but up to 3 cm

Criteria: 4 or more total cysts in both kidneys

Differentiated from ADPKD by lack of family history, small/normal size kidneys, smooth contoured kidneys

Incidence increases with increased time on dialysis; also occurs in children

Pathogenesis unknown; believed to be result of compensatory hypertrophy leading to tubular hyperplasia and cysts

Cysts may regress following transplant

Commonest symptoms: hematuria, lumbar pain, UTI

RCC has varied incidence, ~5%; malignancy develops after 8-10 years on dialysis; risk factors are male and large cysts

No guidelines for screening; some suggest radiological studies only for new symptoms (hematuria/flank pain), or young pts (long duration of HD)

The term is histopathological (descriptive); Can only be distinguished from tubular cystic disease by biopsy

A rare disease that may be seen independently; but more commonly in association with other pathology

Often a pediatric diagnosis

Classifications of glomerulocystic kidney

diseaseExample

Familial nonsyndromicAutosomal dominant polycystic kidney disease in young infants

Associated with inheritable malformation syndromes

Tuberous sclerosis complex

Syndromic, non-Mendelian Trisomy 9, 13, or 18

Sporadic New mutations

Acquired and dysplastic kidneysHemolytic uremic syndrome and

obstructive uropathy