POLYCYSTIC RENAL DISEASES Katie Westreich, MD

CONTEXT

Solitary cysts (simple vs multilocular)

Genetic cystic: ARPKD, ADPKD

Cystic dysplasia

Medullary sponge kidney

Nephronophthisis/medullary cystic

Dialysis cystic

Glomerulocystic disease

pathguy.com

PRIMARY RENAL EPITHELIAL CILIA

Habbig, 2015

AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE

PRENATAL CONSULT

23 weeks gestation

Anhydramnios

Large echogenic kidneys

Courtesy of Prof Frank Gaillard, Radiopaedia.org

ARPKD - GENETICS

6p21 PKHD1 gene Polycystic Kidney and Hepatic Disease 1

Gene protein product: fibrocystin aka polyductin

Protein function: not exactly known, involved in primary cilia

Habbig, 2015

ARPKD – KEY FEATURES

Renal: microcysts and cystic dilation of collecting tubules; normal glomeruli

Hepatic: congenital hepatic fibrosis is universal histologically, 50% with clinical evidence liver involvement at birth

Pulmonary: hypoplasia depending on oligohydramnios (30% of these die within first year of life)

Presentation: High degree of variation in severity of clinical presentation and therefore timing of diagnosis

ARPKD –NATURAL HISTORY

OVERALL Mortality highest for neonates with severe renal and pulmonary manifestations --30% Patient survival at 1 year: 85% At 10 years: 82%

RENAL 14% ESRD by age 5 29% by age 10 58% by age 20

ARPKD – RENAL MANIFESTATIONS

Large echogenic kidneys, cysts not visible on ultrasound in fetal/newborn period

Sometimes oligohydramnios during pregnancy

HTN during newborn period common and hard to control

Concentrating defect universal

Hyponatremia in newborn period very common

ARPKD – HEPATIC MANIFESTATIONS

Biliary dysgenesis congenital hepatic fibrosis, universally present histologically

50% have clinically apparent liver involvement at time of diagnosis

Dilation of the intrahepatic bile ducts (Caroli Disease) in 60%, increasing risk of ascending bacterial cholangitis

Can lead to progressive portal HTN, varices, protein losing enteropathy, GI bleeds

If they survive neonatal period, many need portocaval shunting or liver transplant

ARPKD – PULMONARY MANIFESTATIONS

Pulmonary hypoplasia very variable

Some die early on from this

Some do better than expected given degree of oligohydramnios

Long-term: pulmonary function good unless require mechanical ventilation in the newborn period

ARPKD – MANAGEMENT

Screen for complications

Manage complications

Sometimes have to remove a kidney or both (try not to) in order to ventilate, oxygenate, and feed

ACE-I is treatment of choice for HTN

Aggressively support growth

WHAT’S IT LIKE IN ADULTHOOD?

Wide spectrum of disease

--CKD stage 3, s/p liver transplant

--nearing liver transplant with esophageal varices and portal hypertension, cholangitis

--already had 2 liver/kidney transplants by age 20

AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

ADPKD – KEY FEATURES

Bilateral renal cysts that occur all along the nephron Hypertension Nephrolithiasis

Cysts in other organs

Liver most common – but liver works fine

Seminal vesicles, pancreas, arachnoid membrane

Vascular anomalies

Intracranial aneurysms, subarachnoid hemorrhage, dilation of aortic root, aortic regurgitation, dissection of thoracic aorta, mitral valve prolapse

ADPKD – GENETICS

85% of patients with ADPKD

16p13 PKD1 – Polycystin 1, primary cilia of renal epithelium

15%

4q22 PKD2 – Polycystin 2, primary cilia of renal epithelium

PKD1 and TSC2 (causing tuberous sclerosis) are contiguous

Hard to figure out since TS can also have renal cysts

5-10% of mutations are spontaneous

100% penetrant

Habbig, 2015

ADPKD – PATHOGENESIS

Primary cilia don’t work → cyst formation and exponential growth→ compression of renal vessels → RAAS activation → increased systemic vascular resistance → poor renal blood flow → sodium retention, renal fibrosis, decreased eGFR

ADPKD – PRESENTATION

Often come to us with family history to be screened

Cysts incidentally found on imaging for other reasons

HTN or microscopic hematuria

Flank pain

Due to renal capsular distension, infection of cyst, hemorrhage into cyst, stones

Children often have enlarged but normal appearing kidneys as the only renal manifestation until they start developing cysts

ADPKD – DIAGNOSIS

If you have a parent with ADPKD, diagnostic criteria by ultrasound are:

15-39 years: >3 cysts in each kidney

40-59 years: >4 cysts in each kidney

If a kid has a single cyst and an affected parent, it’s probably ADPKD

ADPKD – NATURAL HISTORY

PKD1

Cysts/kidneys/liver enlarge

GFR declines ~5ml/min/year

50% ESRD by age 50-60

75% ESRD by age 70

PKD2

Later presentation

Slower cyst growth, slower GFR decline

Natural history best predicted by other family members

Poor prognostic factor: them seeing us (early detection)

Main cause of death: CVD (control that HTN)

ADPKD – NATURAL HISTORY

Acute and chronic pain are common (60%) --Cyst growth/capsular distension of liver or kidney

--Renal or liver cyst infection

--Renal or liver cyst hemorrhage

--Biliary or venous obstruction due to liver cyst growth

--Nephrolithiasis (~30%)

Typical pain management ineffective Novel pain management techniques --Renal cyst decortication

--Nerve blocks, or renal denervation

--Nephrectomy

pkdcure.org

ADPKD – ANEURYSMS/SUBARACHNOID BLEED

If family history of it, prevalence is 22%

If no family history of it, 6%

MRA brain after age 20 if family history, earlier if headaches

Intervene when they get to >7-10mm or symptomatic

ADPKD – SURROGATE OUTCOMES

The bigger your kidneys are, the faster your cysts will grow and the faster your GFR will decline

CRISP study: In all comers, cyst growth is exponential, averages 5% per year over 3 years

ADPKD – MANAGEMENT

Drink, drink, drink Polyuria → high levels vasopressin → cystogenesis Pravastatin (pediatric RCT!) Tested in kids 8+, less rapid renal growth over 3 years of study Tolvaptan works in adult to slow renal growth and eGFR decline Hypertension: due to reduced renal blood flow→ high renin → sodium avidity Control of blood pressure has been shown to slow disease progression

ACE-I, sodium avoidance

ACE-I/ARB combinations are not advantageous to single drug

Habbig, 2015

NEPHRONOPHTHISIS & MEDULLARY CYSTIC KIDNEY DISEASE

NEPHRONOPHTHISIS VS MCKD Gene ESRD onset Histology

Autosomal Recessive Nephronophthisis -- Children

Type 1 “juvenile” NPHP1 – nephrocystin Child

Medullary cysts, classic thickening

of tubular BM

Type 2 “infantile” NPHP2 – inversin Infant

Type 3 “adolescent” NPHP3 – unknown Adol

Type 4 NPHP4 – nephrocystin 4

Type 5 NPHP5 – nephrocystin 5

Type 6 NPHP6

Type 7 NPHP7

Type 8 NPHP8

Type 9 NPHP9

Autosomal Dominant Medullary Cystic Kidney Disease -- Adults

Type 1 Unknown 60s Medullary cysts; NO thickening of

tubular BM Type 2 UMOD – uromodulin AKA tamm-

horsfall protein 30s

Nephronophthisis – genes

NEPHRONOPHTHISIS/MCKD – KEY FEATURES

Chronic tubulointerstitial nephritis

Bland UA (this is not a glomerular disease)

Urine concentrating defect – bedwetting common

Often diagnosed at or near ESRD <20yo (commonly with severe anemia)

Usually not hypertensive (helps differentiate from ADPKD)

Ultrasound findings

Normal or small kidneys

Normal appearing tissue or increased echogenicity

Cysts (often seen late in disease course) at corticomedullary junction

SYNDROMIC NEPHRONOPHTHISIS

Senior-Loken syndrome

NPH + retinitis pigmentosa

This is why everyone with NPH needs an eye exam

Oculomotor Apraxia, Cogan type (OMS)

Defective of absent horizontal voluntary eye movements

Looks like head jerking

Joubert syndrome

Meckel-Gruber syndrome

Mainzer-Saldino syndrome

ACQUIRED CYSTIC KIDNEY DISEASE

ACQUIRED CYSTIC KIDNEY DISEASE

CKD or ESRD associated cysts

At least 3 cysts in each kidney and no features or other cystic kidney diseases or affected family member

8-13% of adult patients initiating RRT

90% at 9 years on dialysis

3-6% of those with acquired cystic kidney disease develop RCC

Children with liver transplantation (30%) also develop acquired renal cysts

Cyclosporine is an independent risk factor, as is chronic liver rejection, and thrombosis of vena cava

BONUS DISEASES INCLUDING RENAL CYSTS

Tuberous sclerosis

Unique hyperplastic tall columnar epithelium (unlike cuboidal epithelium of other cystic diseases

Von Hippel Lindau

Renal cysts and renal cell carcinoma

Extra renal manifestations (pheo, hemangioblastoma, retinal angiomas, endolymphatic sac tumors of middle ear, neuroendocrine pancreatic tumors, cystadenomas of epididymis and broad ligament)