The Kidney in Bardet-Biedl Syndrome Robert Haws, M.D. Pediatric Nephrology Marshfield, Wisconsin Bardet-Biedl Syndrome Everything important that I have learned about Bardet-Biedl syndrome I have learned from my friends- the children and their families that allow me to be their doctor Diagnostic Criteria Primary Features Rod-cone dystrophy Post-axial polydachtyly Truncal obesity Learning disabilities Hypogonadism Renal anomalies Diagnosis of BBS based on four primary features or three primary features plus two secondary features Based on the pioneering work of Dr Philip Beales Secondary Features Speech delay/disorder Behavioral abnormalities Eye abnormalities Brachydactyly/syndactylly Ataxia/poor coordination/imbalance Mild hypertonia Diabetes mellitus Orodental abnormalties Cardiovascular anomalies Hepatic Involvement Craniofacial dysmorphisms Hirschsprung disease Anosmia Bardet-Biedl syndrome and the kidney Bardet-Biedl syndrome and the kidney Bardet-Biedl syndrome and the kidney Electron micrograph courtesy of Dr John A. Sayre, University of Newcastle upon Tyne From Pediatr Nephrol (2006) 21: 1369–1376 Lisa M. Guay-Woodford So how does the BBS affect kidney health? Function Urine Volume Removal of waste products Blood pressure control Structure (anatomy) Size of Kidneys Drainage of urine Filters and Tubes Cysts Bardet-Biedl syndrome and urine output •Impaired ability of the kidney to concentrate urine • Polyuria & Polydipsia • May be present in the absence of impaired kidney function • Fluid restriction is not a valid recommendation • Importance of extra fluid on “sick days” • Enuresis • Avoidance of DDAVP • Need to evaluate for posterior urethral valves and meatal stenosis in boys and detrusor instability of the bladder From Harnett et al. NEJM 319(10); 616 From Putoux A, et al. Pediatric Nephrology (2012) 27:7-15 Bardet-Biedl syndrome and kidney function • Impaired kidney function is highly variable • Differences between family members • • • • • Complex genotype/phenotype relationship? 10% reach CKD stage 5* in pediatric years 25% reach CKD stage 5* by 48 years (O’Dea et al.) May not be recognized in a timely manner Little things can make a difference * CKD stage 5 (person promptly needs dialysis or kidney transplant) Imhoff, O. et al. Clin J Am Soc Nephrol 6:22-29, 2011 Bardet-Biedl syndrome and kidney function •“Typical” Chronic kidney disease •Chronic kidney disease in BBS • Hypertension is present but • Hypertension • Proteinuria (protein in urine) • • Hematuria (blood in urine) • • Anorexia (lack of appetite) • • Fatigue • • Anemia (low blood count) • Declining urine output and often complete loss of urination after dialysis is started • • usually not severe Proteinuria usually mild Hematuria uncommon Anorexia does not develop Symptoms of fatigue are often absent Anemia often milder Decline of kidney function is usually gradual and urine output remains present even on dialysis Common sense ways to preserve kidney function in Bardet-Biedl Syndrome • • Avoid non-steroidal antiinflammatory medications (NSAIDS) Avoid dehydration • • • • • Potential benefit of increased hydration Treat UTI promptly Control blood sugar & cholesterol Monitor blood pressure and treat if needed • • • • • NSAIDS (partial list) Ibuprofen • Advil, Motrin, Pediaprofen Naproxen • Aleve, Anaprox Aspirin • Bayer, Bufferin Celecoxib • Celebrex Ketorolac • Toradol The kidneys and high blood pressure in BBS • Kidney disease and high blood pressure (hypertension) go hand in hand • Hypertension is common in BBS even in childhood Imhoff, O. et al. Clin J Am Soc Nephrol 6:22-29, 2011 Why is hypertension common in BBS? Potential explanations • Kidney disease (hypertension is common in other cystic kidney diseases such as PKD) • • • • • • Sleep Apnea Obesity Dietary Family genetics Metabolic (e.g. high uric acid levels) Inflammatory factors Thoughts on treatment of hypertension • Encourage your doctor to treat the hypertension • Potential benefit to targeting the 50th percentile • Preferred medications- ACE inhibitors (prils) & ARBs (tans) • Discourage thiazides, beta blockers and perhaps calcium channel blockers So how does the BBS affect kidney health? Function Urine Volume Removal of waste products Blood pressure control Structure (anatomy) Size of Kidneys Drainage of urine Filters and Tubes Cysts Bardet-Biedl syndrome and the fetal kidney •Fetal imaging may show enlarged kidneys that may be mistaken with other disorders • Autosomal Dominant Polycystic • • • • Kidney Disease Autosomal Recessive Polycystic Kidney Disease Meckel Gruber syndrome “Meckel-like” syndrome without encephalocele Joubert syndrome Bardet-Biedl syndrome and the fetal kidney The clinical evolution in one patient 30 Weeks Gestation Bardet-Biedl syndrome and the fetal kidney The clinical evolution in one patient Newborn (1 day old) Bardet-Biedl syndrome and the fetal kidney The clinical evolution in one patient Same child at 8 years old Bardet-Biedl syndrome and the fetal kidney The clinical evolution in one patient Bardet-Biedl syndrome and the kidney •A variety of urinary tract abnormalities have been identified in Bardet-Biedl syndrome • We don’t know how common urinary tract problems are present in BBS because of incomplete investigation • Probably 50% or more of patients with BBS will have an identified urinary tract abnormality • A variety of abnormalities have been reported Bardet-Biedl syndrome and the kidney Bardet-Biedl syndrome and the kidney Bardet-Biedl syndrome and the kidney Bardet-Biedl syndrome and the kidney Bardet-Biedl syndrome and the kidney Bardet-Biedl syndrome and the kidney Reported structural abnormalities in BBS • Calyceal diverticulum • Ectopic Kidney (kidney in • Calyceal blunting abnormal location) • Vesicoureteral reflux • Bladder outlet obstruction • Fetal lobulation • Renal cysts • Dysplastic kidneys (malformed • • • • kidney tissue) Renal agenesis (absent kidney) Kidney infections Kidney scars Horseshoe Kidney (two kidneys fused together) • Including severe meatal stenosis & posterior urethral valves • Urogenital sinus • Vesicovaginal fistulae (connection between bladder and bowel) • Kidney stones • Kidney cancers Bardet-Biedl syndrome and the kidney • Should imaging of the urinary tract occur in all individuals with BBS? • Yes, at least a renal ultrasound in everyone with BBS • Additional studies should be considered when urinary tract infections, bedwetting, blood in the urine or pain or discomfort in the abdomen is present and of course if the kidney function is impaired Bardet-Biedl syndrome and kidney failure • At what age does this happen? • Highly variable from infancy to never • Can the different BBS genes predict kidney failure? • Maybe • What are my options if my child or I develop kidney failure (CKD stage 5)? Bardet-Biedl syndrome and kidney function When dialysis is needed Bardet-Biedl syndrome and renal transplantation •Transplantation in BBS has some specific issues but it is absolutely possible •Reported complications • Increased risk of UTI • Previously unidentified • • Need for comprehensive evaluation of urogenital system • • • • urogenital abnormalities Obesity even in previously nonobese pretransplant patients Tacrolimus & Steroid induced DM Drug induced mood changes Hyperlipidemia Cholelithiasis (gall bladder stones) Bardet-Biedl syndrome and renal transplantation • The pros and cons of steroid free renal transplantation • Pros • Decreased appetite stimulation • Decreased mood alterations • Decreased infection risk • BBS is a non-immune based disorder • Cons • Increased rejection risk • May need increased doses of other agents including tacrolimus So how does the BBS affect kidney health? Function Urine Volume Removal of waste products Blood pressure control Structure (anatomy) Size of Kidneys Drainage of urine Filters and Tubes Cysts Questions? BBS and renal disease in family members •Beales, et al in his 1999 article in the •Hjortshoj, et al in 2007 in the Journal of Medical Genetics identified in 3 individuals in 180 (1 in 60) family members with renal cell carcinoma •Renal dysgenesis/agenesis in 1.6% of the family members compared to 0.1% in the general population •Croft et al in 1990 in the American Journal of Medical Genetics that there was an increased risk of obesity, hypertension and renal disease. American Journal of Genetics examined 116 patients with BBS and 428 relatives and found an overall tendency towards fewer cancers than anticipated. •Webb, et al in 2009 in Kidney International reported that there was no increase in hypertension, chronic kidney disease or obesity compared to the general population.