RGR06102008

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Published on August 3, 2008

Author: nathanhellman

Source: authorstream.com

Slide 1: Renal Grand Rounds Case: a 27 year-old man with a family history of cystic kidney disease presents as a potential kidney transplant donor. June 10, 2008 Fellow: Nathan Hellman, MD, PhD Attending: Julie Lin Slide 2: HPI: M.M. is a 27 year old male from the country of Cape Verde who wishes to be a kidney donor for his aunt, who is an ESRD patient 2/2 polycystic kidney disease on dialysis for several years. He is a generally healthy male with no history of HTN, diabetes, and no prior hospitalizations. PMH: none All: NKDA Current Medications: none, denies NSAIDs. SH: no tob, social EtOH use, no drugs. Works as musician in Africa. Slide 3: Where is Cape Verde? Slide 4: Family History: All younger than 27 27 51, HTN 47 55 57 36 ? ? Slide 5: Physical Exam: BP 112/66, P 58, BMI 21 Gen: healthy-appearing thin pleasant M in NAD HEENT: OP clear, anicteric sclera Lungs: CTA bilaterally CV: RRR no murmurs or rubs ABD: soft, NT/ND, benign Ext: no LE edema; warm, well-perfused extremities Neuro: grossly non-focal exam ROS: negative for hematuria, flank pain, kidney stones, hernias, neurologic symptoms. Data: Na 142, K 3.7, Cl 104, HCO3 30, BUN 8, Cr 0.72, glucose 98 Ca 9.8, PO4 2.3, alb 4.8, uric acid 4.6 T-bili 1.8, ALT 13, AST 15, ALKP 57 No microalbuminuria HIV, hepatitis B, hepatitis C negative Urinalysis: bland, unremarkable; no RBCs Slide 6: Questions for Discussion: -Should the patient be approved as a potential donor? -What additional tests (if any) should be performed before the patient is approved as a potential donor? -How would the situation change if the patient’s father definitely had PKD? Slide 7: Autosomal Dominant Polycystic Kidney Disease -must first differentiate from other (more rare) causes of cystic kidney disease. -AD-inherited disorder caused by mutations in PKD1 (85%) or PKD2 (15%) gene characterized by progressive cyst development, bilaterally enlarged cysts, and eventual renal failure. -de novo mutations in PKD1 or PKD2 have been described. -extrarenal manifestations such as liver cysts, abdominal wall hernias, valvular abnormalities, and CNS aneurysms may be present. Slide 8: Lancet (1994) 343: 824-827 Review of Ultrasound Criteria for Diagnosis of ADPKD “The main questions in renal imaging are how much confidence to place in apparently negative results in younger family members and how to avoid over-diagnosis in elderly members who have merely multiple simple cysts rather than ADPKD.” -performed linkage analysis in 128 sibships from 18 families with known ADPKD. -each patient with a 50% chance of ADPKD (but no previous diagnosis) underwent Renal U/S. -post-scan positive and negative predictive values were used to assess the ultrasonographic diagnostic criteria for PKD1. Slide 9: Review of Ultrasound Criteria for Diagnosis of ADPKD Slide 10: Autosomal dominant polycystic kidney disease type 1 and 2: assessment of US sensitivity for diagnosis. Nicolau et al, Radiology (1999): 213: 273-276. -performed renal U/S and DNA analysis for ADPKD in 319 patients « at risk » for ADPKD, 161 of whom were younger than 30 years from 54 families with ADPKD. -the sensitivity of US for diagnosis was estimated by comparing the US results with genotypes from linkage studies. -sensitivity of US in individuals younger than 30 years who were at risk was 95% for ADPKD type 1 but only 67% for ADPKD type 2. -the sensitivity of US for either ADPKD type 1 or ADPKD type 2 in individuals aged 30 years or older who were at risk was 100%. Slide 11: BWH Renal Transplant Clinic Policy for Patients with a Family History of ADPKD: “If donor <30, 2 cysts establishes PCKD, either unilateral or bilateral by CT or MRI. If donor 30-59 yo, 2 cysts in each kidney, and if donors >60 yo 4 cysts in each kidney establishes PCKD. No donor candidates are accepted below age 30 unless genetic testing is normal.” Slide 12: Molecular Genetic Testing in ADPKD Two genes responsible for virtually all ADPKD: PKD1 (85%): chromosome 16, 46 exons PKD2 (15%): chromosome 4, 15 exons Ong and Harris, KI (2005), 67: 1234-1247. Slide 13: ADPKD: The Ciliary Hypothesis Nauli et al, Nature Genetics (2003), 33: 129-137 Slide 14: Molecular Genetic Testing in ADPKD DNA Linkage Analysis -requires both genotype & clinical information from multiple affected and unaffected family members. -Seeks to identify a segment of the chromosome at either the PKD1 or PKD2 locus that completely co-segregates with the disease. B. Gene-Based Mutation Screening -direct sequencing of all PKD1 and PKD2 exons. -a real challenge given the genetic complexity of PKD1 gene. -approximately 200 different PKD1 mutations and >50 PKD2 mutations have been reported. Pei, CJASN (2006), 1: 1108-1114. Slide 15: How accurate is genetic screening? CRISP = Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease JASN 2007 18: 2143-2160. -analyzed cohort of 202 individuals with ADPKD. -screened for mutations by denaturing HPLC followed by direct sequencing of those patients with no definite mutations. -definite mutations were identified in 62.9% of probands. -”probably pathogenic” (e.g., splice site or missense mutations mutations were identified in 26.2% probands). -Mutations were thus defined in 89.1% of probands. -Majority of mutations were unique to a single family. -Multiple polymorphisms (average of 10.1 per patient) in PKD1 gene were identified. Slide 16: http://www.athenadiagnostics.com/ Cost of sequencing PKD1 & PKD2 loci: about $3000. Slide 17: Options for Our Patient: Option 1: Have the patient’s father get a renal ultrasound. If he has no cysts, he is virtually assured of not having ADPKD, and therefore our patient can be approved as a donor. Option 2: Perform sequence analysis of the patient’s PKD1 and PKD 2 gene looking for definite mutations. Option 3: Perform sequence analysis on the recipient’s PKD1 and PKD2 gene loci; if a definite mutation is found, look to see whether the potential donor has it. Option 4: Linkage analysis of the family. Option 5: MRI of the kidneys to look for cystic disease not seen on ultrasound. Slide 18: Thanks! Julie Lin Jagdeep Obhrai Ted Steinman

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