Cystinosis Tissue Repository Study of Atubular Glomeruli

Cystinosis Tissue Repository

Study of Atubular Glomeruli

Jess Thoene, M.D.

Background

• The description of atubular glomeruli (ATG) in diabetic nephropathy , and the occurrence of the "swan neck" deformity in the proximal renal tubule in cystinosis prompted a pilot study in one cystinotic kidney to determine the occurrence of ATG in cystinotic kidney specimens. CRN funded a cystinosis tissue repository at the University of Michigan that has enabled us to obtain renal tissue post transplantation

“Swan-neck Deformity”

Atubular Glomeruli and Glomerulotubular Junction

Abnormalities in Diabetic Nephropathy

BEHZAD NAJAFIAN, YOUNGKI KIM, JOHN T. CROSSON, and MICHAEL MAUER

J Am Soc Nephrol 14: 908–917, 2003

Prior studies:

Method

• Obtain renal tissue from cystinosis patients at time of renal transplantation

• Cut 4 µ paraffin sections

• Reconstruct glomeruli using sequential sections performed by Patrick Walker and associates at Nephropath in Little Rock, Arkansas.

• Determine the incidence of ATG

Case Reports, ATG Study

• Case number one: This boy had a renal transplant at age 10 years having been diagnosed with nephropathic cystinosis at age 5 years. From the time of diagnosis until real transplantation he had been maintained on optimal doses of cysteamine and displayed excellent compliance. At transplantation the kidney was embedded in paraffin and sent for three-dimensional reconstruction analysis. Measurement of the cystine content showed 530 nmol/mg protein in the renal cortex and 740 nmol /mg protein in the medulla, consistent with previous such measurements in cystinotic renal tissue.

Case Reports, ATG Study

• Case number two: No clinical information is available on this sample from kidneys removed at renal transplantation for ESRD due to cystinosis. The pathology report included extensive glomerulosclerosis, interstitial lymphocytic inflammation, and calcifications with tubular atrophy.

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Case Reports, ATG Study

• Case number three: This patient came to renal transplantation due to end-stage renal disease at age 24 years. He had been diagnosed at age 13 months , and at the time of transplantation was receiving Cystagon 2400 mg/day divided q6h. His creatinine had risen to 2.8 mg/dL at 23 years of age and he underwent a transplantation using a renal allograft at 24 years.

Control Sections

• Tubule has a clear connection with Bowman’s Capsule

Tubular Takeoff Point

Tubular Takeoff Point

Cystinotic Sections

• Few glomeruli show tubular connections

Tubular Takeoff Point

Next sectionNo connection

Tubular Takeoff Point

Previous sectionNo connection

Tubular Takeoff Point

Tubular Takeoff Point

Tubular Takeoff Point

Tubular Takeoff Point

ALMOST…

Frequency of ATG in Cystinosis

Glomeruli with normal GTJ

Glomeruli with atrophic GTJ

Atubular glomeruli

Cystinosis patients

1/106 (1%) 19/106 (18%) 86/106 (81%)

Normal controls 68/71 (96%) 0/71 (0%) 3/71 (4%)

p <0.0001 <0.0001 <0.0001

Conclusions

• There is a large incidence of ATG in end stage renal disease in cystinosis

• The finding is highly statistically significant

• This finding may account for progressive renal failure in cystinosis