Pathogenesis of Kidney Disease in Type 1 Diabetes: a Modern Kidney Biopsy Cohort (The PANDA Study)

Summary

Diabetic kidney disease (DKD) occurs in up to 40% of people with type 1 diabetes (T1D), often leading to kidney failure and markedly magnifying risks of cardiovascular disease and premature death. Landmark T1D kidney biopsy studies identified the classic pathological lesions of DKD, which have been attributed largely to hyperglycemia. Recent advances in continuous glucose monitoring (CGM) and automated insulin delivery have facilitated improved glycemic control, but the residual risk of DKD continues to be high. In addition, obesity and insulin resistance (IR) have accompanied intensive glycemic therapy and may promote mitochondrial dysfunction and inflammation. Deciphering the molecular underpinnings of DKD in modern-day T1D and identifying modifiable risk factors could lead to more effective and targeted therapies to prevent DKD.

Eligibility

Inclusion Criteria:

* Age ≥ 18 years at enrollment (rationale: this study focuses on determinants of early DKD over the course of T1D in adults)
* T1D duration \>5 years (rationale: DKD in T1D rarely manifests prior to 5 years of disease duration)
* HbA1c \<11% (rationale: HbA1c ≥ 11% exceeds the average HbA1c at most academic center and would limiting the generalizability of our study findings)

Exclusion Criteria:

* T2D and monogenic diabetes (rationale: our study focuses on T1D)
* Recent diabetic ketoacidosis, i.e., \<1 month (rationale: safety and insulin resistance and tubular dysfunction of DKA can confound study findings)
* eGFR \< 30 ml/min/1.73m2 or dialysis treatment (rationale: to reduce the likelihood of identifying secondary pathways that are not specific to kidney injury from T1D)
* Kidney transplant recipients (rationale: molecular confounding from immunosuppression)
* Kidney biopsy contraindications (rationale: safety - kidney biopsy):

  * Evidence of bleeding disorder or complications from bleeding
  * Use of aspirin, Nonsteroidal anti-inflammatory drugs (NSAIDS) or other blood thinner that cannot be safely stopped for a sufficient time before and after the biopsy to avoid additional risk of bleeding.
  * INR \> 1.4
  * Hemoglobin (Hgb) \< 10 mg/dL (Colorado) \[altitude\]
  * Hemoglobin (Hgb) \< 9 mg/dL (Washington)
  * Platelet count \< 100,000 / µL
  * Uncontrolled or difficult to control hypertension (\> 150/90 mmHg at the day of biopsy)
  * Single kidney (either by history, documented by prior imaging or ultrasound performed prior to the biopsy)
  * Kidney size: One or both kidneys \< 8 cm
  * Hydronephrosis or other important renal ultrasound findings such as significant stone disease
  * Any evidence of a current urinary tract infection as indicated on day of biopsy
  * Clinical evidence of non-diabetic renal disease
  * Positive urine pregnancy test or pregnancy

Conditions6

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