An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes.

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

Impaired Regeneration Potential in Urinary Stem Cells Diagnosed from the Patients with Diabetic Nephropathy.

Stem cells present in urine possess regenerative capacity to repair kidney injury. However, the unique characteristics of urinary stem cells (USC) from patients with diabetic nephropathy (d-USC) are unknown. The goal of this study was to investigate stemness properties in cell phenotype and regenerative potential of d-USC, compared to USC from healthy individuals. Methods: Thirty-six urine samples collected from patients (n=12, age range 60-75 years) with diabetic nephropathy (stages 3-4 stage chronic kidney disease [CKD]) were compared with 30 urine samples from healthy age-matched donors (n=10, age range 60-74 years). Results: There were approximately six times as many cells in urine samples from patients with diabetic nephropathy, including twice as many USC clones as healthy donors. However, approximately 70% of d-USC had weaker regenerative capacity as assessed by cell proliferation, less secretion of paracrine factors, weaker telomerase activity, and lower renal tubular epithelial differentiation potential compared to healthy controls. In addition, the levels of inflammatory factors (IL-1ß and Cx43) and apoptotic markers (Caspase-3, and TUNEL) were significantly increased in d-USC compared to USC (p<0.01). Protein levels of autophagy marker (LC3-II) and mTOR signaling molecules (p-mTOR/mTOR, p-Raptor/Raptor and p-S6K1) were significantly lower in patient with diabetic nephropathy (p<0.01). Nevertheless, up to 30% of d-USC possessed similar regenerative capacity as USC from healthy donors. Conclusions: Regenerative performance of most d-USC was significantly lower than normal controls. Understanding the specific changes in d-USC regeneration capability will help elucidate the pathobiology of diabetic nephropathy and lead to prevent USC from diabetic insults, recover the stemness function and also identify novel biomarkers to predict progression of this chronic kidney disease.