Over the past four years, all patients with unexplained rapid progression of their renal disease were subjected to kidney biopsy, despite their small size (<9 cm), to define its etiology. Children, pregnant women, morbidly obese patients, and those with an unstable cardiovascular state, septicemia, bleeding diathesis as well as those kidney size with size <6 cm were excluded from the study. Doppler ultrasound was used to exclude renovascular/ischemic nephropathy. The procedure was performed by an interventional radiologist using a biopsy gun technique and under ultrasound guidance. The actual diagnosis was established in 29 cases while seven had advanced sclerosing glomerulonephritis. Eleven cases had evidence of vasculitis, of which two were due to polyarteritis nodosa and two were due to crescentic immunoglobulin A disease. The remaining patients had a secondary form of focal segmental glomerulosclerosis (n = 4), interstitial nephritis (n = 4), malignant nephro-angiosclerosis (n = 2), and single patient with primary hyperoxaluria, light chain cast nephropathy, amyloidosis, and thrombotic microangiopathy. All, except eight with advanced glomerulosclerosis, had improved or became stable with specific treatment. Our study shows that biopsy of small-sized kidneys, in patients with unexplained renal deterioration, is safe, and its diagnostic value can improve their morbidity and even mortality.