1. Renal Failure, characterized by Azotemia and Isosthenuria. The combination of elevated blood urea nitrogen (BUN) and creatinine concentrations with isosthenuric urine indicates the presence of renal failure. BUN is normally equal to the serum urea nitrogen because of equilibration within the total body water compartment, and the kidney is the most important route of urea excretion. Urea is passively filtered through the kidneys, and an increased BUN indicates a decreased glomerular filtration rate (GFR). Creatinine is freely filtered by the glomerulus, and tubular resorption does not occur. An increased creatinine concentration with an elevated BUN is termed azotemia, and can be due to pre-renal, renal, and post-renal causes. When azotemia occurs with isosthenuric urine, especially in the face of dehydration, this indicates renal azotemia is an indication of renal failure. Renal azotemia occurs when at least ¾ of the nephrons are nonfunctional. The GFR becomes significantly decreased, and the animal is not able to concentrate urine, even in the face of dehydration. Renal azotemia can be either acute or chronic; causes of acute renal failure include infectious agents such as leptospirosis, Rocky Mountain Spotted Fever, and ehrlichiosis; prolonged anesthesia/hypoperfusion, and nephrotoxins (non-steroidal anti-inflammatory agents, aminoglycosides, sulfonamides, ethylene glycol, heavy metals, and grape/raisin toxicity). Other diseases such as glomerulonephritis, arteritis, and pancreatitis may cause acute renal failure. Chronic renal failure may be due to congenital defects, such as ectopic ureters that may lead to a pyeolonephritis, nephrotoxins, glomerulonephritis, amyloidosis, other congenital defects, polycystic kidney disease, and diabetes mellitus. Regarding this patient, the ultrasound finding of hyperechogenicity of the kidneys may occur in animals with both acute and chronic renal failure. However, the normal size and shape of the kidneys support more of an acute problem. Conversely, the presence of clinical signs for 1 ½months suggests a more chronic cause of renal failure. A kidney biopsy was performed to identify the etiology of the renal failure, to distinguish between acute and chronic renal failure, and to discern reversible versus nonreversible damage to the kidneys. 3. Anemia. Anemia is present due to a low hematocrit of 32.9, a low RBC of 4.23, and a low Hgb of 11. The anemia is classified as mildly macrocytic (due to increased MCV) and normochromic (due to normal MCHC). In this case, the anemia is most likely due to the renal failure (decreased renal production of erythropoietin) and possibly loss of blood through the intestinal tract. The dog had a history of black tarry stool/melena, indicating the presence of digested blood in the feces. Additional rule-outs include a mild anemia that is commonly present in puppies, and anemia of chronic disease. 4. Hypoproteinemia, Proteinuria, and Elevated Urine Protein:Urine Creatinine Ratio. Hypoproteinemia may be either relative (due to dilution of plasma proteins by excess fluids), or absolute (due to loss of albumin and globulins). An absolute hypoproteinemia is most likely in this dog, because the 2+ proteinuria and an isosthenuric urine specific gravity, suggests a marked loss of protein in the urine. Decreased glomerular function allows small proteins to be lost through the glomerulus into the urine. A urine protein:urine creatinine (UP:UC) ratio was performed to better characterize the urinary protein loss. A UP:UC < 0.5 is within reference limits. A ratio between 0.5-1.0 is questionable. However, a UP:UC > 1.0 indicates a true renal proteinuria, and may be due to hemorrhage (presence of occult blood in urine, >5 RBC’s/hpf, and the presence of trauma, inflammation, or neoplasia), inflammation (>5 WBC/hpf, bacteruria), or renal disease (absence of occult blood in urine, significant cellular sediment, +/casts). This dog had an initial UP:UC of 5.4, which subsequently increased to 8.83. A UP:UC ratio > 1.0 and < 3.0 indicates a primary tubular disease, where the major proteins lost are low molecular weight globulins. A UP:UC > 3.0, and often greater than 5.0, indicates primary glomerular disease, which was most likely in this dog. With primary glomerular disease, the major protein lost is albumin, due to either glomerulonephritis (UP:UC 5-15) or amyloidosis (UP:UC > 18). It is possible to have both glomerular and tubular disease present simultaneously, as this patient had hypoalbuminemia and an A:G ratio within reference limits. 5. Hyperkalemia. An elevated potassium level may be due to either increased dietary intake or, as most likely in this case, decreased urinary excretion of potassium. With the presence of renal failure and a decreased GFR, this patient had a decreased ability to filter potassium through the glomerulus and into the urine. 6. Decreased bicarbonate concentration. A decreased bicarbonate concentration with a normal anion gap is most likely due to bicarbonate loss through the kidneys as well as with the diarrhea. A fractional excretion of bicarbonate could be performed to quantify bicarbonate lost in the urine. 7. Hyperphosphatemia. Hyperphosphatemia can be caused by increased dietary intake, a shift in phosphorus from the intracellular to extracellular compartment, or decreased excretion in the urine. The most common cause, as demonstrated by this case, is renal failure. Other causes of hyperphosphatemia include to consider are Vitamin D toxicosis and hypoparathyroidism. This patient was treated with aluminum hydroxide to bind the excess phosphorus and aid in its excretion. 8. Hypermagnesemia. Hypermagnesemia may be caused by either increased dietary intake or decreased renal excretion. The mildly increased magnesium concentration in this patient was likely due to its renal failure. 9. Hypercholesterolemia. A hypercholesterolemia can be due to the post-prandial increase in serum cholesterol, a high fat and cholesterol diet, diabetes mellitus, hypothyroidism, hyperadrenocorticism, and protein-losing disorders such as renal disease. In this dog, the hypercholesterolemia (along with azotemia, hypoalbuminemia, and proteinuria), is most likely due to the nephrotic syndrome. While the pathophysiologic mechanism is still poorly understood, it is believed to be caused by an increase in hepatic synthesis of cholesterol and a reduction in lipoprotein catabolism in plasma. 10. Decreased PT. Prior to the kidney biopsy, a hemostasis profile was performed to evaluate clotting ability. The prothrombin time (PT) was mildly decreased, at 5.2 seconds, with a reference range of 5.8-9.8 seconds. Both the APTT and TT were within the normal reference range. A decreased prothrombin time suggests a hypercoagulable condition, which in animals with severe proteinuric renal disease may be due to loss of anticoagulant molecules such as antithrombin III in the urine. 11. Presence of Coarse Granular Casts in the Urine. Casts are composed of Tamm-Horsfall protein that is produced by the distal tubular epithelial cells. They are formed when the urine is more acidic. Granular casts are the most common type of casts observed and are composed of mucoprotein, plasma proteins, degenerate cells, and tubular debris. The presence of casts indicates tubular change, and while small numbers may occasionally be present in healthy individuals, they likely indicate significant tubular disease in this patient. Kidney Biopsy Summary — The significant glomerular changes found, such as cystic dilation of Bowman’s capsule and the atrophic glomerular tufts, are consistent with a "juvenile nephropathy," which is suspected of being familial. Familial and juvenile nephropathies are documented in many dog breeds, with the onset of renal failure occurring from a few weeks of age to several years, but in most cases between 4-18 months of age. Such congenital nephropathies, often characterized by membranoproliferative glomerulonephritis with glomerulocystic changes, have been documented in Doberman Pinschers, and similar lesions have been reported in four related Rottweiler pups. The glomerular changes in this dog may be due to ultrastructural abnormalities in basement membrane collagen, as suggested the discovery of similar lesions in two Rottweiler puppies (personal communication, Dr. Cathy Brown, Athens Diagnostic Laboratory, College of Veterinary Medicine, University of Georgia).