Genetic basis of Autosomal Hereditary Recessive Nephropathy - in dogs this is a genetic disease caused most often by pathogenic mutations in the COL4A4 gene. This gene encodes a component of type IV collagen found in the glomerular basement membrane of the kidneys. The disease follows an autosomal recessive inheritance pattern—meaning affected dogs must inherit two copies of the defective gene, one from each parent. Both males and females are equally susceptible. Carriers (with only one mutant copy) do not show symptoms but can pass the mutation to offspring. Mutations identified include specific single-nucleotide substitutions causing a premature stop codon, leading to loss of normal protein function.

Pathophysiology - The core defect in familial nephropathy is an abnormal glomerular basement membrane caused by the loss of functional type IV collagen. This defective filtration barrier disrupts the kidney's ability to retain vital proteins, resulting in protein leakage into urine (proteinuria) occurring as early as five months of age. Over time, structural changes in the kidney progress, impairing the filtration of waste products and water balance. Initially, proteins are generally absent from urine in healthy dogs, but affected dogs show increasing proteinuria and progressive kidney dysfunction as the disease advances. The irreversible damage culminates in chronic kidney failure.

Complications - Familial nephropathy is characterized by a rapid and fatal progression. The persistent leakage of protein into urine damages kidney tubules, leading to chronic kidney failure. Severely affected dogs typically die within a year of clinical onset due to:

• End-stage renal disease with accumulation of toxic waste

• Inability to regulate body fluids and electrolytes

• Secondary complications, such as hypertension or infections

Because the disease is progressive and irreparable, early diagnosis is critical, but even with optimal support, prognosis remains poor.

Why this matters to Breeders and Vets
Breeding: As an autosomal recessive disorder, both parents of an affected dog are carriers. It is essential to use DNA testing to identify carriers and affected dogs before breeding. Responsible breeding requires pairing only clear dogs or a clear with a carrier; breeding two carriers or affected animals will produce offspring with a high risk of developing the disease.
Veterinary importance: Veterinarians play a key role in early recognition, genetic counseling, and supportive care. Regular urine protein testing in at-risk breeds can detect disease before symptoms arise, and prompt intervention can help manage clinical signs.
Management: There is no cure; management is supportive, focusing on diet, hydration, and treating complications. Breeders and veterinarians must educate owners about the risks and realities of this condition to help prevent its spread. 

Summary - Autosomal Hereditary Recessive Nephropathy is a fatal, inherited kidney disorder in dogs caused by mutations in the COL4A4 gene, most notably affecting Cocker Spaniels and Springer Spaniels. The disease manifests early in life, with proteinuria and symptoms of chronic kidney disease, and leads to early death from renal failure. Diagnosis relies on clinical suspicion and DNA testing. Prevention hinges on responsible breeding programs utilizing genetic screening, while affected dogs benefit most from early support and ongoing veterinary care.