Dr. Emanuelle Plaisier (Department of Nephrology and Dialysis INSERM, Tenon Hospital, Pierre and Marie Curie University, Paris, France), in her presentation titled “Kidney manifestations in COL4A1/COL4A2 related disease: how to detect and how to treat,” described the kidney manifestations related to COL4A1/COL4A2 gene mutations, how to diagnose them, and how to treat them.

The nephron is the functional unit of the kidney and is a very complex structure, with about 1 million nephrons per kidney. Each nephron has a glomerulus, which is crucial for the ultrafiltration of plasma, followed by tubules with distinct functional properties that produce the final urine containing everything necessary to maintain body homeostasis and balance. Regarding the expression of type IV collagen in the kidney, it is present in the basement membrane of the tubule, glomerulus, blood vessels, and Bowman’s capsules (the cup-shaped structure at the beginning of each nephron that contains the glomerulus). Type IV collagen molecules are highly expressed in the basement membrane of tubules and vessels in the adult kidney, while the glomerular basement membrane primarily contains type II, III, and V collagen molecules. However, in the human glomerulus, type I and II collagen molecules are the only ones present in the glomerular basement membrane (GBM).

In the kidney, as in other organs, type IV collagen plays a key role in building the complex architectural organisation of the mature kidney and supporting renal functions, such as ultrafiltration in the glomerulus, water and electrolyte balance in the tubules, and blood pressure regulation. Besides the structural role, type IV collagen also has a signalling role during physiological and pathological processes, such as oncogenesis, although little is known about this signalling role.

Alport syndrome is a known hereditary type IV collagen disease, caused by a genetic defect encoding type III, IV, and V collagen chains. This syndrome is associated with glomerular disease characterized by hematuria, proteinuria, and in severe cases, chronic and end-stage renal disease, as well as hearing loss and various ocular defects due to the limited expression of these type IV collagen isoforms in the renal GBM and different segments of the eye. As nephrologists, we have paid little attention to type I and II collagen molecules, and what we have learned from early preclinical mouse models is that only mice with a specific mutation showing deletion of exon 41 exhibit subclinical renal defects with low levels of albuminuria and mild alterations of the glomerular basement membrane.

Dr. Plaisier, after discussing collagen diseases and the kidneys, talked about a case study of a family followed at her nephrology center for four decades, with two initial patients presenting with kidney disease. The kidney disease was associated with extrarenal manifestations, including retinal arteriolar tortuosity, cerebral small vessel disease, clinically asymptomatic cerebral aneurysms, muscle cramps, and Raynaud’s phenomena. In all affected patients, kidney disease presented with hematuria appearing early in childhood, and most patients had multicystic kidney disease. Only older patients developed proteinuria, hypertension, and chronic kidney disease.

Dr. Plaisier and her team had the opportunity to perform renal biopsies in young patients but not in those with multicystic disease due to the risk of hemorrhage. Microscopic observation did not reveal significant changes in the glomeruli or tubules, except for the presence of red blood cells in the tubular sections, reflecting hematuria. Only through electron microscopy did they observe significant alterations in the basement membranes of the tubules and Bowman’s capsules, showing an altered structure of the vessels, including arterioles and capillaries. However, they did not observe significant changes in the main glomerular basement membrane, which is not surprising because type I and II collagen molecules are weakly expressed in the adult GBM.

They performed various linkage analyses, testing the Alport locus and loci containing genes encoding matrix proteins, and when they tested the collagen 4 locus, they identified a missense mutation substituting a glycine residue. They quickly collected other families or patients with the same phenotypic presentation and named this syndrome HANAC (Aneurysm, Nephropathy, Arteriopathy, and Cramps). Surprisingly, all mutations involved glycine residues located in exons 24 and 25, found in the conformational triple helix domain called CB3. This domain is characterized by the presence of several integrin-binding sites, suggesting a possible genotype-phenotype correlation in HANAC syndrome.

Recently, a Japanese group reported a family with the same phenotype and a glycine substitution in the same gene and location. Understanding the progression of kidney disease in patients with HANAC syndrome is important. Nearly all patients present with hematuria appearing early in childhood and persisting throughout life. Some patients have episodes of macroscopic hematuria, renal cysts, and only some older patients develop hypertension and chronic kidney disease. The renal manifestation in HANAC syndrome is highly penetrant, but the progressive phenotype of kidney disease is less frequent and progresses with age. Proteinuria is an early stage that can evolve into chronic and end-stage renal disease. Renal manifestation in patients with pathogenic collagen IV variants outside exons 24 and 25 is less frequent and often not reported.

To understand the pathophysiology of organ involvement in HANAC syndrome, Dr. Plaisier and collaborators generated mice with an HANAC mutation. In neonatal mice, the phenotype is less severe than that reported in humans, with hematuria, massive albuminuria, and delayed glomerulogenesis. In adult mice, however, they observed hypotension and multicystic kidney disease, with cysts developing from glomeruli instead of tubules, likely due to abnormalities in Bowman’s capsules exposed to high ultrafiltration pressure.

The question they posed is how to screen for renal manifestations in disease associated with pathogenic collagen IV variants. Dr. Plaisier suggests checking the family history of kidney disease, risk factors for kidney disease, microscopic hematuria, blood pressure, serum creatinine, and urine analysis. Renal ultrasound is useful for detecting renal cysts and congenital urinary tract anomalies. Diagnosis should be made in all individuals with pathogenic collagen IV variants, with annual assessments of GFR, blood pressure, and proteinuria. In children with negative screens, re-evaluation is necessary in adulthood. Morphological follow-up of renal cysts is not required, but monitoring proteinuria is important as an indicator of chronic kidney disease progression.

In the absence of specific therapy, a nephroprotective approach is crucial, addressing all risk factors for kidney and cardiovascular diseases, treating hypertension, quitting smoking, managing cholesterol and diabetes, avoiding nephrotoxic drugs, and controlling weight and obesity. Patients with proteinuria should be followed by a nephrologist and treated with renin-angiotensin system blockers or SGLT2 inhibitors to control proteinuria and prevent chronic kidney disease progression.

In conclusion, the kidney is a potential target organ in diseases associated with pathogenic collagen IV variants, but it is important not to overlook other differential diagnoses. Renal manifestations are generally clinically silent in the early stages, necessitating regular screening. Kidney disease is highly prevalent in HANAC syndrome, suggesting a strong genotype-phenotype correlation. Hematuria is common but not predictive of a severe outcome, while proteinuria can precede the progression of chronic kidney disease. Prevention and treatment of renal and cardiovascular risk factors are crucial to prevent kidney disease progression.