NEPHROLOGY, DIALYSIS AND TRANSPLANTATION CASE STUDIES

 

 

A 46-year-old caucasian male was referred to our Division for a five-year lasting hypertension and apparently recent diagnosis of renal abnormalities (microscopic hematuria and proteinuria less than 0.5 g/24h). Family history was positive for hypertension and diabetes and his father was on hemodialysis treatment since 70 years age for presumptive not-biopsied diabetic nephropathy-ESRD. His blood pressure was 160/90 mmHg, on atenolol therapy. Serum creatinine was 150 mmol/L and creatinine clearance 78 ml/min/1.73 m2. There were no evidence of diabetes or other systemic diseases; no history of UTI or radiological signs of pyelonephritis; no sensorineural deafness at audiogram. Left ventricular hypertrophy and hypertensive retinopathy (Keith-Wagener grade II) were found as organ evidence of hypertensive damage.
A clinical diagnosis of hypertensive nephrosclerosis was made.

QUESTION 1

Renal biopsy was then performed and showed, at light microscopy (LM), some glomeruli with ischemic changes characterized by collapse of peripheral capillary loops, thickening and multilamination of the basement membrane of Bowman's capsule, periglomerular fibrosis. Some glomeruli were small, shrunken, others were globally obsolescent (Fig1). Vessels showed disproportionately severe lesions relative to sclerosis. Interstitial fibrosis and tubular atrophy were present in a patchy distribution. Immunofluorescence (IF) showed focal C3 traces. The light microscopy and the IF studies were suggestive of Hypertensive Nephropathy.

QUESTION 2

The kidney biopsy study was completed by EM examination: the glomerular basement membrane (GBM) appeared in part corrugated and uniformly thin (<200 nm) (Fig 2). No deposits or other lesions were described.

Fig. 2 . Electron micrograph of the basement membrane of a glomerular capillary loop from a normal adult (top) and from a case of TBMD (bottom) of the same age and sex. Magnification is the same in both images and the difference in thickness is mainly due to reduction of the lamina densa

QUESTION 3

Given these biopsy findings, the immunohistologic study on renal basement membrane was performed.

QUESTION 4

Alpha3 (IV) and Alpha5 (IV) chains were normally expressed in the kidney biopsy.
The patient (proband) was again examined by the ophtalmologist with a slit lamp: lenticonus, macular flecks and corneal erosion were ruled out. Furthermore, a clinical screening of first-degree relatives was proposed. No consanguinity of parents, no mild hearing loss was found in his relatives. His father was on HD treatment. Three of seven patient's siblings had microscopic hematuria and no extrarenal abnormalities at eye examination and audiogram. One of them was diabetic with mild renal insufficiency.

QUESTION 5

Despite clinical, LM and IF kidney biopsy findings suggestive of hypertensive nephrosclerosis, the ultrastructural study allowed us to better define the disease: Thin Glomerular Basement Membrane nephropathy with superimposed hypertensive damage. Analysis of type IV collagen expression in the kidney biopsy, combined with a careful collection and analysis of family history and clinical features is the right approach to the definition of diagnosis. The molecular genetic analysis, either through linkage analysis or mutation identification, provides the only conclusive diagnosis, when it remains doubtful.
Genetic studies suggest that TGBM disease is a heterogeneous disease, but some cases may be related to mutations of COL4A3/COL4A4 genes, thus belonging to the spectrum of type IV collagen diseases (4).

Acknowledgements: The author is indebted to Prof. G. Maschio for revising the manuscript and to Prof. Andrea Onetti Muda for the histologic study of the kidney biopsy.

References
1. Zarif L, Covic A, Iyengar S, Sehgal A, Sedor JR, Schelling JR. Inaccuracy of clinical phenotyping parameters for hypertensive nephrosclerosis. Nephrol Dial Transplant 15:1801-1807, 2000. Pubmed Link
2. Pirson Yves. Making the diagnosis of Alport's syndrome. Kidney Int 56:760-775, 1999 Pubmed Link
3. Kashtan Ce. Alport syndrome: is diagnosis only skin-deep? Kidney Int 55:1575-1576, 1999 Pubmed Link
4. Dagher H, Buzza M, Colville D, et al. A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport'' syndrome. Am J kidney Dis 38, 6:1217-1228, 2001. Pubmed Link