Suzanne Meleg-Smith

X-linked alport syndrome in females

Alport syndrome (AS) is in the differential diagnosis of hematuria. Variability in clinical presentation and in the ultrastructural changes of the glomerulus can make the diagnosis of AS a challenge in female patients. The purpose of this report is to present immunostaining for glomerular basement membrane (GBM) expression of alpha5(IV) as an adjunctive diagnostic method. Renal biopsy specimens from eight female patients with clinical presentation suggestive of AS were studied. The patients were between 7 and 36 years of age; six were between 12 and 15 years. Light microscopy and immunohistochemistry using a monoclonal antibody to alpha5(IV) were performed. Controls showed a continuous linear pattern along the GBM in normal kidneys and absence in renal biopsy specimens from male X-linked AS patients. To express the variability of the ultrastructural GBM changes among the patients in the series, we developed a semi-quantitative Alport Index, obtained by quantification of severity and extent of ultrastructural GBM changes. With immunohistochemistry, we showed an interrupted, discontinuous linear pattern for alpha5(IV) in glomeruli from the eight patients in the series, confirming the diagnosis of X-linked AS. The ultrastructural Alport Index varied between 6 and 47, showing the heterogeneity in the severity of the GBM changes, even among the six patients aged between 12 and 15 years. In three of the eight biopsy specimens, the predominant change was thin GBM, and the Alport Index was below 20. Immunohistochemistry for alpha5(IV) in renal biopsy specimens can identify female patients heterozygous for X-linked AS. In this series, the method led to the diagnosis of AS in female patients in whom the predominant ultrastructural change was thin basement membrane.

Fetal ontogeny and role of metanephric bradykinin B2 receptors.

Abstract Previous studies in rats have shown that blockade of bradykinin B2 receptors (B2R) in combination with a high-salt intake during gestation result in poor postnatal survival and long-term hypertension in the offspring. In this study, we examined the fetal ontogeny of B2R and determined the consequences of gestational B2R blockade and high salt on kidney development. B2R gene expression is induced on embryonic day (E16) of fetal metanephrogenesis and remains sustained until term. The earliest expression of the B2R protein is observed on apical membranes of ureteric bud branches and in capillary loop stage glomeruli. By the end of gestation, B2R becomes restricted to more-differentiated tubules in the deep cortex and medulla. Pairs of rats on normal (0.12 mmol/g) or high (0.84 mmol/g) salt diets were mated at 14 weeks of age. The B2R antagonist, Icatibant (previously known as Hoe-140) (300 nmol/kg per day) or saline (vehicle) was infused intraperitoneally during gestation via osmotic minipumps. Fetuses were examined on E20 (n=27–36 per group). No significant differences in litter size or body weight were observed among the groups. Combined high-salt and Icatibant treatment caused aberrant fetal renal development characterized by tubular dysgenesis, widened stromal mesenchyme, and glomerular cysts. The dysgenetic tubules stained positively for the distal nephron lectin, Dolichos biflorus, and exhibited enhanced Bax expression and apoptosis. Renal microvascular development, the number of mature glomeruli, and percentage of proliferating glomerular cells were not affected. Gestational Icatibant or high salt alone had no deleterious effects on fetal nephrogenesis. We conclude that gestational blockade of the kallikrein-kinin system impairs fetal nephrogenesis if combined with an intrauterine stressor such as high-salt intake. B2R may play a protective role during segmental nephron differentiation.

Value of Electron Microscopy in the Diagnosis of Childhood Nephrotic Syndrome

The value of the ultrastructural study of the renal biopsy was investigated in a series of pediatric patients with nephrotic syndrome. Forty-eight cases of renal biopsies with clinical data were reviewed and divided into diagnostic groups. The contribution of electron microscopy to the final diagnosis was graded as essential — diagnosis could not be reached without it; supportive — it increased the level of confidence in the final diagnosis; and noncontributory. In this series of renal biopsies from 48 children with nephrotic syndrome resistant or nonresponsive to therapy, the mostfrequent diagnosis was minimal change disease, present in 42%of the patients. The contribution of the electron microscopic study to the final diagnosis was essential in 73%of the series, and was supportive in a further 27%.Therefore, it is concluded that the ultrastructural study was an essential component in the study of the renal biopsy in children with nephrotic syndrome, suggesting that electron microscopy needs to continue to be performed for all these patients.

Evaluation of Lupus Nephritis during Pregnancy by Renal Biopsy

Patients with lupus nephritis frequently exhibit increasing proteinuria, hypertension and deterioration of renal function due to either active lupus nephritis, chronic lupus nephritis and/or superimposed preeclampsia during pregnancy. Percutaneous renal biopsies were therefore performed in 3 women with systemic lupus erythematosus during pregnancy and immediately postpartum in a fourth woman to evaluate their renal disease during pregnancy. Mean serum creatinine at renal biopsy was 2.9 mg/dl, with a mean creatinine clearance of 66 ml/min and protein excretion of 5.3 g/day. All patients had grade IV lupus nephritis and received pulse methylprednisolone immediately; 3 received cyclophosphamide. All 3 patients with crescent formation developed endstage renal disease within 3 years. The fourth patient has normal renal function 3 years after biopsy. Percutaneous renal biopsies during pregnancy in women with lupus nephritis provide an accurate histopathologic diagnosis and are important in providing appropriate therapy, counseling and prognosis.

DIAGNOSIS OF CONGENITAL NEPHROTIC SYNDROME: A CLINICAL AND A PATHOLOGIC CHALLENGE

The diagnosis of congenital nephrotic syndrome (NS) is a challenge both for clinicians and for pathologists. We observed three cases in a series of 50 children with NS nonresponsive to therapy, corresponding to one case each of minimal change disease, Finnish-type glomerulopathy, and diffuse mesangial sclerosis--two histopathologic studies were performed in each case. The age at presentation did not predict the diagnosis nor the prognosis: The NS presented at 7 months of age in the patient with diffuse mesangial sclerosis, but it was present at birth in the patient with minimal change disease. In these 2 patients the final diagnosis was made with the first renal biopsy. Conversely, in the patient with Finnish-type glomerulopathy, the diagnosis was only possible in the repeat biopsy, as the early pathologic changes were nonspecific. This study shows the essential role of the renal biopsy in determining the etiologic diagnosis and prognosis in patients with congenital nephrotic syndrome.

The many faces of C3 glomerulopathy

To the Editor: The recent article by Sethi et al., ‘Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion’, made me revisit a 12-year-old publication. In ‘Apparent progression of acute glomerulonephritis to dense deposit disease’ we described an 8-year-old boy with hypocomplementemia and meningococcemia. The first kidney biopsy showed glomeruli with abundant deposits of C3 and scarce deposits of IgG. Typical subepithelial humps were observed ultrastucturally, with only occasional subendothelial and intramembranous deposits. Two years later, a new biopsy was again positive for C3, and intramembranous, electron dense ribbon-like change, typical of dense-deposit disease (DDD), was present along the capillary loops, with only occasional subepithelial humps. In view of the clinical history of our patient, and the typical findings of DDD in the second biopsy, I suggest that the first biopsy, with its scarce subendothelial deposits and no membranoproliferative pattern, might also represent C3 glomerulopathy, similar to cases described by Fakhouri et al. and Servais et al. One might propose that our case illustrates that C3 glomerulopathy can present with variable faces in the same patient.

Glomerulopathy in Adult Recipients of Pediatric Kidneys

Abstract To compare “for cause” renal biopsies (bx) from adult recipients of pediatric-donor kidneys (PDK) versus adult-donor kidneys (ADKs), we reviewed 103 graft bx from 50 PDK recipients and 85 bx from 49 ADK recipients. PDK bx displayed more frequent glomerular pathology with immune complex-mediated glomerulonephritis present in 11/103 PDK versus 1/85 ADK (p < 0.05). In 15/103 PDK bx and 1/85 ADK (p = 0.001), the association of glomerular sclerosis, expanded mesangium, and halo of prominent podocytes by light microscopy, and ultrastructural glomerular basement membrane lamellation, configured a characteristic glomerulopathy.