Dominique Droz

Tenofovir-Related Nephrotoxicity in Human Immunodeficiency Virus-Infected Patients: Three Cases of Renal Failure, Fanconi Syndrome, and Nephrogenic Diabetes Insipidus

We report 3 cases of renal toxicity associated with use of the antiviral agent tenofovir. Renal failure, proximal tubular dysfunction, and nephrogenic diabetes insipidus were observed, and, in 2 cases, renal biopsy revealed severe tubular necrosis with characteristic nuclear changes. Patients receiving tenofovir must be monitored closely for early signs of tubulopathy (glycosuria, acidosis, mild increase in the plasma creatinine level, and proteinuria).

Renal vascular lesions in lupus nephritis

We retrospectively studied the prevalence, histologic features, clinical correlations, and long-term outcome of the intrarenal vascular lesions of lupus nephritis (LN) in a series of 169 renal biopsies performed between 1980 and 1994 in 132 patients with systemic lupus erythematosus. The most common vascular lesions were nonspecific sclerotic changes, found in 37% of the biopsies (24% if only the cases with moderate to severe changes are considered). The other common vascular lesions were immunoglobulin microvascular casts, found in 24% of the biopsies. Vasculitis and thrombotic microangiopathy were rare lesions and were seen in only 4 (2.4%) and 1 (0.6%) cases, respectively. Isolated sclerotic vascular changes were present in biopsies from older patients with a longer duration of LN, compared with the group with no vascular lesions, and were associated with a significantly higher prevalence of hypertension. Overall, however, the long-term renal and patient survival of this group did not differ significantly from that of the patients without vascular changes. Immunoglobulin microvascular casts (IMCs) (lupus vasculopathy) were characterized by the presence of immunoglobulin deposition within the glomerular capillaries and small arterioles. In the present study we extensively investigated the morphologic and immunologic features of this lesion. The lesions were notable for the absence of endothelial or parietal vascular lesions and of fibrin, platelets, and leukocytes, which indicates that thrombosis is not involved in the vascular obstruction. According to our data immunoglobulin precipitation in the microvasculature seems to play a central role in the pathogenesis of this lesion, which is why we propose the term immunoglobulin microvascular casts. In general, IMCs were associated with the most severe and active forms of diffuse proliferative lupus nephritis (World Health Organization [WHO] class IV). However our data show that, in contrast to previous studies, the long-term outcome of patients with IMCs is not worse than that of other patients with class IV LN. It may even be somewhat better, suggesting that this type of lesion may reverse with immunosuppressive therapy. In addition, we did not find any association between the presence of IMCs and the lupus anticoagulant, IgG anticardiolipin antibodies, or extrarenal vascular manifestations. Concerning vasculitis and thrombotic microangiopathy, our results confirm that their occurrence is quite rare in-lupus nephritis. The outcome of our 4 patients with vasculitis was not particularly poor, which could be related to early and/or aggressive treatment. Taken as a whole, our data confirm that the presence of active and severe forms of diffuse proliferative LN (WHO class IV) carries a worse prognosis compared with the other forms of LN. In our study, and in agreement with previous reports (23), the long-term renal survival of patients with class IV LN was significantly worse than that of patients with other forms of LN, with a 10-year renal survival of 70% compared with 85%, respectively. However our data do not support the conclusions of some previous studies that the presence of intrarenal vascular lesions is a marker of poor renal prognosis in lupus nephritis. More precisely, our data show that the somewhat poorer renal outcome observed in patients with IMCs is related to the fact that in most cases these lesions are associated with class IV lupus nephritis, and not related to the presence of the vascular lesion per se.

Molecular Cytogenetic Aberrations in Autosomal Dominant Polycystic Kidney Disease Tissue

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder characterized by focal cyst formation from any part of the nephron. The molecular bases include germinal mutation of either PKD1 or PKD2 genes, enhanced expression of several protooncogenes, alteration of the TGF-alpha/EGF/EGF receptor (EGFR) axis, and disturbed regulation of proliferative/apoptosis pathways. To identify new locations of ADPKD related oncogenes and/or tumor suppressor genes (TSG), comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses were performed for a series of individual cysts (n = 24) from eight polycystic kidneys. By CGH, imbalances were detected predominantly on chromosomes 1p, 9q, 16p, 19, and 22q in all tissues. DNA copy number gain was seen on chromosomes 3q and 4q in five samples. The CGH data were supplemented by LOH analysis using 83 polymorphic microsatellite markers distributed along chromosomes 1, 9, 16, 19, and 22. The highest frequency of LOH was found on the 1p35-36 and 16p13.3 segments in cysts from seven samples. Allelic losses on 9q were detected in six, whereas deletions at 19p13 and 22q11 bands were observed in three polycystic kidneys. These results indicate that the deleted chromosomal regions may contain genes important in ADPKD initiation and progression.

Aberrant expression of polycystin-1 in renal cell tumors.

Aberrant Expression of Polycystin-1 in Renal Cell Tumors Polycystin-1 (PC1) is a cellular transmembrane protein coded by the polycystic kidney disease (PKD1) gene, prevalently expressed in developing/mature kidney and in autosomal polycystic kidney disease (ADPKD). Limited data are available concerning the PC1 involvement in renal tumorigenenesis. Polycystin-1 expression was evaluated in 8 clear cell renal cell carcinomas (RCCs), 7 tubulopapillary cell type tumors, 3 solid RCCs developed in patients with von Hippel-Lindau disease (VHLD), one RCC developed in a patient on chronic haemodialysis and one angiomyolipoma in a patient with Tuberous sclerosis (TS). In the normal kidney, consistent level of polycystin-1 was detected in distal tubules, collecting duct, glomerular podocytes and vascular smooth muscle cells. The strongest immunoreactivity against polycystin-1 was observed in epithelial cells lining the cystic components in all ADPKD tissues. Five cases of clear cell type RCCs and two-tubulopapillary cell type RCCs consistently expressed PC1. In the VHL disease associated renal carcinomas, both the neoplastic cells and cystic tissue areas weakly expressed PC1. In TS-associated angiomyolipoma, the vascular component was PC1 positive, while the tumoral cells were scarcely stained. The present report indicates consistent expression of the PKD1 gene product polycystin-1, in normal kidney, ADPKD tissues, and renal cell carcinomas. The findings suggest that the level of PC1 expression is linked to tumor cell type, being a more frequent event in clear cell RCC.