Alejandro Darnell

Influence of the ACE gene polymorphism in the progression of renal failure in autosomal dominant polycystic kidney disease

The recent description of a polymorphism in the gene for angiotensin-converting enzyme (ACE), with the D allele associated with greater plasma levels of ACE, allows us to perform studies of the relationship between this polymorphism and chronic renal diseases in which the renin-angiotensin system could be implicated. We examined 155 patients with autosomal dominant polycystic kidney disease (ADPKD) with linkage to the PKD1 locus. The ACE insertion/deletion (I/D) polymorphism was amplified with the previously published flanking primers, and the polymerase chain reaction product was separated, sized on a 2% agarose gel, and visualized by ultraviolet transillumination. The ACE genotype distributions were 11.6%, 63.8%, and 24.5% for II, ID, and DD, respectively. There were no significant differences among the three genotypes with respect to mean age, sex distribution, and prevalence of hypertension. The ACE genotype distribution in patients with end-stage renal failure at the time of data compilation was similar to that of the entire study population. In the subgroup of patients who received renal replacement therapy before the age of 50 years, we found a significant association between DD genotype and onset of end-stage renal disease (ESRD) before the age of 50 years compared with II and ID (P = 0.017). We calculated the estimated median renal survival time as 51 years for the II genotype, 53 years for the ID genotype, and 48 years for the DD genotype. There were statistically significant differences between DD and ID patients (P = 0.025). In conclusion, we found DD genotype implies a worse renal prognosis based on both the significantly lower median renal survival time and significantly greater percentage of patients who reach ESRD before the age of 50 years, without implying a greater prevalence of hypertension.

High prevalence of TT virus (TTV) infection in patients on maintenance hemodialysis: frequent mixed infections with different genotypes and lack of evidence of associated liver disease.

Recently, a novel DNA virus, TT virus (TTV), was identified in patients with post‐transfusion non‐A‐G hepatitis. We analyzed the prevalence and clinical implications of TTV infection in a cohort of 96 Spanish patients on long‐term hemodialysis. TTV DNA was detected by nested PCR in 51 (53%) of 96 patients, a prevalence significantly higher than that found in healthy blood donors. Persistent liver test abnormalities were found in only 2 (7.7%) of 26 patients infected with TTV alone, compared with 12 (75%) of 16 patients infected with hepatitis C or hepatitis B virus, or both (P < 0.01). Mixed infections with multiple strains of TTV, including different major genotypes, were common in patients on hemodialysis. These patients had received a significantly greater number of blood units (22.7 ± 20) compared with patients apparently infected with a single strain of TTV (8.9 ± 11) (P = 0.01). Phylogenetic analyses of TTV from infected patients identified strains of genotypes 1, 2, 3, and 4. In summary, TTV infection was common in patients on hemodialysis but was not associated with liver disease J. Med. Virol. 59:313–317, 1999.

A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2

Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous, with at least three chromosomal loci (PKD1, PKD2, and PKD3) that account for the disease. Mutations in the PKD2 gene, on the long arm of chromosome 4, are expected to be responsible for approximately 15% of cases of ADPKD. Although ADPKD is a systemic disease, it shows a focal expression, because <1% of nephrons become cystic. A feasible explanation for the focal nature of events in PKD1, proposed on the basis of the two-hit theory, suggests that cystogenesis results from the inactivation of the normal copy of the PKD1 gene by a second somatic mutation. The aim of this study is to demonstrate that somatic mutations are present in renal cysts from a PKD2 kidney. We have studied 30 renal cysts from a patient with PKD2 in which the germline mutation was shown to be a deletion that encompassed most of the disease gene. Loss-of-heterozygosity (LOH) studies showed loss of the wild-type allele in 10% of cysts. Screening of six exons of the gene by SSCP detected eight different somatic mutations, all of them expected to produce truncated proteins. Overall, >/=37% of the cysts studied presented somatic mutations. No LOH for the PKD1 gene or locus D3S1478 were observed in those cysts, which demonstrates that somatic alterations are specific. We have identified second-hit mutations in human PKD2 cysts, which suggests that this mechanism could be a crucial event in the development of cystogenesis in human ADPKD-type 2.

Abdominal sonographic study of autosomal dominant polycystic kidney disease

The purpose of this study was to determine whether kidney size in patients who have autosomal dominant polycystic kidney disease (ADPKD) is related to renal function, hypertension, or extrarenal manifestations of the disease and to sonographically evaluate the abdominal manifestations of ADPKD.

Outcomes in biopsy-proven lupus nephritis: evaluation of 190 white patients from a single center.

We describe the natural history of lupus nephritis (LN) in a historical cohort of 190 white patients with the diagnosis of biopsy-proven LN followed in a single reference center. We evaluated 670 patients with systemic lupus erythematosus (SLE) consecutively followed in our department from 1970 until 2006. All patients fulfilled the 1997 revised criteria for the classification of SLE. White patients (Spanish-born) with biopsy-proven LN were selected as the study population. The cohort included 190 patients (170 female patients and 20 male) with a mean age at LN diagnosis of 31 years. Renal biopsy revealed type I LN in 8 (4%) patients, type II in 33 (17%), type III in 46 (24%), type IV in 72 (38%), type V in 28 (15%), and type VI in 3 (2%) patients. Induction remission was achieved in 85% of patients with types I and II, 78% with type III, 70% with type IV, and 32% of patients with type V. After a mean follow-up of 2391 patient-years, 62 (33%) patients developed chronic renal failure and 18 (9%) evolved to end-stage renal disease. Adjusted multivariate Cox regression analysis identified male sex (hazard ratio [HR], 4.33) and elevated creatinine at LN diagnosis (HR, 5.18) as independent variables for renal failure. Survival was 92% at 10 years of follow-up, 80% after 20 years, and 72% after 30 years. Our results suggest that biopsy-proven LN in white patients has an excellent prognosis. Ethnicity should be considered a key factor when evaluating the prognosis and therapeutic response to different agents in patients with LN. Abbreviations: CI = confidence interval, ESRD = end-stage renal disease, HR = hazard ratio, ISN/RPS = International Society of Nephrology/Renal Pathology Society, LN = lupus nephritis, SEM = standard error of the mean, SLE = systemic lupus erythematosus.

Acute and Rapidly Progressive Forms of Glomerulonephritis in the Elderly

This article presents a comparison of acute glomerular nephritis (AGN) with rapidly progressive glomerular nephritis (RPGN) in patients aged 60 or older. In 7 elderly patients with AGN, the renal disease was preceded by skin infection (4 cases), sore throat (2 cases), or pneumonia (1 case). The 7 patients with RPGN had no history of prior infection. Both AGN and RPGN were manifested clinically as acute renal failure, but the RPGN patients had significantly higher serum creatinine levels and lower hematocrit readings. Hypocomplementemia was a feature only of AGN. The biopsy specimens from patients with RPGN showed crescents in 50–100 percent of the glomeruli, whereas specimens from patients with AGN showed no significant extracapillary proliferation. Six AGN patients recovered and 1 died. Despite dialysis, 4 RPGN patients died and the remaining 3 require maintenance dialysis. It is concluded that AGN in the elderly is more common than previously believed, frequently follows skin infections, and has a reasonably good prognosis. In contrast, RPGN, also not rare in the elderly, has a much worse prognosis.

Cellular Immunity Analysis Using Monoclonal Antibodies in Human Glomerulonephritis

Monoclonal antibodies against class II antigens of the human major histocompatibility complex (MHC) (Edu 1), von Willebrand factor-related antigen marker of endothelial cell, T cells (Cris 1), helper/inducer T cells (T4) and cytotoxic/suppressor T cells (T8) by indirect immunofluorescence, and stain for nonspecific esterase characterizing monocytes-macrophages (Mo-Ma) were applied in 64 renal biopsies--54 glomerulonephritis (GN), 10 non-GN- and in 14 normal kidneys. Class II antigens were expressed on the endothelium of renal microvasculature in all specimens. Intraglomerular T cells and Mo-Ma were only present in GN. Mo-Ma appeared associated with endo- and extracapillary proliferation (Xc2 = 4.68; p less than 0.05), C3 (X2 = 4.21; p less than 0.05), and fibrinogen (X2 = 3.84; p less than 0.05) deposition; and those were most numerous in biopsies with intraglomerular T cells. Interstitial MHC-class II+ cells (Xc2 = 5.5; p less than 0.02), T cells (F = 3.37; p less than 0.005) and Mo-Ma (F = 2.45; p less than 0.05) were significantly higher in GN with endo- or extracapillary proliferation than in the remaining. In GN, correlations were seen between T cells and MHC-class II+ cells (r = 0.63; p less than 0.001), and Mo-Ma (r = 0.38; p less than 0.02), infiltrating the interstitium. Our results suggest that both humoral and cellular immunity contribute to macrophage glomerular infiltration in the human GN. Mononuclear cells, and no intrinsic renal cells, would be implicated in the cellular immune interactions in situ.

Glomerular Disease in Cirrhosis of the Liver: Low Frequency of IgA Deposits

Twelve HBsAg-negative patients with histologically documented cirrhosis of the liver of either alcoholic (8 of 12) or cryptogenic (4 of 12) origin underwent renal biopsy to investigate proteinuria, hematuria and/or renal failure. Immunofluorescence was positive for IgA in 2 patients with mesangiocapillary glomerulonephritis (MCGN) and could not be performed in 2 additional patients with the same diagnosis. However, in the remaining 8 patients, immunofluorescence was negative for IgA and frequently positive for C3, IgG, IgM and/or fibrinogen. These 8 patients without IgA were classified as follows: MCGN with subendothelial electron-dense deposits (2 cases), IgM-IgG cryoglobulinemia with diffuse endocapillary glomerulonephritis (1 case), membranous nephropathy (1 case), diffuse endocapillary proliferative glomerulonephritis (1 case), vasculitis with focal segmental necrotizing glomerulitis and crescentic glomerulonephritis (2 cases). These results show that cirrhosis of the liver can be associated with a wide variety of glomerular disorders. Contrary to previous belief, IgA is absent in two thirds of patients with cirrhosis and glomerulopathy. Therefore, the pathogenetic importance of IgA in the development of glomerular disease in such patients is doubtful.

Acute Renal Failure Complicating Viral Hepatitis in the Absence of Severe Hepatic Insufficiency

Four patients (2 were HBsAg positive) with acute icteric viral hepatitis (VH) developed acute renal failure (ARF) in the course of their illness and in the absence of other complications. Their peak serum creatinine values (4.7-10, mean 7 mg/dl) were reached either before or simultaneously with their maximum serum aminotransferase values (1,390-2730, mean 2,032 mU/ml). Apart from VH no other factors responsible for precipitating ARF could be identified. In the HBsAg-negative patients, serological investigations for infectious mononucleosis, cytomegalovirus infection, and leptospirosis were negative. In 2 patients liver biopsy showed changes consistent with VH. Proteinuria was absent in all cases, making glomerulonephritis unlikely. The urinary sodium excretion was uniformly high (57-104, mean 78 mmol/l in random samples). Two patients required short courses of dialysis. All cases recovered completely with return of serum creatinine to normal values after a mean duration of 25 days. After a normal serum creatinine level had been achieved, 1 case was lost to follow-up, and the other 3 cases maintain normal renal and liver function tests 9 months (mean) after the initial episode. Otherwise uncomplicated VH is a potential cause of ARF, even in the absence of severe hepatic insufficiency. The mechanism of ARF in VH is unknown, but vasoconstriction phenomena induced by endotoxemia might contribute.

Silent Renal Microangiopathy after Mitomycin C Therapy

Mitomycin C (MMC) is an alkylating agent which has been associated with microangiopathic hemolytic anemia and acute renal failure, with an overall incidence between 2 and 10%. This complication can develop several months after the initiation of chemotherapy. Isolated renal impairment without overt microangiopathic hemolytic anemia, although reported, is less frequently documented. We describe a 63-year-old man who developed progressive renal failure without any evidence of hemolysis or thrombopenia 10 months after beginning chemotherapy with MMC and Ftorafur. A renal biopsy displayed features of microangiopathy. The patient required the institution of chronic hemodialysis. In conclusion, it is important to be aware of this indolent but severe renal complication in patients treated with MMC. Urinary parameters and renal function should be monitored over a long period for an early diagnosis.