Familial aggregation of primary glomerulonephritis in an Italian population isolate: Valtrompia study.

Hereditary factors are suspected to contribute to the pathogenesis of sporadic primary glomerulonephritis, but their contribution is difficult to delineate in the general population. We studied the prevalence of primary glomerulonephritis in an isolated population from the extreme northern Valtrompia valley, Northern Italy. Investigation of medical records, community urinary screening program and molecular characterization of the population's ancestry were performed; genealogies of affected individuals were researched. Forty-three patients with primary glomerulonephritis were identified: 25 had biopsy-proven disease (11 immunoglobulin A (IgA) nephropathy; eight mesangial proliferative glomerulonephritis without IgA deposits; four focal segmental glomerular sclerosis; two membranous nephropathy), and 18 had clinical glomerulonephritis. All 43 patients originated from three mountain villages (Collio, San Colombano, and Bovegno). In contrast, we found only four cases of primary glomerulonephritis in two nearby villages (Pezzaze and Tavernole) that shared similar population histories and lifestyles, demonstrating heterogeneity of risk factors for glomerulonephritis (P=3 x 10(-5)). All 43 affected individuals could be traced back to common ancestors (XVI-XVII centuries), enabling the construction of three large pedigree including three parent-child affected pairs and five affected siblings pairs. Molecular data showed lower genetic diversity and increased inbreeding in the Valtrompia population compared to the control population. Molecular and genealogical evidence of limited set of founders and the absence of shared nephritogenic environmental factors suggest that our patients share a common genetic susceptibility to the development of primary glomerulonephritis. Further molecular study of our families will offer the possibility to shed light on the genetic background underlying these glomerular disorders.

Clinical and morphological features of kidney involvement in primary Sjögren's syndrome.

BACKGROUND: Primary Sjögren's syndrome is a connective tissue disorder affecting primarily the lacrimal and salivary glands, resulting in xerophtalmia and xerostomia. Extraglandular manifestations are frequent and may include renal involvement. METHODS: We studied the prevalence and nature of kidney involvement in 60 Italian patients with primary Sjögren's syndrome, diagnosed according to the European classification criteria. The following renal laboratory tests were performed in all patients: electrolytes in serum and in 24-h urine, creatinine in serum and in 24-h urine, venous pH and HCO(3)(-), urinalysis, urine culture, urinary osmolality and urine pH. A water deprivation test was performed in patients with morning urine osmolalities below the reference values adjusted for age. An oral ammonium chloride loading test was performed in patients with urine pH above 5.5 from morning samples. Renal biopsy was performed in patients with renal involvement. RESULTS: Sixteen patients (27%) had laboratory evidence of tubular and/or glomerular dysfunction. A variable degree of creatinine clearance reduction was found in eight patients (13%); frank distal tubular acidosis in three (5%); hypokalaemia in four (7%); and pathological proteinuria in 12 (20%). Urine concentrating capacity was defective in 10 out of 48 (21%) tested patients. Only four patients presented with overt clinical manifestations, including hypokalaemic tetraparesis (1), nephrotic syndrome (2), recurrent renal stones with flank pain and haematuria (1). In two patients, signs of renal involvement preceded the onset of sicca syndrome. Renal biopsies from nine patients showed tubulo-interstitial nephritis in six and glomerular disease in three. Patients with renal involvement had a significantly shorter disease duration compared with patients without renal abnormalities. CONCLUSIONS: Kidney involvement is a frequent extraglandular manifestation of primary Sjögren's syndrome. It is rarely overt and may precede the onset of subjective sicca syndrome.

Molecular analysis of uromodulin and SAH genes, positional candidates for autosomal dominant medullary cystic kidney disease linked to 16p12.

BACKGROUND: The location of a second genetic locus for autosomal dominant medullary cystic kidney disease (ADMCKD) at chromosome 16p12 led us to further investigate the molecular analysis of the critical region where two genes coding for uromodulin and SA proteins with renal specific functions, UMOD and SAH, are localized. METHODS: We characterized the intron-exon boundary sequences by screening phage and BAC DNA genomic clones for the development of new molecular tools functional to the mutation analysis of UMOD and SAH genes. RESULTS: No consistent mutations for ADMCKD2 were found in the UMOD and SAH genes. We identified a silent polymorphism in the UMOD gene at codon C174 which co-segregates with the disease in the ADMCKD2 family. CONCLUSIONS: This study excludes the involvement of uromodulin and SAH genes in ADMCKD2, and provides new tools for their molecular analysis in other diseases.

Cholesterol crystal embolism: A recognizable cause of renal disease.

Cholesterol crystal embolism, sometimes separately designated atheroembolism, is an increasing and still underdiagnosed cause of renal dysfunction antemortem in elderly patients. Renal cholesterol crystal embolization, also known as atheroembolic renal disease, is caused by showers of cholesterol crystals from an atherosclerotic aorta that occlude small renal arteries. Although cholesterol crystal embolization can occur spontaneously, it is increasingly recognized as an iatrogenic complication from an invasive vascular procedure, such as manipulation of the aorta during angiography or vascular surgery, and after anticoagulant and fibrinolytic therapy. Cholesterol crystal embolism may give rise to different degrees of renal impairment. Some patients show only a moderate loss of renal function; in others, severe renal failure requiring dialysis ensues. An acute scenario with abrupt and sudden onset of renal failure may be observed. More frequently, a progressive loss of renal function occurs over weeks. A third clinical form of renal atheroemboli has been described, presenting as chronic, stable, and asymptomatic renal insufficiency. The renal outcome may be variable; some patients deteriorate or remain on dialysis, some improve, and some remain with chronic renal impairment. In addition to the kidneys, atheroembolization may involve the skin, gastrointestinal system, and central nervous system. Renal atheroembolic disease is a difficult and controversial diagnosis for the protean extrarenal manifestations of the disease. In the past, the diagnosis was often made postmortem. However, in the last decade, awareness of atheroembolic renal disease has improved, enabling us to make a correct premortem diagnosis in a number of patients. Correct diagnosis requires the clinician to be alert to the possibility. The typical patient is a white man aged older than 60 years with a baseline history of hypertension, smoking, and arterial disease. The presence of a classic triad characterized by a precipitating event, acute or subacute renal failure, and peripheral cholesterol crystal embolization strongly suggests the diagnosis. The confirmatory diagnosis can be made by means of biopsy of the target organs, including kidneys, skin, and the gastrointestinal system. Thus, Cinderella and her shoe now can be well matched during life. Patients with renal atheroemboli have a dismal outlook. A specific treatment is lacking. However, it is an important diagnosis to make because it may save the patient from inappropriate treatment. Finally, recent data suggest that an aggressive therapeutic approach with patient-tailored supportive measures may be associated with a favorable clinical outcome.

IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23.

End-stage renal disease (ESRD) is a major public health problem, affecting 1 in 1,000 individuals and with an annual death rate of 20% despite dialysis treatment. IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of ESRD worldwide; it affects up to 1.3% of the population and its pathogenesis is unknown. Kidneys of people with IgAN show deposits of IgA-containing immune complexes with proliferation of the glomerular mesangium (Fig. 1). Typical clinical features include onset before age 40 with haematuria and proteinuria (blood and protein in the urine), and episodes of gross haematuria following mucosal infections are common; 30% of patients develop progressive renal failure. Although not generally considered a hereditary disease, striking ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested a heretofore undefined genetic component. By genome-wide analysis of linkage in 30 multiplex IgAN kindreds, we demonstrate linkage of IgAN to 6q22-23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked. These findings for the first time indicate the existence of a locus with large effect on development of IgAN and identify the chromosomal location of this disease gene.

Diet or dialysis in the elderly? The DODE study: a prospective randomized multicenter trial.

There are no solid data on the real advantage of an early start of dialysis, as suggested by the DOQI guidelines. Uremic patients frequently have a poor nutritional status. However, we cannot distinguish between the detrimental effect on nutrition of too low a residual renal function or too long a period of low protein-diet, per se. However, it appears that a very-low-protein diet (VLPD) supplemented with essential amino acids and keto-analogs of amino acids, and with an adequate quantity of calories, can prevent hypoalbuminemia at the start of dialysis and can slow the progression of chronic renal failure. EDTA and USRDS data suggest that most patients starting dialysis nowadays are elderly, who also have the highest incidence of morbidity and mortality. Moreover, hospitalization rate becomes higher after the start of dialysis compared to the pre-dialysis period. Can an aminoacid-supplemented VLPD, prolonged beyond the GFR limits suggested by DOQI, offer elderly patients better survival and better quality of life than dialysis? The answer can only come from a prospective, randomized trial, in elderly patients, starting at the GFR values suggested by the NKF-DOQI for starting dialysis, comparing outcomes with a vegetarian VLPD supplemented with a mixture of keto-analogs of amino acids and essential amino acids, and with dialysis.

Familial clustering of IgA nephropathy: further evidence in an Italian population.

Several lines of evidence suggest that genetic factors have an important role in the pathogenesis of immunoglobulin A (IgA) nephropathy. We report the prevalence of familial IgA nephropathy in a referral center in northern Italy and present the data on HLA genotypes in the families identified. Twenty-six of 185 patients (14%) with IgA nephropathy investigated in Brescia, Italy, were related to at least one other patient with the disease. Restriction fragment length polymorphism (RFLP) analysis of HLA-DR beta and HLA-DQ alpha and beta genes, as well as polymerase chain reaction-based oligonucleotide typing, was performed in family members. The 26 patients with IgA nephropathy belonged to 10 families. Familial relationships between the patients varied greatly, ranging from parent-child to sib-pair to more distant familial relationships. No common nephrotoxic factor was identified in the families. The intervals separating the apparent onset of disease in relatives with IgA nephropathy varied from 8 months to 13 years. In patients with a family history of IgA nephropathy, there was an increased incidence of HLA-DRB1*08 compared with those with sporadic IgA nephropathy. The study shows that a significant number of the patients with IgA nephropathy followed up in Brescia had a family history of disease. The fact that the Italian population, an ethnic group not previously examined, also presents an increased familial susceptibility to IgA nephropathy suggests that familial predisposition is a very common finding for IgA nephropathy. Thus, clinicians should become aware that IgA nephropathy may aggregate within families in a substantial number of cases. In addition, this subgroup of patients with IgA nephropathy offers an ideal opportunity to elucidate the molecular genetics of this disease.

Autosomal dominant medullary cystic disease: a disorder with variable clinical pictures and exclusion of linkage with the NPH1 locus.

BACKGROUND: The nephronophthisis-medullary cystic disease (NPH/MCD) complex represents a heterogeneous group of hereditary tubulointerstitial nephritis. The most common variant is juvenile recessive NPH, for which a gene locus (NPH1) has been mapped on chromosome 2q13. MCD is a less common dominant condition usually recognized later in life, which resembles NPH in many aspects, still presenting remarkable clinical differences. Nothing is known about the chromosome locus of MCD. METHODS: Five MCD families were studied. Diagnosis was made by inference from family history, type of inheritance, clinical signs and histology. Multipoint linkage analysis was performed by markers D2S293, D2S340 and D2S160 spanning the entire NPH1 locus. RESULTS: Diagnosis of MCD was made in 28 affected members (16 males; 12 females), belonging to five families. Histological diagnosis was available in 10 patients; clinical diagnosis in 11; seven deceased relatives had diagnosis of chronic nephritis. The age at diagnosis ranged from 8 to 65 years. Renal medullary cysts were found in a minority of patients. In family 1, the disease was associated with hyperuricaemia and gouty arthritis. Progression of renal disease presented intra- and extra-family variability with members of the same family showing mild elevation of creatinine or terminal renal failure. The NPH1 locus associated to recessive NPH was excluded from linkage to the dominant MCD. CONCLUSIONS: MCD might be more common than previously assumed. Variability in clinical presentation and absence of histopathological hallmarks contribute to make the diagnosis uncommon. The most remarkable clinical difference with NPH is the age of onset in some kindreds and a delayed progression towards renal failure. The exclusion of linkage to the NPH1 locus suggests the existence of an MCD responsible locus, still to be mapped.

Evidence for an independent role of metabolic acidosis on nutritional status in haemodialysis patients.

BACKGROUND: Malnutrition in haemodialysis (HD) patients has been referred to underdialysis with low protein intake, and to acidosis. However, the separate effects of underdialysis and acidosis on nutrition have not been clearly demonstrated. To evaluate the role of the dialysis dose and of metabolic acidosis on nutrition, we measured the predialysis serum HCO3, pH, serum albumin, PCRn, Kt/V, and BMI in 81 uraemic patients on maintenance bicarbonate HD for 93+/-80 months. Patients with chronic liver diseases, malignancies, and cachexia were excluded. RESULTS: Mean age was 59+/-17 years, Kt/V was 1.29+/-0.21, PCRn 1.06+/-0.22 g/kg/day, serum albumin 4.07+/-0.28 g/dl, BMI 23+/-4 kg/m2, HCO3 21.1+/-1.9 mmol/l, pH 7.36+/-0.04. Serum albumin showed a significant direct correlation with: PCRn (P=0.001), HCO3 (P=0.001), pH (P=0.002), but no correlation with Kt/V and BMI. Serum HCO3 correlated inversely with PCRn (P=0.027). Multiple regression analysis confirmed the significant role of serum bicarbonate and age, but not of Kt/V, on serum albumin concentrations. The role of PCRn appeared to be marginal compared to serum bicarbonate in determining serum albumin levels. Dividing patients into two groups, serum albumin was 3.96+/-0.22 g/dl with HCO3 < or = 20 mmol/l and 4.18+/-0.31 g/dl in those with serum HCO3 > or = 23 mmol/l (P=0.002). PCRn in the same groups was respectively 1.14+/-0.24 g/kg/day and 1.01+/-0.23 g/kg/day (P=0.03). Most importantly, serum albumin levels did not appear to be affected by the dialysis dose, with Kt/V ranging from 0.90 to 1.88. CONCLUSIONS: In HD patients with adequate Kt/V, metabolic acidosis exerts a detrimental effect on serum albumin concentrations partially independently of the protein intake, as evaluated by PCRn. In the presence of moderate to severe metabolic acidosis, PCRn does not reflect the real dietary protein intake of the patients, probably as a result of increased catabolism of endogenous proteins. For this reason PCRn should be considered with caution as an estimate of the dietary protein intake in HD patients in the presence of metabolic acidosis.

Blood volume changes during three different profiles of dialysate sodium variation with similar intradialytic sodium balances in chronic hemodialyzed patients.

The aim of this study was to evaluate the effects on blood volume (BV) preservation of three different profiles of dialysate sodium variation with similar intradialytic sodium balances. Ten uremic patients aged 50 +/- 11 years receiving regular bicarbonate hemodialysis for 49 +/- 57 months were studied. Each patient underwent three hemodialysis treatments with different modalities of dialysate sodium profiles: constant sodium hemodialysis (CHD), high-low sodium hemodialysis (H-LHD), and low-high sodium hemodialysis (L-HHD). In CHD, the dialysate sodium concentration was 141 mEq/L and did not change during treatment. In H-LHD and L-HHD, the dialysate sodium concentration at the start of dialysis was 160 mEq/L and 133 mEq/L, respectively, and remained constant for 60 minutes. At this time, a single-step break point of variation of dialysate sodium concentration occurred. The dialysate sodium concentration changed according to a model aimed to keep identical the amount of dialysate sodium exchanged in the three different dialysis procedures. The duration of hemodialysis, the blood flow rate, the dialysate flow rate, and the dialysis membrane were the same for all three different hemodialysis modalities. The ultrafiltration rate was kept constant during treatment. Total dialysate collection and intradialytic sodium balance were calculated for each hemodialysis session. Blood pressure and heart rate were monitored at 10-minute intervals; percent reductions of BV (%R-BV) were continuously monitored by an online optical reflection method (Hemoscan; Hospal-Dasco, Medolla, Italy). The results have shown a lower intradialytic %R-BV with H-LHD compared with L-HHD and CHD. No differences in total ultrafiltration rate, systolic and diastolic blood pressures, and heart rate were observed among the three different dialysis procedures. The total dialysate sodium collected and the intradialytic sodium balances were very similar among the three different dialysis procedures, confirming the accuracy of the precision of the sodium model used. The H-LHD sodium profile may be a useful tool in the prevention of excessive %R-BV and of dialysis intolerance episodes.