Holoprosencephaly and low molecular weight proteinuria: the human homologue of murine megalin deficiency.

We encountered a child with holoprosencephaly, pulmonary insufficiency, absent circulating vitamin D metabolites, mild albuminuria, and urinary excretion of vitamin D-binding protein. The child displayed a phenotype highly reminiscent of that observed in mice genetically deficient for megalin, a member of the low-density lipoprotein receptor superfamily. Only the Guthrie card was available from the child; the DNA sufficed for a limited haplotype analysis. We were not able to implicate the megalin gene locus directly; however, the possibility of a functional megalin defect in this child remains. To the best of our knowledge, this patient represents the first report that pathologic abnormalities consistent with megalin deficiency are present in humans.

Association of a uteroglobin polymorphism with rate of progression in patients with IgA nephropathy.

Uteroglobin gene-disrupted mice develop a nephritis very similar to immunoglobulin A (IgA) nephropathy. Megsin codes for a protein overexpressed in mesangium in patients with IgA nephropathy. Both are candidate genes that might have variants associated with an accelerated progression in patients with IgA nephropathy. We performed an association study of patients with IgA nephropathy and matching control subjects to test whether the G38A polymorphism in the uteroglobin gene, the C2093T polymorphism in the megsin gene, or the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism is associated with IgA nephropathy or rate of disease progression in patients with IgA nephropathy. Of 110 patients with IgA nephropathy, 87 patients were followed up for at least 3 years for the progression study. We also studied 104 healthy volunteers. The uteroglobin, megsin, and ACE polymorphisms were not distributed differently in the 110 patients with IgA nephropathy compared with healthy controls; Hardy-Weinberg equilibrium criteria were fulfilled. The GG genotype of the G38A uteroglobin polymorphism was more common in patients with progression (odds ratio [OR], 3.5; P< 0.006) than the AG+AA genotypes. The G allele was also more common (OR, 2.6; P< 0.009) in patients with versus without progression. The 1/serum creatinine over time plot (in deciliters per milligram per day) was sevenfold steeper in GG patients than the other two genotypes (P = 0.08). No significant associations with disease progression were found for the other gene polymorphisms, and a multivariate analysis showed no interactions. We suggest the hypothesis that the uteroglobin gene contains variant(s) with a bearing on progression rate in patients with IgA nephropathy.

[Comparative study of the reno-protective effect of short- and long-acting antihypertensive agents in IgA nephropathy]. / A rövid és a hosszú hatású antihypertensiv szerek renoprotective hatásának összehasonlító vizsgálata IgA nephropathiás betegekben.

The progression of IgA-NP is influenced unfavourably by development and existence of hypertension. The treatment of hypertension (HTN) has an important role in these patients. Both short- and long-acting formulations of angiotensin convertase enzim inhibitors (ACEi) and calcium channel blockers (CCB) lower blood-pressure, however long-acting preparations may provide better control and may have more renoprotective effect. Verifying this hypothesis, 22 IgA-NP patients were followed for 7.25 +/- 2.36 years. The patients were on short-acting ACEi (captopril, n = 9) or dihydropyridine type CCB (nifedipin, n = 2) or both (captopril + nifedipine n = 11), after at least 3 years the medication was changed to long-acting ACEI (enalapril, n = 4; cilazapril, n = 1), or non dihydropyridine type CCB (diltiazem hydrochlorid, n = 1) or both (n = 16). Just before changing the medication these patients underwent 24 hour ambulatory blood pressure monitoring and at the same time the level of proteinuria and the creatine clearance were measured. Values of serum-creatinine were measured in every 3-4 months within a 3 years period before and after the exchange of antihypertensive drugs. The regression of 1/creatinine was a = -5.28.10(-5) +/- 1.16.10(-4) before and a = 1.03.10(-4) +/- 2.05.10(-4) after the change of medication. Using paired t-test there was a significant difference between the regressions of 1/creatine (p < 0.005). Systolic blood pressure (SBP) (128 +/- 81 Hgmm vs. 126.09 +/- 11.67 Hgmm) was not different, however, diastolic blood pressure (DBP) (84.15 +/- 7.94 Hgmm vs. 79.78 +/- 7.17 Hgmm), diastolic percent time elevation index (HTI) (43.58 +/- 23.57% vs. 25.61 +/- 20.1%) and 24-hour diastolic hyperbaric impact (114.71 +/- 81.9 vs. 51.51 +/- 51.4, p < 0.05) was lower with long-acting antihypertensive agents, as was the proteinuria (1.18 +/- 0.94 g/die vs. 0.69 +/- 1.08 g/die, p < 0.05). Diurnal variation and systolic percent time elevation index were not different. We conclude that long-acting ACEi and non dihydropyridine type CCB formulations result in better outcomes in IgA nephropathy patients compared to short-acting drugs, probably because of better and smoother blood pressure control, lowering of proteinuria and better compliance of the patients.

Circadian blood pressure changes and cardiac abnormalities in IgA nephropathy.

The absence of diurnal blood pressure rhythm is characteristic of patients with chronic glomerulonephritis already before they develop hypertension. The prognostic importance and possible target organ-damaging effect of the absence are unknown. Simultaneously, 24-hour ambulatory blood pressure monitoring and echocardiographic investigations were done in 12 normotensive and 38 hypertensive IgA nephropathy patients. The hypertensive patients were treated with either angiotensin-converting enzyme inhibitor (ACEI) alone or in combination with a non-dihydropyridine calcium channel blocker. The absence of a night-time blood pressure reduction was frequent in both groups (5/12 vs. 20/38). In the hypertensive patients, blood pressure and left ventricular mass index were higher (124.6 +/- 23. 3/81.2 +/- 15.3 vs. 106.6 +/- 33.4/67.4 +/- 21.8 mm Hg, p < 0.001, and 124.1 +/- 46.2 vs. 89.2 +/- 45.6 g/m(2), p < 0.01). Diastolic left ventricular function was better in normotensive patients, in whom E wave/A wave ratio (E/A) and decelaration time values correlated closely with the diastolic diurnal index (E/A, r = 0.86, p < 0.01; DT, r = -0.70, p < 0.01). In the hypertensive patients, both the left ventricular wall thickness and diastolic function were significantly related to nighttime blood pressure and diurnal index values, but there was no relationship with daytime blood pressure. In conclusion, in IgA nephropathy patients there are mild cardiac abnormalities before they develop hypertension, the abnormalities bearing the closest correlation with the decrease in diurnal blood pressure rhythm. These data suggest the inefficacy of ACEI and calcium channel blockers in treating nighttime hypertension and in reestablishing diurnal rhythm. These phenomena are of great importance in the development of left ventricular hypertrophy and diastolic malfunction.