More adverse renal prognosis of autosomal dominant polycystic kidney disease in families with primary hypertension.

Marked variability of age at renal death is noted in autosomal dominant polycystic kidney disease (ADPKD). The hypothesis that the coexistence of primary hypertension and ADPKD within families is associated with earlier renal death was tested. Of a total of 162 ADPKD patients treated in one Austrian and three German centers, 57 propositi were identified whose families provided (1) information concerning blood pressure; (2) documented presence of ADPKD (by sonography or autopsy) in one parent; and (3) age at renal death in the propositus. Hypertension of the unaffected parent was defined as blood pressure above 140/90 mm Hg or antihypertensive treatment before age 60 yr. Age at renal death in the propositus was defined as the start of renal replacement therapy. Median age at renal death of 23 offspring (11 male, 12 female) from families with a history of primary hypertension of the nonaffected parent was lower than that of 34 offspring (16 male, 18 female) from families without a known history of primary hypertension of the nonaffected parent, i.e., 49 yr (26 to 64) versus 54 yr (28 to 82) (P < 0.03). The data are consistent with the notion that genetic predisposition to primary hypertension is associated with an earlier onset of terminal renal failure in families with ADPKD.

Anticipation of age at renal death in autosomal dominant polycystic kidney disease (ADPKD)?

It has been claimed that anticipation occurs in ADPKD, i.e. endstage renal failure at progressively earlier age in successive generations. This observation might possibly point to unstable DNA as the molecular basis of ADPKD. We analysed 74 parent-offspring pairs of 148 families in Germany and Austria in whom (i) ADPKD was verified by appropriate imaging procedures and (ii) age at renal death was accurately known. The median difference for age at renal death between parent and offspring was 0 years, range -26.3 to +27.2 years. There was no deviation from normal (Gaussian) distribution according to the Shapiro-Wilk test (P = 0.75). We conclude that systematic anticipation cannot be demonstrated with this sample which had sufficient size for meaningful biostatistical analysis.

[Cystic kidneys (autosomal dominant polycystic kidney disease)]. / Zystennieren (autosomal dominante polyzystische Nierenerkrankung).

Polycystic kidney disease is a rather common genetic disorder, with an estimated amount of 8 to 10% of patients in the dialysis population. Meanwhile the defective gene of autosomal dominant polycystic kidney disease [ADPKD], another common terminus for this disorder, has been localized on the short arm of chromosome 16. The genetic disorder is not strictly localized on the kidney, whereas other organ systems like cardiac valves, brain arteries, liver, colon, etc. may be involved in the disease process. Hypertension is an early and common feature of the disease and its probably an important factor for progression of renal failure in ADPKD. Not all carriers of the ADPKD-trait progress to endstage renal failure, about 50% at the age of 50 years. Patients with ADPKD have a good prognosis in renal replacement therapy programs such as dialysis or renal transplantation.

Elevated blood pressure profile and left ventricular mass in children and young adults with autosomal dominant polycystic kidney disease.

Twelve children (< 15 yr) and 12 young adults with autosomal dominant polycystic kidney disease (ADPKD) confirmed by ultrasonography and 24 nonaffected individuals matched for age, sex, and body surface area were examined with ambulatory blood pressure monitoring and echocardiography. All patients and controls had normal renal function (median serum creatinine, 0.85 mg/dL; range, 0.5 to 1.1). In children, daytime and nighttime blood pressures were not significantly different from those of controls; the median left ventricular mass index (in grams per square meter) was higher in patients (66.6 g/m2) than in controls (61.3 g/m2; P < 0.002), although all values remained within the normal range. In young adults with ADPKD, mean arterial blood pressure was significantly higher than that in controls both during daytime (98.3 mm Hg; range, 74 to 126 versus 90.6 mm Hg; range, 73 to 116; P < 0.006) and during nighttime (83.2 mm Hg; range, 66.5 to 125 versus 79.0 mm Hg; range, 63 to 91; P < 0.05). In parallel, the median left ventricular mass index was significantly higher in young adults (81.8 g/m2; range, 62 to 174 versus 64.3 g/m2; range, 52 to 102; P < 0.02). The results document that ambulatory daytime and nighttime blood pressures and left ventricular mass indices are higher in asymptomatic carriers of the ADPKD trait compared with controls, although most values are still within the normal range.

Autosomal dominant polycystic kidney disease (ADPKD)--mechanisms of cyst formation and renal failure.

None of the hypotheses proposed so far to explain cyst formation in autosomal dominant polycystic kidney disease (ADPKD) is entirely satisfactory, e.g. the theory of tubular obstruction by intraluminal polyps or dilatation of nephron segments as a consequence of abnormal compliance of the basement membrane. Recent in vitro studies show that (i) synthesis of basement membrane material is abnormal and that (ii) the direction of transepithelial resorptive flux into a secretory mode is reversed as a consequence of faulty insertion of Na, K-ATP'ase into the luminal membrane. It remains unclear why cystic transformation of a few percent of nephrons should cause endstage renal failure. Our clinical and experimental studies do not provide evidence to support some hypotheses proposed in the past, i.e. that renal parenchyma is compressed by expanding cysts and that glomeruli are overperfused. Our histological studies show that progression to endstage renal failure is associated with (i) progressive arteriolar lesions (out of proportion to the vascular lesions seen in extrarenal vascular beds; and (ii) progressive interstitial fibrosis. It appears that fibroblasts in ADPKD are particularly sensitive to platelet derived growth factor (PDGF) which is secreted by epithelial cells of the cyst wall in a paracrine fashion. In contrast to previous opinion, which was presumably skewed by ascertainment bias, it appears that not all, and perhaps not even a majority, of ADPKD patients progress to endstage renal failure. Factors related to progression are gender, family history and hypertension. Both abnormal sodium excretion and inappropriate renin secretion play a role in the genesis of hypertension. Elevated blood pressure, albeit within the normotensive range, is demonstrable even in prepubertal children. The involvement of renin in renal vasoconstriction of normotensive ADPKD patients suggests a particular role of ACE inhibitors in the management of these patients.

The effect of uninephrectomy on progression of renal failure in autosomal dominant polycystic kidney disease.

The evolution of renal failure was compared in 47 patients (21 male, 26 female) with autosomal dominant polycystic kidney disease (ADPKD) in Germany, France, Spain, and Portugal who had undergone uninephrectomy (UNX) (median age at uninephrectomy, 41 yr; range, 22 to 54) and 47 non-UNX matched controls. UNX was usually performed because of uncontrolled urinary tract infection (N = 30), stones (N = 8), trauma (N = 2), or hemorrhage (N = 7). Median serum creatinine at UNX was 2.1 mg/dL (0.9 to 4.3). Twenty-eight of the 47 uninephrectomized patients progressed to end-stage renal failure. When the age at renal death was evaluated by survival analysis, only minor and nonsignificant acceleration was seen in the uninephrectomized patients (median, 50 yr; p25 = 43.6 yr; p75 = 58.3 yr, where p is the percentile) compared with non-UNX patients matched for age, sex, and serum creatinine at the time of UNX in the propositus (51.2 yr; p25 = 48.6 yr; p75 = 56.1 yr). In addition, the median interval for serum creatinine to rise from 4 to 8 mg/dL was similar in UNX (21.3 months) versus nonuninephrectomized ADPKD patients (21.9 months). Renal survival differed in the two genders. In females, no significant difference of age at renal death was found between UNX (median age, 51.6 yr) and non-UNX ADPKD patients (53.7 yr). In male UNX patients, age at renal death was slightly (but not significantly) less than in non-UNX patients (median age, 47.3 versus 52.7 yr). All male patients reaching end-stage renal failure before age 44 were severely hypertensive.

Renal histology in polycystic kidney disease with incipient and advanced renal failure.

Renal specimens were obtained at surgery or postmortem from patients with autosomal dominant polycystic kidney disease (ADPKD). Patients had either serum creatinine (SCr) below 350 mumol/liter (N = 12) or terminal renal failure (N = 50). Specimens were examined by two independent observers using a carefully validated score system. Mean glomerular diameters were similar in ADPKD patients with early renal failure (176 +/- 38 microns) and in victims of traffic accidents (177 +/- 23 microns), while they were significantly greater in diabetics with comparable renal function (205 +/- 16 microns). Glomerular diameters in ADPKD patients with terminal renal failure (191 +/- 45 microns) and with early renal failure were not significantly different. On average, 29% of glomeruli (17 to 62) were globally sclerosed in early renal failure, and 49% (19 to 93) in terminal renal failure. The proportion of glomeruli with segmental sclerosis was less than 4% in both groups. Marked vascular sclerosis, interstitial fibrosis, and tubular atrophy were present in early renal failure, and even more so in terminal renal failure. Interstitial infiltrates were scarce and consisted mainly of CD4 positive lymphocytes and CD68 positive macrophages. Immunestaining with monoclonal renin antibodies showed an increased juxtaglomerular index and expression of renin by arterioles adjacent to cysts, as well as by cyst wall epithelia. The data show more severe vascular and interstitial, but not glomerular, changes in ADPKD with advanced as compared to early renal failure.

Frusemide therapy and intact parathyroid hormone plasma concentrations in chronic renal insufficiency.

It has been suggested that frusemide affects plasma parathyroid hormone (PTH) concentrations. To further investigate this issue we analysed plasma intact PTH in 77 patients with chronic renal failure (CCr 8.0-89.8 ml/min per 1.73 m2) as a function of frusemide therapy. The rate of increase of plasma PTH observed with progression of renal failure was faster in patients who received frusemide as compared to patients who did not receive the drug. The slope of the regression line of PTH on CCr was steeper (P less than 0.02) for patients with frusemide (n = 40, slope -0.34) than without frusemide (n = 37, slope -0.20). This effect was specific for frusemide therapy since therapy with other antihypertensive drugs (including thiazides and beta-blockers) was not correlated with PTH plasma concentrations. Frusemide therapy was also associated with a significantly greater urinary calcium excretion in uraemic patients but did not influence other parameters of calcium metabolism. To clarify mechanisms involved in the effect of frusemide on plasma PTH values, seven normal subjects were studied for 24 h before and for 24 h after oral administration of 80 mg frusemide. The main findings were: (1) Median PTH values were higher than on a control day (P less than 0.05) 3 h after frusemide (3.9 pmol/l vs 1.8) and 6 h after frusemide (4.0 vs 2.6); (2) ionised plasma calcium did not change significantly, whereas mean calcium/creatinine ratio increased from 0.20 to 0.46 after frusemide treatment through an increase in absolute calcium excretion; (3) plasma 1 alpha,25-dihydroxyvitamin D3, catecholamines, and magnesium concentrations did not change significantly after frusemide.(ABSTRACT TRUNCATED AT 250 WORDS)

[Ambulatory 24-hour blood pressure monitoring of children and young adults with autosome dominant polycystic kidney degeneration]. / Ambulante 24-Stunden-Blutdruckmessung bei Kindern und jugendlichen Erwachsenen mit autosomal dominanter polyzystischer Nierendegeneration.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited kidney disorder leading to terminal renal failure. About 8% of the dialysis patients suffer from ADPKD, the gene frequency in the general population being about 1:1000. Many facts contribute to the hypothesis that arterial hypertension plays a major role in the pathophysiology of ADPKD. We observed a prevalence of 30% of hypertension in patients with ADPKD and normal serum-creatinine, and of 80% in patients with terminal renal failure. The time of onset of abnormalities of blood pressure regulation is of great interest, since an increase of blood pressure, even in the normotensive range, accelerates the rate of progression. To answer this question, we examined the time of onset of abnormalities in blood-pressure regulation in 23 probands and 23 control patients in a cross-sectional study. The results document abnormal circadian blood-pressure changes and higher blood pressures, although still within the normotensive range, in asymptomatic carriers of the ADPKD-trait, even before and more definitely after onset of puberty. Even at an age when circadian blood pressure is not significantly different, there is an increased LVM as evidence of target organ damage. The findings suggest that (intermittent) increases in blood pressure and blood-pressure-dependent target organ damage precede overt hypertension and renal failure by years or decades.

Is gender a determinant for evolution of renal failure? A study in autosomal dominant polycystic kidney disease.

More males than females enter renal replacement therapy programs. This may reflect greater propensity of men to acquire renal disease, faster progression of renal disease, or a combination of both. In order to address this problem, autosomal dominant polycystic kidney disease (ADPKD), a well-defined genetically homogenous hereditary disorder, was studied. One hundred fifty-eight cases of the disease in adults were diagnosed by sonography and studied (73 men, 85 women); 58 of the patients had reached end-stage renal failure. Survival analysis of age at renal death revealed a significant gender difference (log-rank test, P = 0.0072): median age at renal death was 52.5 years in men and 58.0 years in women. In 64 patients with adequate sequential measurements of serum creatinine, progression of renal failure was followed retrospectively. When serum creatinine was greater than 3 mg/dL, the average rate of progression was similar in both sexes. In contrast to ADPKD, a sex difference for the age at renal death was not found in prepubertal individuals with hereditary renal diseases, ie, cystinosis or nephronophthisis. The data suggest that sex (hormones) influences evolution of renal failure.