Antonia Fabris

Hypertension of Polycystic Kidney Disease: Mechanisms and Hemodynamic Alterations

32 polycystic kidney disease (PKD) patients, 16 with normal 16 with variably decreased renal function, were studied; 12 were normotensive, 20 were hypertensive. Mean arterial pressure (MAP) was 90 +/- 8 mm Hg in the normotensive group and 117 +/- 17 in hypertensive patients; plasma renin activity (PRA) was similar. The glomerular filtration rate (GFR) was lower, but not significantly, in the hypertensive group and plasma volume (PV) was higher in hypertensive patients (normotensive 40.25 +/- 3.47 ml/kg body weight; hypertensive 46.30 +/- 3.54). No correlation was found between MAP, and PRA or GFR but MAP correlated with PV. Cardiac output was higher in hypertensive patients (normotensive 3.48 +/- 0.70 l/min/m2; hypertensive 3.89 +/- 1.47), also total peripheral resistance was higher in the hypertensive group (normotensive 2,035 +/- 503 dyn/s/cm-5/m2; hypertensive 2,577 +/- 808). Cardiac output and PV showed a high degree of correlation, but no correlation was seen between total peripheral resistance and PV, or PRA. The hypertensive patients were divided into two groups: one with hypertension of less than 2 years duration and one with more than 2 years but with similar GFR, PRA, PV and hemodynamic pattern. Our data indicate that hypertension in PKD is volume-dependent; that the increase in PV was not related to the loss of GFR, and that the role of the renin-angiotensin system in maintaining the hypertensive state is not well defined. Hemodynamically hypertension is characterized by high cardiac output and total peripheral resistance independent of the duration of hypertension.

Clinical Features of Patients with Solitary Kidneys

A clinical study was performed in 2 groups of patients with solitary kidneys, followed for 11-146 months. Group 1 had 9 patients (7 males and 2 females, aged between 23 and 68 years) with unilateral renal agenesis. Group 2 had 13 patients (9 females and 4 males, aged between 27 and 70 years) who underwent unilateral nephrectomy for the following reasons: hydronephrosis secondary to ureteropelvic junction stenosis, 7 patients; renal trauma, 4 patients; benign neoplasia, 2 patients. During the follow up, urinary protein excretion of more than 300 mg/day was observed in 9 patients, 3 in group 1 and 6 in group 2. Eleven patients, 8 in group 1 and 3 in group 2, were hypertensive (diastolic blood pressure higher than 95 mm Hg). Hyperuricemia was observed in 14 patients, 10 in group 1 and 4 in group 2. Seven patients, 4 in group 1 and 3 in group 2, had a significant deterioration of renal function. Neither proteinuria nor renal failure were observed before at least 10 years had elapsed since the anatomic condition of solitary kidney had been established. A surgical renal biopsy was performed in 1 patient with unilateral renal agenesis and showed focal glomerular sclerosis. This study adds support to the view that the reduction of 50% of the renal tissue may be a risky situation in humans as well as in animals.

Lithiasis in cystic kidney disease and malformations of the urinary tract

The prevalence of renal stones in renal cystic and malformative conditions exceeds the prevalence of renal stones in the general population, suggesting that the above-mentioned cystic and malformative disorders favor stone formation. Urinary stasis is generally assumed to play a major part in the pathogenesis of the nephrolithiasis associated with distorted renal anatomy due to a delayed washout of crystals and risk of urinary infections. However metabolic factors are also important in the pathogenesis of stones in these conditions. Indeed, metabolic abnormalities have been observed in the majority of stone-forming patients with conditions such as horseshoe kidney and ureteropelvic junction obstruction. Five different models of stone formation can be identified, depending on stone composition, risk of infection stones, and pathogenesis of renal cystic and malformative conditions. A proper metabolic evaluation should be conducted to diagnose specific, treatable metabolic disorders, thereby reducing the frequency of recurrent stone disease in these conditions as well.

Bone Histology and Calcium Metabolism in Patients with Nephrotic Syndrome and Normal or Reduced Renal Function

Bone histology and its relationship with calcium metabolism was evaluated in adult patients with nephrotic syndrome: 29 had normal renal function (GFR 103 +/- 4 ml/min/1.73 m2) (group 1) and 20 had renal insufficiency (GFR 31 +/- 4 ml/min/1.73 m2) (group 2). In group 1, serum PTH, 1.25-HCC and 24.25-HCC levels were normal, while 25-HCC values were reduced. Bone histology was normal in 76% of the patients, while 17% had isolated osteomalacia and 7% an associated bone resorption. Group 2 showed a higher incidence of bone resorption when compared with a matched group of patients with renal failure and no proteinuria (40% vs. 13%) and a comparable frequency of isolated mineralization defect (25% vs. 34%). PTH levels were definitely increased and serum total calcium and all the vitamin D metabolites were reduced. A significant correlation between the apparent duration of the disease and the severity of osteodystrophy was found only in group 2. In conclusion, no constant derangement of calcium metabolism and bone histology is evident in patients with nephrotic syndrome and normal renal function, while patients with persistent proteinuria are at high risk of osteodystrophy even in the early phases of renal failure.

Medullary sponge kidney: state of the art

Medullary sponge kidney (MSK) is a kidney malformation that generally manifests with nephrocalcinosis and recurrent renal stones; other signs may be renal acidification and concentration defects, and pre-calyceal duct ectasias. MSK is generally considered a sporadic disorder, but an apparently autosomal dominant inheritance has also been observed. As MSK reveals abnormalities in both the lower and the upper nephron and is often associated with urinary tract developmental anomalies, its pathogenesis should probably be sought in one of the numerous steps characterizing renal morphogenesis. Given the key role of the GDNF-RET interaction in kidney and urinary tract development and nephrogenesis, anomalies in these molecules are reasonable candidates for explaining a disorder such as MSK. As a matter of fact, we detected two, hitherto unknown, rare variants of the GDNF gene in MSK patients. We surmise that a defective distal acidification has a central role in MSK and is followed by a chain of events including defective bone mineralization, hypercalciuria, hypocitraturia and stone formation.

Familial clustering of medullary sponge kidney is autosomal dominant with reduced penetrance and variable expressivity

Medullary sponge kidney (MSK) is a renal malformation typically associated with nephrocalcinosis and recurrent calcium nephrolithiasis. Approximately 12% of recurrent stone formers have MSK, which is generally considered a sporadic disorder. Since its discovery, three pedigrees have been described in which an apparently autosomal dominant inheritance was suggested. Here, family members of 50 patients with MSK were systematically investigated by means of interviews, renal imaging, and biochemical studies in an effort to establish whether MSK is an inheritable disorder. Twenty-seven MSK probands had 59 first- and second-degree relatives of both genders with MSK in all generations. There were progressively lower mean levels of serum calcium, urinary sodium, pH, and volume, combined with higher serum phosphate and potassium from probands to relatives with bilateral, to those with unilateral, and to those unaffected by MSK. This suggests that most affected relatives have a milder form of MSK than the probands, which would explain why they had not been so diagnosed. Thus, our study provides strong evidence that familial clustering of MSK is common, and has an autosomal dominant inheritance, a reduced penetrance, and variable expressivity.

Medullary sponge kidney.

Purpose of reviewAfter it was first described in 1939, medullary sponge kidney (MSK) received relatively little attention. This was because it was believed to have a low prevalence and because it was considered a benign condition. Studies in recent years have been changing these convictions however, hence the present review. Recent findingsInsight has been obtained on the genetic basis of this disease, supporting the hypothesis that MSK is due to a disruption at the ‘ureteric bud–metanephric mesenchyme’ interface. This explains why so many tubular defects coexist in this disease, and particularly a distal tubular acidification defect of which the highly prevalent metabolic bone disease is one very important consequence. In addition to the typical clinical phenotype of recurrent stone disease, other clinical profiles have now been recognized, that is, an indolent, almost asymptomatic MSK, and a rare form characterized by intractable, excruciating pain. SummaryFindings suggest the need for a more comprehensive clinical characterization of MSK patients. The genetic grounds for the condition warrant further investigation, and reliable methods are needed to diagnose MSK.

The relationship between calcium kidney stones, arterial stiffness and bone density: unraveling the stone-bone-vessel liaison

Background and objectivesKidney stone disease is associated with a higher incidence of cardio-vascular (CV) events for still unclear reasons. Reduced bone density is also a frequent finding in calcium kidney stones. The association of reduced bone density with increased vascular stiffness and calcification has been discovered in a number of conditions. We investigated the hypothesis that patients with calcium kidney stones have increased arterial stiffness, which would be associated with reduced bone density and higher CV risk.Design, setting, participants, and measurementsWe compared measures of arterial stiffness [carotid-radial pulse-wave velocity (CR-PWV), carotid-femoral pulse-wave velocity (CF-PWV) and augmentation index (AI)] and of bone density (T-scores determined at lumbar spine, neck and hip) among 42 idiopathic calcium stone formers compared with 42 age- and sex-matched healthy volunteers.ResultsStone formers had higher values of CR-PWV, CF-PWV and AI, and lower values of all T-scores. Furthermore, the prevalence of abnormal arterial stiffness and reduced bone density was significantly higher among stone formers. Statistical adjustment for age, sex, body mass index and other covariates did not change the results.ConclusionsOur study confirms that stone formers have increased arterial stiffness and reduced bone density. Abnormal arterial stiffness appears to be independent of reduced bone density and may explain the higher CV risk observed in stone formers.

Spontaneous calcification process in primary renal cells from a medullary sponge kidney patient harbouring a GDNF mutation

Medullary nephrocalcinosis is a hallmark of medullary sponge kidney (MSK). We had the opportunity to study a spontaneous calcification process in vitro by utilizing the renal cells of a patient with MSK who was heterozygous for the c.‐27 + 18G>A variant in the GDNF gene encoding glial cell‐derived neurotrophic factor. The cells were obtained by collagenase digestion of papillary tissues from the MSK patient and from two patients who had no MSK or nephrocalcinosis. These cells were typed by immunocytochemistry, and the presence of mineral deposits was studied using von Kossa staining, scanning electron microscopy analysis and an ALP assay. Osteoblastic lineage markers were studied using immunocytochemistry and RT‐PCR. Staminality markers were also analysed using flow cytometry, magnetic cell separation technology, immunocytochemistry and RT‐PCR. Starting from p2, MSK and control cells formed nodules with a behaviour similar to that of calcifying pericytes; however, Ca2PO4 was only found in the MSK cultures. The MSK cells had morphologies and immunophenotypes resembling those of pericytes or stromal stem cells and were positive for vimentin, ZO1, αSMA and CD146. In addition, the MSK cells expressed osteocalcin and osteonectin, indicating an osteoblast‐like phenotype. In contrast to the control cells, GDNF was down‐regulated in the MSK cells. Stable GDNF knockdown was established in the HK2 cell line and was found to promote Ca2PO4 deposition when the cells were incubated with calcifying medium by regulating the osteonectin/osteopontin ratio in favour of osteonectin. Our data indicate that the human papilla may be a perivascular niche in which pericyte/stromal‐like cells can undergo osteogenic differentiation under particular conditions and suggest that GDNF down‐regulation may have influenced the observed phenomenon.

New non-renal congenital disorders associated with medullary sponge kidney (MSK) support the pathogenic role of GDNF and point to the diagnosis of MSK in recurrent stone formers

Medullary sponge kidney (MSK) is a congenital renal disorder. Its association with several developmental abnormalities in other organs hints at the likelihood of some shared step(s) in the embryogenesis of the kidney and other organs. It has been suggested that the REarranged during Transfection (RET) proto-oncogene and the Glial cell line-Derived Neurotrophic Factor (GDNF) gene are defective in patients with MSK, and both RET and GDNF are known to have a role in the development of the central nervous system, heart, and craniofacial skeleton. Among a cohort of 143 MSK patients being followed up for nephrolithiasis and chronic kidney disease at our institution, we found six with one or more associated non-renal anomalies: one patient probably has congenital hemihyperplasia and hypertrophic cardiomyopathy with adipose metaplasia and mitral valve prolapse; one has Marfan syndrome; and the other four have novel associations between MSK and nerve and skeleton abnormalities described here for the first time. The discovery of disorders involving the central nervous system, cardiovascular system and craniofacial skeleton in MSK patients supports the hypothesis of a genetic alteration on the RET–GDNF axis having a pivotal role in the pathogenesis of MSK, in a subset of patients at least. MSK seems more and more to be a systemic disease, and the identification of extrarenal developmental defects could be important in arousing the suspicion of MSK in recurrent stone formers.