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Giovanni Gambaro

Publications and source records attributed to Giovanni Gambaro.

At least 19 recordsLinked to original sources
PubMed2026

Integrating machine learning and GWAS for variant prioritization in the INCIPE cohort highlights ABC transporter genes in chronic kidney disease.

INTRODUCTION: Chronic kidney disease (CKD) is a major public health challenge, affecting approximately 674 million people worldwide and representing one of the fastest-growing causes of mortality. Since CKD is frequently asymptomatic in its early stages, the identification of novel genetic biomarkers may improve early detection and risk stratification. Genome-Wide Association Studies (GWAS) have identified numerous genetic loci associated with CKD and related traits; however, their performance is often limited in small and imbalanced cohorts, where reduced statistical power increases both false-positive and false-negative findings. Machine learning (ML) approaches can complement conventional GWAS by prioritizing biologically relevant genetic signals from high-dimensional genomic data. METHODS: In this study, we implemented a nested ensemble (NCBC) model composed of an undersampler and a CatBoostClassifier (CBC) to prioritize candidate genetic variants associated with CKD in the INCIPE cohort. Prioritized variants were functionally annotated and evaluated through enrichment analyses, GTEx gene expression profiling, and protein-protein interaction network analyses. Genes identified by the CKDGen Consortium were analysed as an external reference set and used to validate the biological relevance of the prioritized results. RESULTS: The NCBC model outperformed conventional ML classifiers, achieving a ROC AUC score of 87.77%, compared to 50%-53% for the other evaluated models. Among the prioritized genes, 56.25% showed protein-protein interactions with genes previously reported by the CKDGen Consortium, whereas only 1.9% of randomly generated gene sets showed interactions. DISCUSSION: Our study demonstrates that the NCBC model improves the prioritization of biologically plausible candidate variants in a small and imbalanced CKD cohort. Functional analyses suggested ABC transporter-related genes, including ABCA13, ABCA4, and ABCC4 genes, as promising candidate for future validation, with ABCA4 showing substantial expression in kidney tissues. Overall, these findings support the integration of ML with GWAS to prioritize candidate genes and investigate the genetic architecture of complex diseases.

SNP prioritization↗
PubMed2005

Dent's disease and prevalence of renal stones in dialysis patients in Northeastern Italy.

Dent's disease (DD) involves nephrocalcinosis, urolithiasis, hypercalciuria, LMW proteinuria, and renal failure in various combinations. Males are affected. It is caused by mutations in the chloride channel CLCN5 gene. It has been suggested that DD is underdiagnosed, occurring in less overt forms, apparently without family history. A possible approach to this problem is to search for CLCN5 mutations in patients who may have a high prevalence of mutations: end-stage renal disease (ESRD) patients with previous calcium, struvite, or radio-opaque (CSR) stones. We looked for CLCN5 mutations in 25 males with ESRD-CSR stones selected from all of the patients (1,901 individuals, of which 1,179 were males) of 15 dialysis units in the Veneto region. One DD patient had a new DD mutation (1070 G > T) in exon 7. The new polymorphism IVS11-67 C > T was detected in intron 11 in one patient and one control. We also found 28 females with ESRD and stone history, and seven more males with ESRD and non-CSR stones. The prevalence of stone formers among dialysis patients in our region was 3.2%, much lower than the prevalence observed in older studies. Struvite stones continue to play a major role in causing stone-associated ESRD .

Adult↗
PubMed2005

An unusual association of contralateral congenital small kidney, reduced renal function and hyperparathyroidism in sponge kidney patients: on the track of the molecular basis.

Of unknown pathogenesis, sponge kidney (SK) is variably associated with nephrocalcinosis, stones, nephronic tubule dysfunctions and precalyceal duct cysts. Amongst 72 unrelated renal SK patients with renal stone disease, we detected one with unilateral bifid renal pelvis and six with unilateral small kidneys (longitudinal diameter difference >15%). Secondary causes of small kidney were excluded. Of the seven cases, four had reduced renal function (67 vs 7% in the entire cohort), and three developed hyperparathyroidism during follow-up (43 vs 4%). The pathogenesis of SK ought to explain why anatomical structures of different embryological origin are involved (the precalyceal and collecting ducts and the nephron) and why there is frequent association with hyperparathyroidism. In embryogenesis, the metanephric blastema synthesizes the chemotactic glial-derived neurotrophic factor (GDNF) to prompt the ureteric bud to branch off from Wolff's mesonephric duct, and to approach and invade the blastema. The bud's tip expresses the GDNF receptor (RET). RET-GDNF binding is crucial not only for the correct formation of ureters and collecting ducts (both of Wolffian origin), but also for nephrogenesis. We advance the hypothesis that SK results from a disruption in the ureteric bud-metanephric blastema interface, possibly due to one or more mutations or polymorphisms of RET or GDNF genes. This would explain: the concurrent alterations in precalyceal ducts and the functional defects in the nephron, the occasional association with size and the functional asymmetry between the two kidneys, some degree of renal dysplasia causing the reduction in the glomerular filtration rate and (given the role of RET in parathyroid cell proliferation) the association with hyperparathyroidism.

Adult↗
PubMed2005

Aspergillus fumigatus peritonitis in ambulatory peritoneal dialysis: a case report and notes on the therapeutic approach.

Aspergillus peritonitis is a rare disease in continuous peritoneal dialysis. It is a severe form of peritonitis, which is frequently lethal. We report a case of Aspergillus fumigatus peritonitis in a female patient on automated peritoneal dialysis (APD), who was successfully treated with intravenous amphotericin B and the removal of the peritoneal catheter. As delayed treatment has an increased mortality rate, it is mandatory to remove the catheter and to start intravenous treatment with amphotericin B empirically.

Aged↗
PubMed2004

Nephrolithiasis: why doesn't our "learning" progress?

OBJECTIVE: Stone research is stagnant with minor clinical fall-out. We wonder whether this, in the ESWL era, depends only on ESWL and the consequent change in our clinical management habits, or is rather due to mistakes made by investigators. We feel that indeed we did and do make some: (1) the patients we are investigating may not be appropriate; and (2) we are missing to properly recognise disease heterogeneity. CONCLUSIONS: From the public health side most likely we are not investigating the right patients, and we probably need to address the large part of the problem, i.e. the rarely relapsing stone formers demanding 80% of all urological interventions. Although there is a consensus that urolithiasis is very heterogeneous, this position is presently under reconsideration. It is necessary to investigate the single or "occasional" stone former, and go back to the epidemiology and clinics with multicentre, prospective studies. Being a multifactorial disease, we will need to evaluate as many aspects as possible contemporaneously in the same patient. It is also necessary to "revisit" the disease in an unbiased manner, because its relationship with relevant aspects could be different than previously thought due to our incomplete knowledge of its pathogenesis and pathophysiology.

Biomedical Research↗
PubMed2004

Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms.

Idiopathic calcium nephrolithiasis is a multifactorial disease with a pathogenesis that involves a complex interaction of environmental and individual factors. This review discusses what is known about monogenic renal calcium stone-related disorders, provides an update on genetic research in calcium nephrolithiasis and such intermediate phenotypes as idiopathic hypercalciuria, discusses the problems that these conditions pose to clinicians and geneticists interested in their pathogenesis, and proposes some method tools potentially useful in this research frame of reference.

Animals↗
PubMed2004

Quantitave and qualitative changes in vascular endothelial growth factor gene expression in glomeruli of patients with type 2 diabetes.

OBJECTIVE: Vascular endothelial growth factor (VEGF) exists in three main splice variants, characterized by 121, 165 and 189 amino acids (VEGF 121, VEGF 165 and VEGF 189) and acts via two specific receptors: VEGF-R1 or Flt-1 and VEGF-R2 or KDR. VEGF plays an important role in the pathogenesis of diabetic retinopathy. This study examined the relationship between VEGF and its isoforms and the severity of diabetic nephropathy in type 2 diabetes. DESIGN: We evaluated the glomerular gene expression of VEGF and its receptors and studied the relationships with renal functional and structural parameters in type 2 diabetic patients. METHODS: Glomeruli from 17 kidney biopsies were microdissected; 14 out of 17 biopsies were also subjected to electron microscopic morphometric analysis to estimate glomerular structural parameters. VEGF mRNA was studied by comparative kinetic RT-PCR and real-time RT-PCR in order to identify the three different isoforms and to quantify VEGF, VEGF-R1 and VEGF-R2 mRNA levels. RESULTS: (i) Glomerular VEGF mRNA levels were inversely related to albumin excretion rate (r=-0.66, P=0.004); (ii) both the degree of mesangial and mesangial matrix expansion were inversely related to VEGF 165 mRNA levels (r=-0.73, P=0.005 and r=-0.64, P=0.017), and directly to VEGF 121 mRNA levels (r=0.74, P=0.003 and r=0.73, P=0.004); and (iii) VEGF and VEGF-R2 mRNA levels were directly related (r=0.62, P=0.033). CONCLUSIONS: These findings suggested that quantitative and qualitative changes in VEGF expression are present in type 2 diabetic patients with nephropathy and might be involved in the pathogenesis and progression of diabetic glomerulopathy.

Aged↗
PubMed2003

Identification of a novel splice site mutation of CLCN5 gene and characterization of a new alternative 5' UTR end of ClC-5 mRNA in human renal tissue and leukocytes.

Mutations in the CLCN5 gene have been detected in Dent's disease and its phenotypic variants (X-linked recessive nephrolithiasis, X-linked recessive hypophosphatemic rickets, and idiopathic low-molecular-weight proteinuria of Japanese children). Dent's disease is a tubular disorder characterized by low-molecular-weight proteinuria, and nephrolithiasis associated with nephrocalcinosis and hypercalciuria. ClC-5 is the first chloride channel for which a definitive role in the trafficking and acidification-dependent recycling of apical membrane proteins has been established. In the course of CLCN5 SSCP analysis in patients with hypercalciuric nephrolithiasis, we detected a novel mutation at intron 2 of the CLCN5 gene, a T-to-G substitution, located 17 bp upstream of the AG acceptor site. To determine the effect of IVS2-17 T>G mutation on the correct splicing of intron 2, we studied ClC-5 transcripts in a patient's peripheral blood leukocytes by means of quantitative comparative RT/PCR, and found a new ClC-5 5' UTR isoform characterized by the untranslated exon 1b and by retention of intron 1b. This new isoform--isoform B1--was not correlated with mutation since it was detected also in control leukocytes and in renal tissues of kidney donors, thus confirming its physiological role. By RACE analysis we determined the putative transcriptional start site which is located at intron 1a, 251 nt upstream of the first nucleotide of the untranslated exon 1b. ORF analysis revealed that intron 1b retention in isoform B1 stabilizes the initiation of translation to the AGT at position 297 of the ClC-5 cDNA coding region.

5' Untranslated Regions↗
PubMed2003

Precocious activation of genes of the renin-angiotensin system and the fibrogenic cascade in IgA glomerulonephritis.

BACKGROUND: The renin-angiotensin system (RAS) seems to play a pivotal role in progression of immunoglobulin A (IgA) nephropathy (IgAN). Accordingly, in patients with IgAN a relationship between the RAS and the fibrogenic cascade triggered by transforming growth factor-beta1 (TGF-beta1) should be observed. This study was carried out to obtain deeper insight into the regulation of RAS and the interaction with TGF-beta1 in the diseased kidney. METHODS: Twenty renal biopsies from IgAN patients and five from renal cancer patients (controls) were analyzed in both microdissected glomerular and tubulointerstitial compartments by reverse transcription-polymerase chain reaction (RT-PCR). All patients had normal renal function. The expression of the following genes was determined: angiotensinogen (Agtg), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) type 1 and type II (AT1 and AT2 receptors), TGF-beta1, collagen IV (Coll IV), alpha-smooth muscle actin (alpha-SMA). Quantitative data were confirmed for TGF-beta1 and ACE genes by real-time PCR. Results. RAS genes were overexpressed in IgAN patients vs. control subjects. There was no difference between glomerular and tubulointerstitial RAS gene expression levels. On the contrary, the overactivation of fibrogenic cascade genes (TGF-beta1, Coll IV, alpha-SMA) in the tubulointerstitium was observed (TGF-beta1, glomerular 0.14 +/- 0.10 SD; tubulointerstial 0.34 +/- 0.20; P = 0.000) (alpha-SMA, glomerular 0.08 +/- 0.07; tubulointerstitial 0.35 +/- 0.19; P = 0.000) (Coll IV, glomerular 0.12 +/- 0.11; tubulointerstitial 0.22 +/- 0.10; P = 0.03). This fibrogenic cascade seems to be triggered by RAS as indicated by statistically significant correlations between the expression of their respective genes. A direct relationship between the putative Ang II activity and the expression of AT receptor genes was found in the tubulointerstitium, whereas in the glomeruli this relationship was negative. In the interstitium, statistically significant positive relationships emerged between interstitial infiltrates and the gene expression of Agtg, AT1 receptor, Coll IV, and TGF-beta1. CONCLUSION: This study demonstrates that a tight regulation of the intrarenal RAS exists in IgAN and that it follows the general rules disclosed in animal models. Moreover, the RAS seems to be activated early in the diseased kidney and it appears that such activation drives inflammation and a parallel stimulation of the TGF-beta fibrogenic loop, particularly at the tubulointerstitial level.

Adult↗
PubMed2002

Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. randomized trial.

Diabetic nephropathy may be effectively prevented and treated by controlling glycemia and administering angiotensin-converting enzyme (ACE) inhibitors. However, strict metabolic control can be difficult, and ACE inhibitors may be poorly tolerated and only partially effective, particularly in diabetes mellitus type 2 (DM2), warranting the search for ancillary treatment. Sulodexide is a glycosaminoglycan, a new class of drug that has demonstrated nephroprotective activity in experimental investigations. The Di.N.A.S. study was a randomized, double-blind, placebo-controlled, multicenter, dose-range finding trial to evaluate the extent and duration of the hypoalbuminuric effect of oral sulodexide in diabetic patients. A total of 223 microalbuminuric and macroalbuminuric DM1 and DM2 patients with serum creatinine < or =150 micromol/L and stable BP and metabolic control were recruited. They were randomly allocated to one of four groups: 50 mg/d, 100 mg/d, or 200 mg/d sulodexide daily or placebo for 4 mo (T0 to T4), with 4 mo of follow-up after drug suspension (T4 to T8). Treatment with 200 mg/d sulodexide for 4 mo significantly reduced log albumin excretion rate (logAER) from 5.25 +/- 0.18 at T0 to 3.98 +/- 0.11 at T4 (P < 0.05), which was maintained till T8 (4.11 +/- 0.13; P < 0.05 versus T0). Moreover, the sulodexide-induced percent reductions in AER at T4 were significantly different from the placebo value at T4 and approximately linear to dose increments (30% [confidence limits, 4 to 49%], P = 0.03; 49% [30 to 63%], P = 0.0001; and 74% [64 to 81%], P = 0.0001 in the sulodexide 50, 100, and 200 mg/d groups, respectively. At T8, the sulodexide 200 mg/d group maintained a 62% (45 to 73%) AER significant reduction versus placebo (P = 0.0001). Subanalysis by type of diabetes (DM1 versus DM2, microalbuminuric versus macroalbuminuric, or on concomitant ACE inhibitors versus not on ACE inhibitors) demonstrated similar findings. These effects were obtained without any significant variation in metabolic control and BP or serum creatinine. Very few adverse events were reported; none were serious. In conclusion, a 4-mo course of high doses of sulodexide significantly and dose-dependently improves albuminuria in DM1 and DM2 patients and micro- or macroalbuminuric patients with or without concomitant ACE inhibition. The effect on albuminuria is long-lasting and seemingly additive to the ACE inhibitory effect.

Administration, Oral↗
PubMed2002

Hermann Boerhaave and lithotomy: what he thought about it.

Hermann Boerhaave (1668-1738) was one of the most important figures in 18th-century medicine. With his particular contribution surgery began its transition to a real clinical medical activity becoming increasingly based on linking symptoms with the knowledge of anatomopathological transformations. Lithiasis of the urinary tract was a very common disease throughout Europe. During the early 18th century the surgical approaches for lithotomy to treat lithiasis had very high risks of complications. In the face of the very common and dangerous complications, the doctors and surgeons actively sought all possible solutions short of surgery, and left lithotomy as the last alternative. Boerhaave dedicated a chapter in his "Institutiones medicae" to the treatment of lithiasis of the urinary tract. His recommendations included an increase in liquid intake, a hot bath in order to induce vasodilation, and exercise. Using these methods, Boerhaave felt that stone removal should be achieved, and perhaps reflecting both the status of surgery in the early 18th century and an appreciation of the risks of the surgical procedures available. Boerhaave's opinion of lithomy as a last resort when other approaches failed was, "I think lithotomy is an act of pure faith".

History, 17th Century↗
PubMed2002

Dietary fatty acid supplementation modulates the urinary excretion of calcium and oxalate in the rat. Insight into calcium lithogenesis.

BACKGROUND: An anomalous plasma phospholipid polyunsaturated fatty acid composition has been reported in calcium nephrolithiasis, and was proposed to play a crucial role in the pathogenesis of hypercalciuria and hyperoxaluria, well-known risk factors for lithogenesis. METHODS: To confirm this hypothesis, we administered rats three different diets rich in coconut, soybean and fish oils, and evaluated their effect on plasma urinary calcium and oxalate excretion, since the quality of fatty acids represents an important factor able to influence the activity of delta-6-desaturase, the rate-limiting enzyme in the biosynthetic pathway of highly unsaturated fatty acids. RESULTS: In comparison with coconut and fish oil, dietary supplementation with soybean oil increased plasma phospholipid arachidonic acid and serum 1,25-vitamin D(3) values, as well as renal tissue calcium content and urinary excretion of sodium, oxalate and calcium. CONCLUSIONS: Our findings demonstrate that the quality of fatty acids may modify the urine excretion of calcium and oxalate, confirming our previous hypothesis of a pathogenetic link between cellular membrane phospholipid polyunsaturated fatty acid composition and calcium nephrolithiasis. In addition, our study provides new insights into the relationship between dietary, environmental factors and renal stone disease.

Animals↗
PubMed2000

Glycosaminoglycan therapy prevents TGF-beta1 overexpression and pathologic changes in renal tissue of long-term diabetic rats.

Chronic induction of the prosclerotic cytokine transforming growth factor beta (TGF-beta) has been implicated in the pathogenesis of diabetic nephropathy. In a rat model of diabetes mellitus-induced glomerulosclerosis, daily administration of a modified heparin (mH) glycosaminoglycan (GAG) preparation with low anticoagulant activity prevented glomerular and tubular matrix accumulation, as well as overexpression of TGF-beta1 mRNA and albuminuria, without obvious side effects. To elucidate the molecular mechanisms of GAG/mH inhibitory actions on TGF-beta1, studies using cultured mesangial cells were also performed. In these cells, high glucose-induced, dose-dependent increases in TGF-beta1 mRNA and bioactive TGF-beta protein expression were inhibited by GAG/mH treatment, whereas basal TGF-beta1 expression was not affected. Both the heparin-derived GAG and dermatan sulfate were effective, indicating that the heparin chemical structure is not necessary for inhibitory activity. Coincubation of GAG with active TGF-beta1 demonstrated no inhibitory effect on TGF-beta1 bioactivity, excluding a neutralizing effect of GAG on TGF-beta1 a the protein level. Furthermore, it was demonstrated that GAG inhibited phorbol myristate acetate-induced translocation of protein kinase C-alpha (PKC-alpha) and -beta1 and activation of PKC-alpha, as well as high glucose-induced activation of PKC-alpha. These results suggest that GAG inhibit TGF-beta1 overexpression at the transcriptional level, possibly via inhibition of high glucose-activated PKC. The findings indicate the potential of GAG therapy for the prevention of diabetic glomerulosclerosis by the inhibition of chronic disease-induced TGF-beta1 mRNA overexpression.

Animals↗
PubMedDate not supplied

Diuretics and dopamine for the prevention and treatment of acute renal failure: a critical reappraisal.

The efficacy of diuretics and dopamine in preventing and treating acute renal failure (ARF) is still debated, although these drugs are widely used in clinical practice. The present review addresses this debate providing an update on available data. There are very few well controlled and sufficiently large trials testing these agents in different ARF clinical settings, with either a preventive or a curative goal. Unfortunately, most findings rule out any favourable effects of diuretics, mannitol, atrial natriuretic peptides, and dopamine. In fact, at least in some clinical conditions, they can even worsen the risk of ARF or aggravate its course.

Acute Kidney Injury↗