Joaquim Calado

Familial Renal Glucosuria and SGLT2: From a Mendelian Trait to a Therapeutic Target

Four members of two glucose transporter families, SGLT1, SGLT2, GLUT1, and GLUT2, are differentially expressed in the kidney, and three of them have been shown to be necessary for normal glucose resorption from the glomerular filtrate. Mutations in SGLT1 are associated with glucose-galactose malabsorption, SGLT2 with familial renal glucosuria (FRG), and GLUT2 with Fanconi-Bickel syndrome. Patients with FRG have decreased renal tubular resorption of glucose from the urine in the absence of hyperglycemia and any other signs of tubular dysfunction. Glucosuria in these patients can range from <1 to >150 g/1.73 m(2) per d. The majority of patients do not seem to develop significant clinical problems over time, and further description of specific disease sequelae in these individuals is reviewed. SGLT2, a critical transporter in tubular glucose resorption, is located in the S1 segment of the proximal tubule, and, as such, recent attention has been given to SGLT2 inhibitors and their utility in patients with type 2 diabetes, who might benefit from the glucose-lowering effect of such compounds. A natural analogy is made of SGLT2 inhibition to observations with inactivating mutations of SGLT2 in patients with FRG, the hereditary condition that results in benign glucosuria. This review provides an overview of renal glucose transport physiology, FRG and its clinical course, and the potential of SGLT2 inhibition as a therapeutic target in type 2 diabetes.

Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria.

Familial renal glucosuria is an inherited renal tubular disorder. A homozygous nonsense mutation in the SLC5A2 gene, encoding the sodium/glucose co-transporter SGLT2, has recently been identified in an affected child of consanguineous parents. We now report novel compound heterozygous mutations in the son of non-consanguineous parents. One allele has a p.Q167fsX186 mutation, which is expected to produce a truncated protein, and the other a p.N654S mutation involving a highly conserved residue. These findings confirm that mutations in the SLC5A2 gene are responsible for recessive renal glucosuria.

A novel heterozygous missense mutation in the UMOD gene responsible for Familial Juvenile Hyperuricemic Nephropathy

BackgroundFamilial Juvenile Hyperuricemic Nephropathy is an autosomal dominant nephropathy, characterized by decreased urate excretion and progressive interstitial nephritis. Mutations in the uromodulin coding UMOD gene have been found responsible for the disease in some families.Case presentationWe here describe a novel heterozygous p.K307T mutation in an affected female with hyperuricemia, renal cysts and renal failure. The probands only son is also affected and the mutation was found to segregate with the disease.ConclusionsThis mutation is the fourth reported in exon 5. Initial studies identified a mutation clustering in exon 4 and it has been recommended that sequencing this exon alone should be the first diagnostic test in patients with chronic interstitial nephritis with gout or hyperuricemia. However, regarding the increasing number of mutations being reported in exon 5, we now suggest that sequencing exon 5 should also be performed.

Effect of kidney disease on glucose handling (including genetic defects)

Reabsorption of glucose in the proximal renal tubule involves the Na(+)-coupled glucose cotransporter (SGLT) and the facilitative glucose transport (GLUT) multigene glucose transport families. Mutations in SLC5A2, the SGLT2 coding gene, are responsible for familial renal glucosuria (FRG), a genetic disorder characterized by glucosuria in the absence of both hyperglycemia and generalized proximal tubular dysfunction. In this paper we focus on FRG and describe other inherited and acquired clinical conditions associated with glucosuria. In addition, a brief review on the regulation of renal glucose transport in diabetes is provided.

Familial juvenile nephronophthisis

Abstract Familial juvenile nephronophthisis (NPH) is an autosomal recessive interstitial nephritis leading to terminal renal failure around puberty. Associations with extrarenal symptoms have been reported, mainly with Leber amaurosis (termed Senior-Løken syndrome). By means of linkage analysis a gene NPH1 for the purely renal form of NPH has been localized to chromosome 2. Genetic heterogeneity has been shown between NPH and Senior-Løken syndrome and also within the group of isolated NPH cases. Further characterization of the NPH1 region led to the isolation of large homozygous deletions in approximately 70% of patients with NPH. The detection of these deletions by PCR represents a simple noninvasive method for precise diagnosis in the majority of patients suspected of having NPH.

MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2

The renal proximal tubule reabsorbs 90% of the filtered glucose load through the Na+-coupled glucose transporter SGLT2, and specific inhibitors of SGLT2 are now available to patients with diabetes to increase urinary glucose excretion. Using expression cloning, we identified an accessory protein, 17 kDa membrane-associated protein (MAP17), that increased SGLT2 activity in RNA-injected Xenopus oocytes by two orders of magnitude. Significant stimulation of SGLT2 activity also occurred in opossum kidney cells cotransfected with SGLT2 and MAP17. Notably, transfection with MAP17 did not change the quantity of SGLT2 protein at the cell surface in either cell type. To confirm the physiologic relevance of the MAP17-SGLT2 interaction, we studied a cohort of 60 individuals with familial renal glucosuria. One patient without any identifiable mutation in the SGLT2 coding gene (SLC5A2) displayed homozygosity for a splicing mutation (c.176+1G>A) in the MAP17 coding gene (PDZK1IP1). In the proximal tubule and in other tissues, MAP17 is known to interact with PDZK1, a scaffolding protein linked to other transporters, including Na+/H+ exchanger 3, and to signaling pathways, such as the A-kinase anchor protein 2/protein kinase A pathway. Thus, these results provide the basis for a more thorough characterization of SGLT2 which would include the possible effects of its inhibition on colocalized renal transporters.

Secondary Amyloidosis in a Patient with Long Duration Crohn's Disease Treated with Infliximab

Systemic AA amyloidosis is a serious complication of many chronic inflammatory disorders. Its association with Crohns disease implies that the inflammatory burden is high enough for amyloid fibrils to form deposits in tissues. A case is presented in which this complication occurred while the patient was clinically well, with biological and endoscopic markers showing an inactive or mildly active disease under anti-tumor necrosis factor alpha therapy.

Adult presentation of Bartter syndrome type IV with erythrocytosis

Abstract Bartter syndrome comprises a group of rare autosomal-recessive salt-losing disorders with distinct phenotypes, but one unifying pathophysiology consisting of severe reductions of sodium reabsorption caused by mutations in five genes expressed in the thick ascending limb of Henle, coupled with increased urinary excretion of potassium and hydrogen, which leads to hypokalemic alkalosis. Bartter syndrome type IV, caused by loss-of-function mutations in barttin, a subunit of chloride channel CLC-Kb expressed in the kidney and inner ear, usually occurs in the antenatal-neonatal period. We report an unusual case of late onset presentation of Bartter syndrome IV and mild phenotype in a 20 years-old man who had hypokalemia, deafness, secondary hyperparathyroidism and erythrocytosis.

Determination of the Renal Threshold for Glucose Excretion in Familial Renal Glucosuria

Background/Aims: Familial Renal Glucosuria (FRG) is characterized by the presence of persistent isolated glucosuria in the absence of hyperglycemia. Mutations in SLC5A2, the gene coding for the sodium-glucose co-transporter 2 (SGLT2), are responsible for FRG. Phenotype/genotype correlations in FRG have mostly relied on the quantification of Urinary Glucose Excretion (UGE), which is dependent on both the filtered glucose load and the renal glucose reabsorptive capacity. In the current work, the renal threshold for glucose excretion (RTG) was determined in an FRG cohort, with the purpose of characterizing the impact of SGLT2 mutations on renal glucose transport. Methods: From January to December of 2013, eight FRG individuals with identified SLC5A2 mutations were enrolled. Patients were given a Mixed-Meal Tolerance Test during which blood glucose and UGE were measured over a 4 h period and the data was used to calculate RTG, according to a recently validated protocol. Results: In patients with homozygous mutations, RTG values were very low, with a mean (SD) of 0.95 (1.17) mmol/l, compared to commonly reported values of approximately 10-11.1 mmol/l in healthy subjects. In subjects with heterozygous mutations, mean (SD) RTG values were 4.91 (1.23) mmol/l, which are approximately one-half of the values in subjects without mutations. Conclusions: In FRG, mutations in SLC5A2 lead to reductions in RTG and increases in UGE. Because determination of RTG is not influenced by the filtered glucose load, the calculated RTG values provide a more refined measure of the impact of mutations on renal glucose transport than can be obtained from UGE alone.

Hypouricaemia and hyperuricosuria in familial renal glucosuria

Familial renal glucosuria is a rare co-dominantly inherited benign phenotype characterized by the presence of glucose in the urine. It is caused by mutations in the SLC5A2 gene that encodes SGLT2, the Na+-glucose cotransporter responsible for the reabsorption of the bulk of glucose in the proximal tubule. We report a case of FRG displaying both severe glucosuria and renal hypouricaemia. We hypothesize that glucosuria can disrupt urate reabsorption in the proximal tubule, directly causing hyperuricosuria.