Tubular Diseases and Stones Seen From Pediatric and Adult Nephrology Perspectives.

The tubular system of the kidneys is a complex series of morphologic and functional units orchestrating the content of tubular fluid as it flows along the nephron and collecting ducts. Renal tubules maintain body water, regulate electrolytes and acid-base balance, reabsorb precious organic solutes, and eliminate specific metabolites, toxins, and drugs. In addition, decisive mechanisms to adjust blood pressure are governed by the renal tubules. Genetic as well as acquired disorders of these tubular functions may cause serious diseases that manifest both in childhood and adulthood. This article addresses a selection of tubulopathies and the underlying pathomechanisms, while highlighting the important differences in pediatric and adult nephrology care. These range from rare monogenic conditions such as nephrogenic diabetes insipidus, cystinosis, and Bartter syndrome that present in childhood, to the genetic and acquired tubular pathologies causing hypertension or nephrolithiasis that are more prevalent in adults. Both pediatric and adult nephrologists must be aware of these conditions and the age-dependent manifestations that warrant close interaction between the two subspecialties.

Structural Basis for Mutations of Human Aquaporins Associated to Genetic Diseases.

Aquaporins (AQPs) are among the best structural-characterized membrane proteins, fulfilling the role of allowing water flux across cellular membranes. Thus far, 34 single amino acid polymorphisms have been reported in HUMSAVAR for human aquaporins as disease-related. They affect AQP2, AQP5 and AQP8, where they are associated with nephrogenic diabetes insipidus, keratoderma and colorectal cancer, respectively. For half of these mutations, although they are mostly experimentally characterized in their dysfunctional phenotypes, a structural characterization at a molecular level is still missing. In this work, we focus on such mutations and discuss what the structural defects are that they appear to cause. To achieve this aim, we built a 3D molecular model for each mutant and explored the effect of the mutation on all of their structural features. Based on these analyses, we could collect the structural defects of all the pathogenic mutations (here or previously analysed) under few main categories, that we found to nicely correlate with the experimental phenotypes reported for several of the analysed mutants. Some of the structural analyses we present here provide a rationale for previously experimentally observed phenotypes. Furthermore, our comprehensive overview can be used as a reference frame for the interpretation, on a structural basis, of defective phenotypes of other aquaporin pathogenic mutants.

AKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus.

Congenital nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine. Congenital NDI is mainly caused by loss-of-function mutations in the vasopressin type 2 receptor (V2R), leading to impaired aquaporin-2 (AQP2) water channel activity. So far, treatment options of congenital NDI either by rescuing mutant V2R with chemical chaperones or by elevating cyclic adenosine monophosphate (cAMP) levels have failed to yield effective therapies. Here we show that inhibition of A-kinase anchoring proteins (AKAPs) binding to PKA increases PKA activity and activates AQP2 channels in cortical collecting duct cells. In vivo, the low molecular weight compound 3,3'-diamino-4,4'-dihydroxydiphenylmethane (FMP-API-1) and its derivatives increase AQP2 activity to the same extent as vasopressin, and increase urine osmolality in the context of V2R inhibition. We therefore suggest that FMP-API-1 may constitute a promising lead compound for the treatment of congenital NDI caused by V2R mutations.

Wnt5a induces renal AQP2 expression by activating calcineurin signalling pathway.

Heritable nephrogenic diabetes insipidus (NDI) is characterized by defective urine concentration mechanisms in the kidney, which are mainly caused by loss-of-function mutations in the vasopressin type 2 receptor. For the treatment of heritable NDI, novel strategies that bypass the defective vasopressin type 2 receptor are required to activate the aquaporin-2 (AQP2) water channel. Here we show that Wnt5a regulates AQP2 protein expression, phosphorylation and trafficking, suggesting that Wnt5a is an endogenous ligand that can regulate AQP2 without the activation of the classic vasopressin/cAMP signalling pathway. Wnt5a successfully increases the apical membrane localization of AQP2 and urine osmolality in an NDI mouse model. We also demonstrate that calcineurin is a key regulator of Wnt5a-induced AQP2 activation without affecting intracellular cAMP level and PKA activity. The importance of calcineurin is further confirmed with its activator, arachidonic acid, which shows vasopressin-like effects underlining that calcineurin activators may be potential therapeutic targets for heritable NDI.

Folding and stability of the aquaglyceroporin GlpF: Implications for human aqua(glycero)porin diseases.

Aquaporins are highly selective polytopic transmembrane channel proteins that facilitate the permeation of water across cellular membranes in a large diversity of organisms. Defects in aquaporin function are associated with common diseases, such as nephrogenic diabetes insipidus, congenital cataract and certain types of cancer. In general, aquaporins have a highly conserved structure; from prokaryotes to humans. The conserved structure, together with structural dynamics and the structural framework for substrate selectivity is discussed. The folding pathway of aquaporins has been a topic of several studies in recent years. These studies revealed that a conserved protein structure can be reached by following different folding pathways. Based on the available data, we suggest a complex folding pathway for aquaporins, starting from the insertion of individual helices up to the formation of the tetrameric aquaporin structure. The consequences of some known mutations in human aquaporin-encoding genes, which most likely affect the folding and stability of human aquaporins, are discussed.

Evaluation of cellular plasticity in the collecting duct during recovery from lithium-induced nephrogenic diabetes insipidus.

The cellular morphology of the collecting duct is altered by chronic lithium treatment. We have previously shown that lithium increases the fraction of type-A intercalated cells and lowers the fraction of principal cells along the collecting duct. Moreover, type-A intercalated cells acquire a long-row distribution pattern along the tubules. In the present study, we show that these morphological changes reverse progressively after discontinuation of lithium and finally disappear after 19 days from lithium suspension. In this time frame we have identified for the first time, in vivo, a novel cellular type positive for both intercalated and principal cells functional markers, as recognized by colabeling with H(+)-ATPase/aquaporin-4 (AQP4) and anion exchanger-1 (AE-1)/AQP2 and Foxi1/AQP4. This cell type is mainly present after 6 days of lithium washout, and it disappears in parallel with the long-row pattern of the type-A intercalated cells. It usually localizes either in the middle or at the edge of the long-row pattern. Its ultrastructure resembles the intercalated cells as shown both by differential interference contrast and by electron microscopy. The time course of appearance, the localization along the collecting duct, and the ultrastructure suggest that the cells double labeled for principal and intercalated cells markers could represent a transition element driving the conversion of intercalated cells into principal cells.

Characterization of three vasopressin receptor 2 variants: an apparent polymorphism (V266A) and two loss-of-function mutations (R181C and M311V).

Arginine vasopressin (AVP) is released from the posterior pituitary and controls water homeostasis. AVP binding to vasopressin V2 receptors (V2Rs) located on kidney collecting duct epithelial cells triggers activation of Gs proteins, leading to increased cAMP levels, trafficking of aquaporin-2 water channels, and consequent increased water permeability and antidiuresis. Typically, loss-of-function V2R mutations cause nephrogenic diabetes insipidus (NDI), whereas gain-of-function mutations cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD). Here we provide further characterization of two mutant V2Rs, R181C and M311V, reported to cause complete and partial NDI respectively, together with a V266A variant, in a patient diagnosed with NSIAD. Our data in HEK293FT cells revealed that for cAMP accumulation, AVP was about 500- or 30-fold less potent at the R181C and M311V mutants than at the wild-type receptor respectively (and about 4000- and 60-fold in COS7 cells respectively). However, in contrast to wild type V2R, the R181C mutant failed to increase inositol phosphate production, while with the M311V mutant, AVP exhibited only partial agonism in addition to a 37-fold potency decrease. Similar responses were detected in a BRET assay for ß-arrestin recruitment, with the R181C receptor unresponsive to AVP, and partial agonism with a 23-fold decrease in potency observed with M311V in both HEK293FT and COS7 cells. Notably, the V266A V2R appeared functionally identical to the wild-type receptor in all assays tested, including cAMP and inositol phosphate accumulation, ß-arrestin interaction, and in a BRET assay of receptor ubiquitination. Each receptor was expressed at comparable levels. Hence, the M311V V2R retains greater activity than the R181C mutant, consistent with the milder phenotype of NDI associated with this mutant. Notably, the R181C mutant appears to be a Gs protein-biased receptor incapable of signaling to inositol phosphate or recruiting ß-arrestin. The etiology of NSIAD in the patient with V266A V2R remains unknown.

Nephrogenic diabetes insipidus secondary to syphilis infection.

CONTEXT: Nephrogenic diabetes insipidus (NDI) is caused by partial or complete renal resistance to the effects of antidiuretic hormone. Acquired NDI can be caused by electrolyte imbalances (eg, hypercalcemia), renal/extrarenal diseases (eg, chronic pyelonephritis), and drugs (eg, lithium toxicity). Syphilis has never been reported to cause NDI. OBJECTIVE: The aim of this study was to report the case of a 56-year-old man with NDI secondary to syphilis. CASE: The 56-year-old patient presented with polyuria and polydipsia lasting more than 40 days. His urine specific gravity was 1.002. He had no history of chronic kidney disease or contact with toxicants. He had normal blood glucose levels. A water-deprivation test and vasopressin administration indicated NDI. His rapid plasma reagin titer was 1:128. The serum Treponema pallidum-particle agglutination test was positive. He reported engaging in unprotected, extramarital sex 6 months before polydipsia onset and thereafter developing a skin lesion on the external genitalia and arthralgia, both of which resolved spontaneously. Examination of renal biopsy specimens showed abundant plasmacytic and lymphocytic infiltration of the interstitium and low and flat tubular epithelial cells, indicating renal tubular injury. Silver staining revealed T. pallidum-like organisms. Immunohistochemical analysis with T. pallidum-specific antibody confirmed the presence of treponemes. INTERVENTION: The patient received 2.4 million U of benzathine penicillin im once a week for 3 weeks. RESULTS: His urine output gradually reduced; he recovered 1 month later. His urine specific gravity was 1.026, and his syphilis rapid plasma reagin titer was 1:8. CONCLUSION: Syphilis can cause NDI. The manifestations of syphilis and causes of acquired NDI are diverse.

The role of renal water channels in health and disease.

Seven members of the aquaporin (AQP) family are expressed in different regions of the kidney. AQP1-4 are localized in plasma membranes of renal epithelial cells and are intimately involved in water reabsorption by the kidney. AQP7 is also localized in the plasma membrane and may facilitate glycerol transport. AQP6 and AQP11 are localized within the cell, with AQP6 involved in anion transport and AQP11 water transport. Mutations in AQP2 can result in diabetes insipidus, whereas mutations in other AQPs have not yet been shown to be disease-associated. Genetic polymorphisms may contribute to the susceptibility to defects in urine concentrating mechanisms associated with some diseases. Most of the AQPs are subject to transcriptional regulation and post-translational modifications by a range of biological modifiers. As a result a number of chronic kidney and systemic diseases produce changes in the abundance of AQPs. The more recent developments in this field are reviewed.

Wilms tumor arising in a child with X-linked nephrogenic diabetes insipidus.

We report on a child with X-linked nephrogenic diabetes insipidus (NDI) who developed Wilms tumor (WT). Nephrogenic diabetes insipidus is caused by mutations of the arginine vasopressin receptor (AVPR2) or aquaporin-II (AQP2) genes. Wilms tumor is also genetically heterogeneous and is associated with mutations of WT1 (15-20%), WTX (20-30%) and other loci. The boy presented at 5 months with failure to thrive, polyuria, hypernatremia and abdominal mass. Analysis of leukocyte DNA showed a novel missense mutation (Q174H) of the AVPR2 gene, which was not present in his mother. In cells (WitS) isolated from the tumor, WTX mRNA expression and coding sequence were intact. However, we identified a 44-kb homozygous deletion of the WT1 gene spanning exons 4 to 10. The WT1 deletion was not present in leukocyte DNA from the patient or his mother. We also noted strong beta-catenin (CTNNB1) expression in the tumor cells and identified a heterozygote missense Ser45Cys mutation of exon 3 of CTNNB1. However, the mutation was absent both in the constitutional DNA of the patient and his mother. The concurrence of WT and NDI has not been previously reported and may be unrelated. Nevertheless, this case nicely illustrates the sequence of events leading to sporadic Wilms tumor.

Nephrogenic diabetes insipidus with dilatation of bilateral renal pelvis, ureter and bladder.

OBJECTIVE: Nephrogenic diabetes insipidus (NDI) with dilatation of upper urinary tract and bladder is rarely reported. This study evaluated the urological manifestations and treatment results of this rare condition. MATERIAL AND METHODS: According to a fluid deprivation test, seven men and two women were diagnosed as NDI, and underwent ultrasonography, magnetic resonance urography, cystography, and urodynamic and laboratory examination. A micturition diary and symptoms were recorded before and during treatment. All patients were given hydrochlorothiazide and followed up with ultrasonography, the postvoiding residual volume (PVR), urinalysis and kidney function tests. RESULTS: All patients presented with polydipsia and polyuria with severe dilatation of upper urinary tract and bladder. Urodynamics showed that the mean values of the bladder capacity, bladder pressure at the end of filling, maximum flow rate (Q(max)), detrusor pressure and PVR were 1056.3 ml, 40.5 cmH(2)O, 30.8 ml/s, 51.3 cmH(2)O, 436.3 ml, respectively. The total urine volume in all patients decreased by more than 50% after administration of hydrochlorothiazide, which improved the symptoms and hydronephrosis in seven cases. The symptoms of other two cases were relieved after treatment with an electric transurethral incision of the bladder neck and a cystostomy. CONCLUSIONS: NDI should be considered in patients with dilatation of the urinary tract and polyuria. Higher bladder pressure at the end of filling may contribute to the dilatation of urinary tract. Normal detrusor contractility with large PVR is a unique manifestation of this condition. Controlling the urine volume and reducing the PVR are of key importance in the treatment of this condition.

Nephrogenic diabetes insipidus (NDI): clinical, laboratory and genetic characterization of five Brazilian patients

INTRODUCTION: Nephrogenic diabetes insipidus is characterized by a lack of response in the distal nephron to the antidiuretic hormone arginine vasopressin. Manifestations include polyuria, polydipsia, hyposthenuria, recurrent episodes of dehydration and fever and growth failure. Most cases are caused by mutations in the AVPR2 gene. The mutant receptors are trapped intracellularly. METHOD: We studied five boys using clinical, laboratory and molecular data. The mean age at diagnosis was 14.6 months (range 6 to 24) and 12.2 years (7.8 to 19) after the follow-up period. The mean period of follow-up was 132.2 ± 50.9 months. RESULTS: The geometric means of the z-scores of weight and stature were -4.5 and -3.6, respectively, at diagnosis. At the last medical appointment, the z-scores of weight and stature were -0.3 and -0.9, respectively. Three patients were diagnosed with ureterohydronephrosis and exhibited increased post-void urine volume. Mutations in the AVPR2 gene were found in all patients, and the carrier status was confirmed in four of five cases. Two unrelated children presented identical mutations (S167L) in arginine vasopressin R2. Two of the patients had a mutation that has already been described in other Brazilian families (R337X), and one patient showed a de novo mutation (Y128D) in arginine vasopressin R2, since his mother's molecular analysis was normal. The recurrence risk for this family was significantly reduced. CONCLUSION: This study reports the clinical and laboratory characterization of Nephrogenic diabetes insipidus and reiterates the importance of the genetic basis that underlies the disease diagnosis and genetic counseling.

Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus.

We report 3 cases of renal toxicity associated with use of the antiviral agent tenofovir. Renal failure, proximal tubular dysfunction, and nephrogenic diabetes insipidus were observed, and, in 2 cases, renal biopsy revealed severe tubular necrosis with characteristic nuclear changes. Patients receiving tenofovir must be monitored closely for early signs of tubulopathy (glycosuria, acidosis, mild increase in the plasma creatinine level, and proteinuria).

The valve bladder syndrome: 20 years later.

PURPOSE: Just more than 20 years ago a group of associated findings was identified in patients with posterior urethral valves and persistent upper tract dilatation following valve ablation, including a noncompliant thick walled bladder, incontinence and nephrogenic diabetes insipidus. Subsequently the pseudonym "valve bladder syndrome" became associated with this phenomenon. The history of the valve bladder syndrome concept, continuing debate regarding the etiology and management of the valve bladder, and 20 years of urodynamic and histological investigations are reviewed. MATERIALS AND METHODS: Outcome studies, histological findings, animal model experimentation and urodynamic investigations reported in the literature more than the last 20 years were reviewed and compared. RESULTS: Varying degrees of bladder compliance loss are seen in the majority of patients following valve ablation. Severe loss of compliance can lead to persistent upper tract dilatation and later urinary incontinence. A large urine output, secondary to a loss of renal concentrating ability, contributes to the persistent dilatation and incontinence. Correcting bladder compliance loss helps to lessen the dilatation and incontinence. A literature review revealed little to support the belief that previous temporary diversion is the major cause of severe compliance loss. In fact, instances of severe compliance loss were seen following any mode of therapy, including valve ablation alone, and likely represents a persistent finding secondary to the degree of damage incurred in utero. That there are more patients requiring augmentation after temporary diversion should not imply that diversion caused the poor compliance but that an initially poorly compliant bladder lead to diversion as the choice of treatment. Some investigators have found that many temporarily diverted cases have a bladder equal to or even better in function and capacity than those treated with valve ablation alone. Others have made a case but less substantially to conclude that diversion is the most significant cause of a small, poorly compliant bladder. CONCLUSIONS: Valve ablation alone without urodynamic followup is inappropriate. Proactive management must have a significant role. The vast majority of temporarily diverted cases do not result in a fibrotic, noncompliant bladder. Surgeons who strongly favor diversion should be comfortable with such an approach, although in most cases if diversion is considered, those same patients often can be treated just as adequately with proactive urodynamics and anticholinergic therapy without the required surgery for undiversion. With great anticipation, we look forward to studies that will determine if growth factor inhibitors or angiotensin converting enzyme inhibitors will have a role in preventing or reversing the histological changes of the valve bladder.

Cerebral defects and nephrogenic diabetes insipidus with the ARC syndrome: additional findings or a new syndrome (ARCC-NDI)?

We report on 4 children from 2 unrelated families who appear to have the lethal ARC syndrome (arthrogryposis, renal tubular dysfunction, and cholestasis) together with the additional findings of nephrogenic diabetes insipidus and cerebral anomalies, including deafness. With increased survival time in our patients, paucity of the intrahepatic bile ductules and cholestasis progressed to cirrhosis, growth was severely impaired, and severe mental retardation became apparent. No evidence was found for peroxisomal, chromosomal, or mitochondrial disorders. We propose to amend the ARC mnemonic to ARCC-NDI (A-Arthrogryposis, R-renal Fanconi, C-cerebral, C-cholestasis, NDI-nephrogenic diabetes insipidus) to name the major manifestations of this syndrome, several of which have not been appreciated.

A low-affinity vasopressin V2-receptor gene in a kindred with X-linked nephrogenic diabetes insipidus.

In this study, a mutation in vasopressin Type 2 receptor (V2R) in a patient with hereditary nephrogenic diabetes insipidus (NDI) has been identified and characterized. The sequencing of the V2R gene from the patient revealed that there was a missense mutation (TAT to TGT) resulting in the substitution of 205Tyr for Cys in the putative third extracellular domain. The expression analysis in COS cells showed that the binding affinity of the mutant receptor (KD = 19.8 nM) for arginine vasopressin was much lower than that of the wild-type receptor (KD = 1.8 nM) so that intracellular cAMP production stimulated by arginine vasopressin was impaired in cells with the mutant V2R. From these results, it was concluded that the single amino-acid substitution of V2R is responsible for this familial disease.