Defective Urinary Acidification Research Articles

Hearing Loss Related to Gene Mutations in Distal Renal Tubular Acidosis

Introduction: Distal renal tubular acidosis (dRTA) is a disease that may develop either primarily or secondarily, resulting from urinary acidification defects in distal tubules. Hearing loss may accompany primary forms of dRTA. This study aims to determine the characteristics of hearing loss due to different gene mutations in patients with dRTA. Methods: Behavioral and electrophysiological audiological evaluations were performed after otolaryngology examination in 21 patients with clinically diagnosed dRTA. Radiological imaging of the inner ear (n = 9) was conducted and results of genetic analyses using next-generation sequencing method (n = 16) were included. Results: Twenty-one patients with dRTA from 20 unrelated families, aged between 8 months and 33 years (median = 12, interquartile range = 20), participated. All patients with ATP6V1B1 mutations (n = 9) had different degrees of hearing loss. There was one patient with hearing loss in patients with ATP6V0A4 mutations (n = 6). One patient with the WDR72 mutation had normal hearing. Large vestibular aqueduct syndrome (LVAS) was detected in 6 (67%) of 9 patients whose radiological evaluation results were available. Conclusions: LVAS is common in patients with dRTA and may influence the type and severity of hearing loss in these patients. The possibility of both congenital and late-onset and progressive hearing loss should be considered in dRTA patients. A regular audiological follow-up is essential for the early detection of a possible late-onset or progressive hearing loss in these patients.

Anti-carbonic anhydrase II antibody reflects urinary acidification defect especially in proximal renal tubules in patients with primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is a systemic autoimmue disease featured by excessive autoantibody production. It has been demonstrated that anti-carbonic anhydrase II (anti-CA II) antibody is correlated with renal tubular acidosis in pSS; however, no further details about urinary acidification defect have been reported, and the antibody's relationship with other organ impairments remains unknown. This case-control study aimed to examine anti-CA II antibody levels in relation to various systemic complications in pSS, and evaluate its potential role as a organ-specific biomarker in a Chinese cohort. Serum anti-CA II antibody levels were determined using ELISA in 123 patients with pSS and 72 healthy controls. The medical records of the patients were collected, and the correlation between serum anti-CA II antibody and clinical/immunological parameters was investigated. Serum anti-CA II antibody level and its positive rate were significantly increased in pSS patients compared with controls, and ANA-positive patients presented even higher titers of the antibody. In anti-CA II positive group, remarkably higher urine pH and bicarbonate, as well as lower urine titratable acid and serum potassium were observed, which indicated renal tubular acidification dysfunction both involving bicarbonate reabsorption and acid secretion. In addition, platelet count and complement 3, complement 4 levels decreased, whereas serum IgG, IgA and γ-globulin levels increased notably in accord with a higher EULAR SS disease activity index score in these patients. Further analysis showed that anti-CA II antibody was most elevated in patients with defect in bicarbonate reabsorption, reflecting proximal renal tubular injury, rather than in patients with distal renal tubular acidosis as previously reported. In conclusion, anti-CA II antibody reflects renal (especially proximal renal tubular) and hematologic impairment as well as increased disease activity in pSS. It may act as a serum biomarker of systemic damage of pSS.

A Comprehensive Proteomics Analysis of Urinary Extracellular Vesicles Identifies a Specific Kinase Protein Profile as a Novel Hallmark of Medullary Sponge Kidney Disease

Recent advances in the high-throughput technologies and data analysis have led to better understanding of the biological processes involved in several kidney disorders,1,S1,S2 including the medullary sponge kidney (MSK) disease, a rare congenital malformation characterized by dilation of the collecting ducts in the renal papillae, urinary acidification and concentration defects, cystic anomalies of precalyceal ducts associated with a high risk of nephrocalcinosis, and recurrent kidney stones.2

Incomplete distal renal tubular acidosis in children.

To describe incomplete distal renal tubular acidosis (iDRTA) in paediatric patients, a term used for the diagnosis of patients who do not develop spontaneous overt metabolic acidosis but are unable to acidify the urine in response to an ammonium chloride load. Tests used to explore urinary acidification were revised. In addition, publications in English extracted from 161 entries yielded by a PubMed database search, using 'incomplete distal renal tubular acidosis' as keyword, were reviewed. Incomplete distal renal tubular acidosis has mostly been identified in adults with autoimmune diseases, nephrolithiasis, nephrocalcinosis and/or osteopenia. iDRTA has been reported in few paediatric patients with rickets, congenital abnormalities of kidney and urological tract and/or growth failure. The pathophysiological mechanisms potentially responsible for the defect of urinary acidification are discussed as well as the clinical and biochemical findings of iDRTA described in children. The presentation of iDRTA in children differs from adults. The clinical and biochemical features of iDRTA are not well characterised in paediatric patients. The detection of iDRTA in groups of population such as heterozygous carriers of primary DRTA gene mutations and children with hypocitraturia or hypercalciuria might be of clinical interest to better know the pathophysiology and natural history of iDRTA.

Rickets Due to Distal Renal Tubular Acidosis– an Uncommon Presentation of Wilson’s Disease

Rickets is a disease of bone mineralization of growth plate. Refractory rickets can be caused by distal (type 1) renal tubular acidosis (RTA). A number of conditions can result in distal RTA and Wilson’s disease is an uncommon entity. Wilson’s disease is a rare autosomal recessive disorder of copper metabolism with diverse presentations. We describe a case of refractory rickets due to distal RTA, caused by Wilson’s disease. Diagnosis of Wilson’s disease was confirmed with presence of Kayser–Fleischer (K–F) rings and high urinary copper. Further investigations revealed urinary acidification defect with hypercalciuria pointing towards distal RTA. He was treated with penicillamine & oral Zinc and significant clinical improvement was observed.Bangladesh J Medicine Jul 2018; 29(2) : 84-86

Signification of distal urinary acidification defects in hypocitraturic patients.

Background and objectivesHypocitraturia has been associated with metabolic acidosis and mineral disorders. The aim of this study was to investigate the occurrence of urinary acidification defects underlying hypocitraturia.Materials and methodsThis retrospective observational study included 67 patients (32 men), aged 40.7±15.1 years with hypocitraturia (<1.67 mmol/24-h) and nephrolithiasis, nephrocalcinosis, and/or bone demineralization, referred to our center from 2000 to 2015. We aimed to assess renal distal acidification capacity, prevalence and mechanisms of urinary acidification defects. Patients with low baseline plasma HCO3- (<22 mmol/L) were studied by bicarbonate loading or furosemide/fludrocortisone tests. Patients with normal baseline plasma HCO3- had an ammonium-chloride challenge test. A normal response was a decrease in urinary pH <5.3 and an increase in urinary NH4+ ≥33 μmol/min and defined idiopathic hypocitraturia.ResultsEleven patients (16.4%) had low HCO3- and overt distal acidification defect. Three had a mutation in the gene encoding AE1, 4 had Gougerot-Sjögren syndrome and no cause was found in the remaining 4 cases. Fifty-six patients (83.6%) had normal HCO3-; of those, 33 (58.9%) had idiopathic hypocitraturia. Among the 23 (41%) remaining patients, 12 were unable to increase urinary NH4+ excretion (among them, 8 were able to decrease urinary pH and 4 were not) whereas 11 were able to increase urinary NH4+ excretion but unable to decrease urinary pH. These 11 patients had higher fasting urinary calcium, reflecting bone resorption, than the other 12 patients: median 0.41 [0.24–0.47] vs. 0.22 [0.08–0.37] mmol/mmol creatinine (P = 0.04).ConclusionsPatients with hypocitraturia and normal plasma HCO3- frequently show a latent acidification defect that can be further dissected into one of several subtypes based on urinary pH and NH4+ response to the acid load. Those patients with impaired urine acidification capacity but preserved NH4+ excretion exhibit particularly high calciuria and should be identified to optimize nephrolithiasis prevention.

Uric acid, kidney disease and nephrolithiasis

Different types of kidney disease are known to be associated with hyperuricemia. The underlying pathophysiologic mechanisms strongly vary, and different ways of therapeutic approach are therefore required. In tumor lysis syndrome, a rapid, excessive increase of serum uric acid level can cause an acute renal failure. For chronic urate nephropathy, on the other hand, constantly elevated serum uric acid level for a longer period seems to be important. Being still controversial as a disease entity however, the aetiology for putative chronic urate nephropathy might be in fact chronic lead intoxication, as suggested by quite an amount of association data. In terms of uric acid nephrolithiasis, the major risk factor is a urinary acidification defect with persistently acidic urine pH, and not necessarily hyperuricemia or hyperuricosuria. Evidence suggests that metabolic diseases with increased insulin resistance are strongly associated with urinary acidification defect. Patients with uric acid kidney stones should therefore be thoroughly evaluated for such metabolic diseases and in a positive case adequately treated.

Prevalence of distal renal tubular acidosis in primary Sjögren's syndrome

Our objectives were to analyse the prevalence of distal renal tubular acidosis (dRTA) in primary SS (pSS) and to compare a novel urinary acidification test with furosemide and fludrocortisone (FF) with the gold standard ammonium chloride (NH4Cl) to detect dRTA. Urinary acidification was assessed in 57 pSS patients using NH4Cl and FF. A urinary acidification defect was defined as an inability to reach a urinary pH of <5.3 after NH4Cl. The prevalence of complete dRTA (urinary acidification defect with acidosis) was 5% (3/57). All three patients had positive SSA/Ro and SSB/La autoantibodies and impaired kidney function. The prevalence of incomplete dRTA (urinary acidification defect without acidosis) was 25% (14/57). Compared with patients without dRTA, patients with incomplete dRTA had significantly lower venous pH and serum bicarbonate and higher urinary pH. SSB/La antibodies were more prevalent in the dRTA groups (P < 0.05). Compared with NH4Cl, the positive and negative predictive values of FF were 46% and 82%, respectively. Vomiting occurred more often during the urinary acidification test with NH4Cl than with FF (9 vs 0, P < 0.05). Incomplete dRTA is common in pSS and causes mild acidaemia and higher urinary pH, which may contribute to bone demineralization and kidney stone formation. FF cannot replace NH4Cl in testing urinary acidification in pSS, but may be considered as a screening tool, given its reasonable negative predictive value and better tolerability.

ATP6V1B1 mutations in distal renal tubular acidosis and sensorineural hearing loss: clinical and genetic spectrum of five families

Distal renal tubular acidosis (DRTA) is characterized by tubular defects in urinary acidification and hyperchloremic metabolic acidosis, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis and nephrolithiasis. Mutations in ATP6V1B1 cause DRTA associated with sensorineural hearing loss. The objective of this multicenter study is to screen DRTA patients with sensorineural hearing loss for ATP6V1B1 gene mutations and present genotype/phenotype correlation. Clinical data in five unrelated consanguineous families with DRTA and hearing loss were obtained in Turkey. For mutation screening, all coding exons of ATP6V1B1 were PCR-amplified and sequenced from genomic DNA. In our cohort of five families, there were four different homozygous ATP6V1B1 mutations in affected individuals: c.91C>T (p.R31X), c.232G>A (p.G78R), c.497delC (p.T166RfsX9) and c.1155dupC (p.I386HfsX56). Our study shows that rare and family-specific variants in ATP6V1B1 are responsible for DRTA and sensorineural hearing loss syndrome in Turkey. While firm genotype–phenotype correlations are not available, detailed clinical and molecular analyses provide data to be used in genetic counseling.

Adaptor protein 1 complexes regulate intracellular trafficking of the kidney anion exchanger 1 in epithelial cells

Distal renal tubular acidosis (dRTA) can be caused by mutations in the gene encoding the anion exchanger 1 (AE1) and is characterized by defective urinary acidification, metabolic acidosis, and renal stones. AE1 is expressed at the basolateral membrane of type A intercalated cells in the renal cortical collecting duct (kAE1). Two dRTA mutations result in the carboxyl-terminal truncation of kAE1; in one case, the protein trafficked in a nonpolarized way in epithelial cells. A recent yeast two-hybrid assay showed that the carboxyl-terminal cytosolic domain of AE1 interacts with adaptor protein complex 1 (AP-1A) subunit μ1A (mu-1A; Sawasdee N, Junking M, Ngaojanlar P, Sukomon N, Ungsupravate D, Limjindaporn T, Akkarapatumwong V, Noisakran S, Yenchitsomanus PT. Biochem Biophys Res Commun 401: 85-91, 2010). Here, we show the interaction between kAE1 and mu-1A and B in vitro by reciprocal coimmunoprecipitation in epithelial cells and in vivo by coimmunoprecipitation from mouse kidney extract. When endogenous mu-1A (and to a lesser extent mu-1B) was reduced, kAE1 protein was unable to traffic to the plasma membrane and was rapidly degraded via a lysosomal pathway. Expression of either small interfering RNA-resistant mu-1A or mu-1B stabilized kAE1 in these cells. We also show that newly synthesized kAE1 does not traffic through recycling endosomes to the plasma membrane, suggesting that AP-1B, located in recycling endosomes, is not primarily involved in trafficking of newly synthesized kAE1 when AP-1A is present in the cells. Our data demonstrate that AP-1A regulates processing of the basolateral, polytopic membrane protein kAE1 to the cell surface and that both AP-1A and B adaptor complexes are required for normal kAE1 trafficking.

Renal function evaluation in patients with American Cutaneous Leishmaniasis after specific treatment with pentavalent antimonial

BackgroundRenal evaluation studies are rare in American Cutaneous Leishmaniasis (ACL). The aim of this study is to investigate whether specific treatment reverts ACL-associated renal dysfunction.MethodsA prospective study was conducted with 37 patients with ACL. Urinary concentrating and acidification ability was assessed before and after treatment with pentavalent antimonial.ResultsThe patients mean age was 35.6 ± 12 years and 19 were male. Before treatment, urinary concentrating defect (U/Posm <2.8) was identified in 27 patients (77%) and urinary acidification defect in 17 patients (46%). No significant glomerular dysfunction was observed before and after specific ACL treatment. There was no reversion of urinary concentrating defects, being observed in 77% of the patients before and in 88% after treatment (p = 0.344). Urinary acidification defect was corrected in 9 patients after treatment, reducing its prevalence from 40% before to only 16% after treament, (p = 0.012). Microalbuminuria higher than 30 mg/g was found in 35% of patients before treatment and in only 8% after treatment. Regarding fractional excretion of sodium, potassium, calcium, phosphorus and magnesium, there was no significant difference between pre and post-treatment period.ConclusionAs previously described, urinary concentrating and acidification defects were found in an important number of patients with ACL. Present results demonstrate that only some patients recover urinary acidification capacity, while no one returned to normal urinary concentration capacity.

Renal tubular dysfunction in patients with American cutaneous leishmaniasis

Renal dysfunction seen in patients with American cutaneous leishmaniasis (ACL) has been attributed to the use of antimonials for treatment. To determine whether ACL itself causes tubular dysfunction, we measured renal function in 37 patients with ACL prior to their treatment and compared results to that in 10 healthy volunteers of similar mean age. None of the patients presented with glomerular dysfunction; however, 27 had a urinary concentrating defect. There was no statistical difference between groups in the pre- and post-desmopressin test of urine osmolality, but the post-test urine osmolality of the controls was significantly higher. Urinary AQP2 levels, determined by western blot of isolated exosomes, were found to be significantly lower in patients than in controls, whereas that of the cotransporter (NKCC2) was significantly higher. A urinary acidification defect (post-test pH greater than 5.50 following calcium chloride) was found in 15 patients. Pretest plasma bicarbonate was below normal in 12 patients as was the pretest plasma pH in 14. Expression of the Na/H exchanger (NHE3), H(+)-ATPase, and pendrin were all significantly higher in patients with ACL than in controls. A combined urinary concentration and acidification defect was found in 12 patients. Thus, the urinary concentrating defect of ACL may be caused by decreased AQP2, with increased NKCC2 compensatory. Pendrin upregulation may be related to the urinary acidification defect with increased NHE3 and H(+)-ATPase also compensatory. Hence, ACL can cause asymptomatic renal tubular dysfunction.

Urinary pH and stone formation.

The formation of various types of kidney stones is strongly influenced by urinary pH. An alkaline pH favors the crystallization of calcium- and phosphate-containing stones, whereas and acidic urine pH promotes uric acid or cystine stones. The activity of many transport processes involved in calcium, citrate and phosphate handling are sensitive to changes in systemic or local pH as shown for several phosphate transporters, the citrate transporter NaDC1 and the TRPV5 calcium channel. Defects in urinary acidification (excretion of inappropriately alkaline or acidic urines, respectively) contribute to kidney stone disease. The low excretion of ammonium in patients with metabolic syndrome has been linked to more acidic urine and a higher incidence of uric acid stones. In this state, insulin resistance may reduce ammonium excretion by the proximal tubule. On the other hand, defensive mechanisms may protect from kidney stone formation in conditions such as hypercalciuria where high luminal calcium concentrations stimulate urinary acidification and reduce urinary concentration via a calcium-sensing receptor, resulting in the excretion of acidic and diluted urine. This review will discuss a few aspects that relate to the capacity of the kidney to regulate pH and its impact on the excretion of solutes that participate in the formation or prevention of stones.

A novel SLC4A1 variant in an autosomal dominant distal renal tubular acidosis family with a severe phenotype

Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger AE1, cause distal renal tubular acidosis (dRTA), a disease of defective urinary acidification by the distal nephron. We searched for SLC4A1 gene mutations in six patients from a Chinese family with a severe phenotype of dRTA (growth impairment, severe metabolic acidosis, with/or without gross nephrocalcinosis and renal impairment). All coding regions of kidney isoform of AE1, including intron-exon boundaries, were analyzed using PCR followed by direct sequence analysis. A novel 1-bp duplication at nucleotide 2713 (c.2713dupG, band 3 Qingdao) in exon 20 of SLC4A1 in this family was identified by direct sequencing analysis. This duplication alters the encoded protein through codon 905, and results in a reading frame for 15 extra condons (instead of 8) before the new stop condon at position 919 (p.Asp905Glyfs15). We suggest that RTA should be considered as a diagnostic possibility in adult subjects with nephrocalcinosis and chronic renal insufficiency, and family survey should be carefully performed.

A clinical study of renal tubular dysfunction in Cleistanthus collinus (Oduvanthalai) poisoning

Introduction. Self-poisoning through the ingestion of Oduvanthalai is common in South India. Mortality may occur because of arrhythmias, renal failure, shock, and respiratory distress. The mechanisms of toxicity are unclear. This prospective, clinical study was designed to assess renal tubular dysfunction because of Oduvanthalai poisoning. Methods. Thirty-two consecutive patients admitted with Oduvanthalai poisoning at a tertiary care hospital in South India, from June 2007 to August 2009 (26 months), were evaluated through history, physical examination, and laboratory studies. Following an interim analysis, additional studies of renal tubular function were performed on a subcohort of eight patients. These included the following: () urinary pH, daily serum, and urine anion gap; () 24-h urine protein and potassium; and () assessment of urine hexosaminidase and amino acid levels. Results. Metabolic acidosis (100%), which persisted at discharge (65.6%), hypokalemia (62.5%), and renal failure (15.6%), was apparent in the total cohort. Tests of renal tubular function on the subcohort revealed a normal anion gap, hyperchloremic, metabolic acidosis of renal etiology, defective urinary acidification, and hypokalemia with kaliuresis, indicative of distal renal tubular acidosis in six patients. Urinary hexosaminidase and amino acid levels, markers of proximal tubular dysfunction, were elevated in seven and two patients, respectively. Conclusions. Distal renal tubular acidosis is an important feature of Oduvanthalai poisoning. Proximal tubular injury and, in more severe forms, global tubular dysfunction with diminished glomerular filtration rate may occur.

Band 3 Edmonton I, a novel mutant of the anion exchanger 1 causing spherocytosis and distal renal tubular acidosis

dRTA (distal renal tubular acidosis) and HS (hereditary spherocytosis) are two diseases that can be caused by mutations in the gene encoding the AE1 (anion exchanger 1; Band 3). dRTA is characterized by defective urinary acidification, leading to metabolic acidosis, renal stones and failure to thrive. HS results in anaemia, which may require regular blood transfusions and splenectomy. Mutations in the gene encoding AE1 rarely cause both HS and dRTA. In the present paper, we describe a novel AE1 mutation, Band 3 Edmonton I, which causes dominant HS and recessive dRTA. The patient is a compound heterozygote with the new mutation C479W and the previously described mutation G701D. Red blood cells from the patient presented a reduced amount of AE1. Expression in a kidney cell line showed that kAE1 (kidney AE1) C479W is retained intracellularly. As kAE1 is a dimer, we performed co-expression studies and found that, in kidney cells, kAE1 C479W and G701D proteins traffic independently from each other despite their ability to form heterodimers. Therefore the patient carries one kAE1 mutant that is retained in the Golgi (G701D) and another kAE1 mutant (C479W) located in the endoplasmic reticulum of kidney cells, and is thus probably unable to reabsorb bicarbonate into the blood. We conclude that the C479W mutant is a novel trafficking mutant of AE1, which causes HS due to a decreased cell-surface AE1 protein and results in dRTA due to its intracellular retention in kidney.

Unilateral Ureteral Obstruction Alters Expression of Acid-Base Transporters in Rat Kidney

Unilateral ureteral obstruction is a common clinical problem that is often associated with a urinary acidification defect caused by decreased net H(+) secretion and/or HCO(3)(-) reabsorption. To clarify the molecular mechanisms of these defects we examined expression levels of key acid-base transporters along the renal nephron segments and collecting duct. Wistar rats (Møllegard Breeding Centre, Eiby, Denmark) underwent 24-hour unilateral ureteral obstruction, unilateral ureteral obstruction release followed for 4 days or unilateral ureteral obstruction release followed for 4 days plus experimental acidosis induced by NH(4)Cl oral administration. After sacrifice kidneys were processed for immunoblotting and immunohistochemistry. Semiquantitative immunoblotting revealed that unilateral ureteral obstruction caused significant mean +/- SE down-regulation of type 3 Na(+)/H(+) exchanger to 53% +/- 9%, electrogenic Na(+)/HCO(3)(-) cotransporter to 60% +/- 9%, type 1 bumetanide sensitive Na(+)-K(+)(NH(4)(+)) -2Cl(-) cotransporter to 64% +/- 7%, electroneutral Na(+)/HCO(3)(-) cotransporter to 43% +/- 4% and anion exchanger (pendrin) to 53% +/- 10% in the obstructed kidney, which was confirmed by immunohistochemistry. After release of unilateral ureteral obstruction down-regulation of these transporters persisted together with marked down-regulation of H(+)-adenosine triphosphatase in the obstructed kidney. In rats with unilateral ureteral obstruction release followed for 4 days with experimental acidosis induced by NH(4)Cl oral administration plasma pH and HCO(3)(-) were dramatically decreased in response to NH(4)Cl for 2 days compared with those in sham operated rats with acid loading, indicating a defect in H(+) excretion and HCO(3)(-) reabsorption after obstruction release. Expression of these transporters did not change in the contralateral nonobstructed kidney of rats with unilateral ureteral obstruction and unilateral ureteral obstruction release followed for 4 days. The expression of renal acid-base transporters is markedly decreased in the obstructed kidney, which may be responsible for the contribution of impaired renal H(+) excretion and HCO(3)(-) reabsorption to the urinary acidification defect in response to unilateral ureteral obstruction.

A 42-Year-Old Woman With Flaccid Paralysis

A 42-Year-Old Woman With Flaccid Paralysis

Reduction of renal triglyceride accumulation: effects on proximal tubule Na+/H+exchange and urinary acidification

One main pathophysiological mechanism underlying the increased risk for uric acid nephrolithiasis in humans with the metabolic syndrome is the excretion of unduly acidic urine, in part because of reduced excretion of the main urinary buffer, ammonium. The Zucker diabetic fatty (ZDF) rat, an established rodent model of the metabolic syndrome, has similar urinary abnormalities, attributed in part to lower expression and activity of the principal mediator of proximal tubule ammonium excretion, brush-border membrane Na+/H+ exchanger 3 (NHE3). These defects are associated with renal tubular steatosis in ZDF rats, but the causal relationship between renal steatosis and defective urinary acidification has not been investigated in vivo. We hypothesized that reduction of renal steatosis would commensurately normalize urinary acidification parameters. We treated ZDF rats with thiazolidinediones to reduce nonadipose tissue steatosis. Four weeks of treatment reduced renal triglyceride accumulation and restored urinary acidification parameters in ZDF rats to levels comparable to their lean littermates; urinary acidification was not affected by treatment in lean rats. To further document the direct effects of fat, we showed that functional abnormalities induced by fat loading in a cell culture model of proximal tubule steatosis and lipotoxicity can be reversed by fat removal but not by thiazolidinediones alone. Together, these findings support the causative role of renal steatosis in the pathogenesis of urinary acidification defects, demonstrate reversibility upon lipid removal, and highlight a potential therapeutic strategy for renal abnormalities in the metabolic syndrome.

Age dependent protein expression of renal acid‐base transporters in rats with congenital ureter obstruction

To clarify the molecular mechanisms of urinary acidification defects in response to congenital partial unilateral ureteral obstruction (PUUO) new born male Wistar rats were subjected to PUUO within the first 24‐48 hours of life to mimic the congenital ureteral obstruction, and were observed for 7 and 14 weeks. PUUO rats were challenged by acid loading with NH4Cl given by gavage for 2 days before termination. Semiquantitative immunoblotting revealed that the abundance of renal acid‐base transporters NHE3, NBC1, NBCn1, pendrin and Na+‐K+‐ATPase were increased in both obstructed and non‐obstructed kidneys 7 weeks after induction of neonatal PUUO. This was confirmed by immunocytochemistry. In contrast, 14 weeks of PUUO caused a reduction in the abundance of NBC1, NBCn1 and Na+‐K+‐ATPase in the obstructed kidney. Consistent with this the plasma pH and HCO3 could maintain normal in PUUO 7 week rats, but dramatically reduced in PUUO 14 week rats under the acid loading. These time/age dependent changes in protein expression were associated with parallel changes in the renal ability to acidify urine in response to acid loading. In conclusion the study demonstrated that 1) the reduction protein abundance of renal acid‐base transporters is time/age dependent in response to PUUO and 2) impairment of urine acidification develops gradually in parallel with the changes in protein expression in response to partial obstruction induced neonatally.