Lipopolysaccharide directly inhibits bicarbonate absorption by the renal outer medullary collecting duct.

Acidosis is associated with E. coli induced pyelonephritis but whether bacterial cell wall constituents inhibit HCO3 transport in the outer medullary collecting duct from the inner stripe (OMCDi) is not known. We examined the effect of lipopolysaccharide (LPS), on HCO3 absorption in isolated perfused rabbit OMCDi. LPS caused a ~ 40% decrease in HCO3 absorption, providing a mechanism for E. coli pyelonephritis-induced acidosis. Monophosphoryl lipid A (MPLA), a detoxified TLR4 agonist, and Wortmannin, a phosphoinositide 3-kinase inhibitor, prevented the LPS-mediated decrease, demonstrating the role of TLR4-PI3-kinase signaling and providing proof-of-concept for therapeutic interventions aimed at ameliorating OMCDi dysfunction and pyelonephritis-induced acidosis.

Primary Sjögren syndrome-associated acute interstitial nephritis and type 3 renal tubular acidosis in a patient with thin basement membrane nephropathy: A case report.

INTRODUCTION: The kidney is one of the common extraglandular sites involved in primary Sjögren syndrome (pSS), with chronic tubulointerstitial nephritis (TIN) the most common pathology type. Renal involvement in pSS often presents as chronic TIN accompanied by type 1 or 2 renal tubular acidosis (RTA). Description of renal involvement as acute TIN with type III RTA in pSS has been rarely reported. PATIENT CONCERNS: A 37-year-old woman was admitted with complaints of dry mouth, dry eyes, and progressive muscle weakness for 17 months. Two months before admission, the patient had a blood potassium level of 1.7 mmol/L. DIAGNOSIS: Further tests confirmed pSS and type III RTA. Renal biopsy demonstrated acute TIN and thin basement membrane nephropathy (TBMN). INTERVENTIONS: Full-dose corticosteroid (1 mg/kg/day) and cyclophosphamide (100 mg/day) were applied. OUTCOMES: The creatinine levels of the patient decreased 0.28 mg/dL (1.18-0.90 mg/dL) during 3-month follow-up. CONCLUSIONS: We reported a patient with pSS-associated kidney injury, presenting as acute TIN with type 3 RTA and TBMN. This case increases the awareness of a rare manifestation of pSS-associated kidney injury. In pSS-associated acute TIN, cyclophosphamide combined with full-dose corticosteroids may achieve good outcomes.

Evaluation of phenotypic and genotypic features of children with distal kidney tubular acidosis.

BACKGROUND: The present study aimed to assess genotype-phenotype correlations with long-term prognosis in children with distal kidney tubular acidosis (dKTA). The kidney function of children with dKTA could be impaired in the long-term. METHODS: Thirty-one children with dKTA from 23 families were included in the present study. Demographic features, growth parameters, clinical manifestations, follow-up results, and genetic analysis results of the patients were recorded. RESULTS: Eighteen children (58.1%) were male. The median age at diagnosis was 3 months. The median follow-up period was 77 months and the longest was 23.5 years. Eight (28.8%) patients had chronic kidney disease (CKD) stage 2 or 3. Three patients aged 24, 23, and 19 years had CKD stage 3 with an estimated glomerular filtration rate of 54, 57, and 48 mL/min/1.73 m2, respectively. Thirteen patients had mutations in the ATP6V0A4 gene, eight had mutations in the ATP6V1B1 gene, and three had mutations in the SLC4A1 gene. There was no significant correlation between molecular diagnosis and CKD. Growth retardation with a height below a standard deviation (SD) score of - 2 was found in 14 patients (45.1%) at the time of diagnosis. The mean height SD score at the last visit was significantly higher in patients who had adequate metabolic control at > 75% of all visits as compared with that in patients who did not. CONCLUSION: Patients with dKTA usually have a good clinical prognosis in childhood with appropriate treatment; however, dRTA is characterized by deterioration of kidney function in adulthood, particularly after puberty.

The natural history of solitary post-nephrectomy kidney in a pediatric population.

INTRODUCTION: Children with a solitary post-nephrectomy kidney (SNK) are at potential risk of developing kidney disease later in life. In response to the global decline in the number of nephrons, adaptive mechanisms lead to renal injury. The aim of this study was to determine the prevalence and time of onset of high blood pressure (HBP), proteinuria, glomerular filtration rate (GFR) disruption and renal tubular acidosis (RTA) in children with SNK. MATERIALS AND METHODS: After obtaining the approval from our institution's ethics committee, we reviewed the medical records of patients under 18 years of age who underwent unilateral nephrectomy between January 2005 and December 2015 in three university hospitals. RESULTS: We identifi ed 43 patients, 35 (81.4%) cases of unilateral nephrectomy (UNP) were due to a non-oncologic pathology and Wilm's tumor was identified in 8 (18.6%) cases. In patients with non-oncologic disease, 9.3% developed de novo hypertension, with an average time of onset of 7.1 years, 25% developed proteinuria de novo, with an average time of onset of 2.2 years. For GFR, 21.8% presented deterioration of the GFR in an average time of 3.4 years. Ten (43.5%) patients developed some type of de novo renal injury after UNP. Patients with oncolo-gic disease developed the conditions slowly and none of them developed proteinuria. CONCLUSIONS: Taking into account the high rate of long term postoperative renal injury, it can be considered that nephrectomy does not prevent this disease. The follow-up of children with SNK requires a multidisciplinary approach and long-term surveillance to detect renal injury.

The natural history of solitary post-nephrectomy kidney in a pediatric population

ABSTRACT Introduction: Children with a solitary post-nephrectomy kidney (SNK) are at potential risk of developing kidney disease later in life. In response to the global decline in the number of nephrons, adaptive mechanisms lead to renal injury. The aim of this study was to determine the prevalence and time of onset of high blood pressure (HBP), proteinuria, glomerular filtration rate (GFR) disruption and renal tubular acidosis (RTA) in children with SNK. Materials and methods: After obtaining the approval from our institution's ethics committee, we reviewed the medical records of patients under 18 years of age who underwent unilateral nephrectomy between January 2005 and December 2015 in three university hospitals. Results: We identified 43 patients, 35 (81.4%) cases of unilateral nephrectomy (UNP) were due to a non-oncologic pathology and Wilm's tumor was identified in 8 (18.6%) cases. In patients with non-oncologic disease, 9.3% developed de novo hypertension, with an average time of onset of 7.1 years, 25% developed proteinuria de novo, with an average time of onset of 2.2 years. For GFR, 21.8% presented deterioration of the GFR in an average time of 3.4 years. Ten (43.5%) patients developed some type of de novo renal injury after UNP. Patients with oncologic disease developed the conditions slowly and none of them developed proteinuria. Conclusions: Taking into account the high rate of long term postoperative renal injury, it can be considered that nephrectomy does not prevent this disease. The follow-up of children with SNK requires a multidisciplinary approach and long-term surveillance to detect renal injury.

Molecular Pathophysiology of Acid-Base Disorders.

Acid-base balance is critical for normal life. Acute and chronic disturbances impact cellular energy metabolism, endocrine signaling, ion channel activity, neuronal activity, and cardiovascular functions such as cardiac contractility and vascular blood flow. Maintenance and adaptation of acid-base homeostasis are mostly controlled by respiration and kidney. The kidney contributes to acid-base balance by reabsorbing filtered bicarbonate, regenerating bicarbonate through ammoniagenesis and generation of protons, and by excreting acid. This review focuses on acid-base disorders caused by renal processes, both inherited and acquired. Distinct rare inherited monogenic diseases affecting acid-base handling in the proximal tubule and collecting duct have been identified. In the proximal tubule, mutations of solute carrier 4A4 (SLC4A4) (electrogenic Na+/HCO3--cotransporter Na+/bicarbonate cotransporter e1 [NBCe1]) and other genes such as CLCN5 (Cl-/H+-antiporter), SLC2A2 (GLUT2 glucose transporter), or EHHADH (enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase) causing more generalized proximal tubule dysfunction can cause proximal renal tubular acidosis resulting from bicarbonate wasting and reduced ammoniagenesis. Mutations in adenosine triphosphate ATP6V1 (B1 H+-ATPase subunit), ATPV0A4 (a4 H+-ATPase subunit), SLC4A1 (anion exchanger 1), and FOXI1 (forkhead transcription factor) cause distal renal tubular acidosis type I. Carbonic anhydrase II mutations affect several nephron segments and give rise to a mixed proximal and distal phenotype. Finally, mutations in genes affecting aldosterone synthesis, signaling, or downstream targets can lead to hyperkalemic variants of renal tubular acidosis (type IV). More common forms of renal acidosis are found in patients with advanced stages of chronic kidney disease and are owing, at least in part, to a reduced capacity for ammoniagenesis.

[Distal hereditary renal tubular acidosis, diagnosis in siblings: About 2 pediatric cases]. / Acidosis tubular renal distal hereditaria, diagnóstico en hermanos: A propósito de 2 casos pediátricos.

Distal renal tubular acidosis is the most common type of renal tubular acidosis in pediatrics and can be hereditary. It is due to an inability in the kidney to excrete hydrogen ion (H+), in the absence of deterioration of renal function, and it is accompanied by hyperchloremic metabolic acidosis with normal anion gap. The symptoms can be growth retardation, vomiting, constipation, lack of appetite, polydipsia and polyuria, nephrocalcinosis, weakness and even muscle paralysis due to hypokalemia. It is often accompanied by sensorineural hearing impairment. Correcting acidosis can have a variety of benefits such as restoring normal growth, decreasing hypokalemia, stabilizing or preventing nephrocalcinosis and decreasing the risk of osteopenia. Timely diagnosis and adequate treatment of patients make them remain asymptomatic and able to lead a good quality of life. We present the cases of two siblings affected by distal renal tubular acidosis, its diagnostic process, treatment and current follow-up.

La acidosis tubular renal distal es el tipo más frecuente de acidosis tubular renal en pediatría y puede ser hereditario. Se debe a una incapacidad del riñón para excretar iones de hidrógeno, en ausencia de deterioro de la función renal, y ocurre con acidosis metabólica hiperclorémica con brecha aniónica (anion gap) normal. Los síntomas pueden ser retraso del crecimiento, vómitos, estreñimiento, falta de apetito, polidipsia y poliuria, nefrocalcinosis, debilidad y hasta parálisis muscular por la hipokalemia. A menudo, se acompaña de deterioro auditivo neurosensorial. Corregir la acidosis puede tener una variedad de beneficios, como restaurar el crecimiento normal, disminuir la hipokalemia, estabilizar o evitar la nefrocalcinosis y disminuir el riesgo de osteopenia. El diagnóstico oportuno y el tratamiento adecuado de los pacientes hacen que permanezcan asintomáticos y sean capaces de llevar una buena calidad de vida. Se presentan los casos de dos hermanos afectados por acidosis tubular renal distal, su proceso diagnóstico, tratamiento y seguimiento actual.

Extrarenal Signs of Proximal Renal Tubular Acidosis Persist in Nonacidemic Nbce1b/c-Null Mice.

BACKGROUND: The SLC4A4 gene encodes electrogenic sodium bicarbonate cotransporter 1 (NBCe1). Inheritance of recessive mutations in SLC4A4 causes proximal renal tubular acidosis (pRTA), a disease characterized by metabolic acidosis, growth retardation, ocular abnormalities, and often dental abnormalities. Mouse models of pRTA exhibit acidemia, corneal edema, weak dental enamel, impacted colons, nutritional defects, and a general failure to thrive, rarely surviving beyond weaning. Alkali therapy remains the preferred treatment for pRTA, but it is unclear which nonrenal signs are secondary to acidemia and which are a direct consequence of NBCe1 loss from nonrenal sites (such as the eye and enamel organ) and therefore require separate therapy. SLC4A4 encodes three major NBCe1 variants: NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A is expressed in proximal tubule epithelia; its dysfunction causes the plasma bicarbonate insufficiency that underlies acidemia. NBCe1-B and NBCe1-C exhibit a broad extra-proximal-tubular distribution. METHODS: To explore the consequences of Nbce1b/c loss in the absence of acidemia, we engineered a novel strain of Nbce1b/c-null mice and assessed them for signs of pRTA. RESULTS: Nbce1b/c-null mice have normal blood pH, but exhibit increased mortality, growth retardation, corneal edema, and tooth enamel defects. CONCLUSIONS: The correction of pRTA-related acidemia should not be considered a panacea for all signs of pRTA. The phenotype of Nbce1b/c-null mice highlights the physiologic importance of NBCe1 variants expressed beyond the proximal tubular epithelia and potential limitations of pH correction by alkali therapy in pRTA. It also suggests a novel genetic locus for corneal dystrophy and enamel hypomineralization without acidemia.

Distal renal tubular acidosis: genetic causes and management.

BACKGROUND: Distal renal tubular acidosis (dRTA) is a kidney tubulopathy that causes a state of normal anion gap metabolic acidosis due to impairment of urine acidification. This review aims to summarize the etiology, pathophysiology, clinical findings, diagnosis and therapeutic approach of dRTA, with emphasis on genetic causes of dRTA. DATA SOURCES: Literature reviews and original research articles from databases, including PubMed and Google Scholar. Manual searching was performed to identify additional studies about dRTA. RESULTS: dRTA is characterized as the dysfunction of the distal urinary acidification, leading to metabolic acidosis. In pediatric patients, the most frequent etiology of dRTA is the genetic alteration of genes responsible for the codification of distal tubule channels, whereas, in adult patients, dRTA is more commonly secondary to autoimmune diseases, use of medications and uropathies. Patients with dRTA exhibit failure to thrive and important laboratory alterations, which are used to define the diagnosis. The oral alkali and potassium supplementation can correct the biochemical defects, improve clinical manifestations and avoid nephrolithiasis and nephrocalcinosis. CONCLUSIONS: dRTA is a multifactorial disease leading to several clinical manifestations. Clinical and laboratory alterations can be corrected by alkali replacement therapy.

Distal renal tubular acidosis and severe hypokalemia: a case report and review of the literature.

BACKGROUND: Distal renal tubular acidosis is a relatively infrequent condition with complex pathophysiology that can present with life-threatening electrolyte abnormalities. CASE PRESENTATION: We describe a case of a 57-year-old Caucasian woman with previous episodes of hypokalemia, severe muscle weakness, and fatigue. Upon further questioning, symptoms of dry eye and dry mouth became evident. Initial evaluation revealed hyperchloremic metabolic acidosis, severe hypokalemia, persistent alkaline urine, and a positive urinary anion gap, suggestive of distal renal tubular acidosis. Additional laboratory workup and renal biopsy led to the diagnosis of primary Sjögren's syndrome with associated acute tubulointerstitial nephritis. After potassium and bicarbonate supplementation, immunomodulatory therapy with hydroxychloroquine, azathioprine, and prednisone was started. Nonetheless, her renal function failed to improve and remained steady with an estimated glomerular filtration rate of 42 ml/min/1.73 m2. The literature on this topic was reviewed. CONCLUSIONS: Cases of renal tubular acidosis should be carefully evaluated to prevent adverse complications, uncover a potentially treatable condition, and prevent the progression to chronic kidney disease. Repeated episodes of unexplained hypokalemia could be an important clue for diagnosis.

Renal Tubular Acidosis.

Renal tubular acidosis should be suspected in poorly thriving young children with hyperchloremic and hypokalemic normal anion gap metabolic acidosis, with/without syndromic features. Further workup is needed to determine the type of renal tubular acidosis and the presumed etiopathogenesis, which informs treatment choices and prognosis. The risk of nephrolithiasis and calcinosis is linked to the presence (proximal renal tubular acidosis, negligible stone risk) or absence (distal renal tubular acidosis, high stone risk) of urine citrate excretion. New formulations of slow-release alkali and potassium combination supplements are being tested that are expected to simplify treatment and lead to sustained acidosis correction.

A physiology-based approach to a patient with hyperkalemic renal tubular acidosis / Abordagem diagnóstica de um paciente com acidose tubular renal hipercalêmica

ABSTRACT Hyperkalemic renal tubular acidosis is a non-anion gap metabolic acidosis that invariably indicates an abnormality in potassium, ammonium, and hydrogen ion secretion. In clinical practice, it is usually attributed to real or apparent hypoaldosteronism caused by diseases or drug toxicity. We describe a 54-year-old liver transplant patient that was admitted with flaccid muscle weakness associated with plasma potassium level of 9.25 mEq/L. Additional investigation revealed type 4 renal tubular acidosis and marked hypomagnesemia with high fractional excretion of magnesium. Relevant past medical history included a recent diagnosis of Paracoccidioidomycosis, a systemic fungal infection that is endemic in some parts of South America, and his outpatient medications contained trimethoprim-sulfamethoxazole, tacrolimus, and propranolol. In the present acid-base and electrolyte case study, we discuss a clinical approach for the diagnosis of hyperkalemic renal tubular acidosis and review the pathophysiology of this disorder.

RESUMO A acidose tubular renal hipercalêmica é uma acidose metabólica de ânion gap normal que invariavelmente indica anormalidade na secreção de íons potássio, amônio e hidrogênio. Na prática clínica, está geralmente atribuída a um estado de hipoaldosteronismo real ou aparente, causado por doenças ou toxicidade por drogas. Descrevemos um paciente de 54 anos, transplantado hepático, que foi admitido com fraqueza muscular associada à hipercalemia, potássio plasmático de 9,25 mEq/L. A investigação adicional revelou acidose tubular renal tipo 4 e importante hipomagnesemia com elevada fração de excreção de magnésio. A história patológica pregressa incluía um diagnóstico recente de Paracoccidioidomicose - uma infecção sistêmica fúngica endêmica que ocorre em algumas partes da América do Sul -, e as medicações de uso habitual continham sulfametoxazol-trimetoprim, tacrolimus e propranolol. No presente relato de caso, discutiremos uma abordagem clínico-laboratorial para o diagnóstico da acidose tubular renal hipercalêmica, assim como da hipomagnesemia, revisando a fisiopatologia desses transtornos.

Distal renal tubular acidosis secondary to vesico-ureteric reflux: A case report with review of literature.

Vesicoureteric reflux (VUR) is the most common congenital anomaly of the urinary tract that occurs in 30%-50% of children presenting with recurrent urinary tract infections. Long-standing untreated VUR results in renal scarring and hydronephrotic changes ultimately leading to chronic renal failure and arterial hypertension. However, it may also result in diffuse tubulopathy compromising the concentrating capacity of tubules and urinary acidification defects. Renal tubular dysfunction should be considered in all children with VUR presenting with failure to thrive, rickets, bony deformity/pain, hypokalemia, and metabolic acidosis. We report such a case of a 16-year-old male adolescent who presented with rickets, failure to gain weight and height, bony pains, and muscle weakness with a history of VUR. On investigation, he was found to have normal anion gap metabolic acidosis with hypokalemia suggestive of distal renal tubular acidosis. He responded well to oral alkali and potassium replacement therapy.

Hypokalemic Distal Renal Tubular Acidosis.

Distal renal tubular acidosis (DRTA) is defined as hyperchloremic, non-anion gap metabolic acidosis with impaired urinary acid excretion in the presence of a normal or moderately reduced glomerular filtration rate. Failure in urinary acid excretion results from reduced H+ secretion by intercalated cells in the distal nephron. This results in decreased excretion of NH4+ and other acids collectively referred as titratable acids while urine pH is typically above 5.5 in the face of systemic acidosis. The clinical phenotype in patients with DRTA is characterized by stunted growth with bone abnormalities in children as well as nephrocalcinosis and nephrolithiasis that develop as the consequence of hypercalciuria, hypocitraturia, and relatively alkaline urine. Hypokalemia is a striking finding that accounts for muscle weakness and requires continued treatment together with alkali-based therapies. This review will focus on the mechanisms responsible for impaired acid excretion and urinary potassium wastage, the clinical features, and diagnostic approaches of hypokalemic DRTA, both inherited and acquired.

Hyperkalemic Forms of Renal Tubular Acidosis: Clinical and Pathophysiological Aspects.

In contrast to distal type I or classic renal tubular acidosis (RTA) that is associated with hypokalemia, hyperkalemic forms of RTA also occur usually in the setting of mild-to-moderate CKD. Two pathogenic types of hyperkalemic metabolic acidosis are frequently encountered in adults with underlying CKD. One type, which corresponds to some extent to the animal model of selective aldosterone deficiency (SAD) created experimentally by adrenalectomy and glucocorticoid replacement, is manifested in humans by low plasma and urinary aldosterone levels, reduced ammonium excretion, and preserved ability to lower urine pH below 5.5. This type of hyperkalemic RTA is also referred to as type IV RTA. It should be noted that the mere deficiency of aldosterone when glomerular filtration rate is completely normal only causes a modest decline in plasma bicarbonate which emphasizes the importance of reduced glomerular filtration rate in the development of the hyperchloremic metabolic acidosis associated with SAD. Another type of hyperkalemic RTA distinctive from SAD in which plasma aldosterone is not reduced is referred to as hyperkalemic distal renal tubular acidosis because urine pH cannot be reduced despite acidemia or after provocative tests aimed at increasing sodium-dependent distal acidification such as the administration of sodium sulfate or loop diuretics with or without concurrent mineralocorticoid administration. This type of hyperkalemic RTA (also referred to as voltage-dependent distal renal tubular acidosis) has been best described in patients with obstructive uropathy and resembles the impairment in both hydrogen ion and potassium secretion that are induced experimentally by urinary tract obstruction and when sodium transport in the cortical collecting tubule is blocked by amiloride.

Renal Tubular Acidosis: H+/Base and Ammonia Transport Abnormalities and Clinical Syndromes.

Renal tubular acidosis (RTA) represents a group of diseases characterized by (1) a normal anion gap metabolic acidosis; (2) abnormalities in renal HCO3- absorption or new renal HCO3- generation; (3) changes in renal NH4+, Ca2+, K+, and H2O homeostasis; and (4) extrarenal manifestations that provide etiologic diagnostic clues. The focus of this review is to give a general overview of the pathogenesis of the various clinical syndromes causing RTA with a particular emphasis on type I (hypokalemic distal RTA) and type II (proximal) RTA while reviewing their pathogenesis from a physiological "bottom-up" approach. In addition, the factors involved in the generation of metabolic acidosis in both type I and II RTA are reviewed highlighting the importance of altered renal ammonia production/partitioning and new HCO3- generation. Our understanding of the underlying tubular transport and extrarenal abnormalities has significantly improved since the first recognition of RTA as a clinical entity because of significant advances in clinical acid-base chemistry, whole tubule and single-cell H+/base transport, and the molecular characterization of the various transporters and channels that are functionally affected in patients with RTA. Despite these advances, additional studies are needed to address the underlying mechanisms involved in hypokalemia, altered ammonia production/partitioning, hypercalciuria, nephrocalcinosis, cystic abnormalities, and CKD progression in these patients.

Renal involvement in primary Sjogren's syndrome: a prospective cohort study.

The objective of the study is to prospectively evaluate the spectrum of clinical and subclinical renal involvement in patients with primary Sjogren's syndrome (pSS). Of the 174 patients screened, seventy patients with pSS underwent renal function tests, urine examination, renal ultrasound, arterial blood gases, urine pH followed by urine acidification test and renal biopsy (if indicated). Renal tubular acidosis (RTA) was treated with alkali replacement and moderate-severe tubulointerstitial nephritis (TIN) was treated with oral prednisolone. Sixty-two patients completed 1-year follow-up. A comparison was made between patients with and without renal involvement. Thirty-five (50%) patients had renal involvement. They had a lower baseline eGFR (71.85 ± 18.04 vs. 83.8 ± 17, p = 0.005). Twenty-nine patients had RTA (25 complete and 4 incomplete). Eleven patients had urinary abnormalities. Patients with RTA (n = 29) were younger (34.9 ± 9 vs. 42 ± 11.3, p = 0.006), had fewer articular (34% vs. 78%, p = 0.001) and ocular sicca (62% vs. 88%, P = 0.01) than those without RTA (n = 41) and commonly presented with hypokalemic paralysis. On biopsy, TIN (9/17) and IgA nephropathy (3/17) were most common. On follow-up, there was no clinically significant change in eGFR; however, one patient with renal calculi and incomplete distal renal tubular acidosis (dRTA) progressed to complete dRTA. Two patients treated with steroids had marginal improvement in eGFR. Renal involvement in pSS is under-recognized with the most common manifestation being RTA presenting with hypokalemic paralysis. These patients are younger with less articular and sicca symptoms. Subclinical RTA may progress to complete RTA. Renal biopsy should be considered in all patients with renal involvement.