Autoimmune polyglandular syndrome type I can have significant kidney disease in children including recurrence in renal allograft - a report of two cases.

BACKGROUND: Autoimmune polyglandular syndrome type 1 (APS 1) is an autosomal recessive disorder characterized by immune injury of multiple organ systems (primarily endocrine) secondary to a mutation in the autoimmune regulator (AIRE) gene. In some cases, patients develop tubulointerstitial nephritis (TIN) and progress to end-stage renal failure (ESRD). CASE DIAGNOSIS/TREATMENT: We describe two patients with APS 1 and TIN. In both cases, TIN was clinically silent and the diagnosis was confirmed by renal biopsy. In one patient, renal function remained stable with immunosuppressive therapy. A second patient progressed to ESRD despite treatment, and received a deceased donor allograft. TIN recurred in the transplanted kidney and was reversed successfully with rituximab. Severe, recurrent esophageal candidiasis also resolved. CONCLUSION: TIN is an important complication of APS 1 that may result in ESRD, and may recur in the transplanted kidney. TIN may be under-recognized, as the presentation is unapparent clinically and urinalysis remains normal. Immunosuppressive therapy may be effective and, therefore, routine monitoring of renal function is warranted in asymptomatic individuals.

Autosomal dominant pseudohypoaldosteronism type 1: mechanisms, evidence for neonatal lethality, and phenotypic expression in adults.

Autosomal dominant pseudohypoaldosteronism type 1 (adPHA1) is a rare condition that is characterized by renal resistance to aldosterone, with salt wasting, hyperkalemia, and metabolic acidosis. It is thought of as a mild disorder; affected children's symptoms respond promptly to salt therapy, and treatment is not required after childhood. Mutations in the mineralocorticoid receptor gene (MR) cause adPHA1, but the long-term consequences of MR deficiency in humans are not known. Herein are described six novel adPHA1-causing MR mutations (four de novo) and evidence that haploinsufficiency of MR is sufficient to cause adPHA1. Furthermore, genotype-phenotype correlation is reported in a large adPHA1 kindred. A number of cases of neonatal mortality in infants who were at risk for adPHA1 were identified; coupled with the frequent identification of de novo mutations in affected individuals, this suggests that the seemingly benign adPHA1 may have been a fatal neonatal disorder in previous eras, preventing propagation of disease alleles. In contrast, it is shown that adult patients with adPHA1 are clinically indistinguishable from their wild-type relatives except for presumably lifelong elevation of renin, angiotensin II, and aldosterone levels. These data highlight the critical role of MR in the maintenance of salt homeostasis early in life and illuminate the sodium dependence of pathologic effects of renin and angiotensin II. They furthermore argue that nongenomic effects of aldosterone play no significant role in the long-term development of cardiovascular disease.

The anion gap (AG): studies in the nephrotic syndrome and diabetic ketoacidosis (DKA).

Although "unmeasured" anions contribute to metabolic acidosis in a variety of disease states, they are generally not measured directly but estimated from the calculation of "gaps." Among the most commonly used method, the anion gap (AG) is not only a function of "unmeasured" anions, but also it is a function of plasma non-carbonate buffers (albumin and phosphate), the plasma pH, and the method of measurement. To clarify the contribution of non-carbonate buffers to the AG, the Figge-Fencl-Waston model of human plasma was applied to laboratory values obtained from two novel populations, patients with nephrotic syndrome and patients with diabetic ketoacidosis (DKA). The model performed adequately, justifying the common clinical practice of correcting the AG for the net protein charge.

An analysis of renal tubular acidosis by the Stewart method.

Renal tubular acidosis (RTA) comprises a group of disorders characterized by a low capacity for net acid excretion and persistent hyperchloremic, metabolic acidosis. To investigate the role of chloride, we performed hypotonic (0.45%) saline-loading experiments in 12 children with alkali-treated distal RTA (dRTA) and compared the results with data obtained from 17 healthy control subjects. In patients, but not in controls, saline loading induced both hyperchloremia and metabolic acidosis. Hyperchloremia was associated with high total and high distal fractional reabsorption of chloride [C(H20)/(C(H20)+C(Cl))]. The increase in plasma chloride varied inversely with the fractional excretion of chloride (C(Cl)) and correlated with the decrease in blood pH. However, the urinary excretion of bicarbonate did not correlate with either changes in blood pH or plasma bicarbonate concentration. Our findings suggest that the mechanism of hyperchloremia was enhanced Cl(-)/HCO(3) (-) exchange by the distal tubule. The resulting metabolic acidosis is better explained by changes in the strong ion difference (the Stewart theory) than by changes in the urine bicarbonate excretion (the traditional theory).

Bench-to-bedside review: Fundamental principles of acid-base physiology.

Complex acid-base disorders arise frequently in critically ill patients, especially in those with multiorgan failure. In order to diagnose and treat these disorders better, some intensivists have abandoned traditional theories in favor of revisionist models of acid-base balance. With claimed superiority over the traditional approach, the new methods have rekindled debate over the fundamental principles of acid-base physiology. In order to shed light on this controversy, we review the derivation and application of new models of acid-base balance.

Stewart and beyond: new models of acid-base balance.

The Henderson-Hasselbalch equation and the base excess have been used traditionally to describe the acid-base balance of the blood. In 1981, Stewart proposed a new model of acid-base balance based upon three variables, the "strong ion difference" (SID), the total weak acids (ATot), and the partial pressure of carbon dioxide (Pco2). Over 20 years later, Stewart's physiochemical model still remains largely unknown. In this review, we will present both the traditional and the Stewart models of acid-base balance and then derive each using an "ion equilibrium method." Modern theories of acid-base balance may be useful toward the understanding of complex acid-base disorders.