Renal Tubular Acidosis Syndromes

, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock

South Med J. 2000;93(11) 

In This Article

Distal Renal Tubular Acidosis

Although described earlier, distal renal tubular acidosis (dRTA) was recognized as a distinct entity by Albright et al[3] in 1946. The clinical syndrome described consisted of hypokalemia, hyperchloremic metabolic acidosis, inability to lower urine pH below 5.5, nephrocalcinosis, and nephrolithiasis. Additional features included osteomalacia or rickets. The syndrome was designated "distal renal tubular acidosis," since the establishment of a large pH gradient between urine and blood is a function of the distal nephron.

Originally, dRTA was thought to have a single pathogenesis. The prevailing view was that the disorder resulted from an inability to generate or maintain a steep hydrogen ion gradient across the distal nephron rather than from failure to secrete protons. This hypothesis was offered because maximal reabsorptive capacity for bicarbonate during bicarbonate loading is either normal or increased in patients with this syndrome. Since proton secretion is thought to be the mechanism responsible for bicarbonate reabsorption, hydrogen ion secretion in the distal nephron was considered to be intact. Furthermore, titratable acid excretion in these patients increased during sodium phosphate administration, which also indicated intact distal proton secretory capacity. Accordingly, dRTA often was referred to as "gradient RTA." However, the expansion of knowledge of the control of distal urinary acidification, new methods to evaluate urinary acidification, and the development of a number of experimental models of dRTA have enlarged and modified our understanding of the pathogenesis of this syndrome.

Pathogenesis of Distal Renal Tubular Acidosis

As stated earlier, the distal convoluted tubule and the collecting tubule reclaim about 15% of filtered bicarbonate, lower the urine pH to its final value, and titrate most of the nonbicarbonate urinary buffers. In the cortical collecting tubule (CCT), acidification is indirectly coupled to sodium transport and is influenced by transepithelial voltage. Active sodium reabsorption in this nephron segment generates a negative electrical potential difference, which facilitates the active secretion of protons. Aldosterone increases this transepithelial voltage and hence CCT acidification. Acidification in the medullary collecting tubule (MCT) is not influenced by sodium transport and occurs against an electrical gradient. The potential difference in this nephron segment is lumen-positive, most likely the result of active proton secretion. The absolute magnitude of proton secretion is greater in the MCT than in the CCT.

Hydrogen ion secretion is mediated by two proton pumps located in the intercalated cells, an H+-ATPase and an H+,K+-ATPase. The H+-ATPase is regulated by aldosterone, while the H+,K+-ATPase responds inversely to the serum potassium level. In the lumen, the secreted hydrogen ions combine with ammonia and other buffers and are excreted in urine.

Distal RTA can occur because of the following defects:

 

  • Impaired proton pump function

    • Defective H+,K+-ATPase (classic hypokalemic dRTA) or

    • Defective H+-ATPase (normokalemic dRTA),

  • Decreased potential difference in CCT (or "voltage-dependent" dRTA),

  • Aldosterone deficiency (or resistance),

  • Decreased capacity to maintain steep pH gradients (or "backleak" dRTA),

  • Rate-dependent dRTA, or

  • Abnormal anion exchange.

 

Each of these defects has been identified in humans or in experimental animals.

Distal Renal Tubular Acidosis With Hypokalemia

Classic Distal Renal Tubular Acidosis. Classic dRTA is a syndrome of hypokalemia, hyperchloremic metabolic acidosis, inability to lower the urine pH below 5.5, nephrocalcinosis and nephrolithiasis, and osteomalacia or renal rickets. The clinical spectrum of dRTA is broad; no single pathogenetic mechanism exists ( Table 2 ). Part of the difficulty in determining such mechanisms relates to the lack of suitable animal models for study (except in the case of toxic nephropathy caused by amphotericin B and possibly toluene), though new insights with transgenic animals and carbonic anhydrase isoform deficiency appear to be emerging.

The measurement of urinary PCO 2 is useful in categorizing acidification defects.[4] The test is done after bicarbonate infusion. When the urine is rich in bicarbonate, it has a PCO 2 usually 40 mm Hg greater than that of blood. This PCO 2 gradient is generated by the distal secretion of protons. Carbonic anhydrase is not present on the luminal membrane of the distal nephron. The H 2 CO 3 formed by H++HCO 3 decomposes to CO 2 slowly, resulting in a high urinary PCO 2 . Thus, defects in acidification resulting from decreased proton secretion are associated with low urinary PCO 2 . Defects arising from other mechanisms are associated with a normal PCO 2 .

A reduced urine PCO 2 in patients with classic dRTA indicates that an impairment of proton secretion, rather than increased backleak of protons, is the cause of the defective acidification. In addition, most patients with classic dRTA fail to have lower urine pH after administration of sodium sulfate, further supporting the presence of impaired distal hydrogen ion secretion. Studies in amphotericin-treated rats, a model of gradient dRTA, show an intact capacity to generate urinary CO 2 .[5]

The discovery of a renal H+,K+-ATPase provided new insight into the basic defect of classic dRTA.[6] The failure of H+,K+-ATPase leads to both an acidification defect and urinary potassium loss, and hence, causes hypokalemic hyperchloremic metabolic acidosis with all the features associated with classic dRTA. Reports from northeastern Thailand showing large numbers of patients with hypokalemic dRTA and achlorhydria suggest possible defects in tissue H+,K+-ATPases.[7] Those affected include not only humans but also water buffaloes, suggesting an environmental inhibitor of the H+,K+-ATPase pump as a cause of this syndrome. In animal experiments, long-term administration of sodium orthovanadate to potassium-replete rats caused hypokalemic dRTA, with a urine pH of greater than 6 and a vanishingly low fractional bicarbonate excretion.[8] Collecting tubule H+,K+-ATPase activity is markedly decreased in the animals, while H+-ATPase activity appears normal.

Immunocytochemical study of a kidney biopsy specimen from a patient with Sjogren's syndrome who had dRTA showed no H+-ATPase staining in the collecting tubule intercalated cells (H+,K+-ATPase staining was not done).[9] Current studies are hampered, since we are just now identifying which isoforms of the H+,K+-ATPase are found in collecting duct tissue. Evidence to date suggests at least two isoforms are present in the distal nephron -- one similar to the colonic H+,K+-ATPase and one apparently unique to the kidney. Further studies will doubtless be forthcoming to clarify this issue.

Hypokalemia and potassium wasting are consistent findings in classic dRTA, however, although the underlying mechanisms are not well-understood. This may be in part a consequence of elevated levels of aldosterone commonly seen during acidosis. Metabolic acidosis results in decreased proximal sodium reabsorption, increased distal delivery of sodium, and, hence, increased kaliuresis. Thus, the sodium wastage causes extracellular volume contraction and secondary hyperaldosteronism. Amelioration of hypokalemia usually occurs after correction of the acidosis with bicarbonate therapy, but the reason for this reduction is not clear. Another explanation for the distal potassium wastage may be that an electrical void is created as a consequence of absent H+-ATPase proton secretion. Since the positively charged protons would not be secreted into the tubular lumen, a more negative transepithelial potential difference could be generated as sodium reabsorption would proceed. Thus, potassium secretion would rise passively in response to this steeper electrical gradient.

The inability to secrete protons in the collecting tubule in patients with classic dRTA results in a severe limitation of the titration of nonbicarbonate buffers (ie, phosphate and ammonia) in the urine and, hence, a marked reduction in net acid excretion (titratable acid + ammonia - bicarbonate). This occurs even when an adequate supply of appropriate luminal buffers is present and ammonia production is normal. In contradistinction to proximal RTA, impaired net acid excretion persists despite severe metabolic acidosis.

Positive hydrogen ion balance and relentless acid retention inevitably develop and rapidly exhaust extracellular buffers. Blood pH can then be defended only by tapping another source of buffer, the skeleton, which is the only pool big enough to serve this need. Accordingly, basic calcium salts are continually mobilized from bone. Furthermore, metabolic acidosis suppresses proximal and distal calcium reabsorption by decreasing apical calcium entry. The clinical sequelae are hypercalciuria, nephrocalcinosis, and osteomalacia or renal rickets. Nephrocalcinosis can occur in patients with dRTA without hypercalciuria. The simultaneous reduction in urinary citrate levels during metabolic acidosis and the persistently alkaline urine enhance the development of nephrocalcinosis. Growth retardation and failure to thrive are predominant clinical features in infants and children.

Since the ability of proximal tubule to reclaim filtered bicarbonate is intact, only a slight degree of bicarbonaturia (fractional bicarbonate excretion less than 5%) is detected in adult patients with classic dRTA. However, infants with dRTA may have significant bicarbonate wasting, a condition previously known as type 3 RTA and now recognized as a variant of classic dRTA.

"Backleak" Distal Renal Tubular Acidosis. Amphotericin B therapy is the usual cause of this syndrome. It is easily recognized by the history of amphotericin therapy in patients with hypokalemic dRTA. These patients can be differentiated from other patients with hypokalemic dRTA by the presence of normal urine-plasma PCO 2 gradients. Recently, a few patients with this syndrome who never took amphotericin have been described.[10] They appear to have a spontaneous defect in maintaining sharp pH gradients in the distal nephron.

Evaluation and Treatment of Classic Hypokalemic Distal Renal Tubular Acidosis. Since normal anion gap hyperchloremic metabolic acidosis is a feature in patients with classic dRTA, diagnosis begins with a history and physical examination to rule out other conditions ( Table 3 ). The laboratory evaluation should be initiated with the examination of the urine. If the acidosis is the result of an extrarenal disorder, such as diarrhea, the urine will be rich in ammonium. This can easily be disclosed by measuring the urinary electrolytes. There will be considerably more chloride than sodium (plus potassium), usually more than 50 mEq/L. In other words, the anion gap will be minus 50 or more. The missing cation is ammonium. Patients with dRTA or related syndromes typically have more cation than chloride in the urine when they are acidemic, indicating reduced ammonium excretion and, hence, defective acidification. Once the diagnosis of an RTA syndrome has been made, the urinary anion gap has no further use, since it is abnormal in all RTA syndromes.

The next step is to categorize patients according to serum potassium -- those with a low (or normal) serum potassium and those in whom it is elevated (Fig 2). The first group can be further subdivided into those patients in whom the urine pH can be lowered below 5.5 and those in whom it cannot. When proximal RTA has been excluded by measuring fractional bicarbonate excretion at a serum HCO 2 greater than 20 mmol/L, distal RTA can be diagnosed with certainty in those whose urine pH is greater than 5.5 at an acid systemic pH. Patients in whom urine pH can be lowered below 5.5 and in whom a proximal lesion has been ruled out can then be given sodium bicarbonate intravenously; if the urine PCO 2 fails to rise normally, the diagnosis of rate-dependent dRTA can be made.

Clinical approach to classification of renal tubular acidosis (RTA) in patients with normal or low plasma potassium; proximal or distal RTA may be present.

Long-term treatment of classic dRTA requires alkali administration equivalent to the sum of endogenous acid production and amount of accompanying bicarbonate wastage. In general, total replacement therapy needed is 1 to 2 mEq/kg daily. Greater amounts are required in children because of the need for base deposition in growing bone and because bicarbonate wastage in children may be greater than in adults. Maintenance of alkali therapy for an indefinite period is necessary. Correction of acidosis will generally ameliorate potassium wasting and hypokalemia. Also, there is an improvement in hypercalciuria; an increase in citrate excretion occurs, which decreases the incidence of nephrocalcinosis and nephrolithiasis.

In children, alkali therapy will allow normal growth and amelioration of hypokalemia, proximal myopathy, polyuria, and listlessness. Alkali administration and glucocorticoid therapy result in improvement in the diminished lacrimal and salivary secretions in Sjogren's syndrome associated with dRTA. Without appropriate therapy, life-threatening systemic acidosis (plasma bicarbonate less than 5 mEq/L) may occur and require emergency intervention, including intravenous bicarbonate and potassium replacement and even respiratory support.

Distal Renal Tubular Acidosis With Normokalemia

Metabolic acidosis develops during renal failure; this occurs when the glomerular filtration rate (GFR) has fallen to about 20% to 30% of normal. This acidosis is the result of reduced nephron mass, and not the consequence of defective proton secretion. In patients with interstitial renal disease, however, a normokalemic form of dRTA may develop, which we have tentatively ascribed to an isolated failure of the H+-ATPase.[11] In these patients, in contradistinction to those with the acidosis of chronic renal failure, the ability to lower urine pH during acidemia and raise urine PCO 2 is not present. An identical form of normokalemic dRTA is seen in patients with chronic transplant rejection and, indeed, may be the first sign of rejection.[12]

Rate-Dependent Distal Renal Tubular Acidosis. A small subset of patients with decreased renal function have a subtle defect in distal urinary acidification. In these patients, the ability to raise urine PCO 2 in response to bicarbonate loading is not present, but in all other respects the ability to acidify the urine appears normal. They typically do not have metabolic acidosis. This particular defect is designated as rate-dependent dRTA. The definition of "incomplete" dRTA could be broadened to include these patients (ie, those without overt acidosis in whom the urine PCO 2 can be raised but in whom urine pH cannot be lowered). The urine PCO 2 reflects the rate of distal acidification; thus, a moderate decrease in that rate might be reflected only by decreased urine PCO 2 . Only a handful of patients with this disorder have been described and whether the defect is of more than marginal clinical importance is uncertain. The syndrome may represent an early stage of one of the other forms of dRTA that ultimately progresses to an overt state.

Defective Anion Exchange. A recently described form of dRTA is believed to be caused by a genetic defect in the distal Cl/HCO 3 exchanger (AE1).[13,14] It has been proposed that dRTA results from insertion of the AE1 into the apical membrane of the tubule instead of the basolateral membrane.[14] This defect would result in secretion of HCO 3 into the lumen of the collecting duct and in titration of the protons secreted by the two apical proton transporters to CO 2 and water. Hyperchloremic metabolic acidosis would ensue. These patients, unlike those with dRTA, should have a normal urinary PCO 2 during HCO 3 loading. They also should be normokalemic, which would distinguish them from patients with a backleak defect.

Patients with hereditary ovalocytosis have a mutation of the red blood cell AE1. They typically do not have defective urinary acidification, but occasionally patients with the disease have been reported to have dRTA. A recent report described one such patient in whom acidosis was associated with a normal urine minus blood PCO 2 .[15] This patient, however, was also hypokalemic. It is not clear whether the defect was due to an abnormal AE1 or to a coexisting backleak defect. As mentioned earlier, backleak defects usually occur after amphotericin therapy but can occur spontaneously.

Incomplete Distal Renal Tubular Acidosis. In some patients with classic dRTA, the systemic acid-base parameters can be maintained at normal levels in the unstressed state. Acid loading in these patients discloses an inability to acidify the urine maximally. These patients have the incomplete type of dRTA. They often have a normal pH response to sodium sulfate administration.

Distal Renal Tubular Acidosis With Hyperkalemia

The CCT actively reabsorbs sodium via an aldosterone-dependent mechanism. Electrogenic sodium reabsorption is accompanied by passive chloride reabsorption and secretion of potassium. The negative intraluminal potential difference generated by sodium reabsorption facilitates active proton secretion by the H+-ATPase. In both the CCT and the MCT, aldosterone stimulates this pump directly, as well. Impairment of CCT sodium transport suppresses secretion of potassium and hydrogen; if the H+-ATPase is also inhibited in the MCT, hyperkalemic hyperchloremic metabolic acidosis will ensue. Such disorders include aldosterone deficiency or resistance (known as type 4 RTA) and voltage-dependent RTA ( Table 4 ).

Aldosterone Deficiency. Aldosterone deficiency is the most frequently seen form of hyperkalemic metabolic acidosis in adults. Although originally described more than 40 years ago, the syndrome of isolated aldosterone deficiency has been recognized with regularity only during the past two decades.[16,17] It is much more common than Addison's disease, in which both glucocorticoid and mineralocorticoid deficiency are combined.

Aldosterone deficiency would be expected to cause both voltage-dependent acidosis and proton secretory failure. In humans and experimental animals with aldosterone-deficiency, however, the ability to generate pH gradient between blood and urine is relatively normal, but the rate of net acid excretion is reduced. Patients with this syndrome can lower urine pH below 5.5, have a normal urine PCO 2 in an alkaline urine, and a normal response to phosphate and sulfate infusion. The rate of titratable acid appears to be normal, whereas urinary ammonium and potassium excretion in response to sodium sulfate infusion is reduced. The decreased ammonia production and excretion likely occurs due to hyperkalemia. When hyperkalemia is treated by cation exchange resins or dietary potassium restriction, ammonia production and excretion rise. Net acid excretion is not completely corrected, however, disclosing a defect in hydrogen ion secretion. In the absence of aldosterone, H+-ATPase activity should markedly fall, while H+,K+-ATPase activity should be unaffected. However, the ensuing hyperkalemia will directly decrease H+,K+-ATPase activity. Correcting hyperkalemia without giving aldosterone should only partially correct acidosis.

Diabetes, tubulointerstitial nephropathy, and nephrocalcinosis are common causes of this disorder. Mild to moderate renal insufficiency is generally a persistent finding. Metabolic acidosis and elevation in potassium concentration are disproportionate for the decline in GFR. Decreased renin activity, which is common, cannot completely explain this syndrome since hyperkalemia, per se, should stimulate aldosterone release. Thus, failure of the zona glomerulosa to respond to hyperkalemia appropriately seems to be an integral feature of this disease.

Treatment of this disorder rarely requires mineralocorticoid replacement. Such therapy may, in fact, result in edema formation and even precipitate congestive heart failure. Furosemide administration can lower plasma potassium and enhance distal hydrogen ion secretion, provided that salt is not restricted from the diet while the diuretic is administered. Dietary potassium should be reduced and potassium exchange resin given if necessary.

Aldosterone Resistance or Pseudohypoaldosteronism. Every endocrine deficiency disease has a corresponding resistance state. The features of the aldosterone resistance are the same as those of aldosterone deficiency except aldosterone levels in the former are normal or increased. In patients with aldosterone deficiency or resistance, the ability to lower urine pH normally is present, but it is not in patients with voltage-dependent dRTA. There are at least two forms of aldosterone resistance: with or without salt wasting.

Aldosterone resistance in children is associated with profound salt wastage greatly in excess of that seen in adults.[18] The difference may be attributable, at least in part, to the normal GFR present in children. The disease results from hyporesponsiveness of the distal tubule to aldosterone. Therapy in this group includes salt supplement, NaHCO 3 , and either potassium restriction or ion exchange resins. Aldosterone resistance without salt wasting occurs in adults and manifests as salt retention rather than wastage. These patients usually have chronic renal disease, and the acidosis is usually mild. Mineralocorticoid administration fails to increase potassium excretion even when coupled with intravenous infusion of sodium chloride. However, infusion of sodium sulfate results in a normal increase in urinary potassium excretion.[19]

Another form of this disorder results from an inability to generate a negative potential difference in the lumen of the distal nephron as a result of increased permeability of the distal nephron to chloride, that is, a "chloride shunt."[20] Increased chloride reabsorption cause NaCl retention and suppression of the renin-aldosterone axis. The combination of the low transepithelial potential difference and hypoaldosteronism results in decreased potassium secretion, hyperkalemia, and reduced ammonia production, which leads to decreased net acid excretion, and hence, acidosis. These patients can be effectively treated with salt restriction and thiazide diuretics.

Voltage-Dependent Distal Renal Tubular Acidosis. The defect responsible for voltage-dependent dRTA originally was thought to be the loss of the lumen-negative potential difference in the CCT, which in turn leads to reduced hydrogen and potassium secretion.[21] The features of this syndrome are hyperkalemic hyperchloremic metabolic acidosis, salt wastage (detectable only with marked salt restriction), normal or increased plasma aldosterone, urine pH greater than 5.5, low urine PCO 2 with bicarbonate loading, and abnormal response to sulfate or furosemide administration. Urinary tract obstruction and the effects of amiloride and lithium administration are prototypic conditions causing voltage-dependent dRTA.[22,23,24] There are, however, major differences among these conditions. Urinary tract obstruction and amiloride administration are associated with hyperkalemia and the inability to lower urine pH below 5.5 after sulfate administration. Lithium administration, however, is not accompanied by hyperkalemia, while the ability to lower urine pH below 5.5 after sulfate administration is preserved. Furthermore, lithium has a greater propensity than amiloride to cause systemic acidosis. Recent studies of renal ATPase activities provide more insight into the pathogenesis of these syndromes.

After 24 hours of unilateral ureteral obstruction, Na+,K+-ATPase activity is depressed along the entire nephron.[25] H+-ATPase activity is decreased slightly in the CCT and markedly in the MCT. H+,K+-ATPase activity is increased in the CCT and decreased in the MCT. Long-term administration of amiloride results in decreased Na+,K+-ATPase activity in both the CCT and the MCT, decreased H+-ATPase activity only in the CCT, and unchanged collecting tubule H+,K+-ATPase activity.[23,24] After long-term lithium therapy, Na+,K+-ATPase activity is depressed in both the CCT and the MCT, and activities of H+-ATPase and H+,K+-ATPase are decreased only in the CCT.

Thus, it appears that besides the effect on potential difference by inhibiting Na+,K+-ATPase activities, these prototypes of voltage-dependent dRTA also influence renal proton pumps. In 24-hour unilateral ureteral obstruction, the enhanced CCT H+,K+-ATPase activity likely mitigates the reduced acid secretion caused by decreased H+-ATPase activity at this site. Thus, the overall acidification defect observed in unilateral ureteral obstruction appears due to impaired MCT proton transport. The potassium retention observed in acute unilateral ureteral obstruction is due to both decreased potassium secretion by reduced Na+,K+-ATPase activity and increased potassium reabsorption via the H+,K+-ATPase, both in the CCT.

With regard to lithium, the inhibitory effect of lithium on both H+-ATPase and H+,K+-ATPase might explain the metabolic acidosis found in this model. The decreased H+,K+-ATPase activity likely mitigates reduced potassium excretion caused by decreased Na+,K+-ATPase activity and prevents hyperkalemia. Amiloride inhibits H+-ATPase but not H+,K+-ATPase, which likely explains its modest effect on acid-base composition. Intact potassium reabsorption (H+,K+-ATPase activity is normal) and the failure of potassium secretion (Na+,K+-ATPase activity is decreased) leads to decreased potassium excretion and hyperkalemia.

Evaluation and Treatment of Hyperkalemic Distal Renal Tubular Acidosis. Since normal anion gap hyperchloremic metabolic acidosis is also a feature in patients with hyperkalemic dRTA, the diagnosis begins with a history and physical examination and an assessment of the features of the acidosis ( Table 3 ). Since diabetes mellitus with hyporeninemic hypoaldosteronism and urinary tract obstruction are two diseases commonly encountered in medicine, they should be easy to rule out. Addison's disease should also be considered, and patients taking long-term, low-dose heparin (or its analogues) should be tested for isolated aldosterone deficiency or adrenal hemorrhage.

Cases of hyperkalemia should also be categorized on the basis of urine pH. In patients with a pH below 5.5, normal plasma cortisol combined with a low aldosterone value establishes the diagnosis of selective aldosterone deficiency (Fig 3). Since hyperkalemia stimulates aldosterone release, plasma aldosterone values cannot be interpreted accurately without reference to serum potassium concentration. When potassium concentration is elevated, the plasma aldosterone concentration should be at least three times higher. Thus, an aldosterone value of 15 ng/mL, while ostensibly normal, is low for a patient with a potassium concentration of 6 mEq/L. If both cortisol and aldosterone measurements are low, the patient has Addison's disease. The finding of a normal or high aldosterone concentration suggests aldosterone resistance. In patients with hyperkalemia and a urine pH persistently greater than 5.5, the diagnosis of hyperkalemic or voltage-dependent dRTA is made without further evaluation, but one should look for a specific cause, such as obstructive uropathy or a sickle hemoglobinopathy.

Figure 3.

Clinical approach to classification of distal renal tubular acidosis in patients with hyperkalemia.

Because of the pattern of plasma aldosterone and urine pH seen in patients with aldosterone deficiency, aldosterone resistance, voltage-dependent dRTA, and the combination of aldosterone deficiency and RTA, patients with the combined disorder are easily distinguished from those with the other disorders ( Table 5 ). High urine pH indicates dRTA, and low plasma aldosterone discloses the steroid deficiency.

In summary, the patient with hyperchloremic metabolic acidosis may have a diagnosis as simple as diarrhea ( Table 3 ) or one as complex as voltage-dependent dRTA. Unraveling the diagnosis and understanding the pathophysiology is not only a rewarding exercise, but also it reinforces the basic concepts of acid-base physiology. Appropriate therapy may then be prescribed, with particular attention paid to the long-term adverse consequences of metabolic acidosis.

Read before the Section on Medicine, 93rd Annual Scientific Assembly, Southern Medical Association, Dallas, Tex, November 10-14, 1999.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....