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Uremic Acidosis

Uremic Acidosis

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Kidney International, Vol. 34 (1988), pp. 278—287 FORUM

Uremic

Principal discussant: DAVID G. WARNOCK

San Francisco Veterans Administration Medical center, San Francisco, california

mg/dl; and , 145 mg/dl. Urinalysis revealed a specific gravity of 1.010; pH 6.0; trace ; occasional white cells; and no red Editors blood cells, casts, or crystals. A 12-hour collection disclosed 638 JORDAN J. COHEN mg of and a creatinine of 13 mI/mm. The patient had dialysis twice via a subclavian catheter, and an JOHN T. HARRINGTON arteriovenous fistula was constructed. All antihypertensive medications JEROME P. KA55IRER were discontinued and the patient was discharged on a regimen of NIcoLAos E. MADIA5 furosemide, aluminum hydroxide, and allopurinol. Despite discontinuation of and carbonate, the patient's calcium remained above 10 mg/dl. The serum PTH level Managing Editor was 4200 dEq/ml when the serum calcium was 10.3 mg/dl. Some CHERYL J. ZU5MAN suppression of the serum PTH level was obtained (to 2400 pJEq/ml) when the serum calcium was raised to 11 mg/dl, but this decrease was followed by rebound of the PTH to the previous level. Subperiosteal University of Chicago Pritzker School of Medicine resorption was not seen on radiographs of the hands, but a sonogram of the neck revealed 2 large (2 x 1.5 cm), solid, cystic parathyroid masses. and A subtotal parathyroidectomy (3.5 glands) therefore was performed. At Tufts University School of Medicine the time of surgery, arterial blood gas measurements revealed a pH of 7.38, PaCO2 of 35 mm Hg, and a plasma of 20.4 mEq/liter. Since surgery, the serum calcium level has remained below 10 mg/dl, and renal function has stabilized with a creatinine clearance of 18 mI/mm. The total co2 stabilized at 22 mEq/liter while the patient was taking furosemide, aluminum hydroxide, and allopurinol. Repeated Case presentation measurement of the PTH level was 800 lEq/ml. The most recent evaluation revealed a creatinine clearance of 14 ml/min; , 144 A 62-year-old male with a 22-year history of albuminuria and pro- mEg/liter; , 5.2 mEg/liter; , 107 mEg/liter; gressive renal insufficiency was admitted to the hospital for placement dioxide, 22 mEg/liter; , 15 mEg/liter; calcium, 9.0 mg/dl; of a vascular access preparatory to dialysis. The left had been , 4.6 mg/dl; BUN, 74 mg/dl; and creatinine, 5.9 mg/dl. found to be hypoplastic when was first noted. The causes of his renal failure were presumed to be chronic glomerulonephritis and hypertension. The patient complained of nocturnal pruritis at the time of admission but no other symptoms. Discussion The medical history was otherwise unremarkable except for several episodes of acute gout. Medications being taken prior to admission Da. DAVtD G. WARNOCK (Chief, Nephrology Section, San included minoxidil, furosemide, metoprolol, allopurinol, calcitriol, alu- Francisco Veterans Administration Medical Center, and Pro- minum hydroxide, and calcium carbonate. Physical examination revealed a blood pressure of 96/60 mm Hg; fessor of Medicine and Pharmacology, University of Califor- pulse, 98 beats/mm; respiratory rate, 20/mm; and oral temperature, nia, San Francisco, California): The patient presented today 94°F. The sclerae were pale and anicteric, and the pupils were equally has clearly established chronic renal insufficiency and surgically reactive. The fundi revealed arteriovenous nicking but no hemorrhages proved diffuse hyperparathyroidism. Although the exact cause or exudates. The chest was clear, cardiac examination revealed an S4 gallop but no murmurs or rubs. The jugular venous pressure was normal of renal insufficiency has not been documented, it is notable and peripheral edema was not present. The abdomen revealed nothat his course has stabilized since he had a subtotal parathy- organomegaly, tenderness, or masses. Guaiac test of the stool wasroidectomy 1.5 years ago. At the time of surgery, determina- negative, and the neurologic examination was unremarkable. Several tions of arterial blood gases documented a mild metabolic excoriated areas were present on the arms and back. Laboratory studies showed a hematocrit of 30.5%; white blood acidosis with appropriate respiratory adaptation, despite ad- count, 8900 mm3 with a normal differential; platelet count, 177,000 vanced renal insufficiency with a creatinine clearance of 13 mm3; BUN, 108 mg/dl; creatinine, 6.8 mg/dl; sodium, 141 mEq/liter; ml/min. For the purposes of our discussion of uremic acidosis, potassium, 3.0 mEq/liter; chloride, 106 mEq/liter; carbon dioxide, 24the questions we need to address include: (1) What is uremic mEg/liter; anion gap, 11 mEg/liter; calcium, 11.0 mg/dl; phosphate, 4,8acidosis? (2) What are the pathophysiologic processes that cause acidosis to develop in the setting of chronic renal insuf- Presentation of the Forum is made possible by grants from Pfizer;ficiency? (3) What are the renal and extrarenal adaptations to Incorporated; Merck Sharp & Dohme; Sandoz, Incorporated; and E. R. chronic renal insufficiency that defend -base ? Squibb & Sons, Incorporated. The case presentation is instructive, particularly if we ask why © 1988 by the International Society of Nephrology acidosis was so mild in this patient.

278 Nephrology Forum: Uremic acidosis 279

Clinical features of uremnic acidosis ganic-acid anions that have not been completely oxidized) with their daily production, just as they are not able to excrete the Chronic progressive renal disease usually results in somedaily endogenous acid load [2]; the retention of these acid degree of systemic acidosis when the glomerular rateanions and hydrogen generates the so-called anion-gap is reduced to 25 mllmin or less [1]. Metabolic acid productionmetabolic acidosis characteristic of [10]. generally is not increased in patients with chronic renal insuf- ficiency [2]; therefore the development of acidosis reflects an Patho genesis of uremic acidosis impairment in the renal acidification mechanisms [3] as well as If serum bicarbonate levels in uremic patients are raised some limitations in the renal homeostatic responses to acidosis.towards normal, the urine pH rises and the already reduced Reduced bicarbonate [4] and impaired ammoniarenal net acid excretion falls further. At times, overt production [5] are thought to be the underlying disturbances inbicarbonaturia occurs [4]. In the absence of bicarbonate sup- the renal acidification process characteristic of uremic acidosis.plementation, however, the urine pH usually is less than 5.4. Hyperchloremic can develop early in theThis finding suggests that the ability of the distal to course of renal disease but the acidosis "converts" to anacidify the urine (that is, maintain a normal pH gradient) is anion-gap form when the glomerular filtration rate falls below 20intact in chronic renal failure. Furthermore, the capacity of the mLfmin [6]. Hyperchloremic metabolic acidosis, well describeddistal nephron's proton secretory systems to respond to an in patients with tubulointerstitial disease [3, 6], also has beenincrease in buffer delivery (such as that following administra- seen in patients with primary glomerular disease [7]. One of thetion of a phosphate load) is also well maintained (reviewed in classic studies analyzing metabolic acidosis in patients withRef. 11). There is an important distinction, however, between chronic renal insufficiency was done here at the New Englandsimple acidification of the urine and renal net acid excretion Medical Center. In a retrospective analysis of 138 ambulatory(defined as the sum of excretion and titratable acid patients with stable renal function, Widmer, Gerhardt, Har-minus the excretion of bicarbonate). Unlike patients with distal rington, and Cohen examined the relationships between serumrenal tubular acidosis, in whom the primary acidification defect and renal function, as assessed by serum creatinineresides in the distal proton secretory mechanisms, patients with measurements [7]. The study excluded patients with vomiting,chronic renal insufficiency appear to have impaired renal net , or volume depletion and those who had receivedacid excretion because of inadequate or inappropriate delivery diuretics, alkali, steroids, potassium-exchange resins, or antac-of buffer to the distal nephron acidification sites. I will now ids. Patients also were excluded who had , oraddress the defects in the renal excretion of ammonium and who had undergone adrenalectomy or parathyroidectomy. Ob-reabsorption of bicarbonate, which are the central factors viously these patients were highly selected; many of the pa-responsible for the development of acidosis in chronic renal tients in a typical renal clinic would not meet these criteria, butinsufficiency. the goal of the investigators was to determine the relationship Ammonium excretion. A major factor in the limitation of between the various serum electrolytes and renal function in therenal net acid excretion in chronic renal insufficiency is inade- steady state. The final analysis included 41 patients who werequate renal ammonium excretion. Although there is an adaptive 16 to 73 years old. There were 25 men and 16 women; 18 hadincrease in renal ammonia production by the remaining neph- glomerular disease, 16 had tubulointerstitial disease, and 7rons, this adaptation is not sufficient to meet the requirement patients had renal insufficiency of unknown cause. An anion-for excretion of daily metabolic acid production; thus, despite gap acidosis was found in patients whose glomerular filtrationadaptation, an absolute decrease in overall renal ammonia rate fell below 20 mI/mm and whose serum creatinine concen-production eventually ensues [1]. Because renal ammonia pro- trations were greater than 4 mg/dl. Somewhat surprisingly,duction can normally increase four- or fivefold, this limitation when the serum creatinine was less elevated (that is, in theonly becomes evident when the glomerular filtration rate falls range of 2 to 4 mg/dl), there was a slight increase in the serumbelow approximately 20% of normal. In the normal rat, most of chloride level (c=5mEq/liter)and a parallel decrease (of =6the ammonia produced by the nephron enters the tubular fluid mEq/liter) in the serum bicarbonate concentration; that is, ain the early (Fig. 1; open bars), but approxi- mild hyperchloremic metabolic acidosis was present. Thesemately one-third of that secreted in the early segments is mild changes in serum electrolytes were found in patients withabsorbed in the late proximal tubule [12]. In chronic metabolic all forms of chronic renal disease and were not markers foracidosis (induced by the administration of NH4C1), the ammo- tubulointerstitial disease. In addition, relative hyperkalemiania secretory process is stimulated, ammonia entry into the was uniformly noted in the patients with moderate renal insuf-early proximal tubule increases, and ammonia is secreted ficiency [7]. Hyporeninemic has been well(rather than absorbed) in the late proximal tubule (Fig. 1; described in patients with moderate renal insufficiency [8], andhatched bars). Buerkert and colleagues examined the ammo- one might be tempted to implicate it in the pathogenesis of thenium excretory response in an animal model of chronic renal associated mild metabolic acidosis. Yet the development ofinsufficiency, the five-sixths renal ablation model [13]. As Table hyperchloremic metabolic acidosis in the patients with moder-1 shows, in this model of chronic renal insufficiency the ate renal insufficiency (serum creatinine levels between 2 and 4glomerular filtration rate is reduced more than 50%, and meta- mg/dl) appears to have been too uniform to be explained bybolic acidosis develops with a systemic pH of approximately insufficiency [91. The development of an anion-gap7.30. Just as in humans with chronic renal insufficiency, the metabolic acidosis in advanced renal insufficiency indicates thaturine pH in these rats is acidic during the systemic acidosis. the surviving are not able to match the daily excretionDespite the excretion of an acid urine, systemic acidosis of "acid anions" (mostly , phosphate, and various or-developed in the rats with the remnant kidney in association 280 Nephrology Forum: Uremic acidosis

4 Table 1. Ammonium excretion in the remnant kidneya Early pci Late pci Absorption Remnant 2 Control GFR (ml/min) 1.37 0.11 0.52 0.06 0 Blood pH 7.37 0.01 7.31 0.02 Urine pH 5.51 0.21 5.51 0.06 —2 Ammonium excretionb 0.87 0.08 0.50 0.05 Net acid excretio&' 1.22 0.11 0.80 0.08 Total ammonia —4 * Data transport rate, from Ref. 13. bUnitsare nEq/min. pmol/min —6

—8 Table 2. Renal handling of ammonium and bicarbonate in the remnant kidney* —10 Control Remnant —12 Secretion End proximal delivery 18 2 666 —14 Ammonium (pmol/min) * HC03 (pmol/min) 54 7 134 20 End distal delivery Fig. 1. Ammonia transport along the proximal tubule. Net rates of Ammonium (pmol/min) 11 2 296 ammonia secretion (negative values) or absorption are shown at early HC03 (pmol/min) 9 7 59 20 and late proximal tubule sites. These data were obtained in micropunc- ture experiments in normal rats (open bars), and in rats made chroni- a Datafrom Ref. 13. cally acidotic with administration of ; *= P<0.01. (Reproduced by permission of the Journal of Clinical Investigation [12].) insufficiency coupled with metabolic acidosis is consistent with the changes observed in metabolic acidosis alone (Fig. 1) [12]. In the control rats (Table 2), ammonium delivery out of the with a reduction in renal net acid excretion from 1.22 to 0.80distal tubule decreased (from 18 pmollmin to 11 pmollmin), due nEq/min. The acid urine results from the relative lack ofto absorption in the intervening loop of Henle. Although available buffer in the urine. Note that renal ammonium excre-evidence existed for ammonia absorption in the loop in the tion fell from 0.87 to 0.50 nEq/min; this reduction in ammoniumremnant kidney studies, the delivery of ammonium out of the excretion can fully account for the fall in net acid excretion [131.late distal tubule was higher in the remnant kidneys than in the Another facet of the abnormalities in renal ammonia produc-controls (29 pmol/min versus 11 pmol/min). These findings tion in chronic renal insufficiency was studied by Tizinello andshould be compared with the whole-kidney measurements from coworkers [14]. They found that ammonia production wasthe same study, which showed an absolute decrease in renal increased fourfold in humans with chronic renal insufficiencyammonium excretion (Table 1) [13]. If the accessible late distal when corrected for reduced glomerular filtration rate. In con-tubule samples are representative of the whole kidney, these trast, glutamine extraction by the kidneys, measured by aPe-results suggest that ammonia absorption is stimulated in more riovenous differences and estimates of renal blood flow, wasdistal nephron segments of remnant kidneys, presumably in the reduced. Total renal ammonia production (calculated fromcollecting system. blood arteriovenous difference + urinary excretion) was re- Although studies are just beginning to clarify the mechanisms duced by 50%, whereas uptake of glutamine was reduced byof nephron ammonia transport [15], the importance of ammonia 90%, as compared with controls. In contrast, renal release oftrapping in relative acidic compartments has long been recog- serine, alanine, and leucine was increased in chronic renalnized. Along these lines, the fact that bicarbonate delivery out insufficiency. Total renal ammonia production was 89of the proximal and distal tubules also was increased in the zmoles/min!lOO ml GFR, and it exceeded glutamine extractionremnant kidney model (Table 2) suggests that the final nephron (13 jimoles/min/l00 ml GFR). These findings indicate thatsegments were presented with tubular fluid with an increased ammonia was being produced from substrates other than gluta-bicarbonate content and thus were relatively alkaline. I will mine. These authors suggested that peptide and protein catab-address causes for increased bicarbonate delivery out of the olism within the diseased kidneys are the sources of most of theearlier segments shortly. These findings do suggest, however, renal ammonia generated in chronic renal insufficiency. If thisthat the decrease in urinary ammonium excretion might be suggestion is true, renal ammonium excretion in this settingexplained simply by a limitation on the ammonia-trapping would reflect local catabolism and would not reflect whole-bodymechanism imposed by increased bicarbonate delivery to distal metabolic acid production. nephronal segments. In addition to decreased urine ammonium excretion, abnor- The suppressive effects of on renal ammonia malities in intrarenal ammonium handling also were observed inproduction are also worth considering. Relative hyperkalemia the renal ablation model referred to earlier [13]. As Table 2was commonly associated with the hyperchloremic acidosis of illustrates, ammonium delivery to the end of the proximalearly chronic renal insufficiency in the retrospective study by tubule was increased by nearly threefold when remnant kidneysWidmer et al that I alluded to earlier [71. Although all patients were compared with controls (66 pmol/min versus 18 pmol/with chronic renal insufficiency do not manifest hyporeninemic mm). This adaptive increase in response to chronic renalhypoaldosteronism and so-called type-IV Nephrology Forum: Uremic acidosis 281

[9], this disorder of renal acid excretion [8, 16, 17] provides an Table 3. Adaptation of Na/H antiporter to metabolic acidosisa important insight into the regulation of ammonia production and ammonium excretion. Type-IV renal tubular acidosis is com- monly observed in patients with a variety of primary renalBlood pH 7.42 0.067.11 0.04 diseases such as mellitus, tubulointerstitial disease, Ymax (fluorescence units/sec. mg protein) Outer cortex 3.6 0.02 5.0 0.02 and nephrosclerosis. In type-IV renal tubular acidosis, aldos- Inner medulla 0.8 0.03 0.9 0.04 terone secretion is driven by hyperkalemia rather than by the usual -angiotensin axis; hyperkalemia does not appear to a Data taken from Ref. 35. fully substitute for renin deficiency, however, because these patients do in fact have hypoaldosteronism despite hyperkale- mia. Because hyperkalemia itself suppresses mitochondrial Cellular mechanisms of acidification ammonia production [18], a suppressive effect on renal ammo- nia production can be manifest in patients with hyperkalemia Transport processes. The reabsorption of water and solute by and chronic renal insufficiency, whether or not they havethe proximal tubule is a dynamic process that can adapt to type-IV renal tubular acidosis. changes in several physiologic factors: glomerular filtration Titratable acid excretion. Urinary phosphate excretionrate, hormones, and acid-base and balance. The makes a substantial contribution to renal net acid excretion inmajor mechanism for proton secretion and bicarbonate reab- its capacity as a urine buffer. As I noted, the distal nephronsorption in the proximal tubule is the Na/H antiporter of the proton secretory systems respond normally to increases inbrush-border membrane [26]. Adaptive increases in the maxi- urine buffer delivery [11]. Given the increased serum level ofmal transport rate (Vmax) of the Na/H antiporter have been phosphate as well as the inhibitory effects of secondary hyper-demonstrated in metabolic acidosis [27—29] and decreases have parathyroidism on renal phosphate absorption [19], it is notbeen shown in the maximal transport rate in [30]. surprising that phosphate excretion and urine titratable acidOther factors, including parathyroidectomy, glucocorticoid ad- formation are relatively well maintained in chronic renal insuf-ministration, unilateral nephrectomy, potassium depletion, and renal ablation, also increase the Vmax of the brush-border ficiency [4]. Na/H antiporter [27, 3 1—34]. Most of the Na/H antiporter Bicarbonate reabsorption. The mechanisms underlying thehas been localized to the first two-thirds of the proximal tubule. deranged renal bicarbonate handling in chronic renal insuffi-This segment also is the site of the adaptive increase in activity ciency are somewhat controversial. Whole-kidney bicarbonateobserved in metabolic acidosis [35]. As Table 3 illustrates, reabsorption is reduced following correction of the serummetabolic acidosis increased the max of the Na/H antiporter bicarbonate to normal levels. Under these circumstances,by 40% in brush-border vesicles prepared from the outer cortex Schwartz and colleagues found that 5 of 12 patients withof rabbit kidneys, presumably representing earlier segments of chronic renal insufficiency had marked bicarbonate excretionthe proximal tubule. In contrast, the basal rate of Na/H and suggested that substantial bicarbonate wasting occurredexchange was much lower in the inner cortical brush-border [4]. Schwartz and coworkers and Relman have suggested thatvesicles, and no adaptive increase occurred in response to impaired renal bicarbonate absorption is common in chronicmetabolic acidosis (Table 3). renal insufficiency and even can occur in patients who do not We and others have described an electrogenic sodium/bicar- manifest overt bicarbonaturia when the serum bicarbonate levelbonate in basolateral membrane vesicles pre- has been corrected to normal levels [4, 5, 10]. Subsequentpared from rabbit renal cortex [36, 37]. This transporter plays studies have demonstrated an important effect of volume ex-an important role in bicarbonate reabsorption and in regulation pansion on renal bicarbonate handling [20, 21]; this effect mightof intracellular pH in the proximal tubular cell [38—46]. Al- have confounded the results of Schwartz et at [4]. Some animalthough the factors regulating the activity of this transporter studies have suggested that absolute bicarbonate absorptivehave not yet been identified, it is believed that the sodium! rates in fact can increase in the remaining nephrons in chronicbicarbonate cotransporter is the primary pathway by which renal insufficiency, and that the defect in renal bicarbonatebase equivalents are transported across the basolateral mem- handling might be relative to the actual filtered load at the singlebrane. nephron level (reviewed in Ref. 11). Several factors that accom- Recent work has established that systemic pH, and therefore peritubular pH, play an important role in the regulation of pany chronic renal insufficiency could impair proximal bicar-bicarbonate reabsorption in the proximal tubule [26, 47]. In- bonate reabsorption, including secondary hyperparathyroidismdeed, the proximal tubule's intrinsic reabsorptive capacity for [22, 23], hyperfiltration in the remaining nephrons [24], andbicarbonate is increased in chronic respiratory [48] and meta- osmotic diuresis [25]. Whatever the mechanisms, findings in thebolic acidosis [49], and is decreased in chronic metabolic remnant kidney model demonstrate that bicarbonate delivery toalkalosis [50]. Bicarbonate reabsorption represents a vectorial the end of the proximal tubule and accessible distal tubule isprocess by which H is secreted across the brush-border augmented (Table 2) and that more bicarbonate is presented tomembrane, and base equivalents are transported across the the collecting system than is normally the case [13]. Evenbasolateral membrane; this scheme raises the possibility that though the final urine pH (Table 1) does not directly reflect thethe activity of the bicarbonate reabsorptive processes in both increase in distal bicarbonate delivery, there appears to be amembranes could be adaptively regulated during states of derangement in intrarenal bicarbonate handling in chronic renalchronic acid-base disturbance. In fact, we have shown that the insufficiency. activity of the Na/H antiporter and the sodium/bicarbonate 282 NephrologyForum: Uremic acidosis

PTH infusion, mm PTH infusion, mm TPTXr 5—30 30—60r 60—90r 90—120r TPTXr 5—30r 30—60r.. 60—90 90—120r 1.50 1100 r

1.20 6OO C I 0.90 100 Fig. 2. In-vivo infusion of parathyroid hormone in the rat. These results were obtained during the 300 7.1 indicated time periods while parathyroid hormone = P<0.01.Shown are the . F was infused in rats; * 3 rates of glomerular filtration (mi/mm),urinary g 204 Ia. bicarbonate and phosphate excretion (nmoi/min), and mE I urine pH. (Reproduced by permission of the 1001 6.8 American Journal of Physiology [60].) cotransporter are coordinately regulated during chronic meta- Table 4. Effect of PTH on opossum kidney cells bolic acidosis and alkalosis [51].Thisfinding has an important ControF +PTW implication for the defense of intracellular pH during chronic 76.0 16.0 58.0 13.0 acid-base derangements. If only the apical Na/H exchangerNa/W Antiporterb were activated in metabolic acidosis, cell pH would increase asNa7PO4 Cotransportere 2.1 0.1 1.2 0.1 more protons were removed from the cell. On the other hand, if a Maximaltransport rates are given in nmoles/min/mg protein. both transporters are activated during acidosis, the overall net bDatafrom Ref. 55. rate of transcellular proton secretion would be increased be- Data from Ref. 56. cause H extrusion across the apical membrane and HC03 exit across the basolateral membrane both would be increased. This adaptation would maintain intracellular pH at a lower levelto cause rather than acidosis [57]. This than that which could result if only the apical Na/H transportdiscrepancy might partially result from the combined renal and system were increased [51]. Furthermore, such an adaptiveextrarenal effects of parathyroid hormone. The buffering capac- process probably would be more sensitive to regulation byity of the skeletal system [58] and the effects of parathyroid intracellular pH than to changes in systemic extracellular pH.hormone and vitamin D metabolites on the [57] cannot be Parathyroid hormone. I now would like to turn to the effectsignored in considering chronic acid-base homeostasis in chronic of parathyroid hormone on renal acidification processes at therenal insufficiency. The importance of this defense of acid-base cellular level. Parathyroid hormone acutely inhibits phosphatehomeostasis is emphasized by the immense carbonate content and bicarbonate reabsorption in the proximal tubule. Our groupof the skeleton [2]; skeletal buffering of H may well explain the has studied these effects in an established renal cell line fromstability of uremic acidosis, that is, the common observation the opossum kidney. A distinguishing feature of this cell line isthat serum bicarbonate levels can remain relatively constant its response to parathyroid hormone at the adenylate cyclasedespite ongoing H retention. Calcium loss from bone (negative level [52]andat the membrane transport level [53]. Thecalcium balance) has been observed during metabolic acidosis opossum kidney cells have many characteristics of cultured[58]; such calcium depletion might play a role in the osteodys- proximal tubular cells, including NC/HP exchange [54, 55],trophy that develops during the course of chronic renal insuf- sodiumlphosphate cotransport [56], and acute regulation officiency [59]. both transport systems by cyclic AMP (Table 4) [54-56]. The The divergent responses to parathyroid hormone are illus- effects on NC/HP antiporter activity could be detected at 10trated in the in-vivo infusion study presented in Figure 2 [60]. picomolar parathyroid hormone concentration and were limitedThe glomerular filtration rate and urine bicarbonate excretion to the amiloride-sensitive component of 22Na exchange [54].rate rapidly increased in response to parathyroid hormone, Kinetic analysis indicates that parathyroid hormone acutelyreturning to baseline levels during the last half of the 2-hour decreases the maximal rate of transport and shifts the internalinfusion period. In contrast, the increase in urine phosphate pH sensitivity of the Na/H exchanger in the acidic (that is,excretion was sustained throughout the entire infusion period. less sensitive) direction [55]. In addition, sodium-dependentOf note are the changes in urine pH, which increased during the phosphate transport is reduced by parathyroid hormone (Tableperiods that corresponded to the increase in bicarbonate excre- 4). These subcellular effects, obtained with short-term exposuretion; however, urine pH fell substantially thereafter. These of the cultured cells to parathyroid hormone, are entirelyeffects are explained in part by the increase in phosphate consistent with the overall renal effects of parathyroid hor-delivery to distal nephron sites, which provokes proton secre- mone, and can well explain the bicarbonaturic and phosphaturiction in response to this increase in buffer (phosphate) delivery. responses to parathyroid hormone. In addition, the fall in urine pH (Fig. 2) also raises the In contrast to these acute effects, administration of parathy-possibility that parathyroid hormone might stimulate proton roid hormone or active metabolites of vitamin D for one to 2secretion in more distal parts of the nephron. An increase in weeks has been found to increase renal net acid excretion andfractional bicarbonate reabsorption was observed during para- Nephrology Forum: Uremic acidosis 283 thyroid hormone infusion in the ioop of Henle [60], a site wherebe striking as renal insufficiency develops, but the underlying a sodium-dependent, amioride-sensitive bicarbonate absorp-pathophysiologic mechanisms will take their toll. tive process was recently identified in the rat [61]. Cyclic AMP-mediated acid jfication. Proton AlPases make a Questions and answers relatively minor contribution to proximal tubule acidification, but they appear to play a major role at more distal sites via Da. JEROME P. KASSIRER (Associate Physician-in-Chief, endocytotic and exocytotic vesicles [26]. It is interesting toNew England Medical Center, Boston, Massachusetts): In the consider the possibility that these systems might be regulatedlate 1950s, Schwartz and Relman showed that a minority of by cyclic AMP (cAMP). Regulation of luminal H secretion inpatients with chronic renal failure did, in fact, have bicarbonate the turtle has been attributed to fusion ofwasting. Could you comment on these data in light of what we intracellular vesicles with the apical membrane [62]. Previousknow today? studies with the turtle urinary bladder showed that 10 mM DR. WARNOCK: Persisting excretion of bicarbonate in this cAMP decreased transepithelial H secretion [63]; these resultssetting could simply reflect mild volume expansion such that the are similar to those observed with parathyroid hormone andfiltered load of bicarbonate exceeds the overall renal bicarbon- cAMP in studies of the proximal tubule apical membraneate absorptive capacity. In terms of the thesis that I have Na/H antiporter [54, 55]. Paradoxically, stimulatory effectsdeveloped today, it seems likely that a derangement exists in of 1 mM dibutyryl cAMP on H transport also have beenintrarenal bicarbonate handling in chronic renal insufficiency. observed in the urinary bladder of the Colombian toad [64].The data summarized in Table 2 demonstrate that bicarbonate Recentstudies in the isolated, perfused rabbit medullary col-delivery to more distal sites is increased, at least in the remnant lecting duct [65] have demonstrated a stimulatory effect of 0.01kidney model. If the distal proton secretory systems do not mM dibutyryl cAMP on H secretion. The effect of cAMP onrespond to this increase in buffer delivery, due for instance to the intact tissue may be complex and could include effects onselective aldosterone deficiency, bicarbonaturia will result. It is the basolateral base exit step and insertion of H ATPase intofortunate that this is observed only in a minority of patients with the apical membrane. Preliminary results from our group sug-chronic renal insufficiency [3] because a persistent loss of gest that inhibition, stimulation, or both of H secretion in abicarbonate in the urine would clearly increase the severity of specific subset of endocytotic vesicles from rabbit renal cortexuremic acidosis. also might contribute to the regulatory effects of cAMP on DR. KASSIRER: In essence, it seems that in chronic renal transepithelial H transport [66]. Therefore, the overall effectfailure the proximal tubule is at fault in not reabsorbing bicar- of parathyroid hormone on renal acidification is complex.bonate, and the distal tubule is unable to catch up. Bicarbonate and phosphate absorption are clearly acutely in- DR. WARNOCK: Exactly. Most patients, however, do elabo- hibited in the proximal tubule by parathyroid hormone, and therate an acid urine and do respond normally to increases in increased buffer delivery would alkalinize the tubular fluidurinary buffers. These observations indicate that usually the delivered to more distal sites. In addition, parathyroid hor-function of distal proton secretion systems is well maintained. mone, or even cyclic AMP generated at its proximal site of DR. JOHN T. HARRINOTON (Chief of Medicine, Newton- action, could regulate H transport systems in the distalWellesley Hospital, Newton, Massachusetts): Dr. Warnock, I nephron. am not sure about some of the quantitative aspects of the data In summary, metabolic acidosis develops during the courseyou presented. I believe that you stated that ammonia produc- of chronic renal insufficiency because of an inadequate adapta-tion could increase twofold in the proximal tubule in metabolic tion of net renal acid excretion to the requirements for acid-baseacidosis, yet there was a four- to fivefold increase in urinary homeostasis. Although the primary defect appears to be inammonia excretion in the same studies. Doesn't this suggest overall renal ammonium excretion, it is not certain that renalthat distal tubule ammonia production increases substantially in ammonia production per se is rate-limiting. Recent studies havechronic renal failure? suggested that intrarenal bicarbonate handling may be de- DR. WARNOCK: Not really. The capacity of the proximal ranged, with increased delivery of bicarbonate out of thetubule cell to produce ammonia is really quite large, but much proximal tubule due to the combined effects of parathyroidof it is usually returned to the systemic circulation rather than hormone, volume expansion, and increased glomerular filtra-being excreted in the urine [14]. Your calculations are correct in tion in the remaining nephrons. As a consequence of thea fractional sense, but when one considers the absolute rate of increase in bicarbonate delivery, relatively alkaline tubule fluidproximal ammonia production compared with the absolute rate is delivered to distal nephron sites, thus decreasing the effi-of urinary ammonium excretion, it is clear that a twofold ciency of ammonia trapping and thereby decreasing urinaryincrease in production rate is more than sufficient to account for ammonium excretion. It also appears that chronic parathyroida fivefold increase in urinary excretion rate. hormone excess might stimulate distal nephron proton secre- DR. KASSIRER: How relevant is the pathogenesis of metabolic tion and increase titration of urinary buffers; urine titratableacidosis as seen in the remnant kidney to that seen in human acid formation is thereby well maintained as chronic renalchronic renal failure? insufficiency develops even though urine ammonium excretion, DR. WARNOCK: I am surprised that the remnant model needs and therefore net acid excretion, are reduced. Bone bufferdefending in Boston, but I share your reservations. Whereas stores defend acid-base homeostasis, and the long-term effectsthis model might not be a perfect analogue of chronic renal of such buffering may contribute to the development of renalinsufficiency, its virtues certainly have not gone unheralded. To osteodystrophy. In any particular patient (as in the one pre-imply that this model is not "relevant" to human chronic renal sented today), the severity of the metabolic acidosis might notfailure is probably a bit strong. 284 Nephrology Forum: Uremic acidosis

Da. NIcoLAos E. MAmAS (Chief Division of Nephrology,Alternatively, if distal proton secretory ystems are in fact New England Medical Center): Although in general the severitystimulated by PTH or by cAMP produced in the proximal of uremic acidosis worsens as a function of the degree of renaltubule and delivered distally, the cell pH (in those cells) failure, several studies have identified patients whose plasmaobviously would rise. bicarbonate concentration has been in the lower limits of the Da. MADIAS: You stated that the ability to acidify the urine normal range despite even severe degrees of renal failure. Inremains intact in chronic renal failure. Although uremic patients such patients, vomiting or exposure to substances that couldwho are free of bicarbonate wasting do indeed excrete an acidic elevate plasma bicarbonate concentration—such as diuretics,urine, their urine pH usually falls short (by at least 0.5 pH units) alkali, and steroids—have been excluded. Do you ascribe thisof the level attained by normal subjects following experimen- phenomenon to relatively better preservation of renal acidifica-tally induced metabolic acidosis. This point is borne out by the tion in these patients, or might it be that they have increaseddata presented in Table 1 in which rats with uremic acidosis had participation of extrarenal buffering? a urine pH no lower than that of control, non-acidotic rats. DR. WARNOCK: My presentation has focused on the renalDoesn't this suggest the presence of a subnormal ability to proton and bicarbonate transport mechanisms at a tubular andacidify the urine in chronic renal failure? cellular level. As your question implies, however, it would be a DR. WARNOCK: We should always allow for that possibility. mistake to lose sight of the important role played by the skeletalHowever, the thesis that I have developed today focuses on the buffer stores in the long-term response to metabolic acidosis.actual increase in delivery of a volatile buffer (bicarbonate) to The buffer power of bone, especially its carbonate content, isdistal sites in chronic renal insufficiency. Therefore, increased immense [2]. It seems quite plausible that skeletal buffering ofproton secretion in the distal tubules could accommodate this H could well explain the commonly observed stability ofincreased buffer load without there being acorrespondingfall in uremic acidosis, that is, the fact that the serum bicarbonatethe urinary pH. level can remain relatively constant despite ongoing retention of DR. MAmAs: I found your analysis of the effects of PTH on hydrogen . In fact, a dramatic finding in the case presentedacidification processes particularly intriguing. These divergent today is the relatively mild acidosis despite well-documentedeffects on the proximal and distal nephron might account for the hyperparathyroidism and severe renal insufficiency. fact that patients with primary hyperparathyroidism usually do DR. KASSIRER: In fact, in the patient we are discussing today,not feature substantial abnormalities in their acid-base status. I could argue that the administration of furosemidc, by increas-On the other hand, I am aware of few published reports on ing distal hydrogen ion secretion, and calcium carbonate, byuremic patients with substantial bicarbonaturia and marked increasing alkali stores, was responsible for the lack of severesecondary hyperparathyroidism whose bicarbonate wasting acidosis. was ameliorated following parathyroidectomy. Do you know of DR. WARNOcK: I certainly agree that these factors could haveany systematic data describing the effects of parathyroidectomy contributed to the maintenance of relatively normal acid-baseon the acid-base status of uremic patients? balance in this patient. It has never been clear to me, however, DR. WARNOCK: I am not aware that this issue has been how furosemide increases distal hydrogen ion secretion. Itcarefully studied. If PTH decreases proximal bicarbonate reab- might be worth speculating that inhibition of an anion exchangesorption but can also stimulate distal H secretion, the effect of process, such as the chloride/bicarbonate exchanger present inparathyroidectomy might not be manifest in the urine even parallel with a Na/H exchanger in the thick ascending limb ofthough substantial changes in thó intrarenal handling of bicar- some species [61], would augment Htm secretion by limitingbonate might have occurred. base entry into the luminal fluid. DR. HARRINOTON: As you know, we have been intetested in DR. KASSIRER: As a followup to my question, is there anythe stimuli to renal acid excretion for many years [67, 68]. One correlation between severity of uremic acidosis and degree ofstriking study strongly suggesting that systemic acidosis is not osteodystrophy? critical to the stimulation of renal acid excretion was reported DR. WARNOCK: That is a difficult question to answer becauseby Lowance and colleagues in the early l970s [69]. These of the heterogeneity of bone lesions that we usually lump underinvestigators demonstrated that the administration of antidi- the term "." It is clear that negativeuretic hormone and water to animals in the steady-state phase calcium balance can be demonstrated in acidosis and that theof chronic metabolic acidosis resulted in an increase in renal resulting calcium depletion may well play an important role inacid excretion and a return of plasma biáarbonate to normal. the development and progression of the renal osteodystrophiesLater studies performed here by the same group in collabora- [59]. tion with Dr. James Mélby at Boston University demonstrated DR. RONALD D. PERRONE (Division of Nephrology, Newthe critical role of aldosterone in producing this response [70]. England Medical Center): You alluded to the possible protec-My question to you is, how do you explain the increase in renal tive effect of increased PTH levels in chronic renal failure byacid excretion in the Lowance studies, while systemic acidemia "keeping acid out." Yet intracellular pH faIls. How do youis waning? reconcile this discrepancy? DR. WARNOcK: It is possible that the central issue is in fact Da. WARNOCK: I didn't mean to imply that PTH plays anycell pH rather than systemic pH. Many of the factors that cause "protective role" in chronic renal insufficiency. As you know,adaptive changes in the renal acidification mechanisms (for some have even concluded that VFH is one of the uremicexample, acidosis, alkalosis, and glucocorticoids) can be dem- toxins. If PTH chronically inhibits the Na/H antiporter in theonstrated when the tubule or membrane is removed from the proximal tubule, the cell pH will be set at a lower level [54, 55],kidney and studied in a defined in-vitro setting. These adaptive which I agree would probably be deleterious in the long run.changes usually take relatively long to be established (days), Nephrology Forum: Uremic acidosis 285 and are manifest by the in-vitro "memory effect" that I havecausality that you find questionable. In fact, the metabolism of just described. Therefore I don't think it is surprising that thesesulfur- and phosphorus-containing organic substances can be transport systems can be acutely dissociated from changes inviewed as producing H7S04 and H3P04. These are very strong acid-base status because it can take hours or even days for theacids that could never be excreted as such in the urine because membrane transport to be "retooled." The recentof the difference between their pKs and the lowest possible demonstration of increased brush border vesicle Na/H ex-urinary pH. Therefore, these anions can only be excreted as change in post-hypercapnic metabolic alkalosis is an excellentsodium salts, whereas the attendant protons are excreted as example of these phenomena [71]. ammonium ions. In this sense, then, the fact that these anions DR. MADIAs: Recent observations by Wallia and colleaguesaccumulate indicates of course that the filtered load and urinary have suggested that, in contrast to the common belief thatexcretion are not sufficient to clear them from the circulation. In high-anion-gap metabolic acidosis typifies advanced uremicaddition, we should not lose sight of the fact that these anions acidosis, normal-anion-gap acidosis or a hybrid type of acidosisdo represent a challenge to the maintenance of normal acid-base (that is, mixed high- and normal-anion-gap acidosis) is commonstatus in that bicarbonate was consumed during the course of among patients with severe renal failure [72]. How do youhydrogen ion liberation from their conjugate . account for these findings, and to what extent do you think this DR. MADIAS: What are your recommendations on the treat- observation is due to a component of hypoaldosteronism orment of uremic acidosis? aldosterone resistance? DR. WARNOCK:Howshould we treat uremic acidosis? Clear- DR. WARNOCK: I wouldn't want to defend the position thatly, bicarbonate supplementation can be beneficial, especially if the distal proton secretory systems are perfectly intact init can be given as calcium carbonate along with vitamin D so chronic renal insufficiency. Clearly, the ability to generate a pHthat the underlying defects in gut calcium absorption are also gradient, especially if buffer delivery is low, is nearly normal.addressed. Evaluation of the renin-aldosterone axis and supple- The maximal capacity to secrete protons is much more difficultmental mineralocorticoids are needed, if indicated. As I previ- to assess. If there is increased bicarbonate delivery to the distalously mentioned, furosemide treatment with added salt if tubule in this setting, then it is difficult to know what the actualneeded also might be useful. Finally, aggressive management of buffer load is that is delivered distally. I think the idea ofhyperkalemia with dietary modification and exchange resins are aldosterone resistance, separate from selective aldosteronehelpful. deficiency, is well worth considering and merits direct experi- As you realize, these approaches are the mainstays of the mental examination. traditional, conservative approach to managing chronic renal DR. KASSIRER: I never have been fond of the designationfailure. Nothing in my presentation would change our current "anion-gap acidosis," principally because this term implies amanagement of uremic acidosis, but I hope that our thinking has causal relation between the anion and the acidosis. In organicbeen more clearly focused on the underlying . acidoses such as and , acidosis is caused by the accumulation of hydrogen ions, and the anion is Reprint requests to Dr. D. Warnock, Nephrology Section (JJJJ,), San merely an accompaniment of hydrogen ion. In fact, in suchFrancisco Veterans Administration Medical Center, 4150 Clement types of acidosis, the anion, when metabolized, is the source ofStreet, San Francisco, California 94121, USA. alkali to replenish lost bicarbonate stores. In renal acidosis, References acidosis is caused by failure of hydrogen ion excretion, and the increase in plasma anions is merely the consequence of a 1. SEBASTIAN A, MCSHERRY E, MORRIS RC JR: Metabolic acidosis retention of anions consequent to a low glomerular filtration with special reference to the renal acidoses, in The Kidney, edited by BRENNER BM, RECTOR FC JR. Philadelphia, Saunders, 1976, pp rate. Because failure of hydrogen ion excretion and failure of 642—645 anion excretion are unlinked processes in chronic renal failure, 2. GOODMAN AD, LEMANN J JR, LENNON EJ, RELMAN AS: Produc- numerous examples exist in which discrepancies occur between tion, excretion and net balance of fixed acid in patients with renal the degree of acidosis and the degree of anion retention. Maybe acjdosis. J Clin Invest 44:495—506, 1965 I'm being a purist, but I believe that the way we describe 3. SCHWARTZ WB, RELMAN AS: Acidosis in renal disease. N Engl J Med 256:1184—1186, 1957 medical concepts is important. Lavoisier also worried about 4. SCHWARTZ WB, HALL PW III, HAYS RM, RELMAN AS: On the this issue nearly 200yearsago. In Traite Elementaire de Chimie mechanism of acidosis in chronic renal disease. J Clin Invest (1789) he wrote, "It is impossible to dissociate language from 38:39—52, 1959 science or science from language, because every natural sci- 5. VAN SLYKE DD, UNDER GC, HILLER A, LEtTER L, MCINTOSH JF: The excretion of ammonia and titratable acid in . J Clin ence always involves three things: the sequence of phenomena Invest 2:225—239, 1926 on which the science is based; the abstract concepts which call 6. LATHEM W: Hyperchloremic acidosis in chronic . N these phenomena to mind; and the words in which the concepts Engl J Med 258:1031—1036, 1958 are expressed. To call forth a concept a word is needed; to 7. WIDMER B, GERHARDT RE, HARRINGTON JT, COHEN JJ: Serum portray a phenomenon a concept is needed. All three mirror one electrolyte and acid base composition: the influence of graded degrees of chronic renal failure. Arch Intern Med 139:1099—1102, and the same reality." Do you have similar concerns? 1979 Da. WARNOCK: I would never dispute Lavoisier, and would 8. SCHAMBELAN M, ST0cKIGT JR. BIGLIERI EG: Isolated hypoaldo- disagree with Kassirer only on rare occasions. In fact, I am steronism in adults: a renin-deficiency syndrome. N Engl J Med somewhat fond of the term "anion-gap acidosis" precisely 287:573—578, 1972 9. LUKE RG: and bicarbonate levels in chronic renal because of Lavoisier's dictum. I find this phrase of great utility failure. Arch Intern Med 139:1091—1092, 1979 in explaining the concepts of metabolic acidosis to medical10. RELMAN AS: The acidosis of renal disease. Am J Med 44:706—713, students. Furthermore, I would even be willing to defend the 1968 286 NephrologyForum: Uremic acidosis

11. CoGANMG,RECTOR FC JR: Acid-base disorders, in The Kidney protein and uninephrectomy. J Clin Invest 74:1979—1987, 1984 (vol 1, 3rd ed), edited by BRENNER BM, RECTOR FC JR. Philadel- 34. SEIFTER JL, HARRIS RC: Chronic K depletion increases Na-H phia, Saunders, 1986, pp 487—488 exchange in rat renal cortical brush border membrane vesicles 12. GOOD DW, DUBOSE TD JR: Ammonia transport by early and late (abstract). Kidney tnt 27:384, 1984 proximal convoluted tubules of the rat. J C/in Invest 79:684—691, 35. JACOBSEN C, KRAGH-HANSEN U, SHEIKH MI:Na/H exchange in 1987 luminalmembrane vesicles from rabbit proximal convoluted and 13. BUERKERT J, MARTIN D, TRIOG D, SIMON E: Effect of reduced straight tubules in response to metabolic acidosis. Biochem J renal mass on ammonium handling and net acid formation by the 239:411—416, 1986 superficial and juxtamedullary nephron of the rat. Evidence for 36. 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