References

Chapter 19, Part 3 August 30, 2023

Joel and Roger mentioned the most common cause seems to be Sjögren’s syndrome for an acquired distal RTA. We mentioned this in an earlier episode and referenced this example of an absence of the H+ ATPase, presumably from autoantibodies to this transporter. Here’s a case report: Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren's syndrome and distal renal tubular acidosis

 Joel mentioned this paper in the New England Journal of Medicine in which there were patients who had hyperkalemia with a distal RTA: Hyperkalemic Distal Renal Tubular Acidosis Associated with Obstructive Uropathy | NEJM in this setting, some patients 

 Anna mentioned this article on “ampho-terrible:” It’s the holes!!!    Yano T, Itoh Y, Kawamura E, Maeda A, Egashira N, Nishida M, Kurose H, Oishi R. Amphotericin B-induced renal tubular cell injury is mediated by Na+ Influx through ion-permeable pores and subsequent activation of mitogen-activated protein kinases and elevation of intracellular Ca2+ concentration. Antimicrob Agents Chemother. 2009 Apr;53(4):1420-6

Josh mentioned this study on furosemide’s effect on the TAL: Furosemide-induced urinary acidification is caused by pronounced H+ secretion in the thick ascending limb 

Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride - Kidney International

Melanie mentioned treatment of patients with cystinosis Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients | Clinical Kidney Journal | Oxford Academic

Amy shared her observations regarding base supplements including Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis - PubMed and Dosage of potassium citrate in the correction of urinary abnormalities in pediatric distal renal tubular acidosis patients - PubMed

Roger mentioned that he has had good luck with Moonstone Nutrition drinks alkali citrates for kidney health

We referred to David Goldfarb’s teaching on kidney stones in patients with acidification defects:  A Woman with Recurrent Calcium Phosphate Kidney Stones (we also referenced this in an earlier episode but this one is a fan favorite). 

Joel mentioned the concern of bone loss in distal RTA: Incomplete renal tubular acidosis in 'primary' osteoporosis and Abnormal distal renal tubular acidification in patients with low bone mass: prevalence and impact of alkali treatment

JC mentioned Ehlers-Danlos syndrome with renal tubular acidosis and medullary sponge kidneys. A report of a case and studies of renal acidification in other patients with the Ehlers-Danlos syndrome

Lety mentioned concerns of encrustation of stents in stone forming individuals Potassium Citrate as a Preventive Treatment for Double-J Stent Encrustation: A Randomized Clinical Trial

Joel schooled us in toluene and the presentation which appears to be an RTA- https://journals.lww.com/JASN/Abstract/1991/02000/Glue_sniffing_and_distal_renal_tubular_acidosis_.3.aspx

Melanie mentioned this work by Alan Yu’s lab on a mechanism of hypercalciuria Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease

Furosemide/Fludrocortisone Test and Clinical Parameters to Diagnose Incomplete Distal Renal Tubular Acidosis in Kidney Stone Formers and an accompanying editorial by Goldfarb Refining Diagnostic Approaches in Nephrolithiasis: Incomplete Distal Renal Tubular Acidosis

Here’s a nice piece on ifosfamide and phosphate from Josh New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2

Here’s this crazy piece on excessive bicarbonate - Gas production after reaction of sodium bicarbonate and hydrochloric acid

Josh points out that the pH can be important for inotropy:  An effect of pH upon epinephrine inotropic receptors in the turtle heart

Mel’s favorite from Halperin because of the pun: Renal tubular acidosis (RTA): recognize the ammonium defect and pHorget the urine pH

Amy’s VOG on RTA and Osteoporosis

KI Review on acidosis and bone health: Effects of acid on bone

Guideline on congenital RTA: Distal renal tubular acidosis: ERKNet/ESPN clinical practice points

AJKD article on acidosis and bone health: Serum Bicarbonate and Bone Mineral Density in US Adults

Citrate reversing CsA induced acidosis effects: Citrate reverses cyclosporin A-induced metabolic acidosis and bone resorption in rats

Outline: Chapter 19 Metabolic Acidosis part 3

Renal Tubular Acidosis

Acidosis from diminished net tubular acid secretion

Three types

Type 1 (Distal)

Type 2 (Proximal)

Type 4 (…)

The acidosis of renal failure could be added to this group

But NH4+ per nephron is normal

This is a problem of too few nephrons, not tubular acidosis

Nephrons able to maximally acidify the urine

Type 1 Distal RTA

Decrease in net H secretion in the collecting duct

Minimal urine pH rises from 4.5 to 5.3

HCO3 can fall below 10

Three mechanisms

Defect in H-ATPase found in cortex and medulla

Sjögren syndrome

Can be genetic chloride bicarbonate exchanger

This pumps bicarbonate out basolateral membrane after it is generated in the splitting of water to form H

Defect in cortical Na reabsorption

Voltage-dependent defect

Concurrent K secretion defect

Found in urinary obstruction and sickle cell

Volume deficiency can decrease Na delivery to distal nephron

Decreased amount of Na reabsorption can cause a reversible type 1 RTA of this type

Increased membrane permeability

Amphotericin

pH of 5.0 is 250× plasma

Table 19-7

Fractional excretion of bicarbonate in distal RTA

Normally negligible since bicarbonate can’t exist with pH down around 5

In distal RTA it may be as high as 6.5; FEHCO3 is 3%

If pH goes up over 7 this can rise to 5–10%

Usually in infants

As they age their urine pH falls a bit

This is called type 3

Plasma K

H-ATPase defects have low K

Patients also have downregulation of H-K-ATPase

Downregulation of NaCl reabsorption in proximal tubule

Decreased filtered bicarbonate means less bicarbonate to absorb with Na, hence more Na excretion from proximal tubule

This increases distal sodium delivery and increases aldosterone

Voltage defect also has decreased renal K clearance → hyperkalemia

Differentiate from type 4 RTA by looking at urine pH

Lower in type 4

Higher in voltage-dependent distal RTA

Nephrocalcinosis

Hypercalciuria, hyperphosphatemia, nephrolithiasis, and nephrocalcinosis are frequent

Comes from bones buffering the acidosis

Kidney decreases reabsorption of these so they are lost in urine

Two other factors

Low urinary citrate

Hypokalemia drives this

Acidosis drives this

High urine pH (CaPhos stones)

All corrected by correcting the metabolic acidosis

Incomplete Type 1

Defective urinary acidification but not acidemic

Increased proximal NH3 production lowers urinary H

Low urinary citrate

Can progress to complete type 1

Etiology of Type 1

Sjögren syndrome, rheumatoid arthritis

19-8

Clinical manifestations

Stones

Hypokalemia

Growth defects

Diagnosis

NAGMA and elevated urine pH

5.3 in adults

5.6 in children

Differentiate Type 1 vs Type 2

Give bicarbonate drip

1 mEq/kg/hr

Urine pH remains high with Type 1

Does not go up as it does with proximal Type 2

Incomplete distal RTA

Give acid load

0.1 mmol/kg

Urine pH remains >5.3 in classic

Falls in normal patients (usually below 5)

Treatment

Treat metabolic acidosis

Minimize potassium loss

Reduce bone catabolism

Prevent stones

Alkali requirement

Adults: 1–2 mEq/kg/day

Children: 4–14 mEq/kg/day

Alkali

Sodium bicarbonate

Sodium citrate

Potassium citrate if hypokalemia persists despite correcting acidosis

Or for calcium stone disease

Treat hypokalemia

Type 2 Proximal RTA

Decreased HCO3 reabsorption

90% of bicarbonate reabsorption happens in proximal tubule

Bicarbonate wasting starts normally at 26–28 mmol/L (Tm for bicarbonate)

In RTA 2 the Tm falls to a lower level (maybe 17)

Serum bicarbonate falls to 17 and stabilizes

Type 2 RTA is self-limiting

Typically HCO3 around 14–20

Distal acidification intact

Carbonic anhydrase inhibitor can block 80% of proximal HCO3 reabsorption

Only 30% of filtered bicarbonate excreted due to distal H secretion

Total absence of proximal reabsorption results in HCO3 11–12

Clinical difference in treatment

In Type 2, giving bicarbonate and raising serum HCO3 above Tm → more wasted in urine

FEHCO3 can reach 15% with normal serum HCO3

Urine pH >7.5

Below Tm, urine pH <5.3

In Type 1, curve relating HCO3 excretion to plasma HCO3 similar to normal (with increased obligatory urine HCO3 due to higher urine pH)

Defect in HCO3 reabsorption

Can be isolated

Or part of Fanconi syndrome

Pathogenesis (three steps)

Na-H exchange (apical membrane)

Na-K-ATPase (basolateral membrane)

Carbonic anhydrase

Intracellular

Luminal

Multiple myeloma most common adult cause

Ifosfamide

Can also cause phosphate wasting, NDI, and Type 1 RTA

K balance

Common but variable

Mild hypokalemia at baseline due to increased Na wasting → hyperaldosteronism

Worse with bicarbonate therapy

Distal delivery of nonreabsorbable anion increases obligate cation loss

Figure 19-7

Bone disease

Rickets (children), osteomalacia/osteopenia (adults)

Up to 20%

Phosphate wasting and vitamin D deficiency may contribute

Impaired growth

No nephrocalcinosis or nephrolithiasis

Lower urine pH

Nonreabsorbable amino acids and organic anions bind calcium

Etiology

19-9

Idiopathic and cystinosis (children)

Carbonic anhydrase inhibitors

Multiple myeloma

Diagnosis

NAGMA and pH <5.3

Look for Fanconi syndrome

Raise serum HCO3 and watch urine pH rise

FEHCO3 15–20%

Treatment

Correct acidosis to allow normal growth

Difficult due to rapid urinary loss

May need 10–15 mEq/kg/day

HCO3 or citrate

More than 20 mEq HCO3 can cause stomach rupture from CO2 generation

Small dose thiazide to increase proximal Na reabsorption and HCO3 reabsorption

Idiopathic Type 2 may improve after years

Type 4 RTA

Aldosterone deficient or resistant

Normally stimulates H secretion and K secretion

Loss causes hyperkalemia and metabolic acidosis

Hyperkalemia antagonizes NH4 generation

High K may outcompete NH4 on Na-K-2Cl in TALH

Less ammonium recycling

Less NH3 available in collecting duct

Correcting hyperkalemia can correct acidosis

Metabolic acidosis generally mild

HCO3 >15

Urine pH <5.3 (generally, not always)

Mineralocorticoid can treat but causes hypertension and sodium retention

Often responds to loop diuretic

Rhabdomyolysis can cause high anion gap metabolic acidosis

Symptoms

Respiratory compensation increases 4–8 fold → dyspnea

pH <7.0–7.1

Fatal ventricular arrhythmias

Reduced cardiac contractility

Decreased response to inotropes

Neurological

Lethargy to coma

More related to CSF pH than plasma

Less neurologic symptoms than respiratory acidosis

BBB more permeable to CO2 than HCO3

Skeletal problems

Decreased growth

Kids/infants: anorexia, nausea, listlessness

Treatment

General principles

Correct with HCO3

No alkali required for lactic or ketoacidosis

Goal: pH >7.2

Equations on page 629 need “log”

Example: pH 7.1, pCO2 20, HCO3 6

Raise HCO3 to 8 if pCO2 stays 20

Raise to 10 if pCO2 rises

Paragraph “regardless…” highlights risks of bicarbonate

Bicarbonate deficit

Deficit = HCO3 space × HCO3 deficit per liter

HCO3 space

50% body weight (normal)

60% (mild–moderate acidosis)

70% (severe, HCO3 <8–10)

Example: 70 kg, raise HCO3 6→10 using 0.7 space = 196 mEq

Rough guideline; does not account for ongoing acid production

Early large bump in bicarbonate

Drifts down as bicarbonate moves intracellularly

Plasma potassium

K depletion can cause metabolic acidosis

Metabolic acidosis increases K

“Normal” K may mask depletion (see DKA)

Beware correcting acidosis in hypokalemia

Heart failure

Bicarbonate comes with sodium load

Comment that bicarbonate moves into cell

But Na remains extracellular

Dialysis can be used