RENAL SYSTEMRENAL TUBULAR ACIDOSIS

INTRODUCTION

Lungs and Kidneys are responsible for Normal acid base balance

Alveolar ventilation removes CO2 Kidneys reabsorb filtered Bicarbonate

and excrete a daily quantity of Hydrogen ion equal to that produced by the metabolism of dietary proteins.

Hydrogen ions are excreted primarily by enhancing the excretion of ammonium ions in the urine

DEFINITION

The term "renal tubular acidosis" (RTA) refers to a group of disorders in which, despite a relatively well-preserved glomerular filtration rate, metabolic acidosis develops because of defects in the ability of the renal tubules to perform the normal functions required to maintain acid-base balance.

INCIDENCE

Predominant age: All ages

Predominant sex: Male > Female (with regard to type II RTA with isolated defect in bicarbonate reabsorption)

TYPES

Distal / type 1 RTA Proximal / type 2 RTA Hypoaldosteronism / type 4

RTA Type 3 / mixed RTA (not in

use)

Type 1-Distal RTA

Distal RTA (dRTA) is the classical form of RTA. Inability of the distal tubule to acidify the urine. Due to impaired hydrogen ion secretion, increased backleak of secreted hydrogen ions, or impaired sodium reabsorption (causing less negative potential in the lumen and hence less hydrogen/potassium secretion).

Urine pH >5.5.

PATHOPHYSIOLOGY failure of acid secretion by the alpha

intercalated cells of the cortical collecting duct of the distal nephron.

it leads to an inability to acidify the urine to a pH <5.3

renal excretion is the primary means of eliminating acid from the body, there is consequently a tendency towards acidemia

There is an inability to excrete H+ while K+ cannot be reabsorbed, leading to acidemia (as H+  builds up in the body) and hypokalemia (as K+ cannot be reabsorbed).

the substance of the kidney develops stones bilaterally

RISK FACTORS

GeneticsAutosomal dominant or recessive. May occur in association with other genetic diseases (e.g., Ehlers-Danlos syndrome, hereditary elliptocytosis, or sickle cell nephropathy). The autosomal recessive form is associated with sensorineural deafness.

ETIOLOGY• Genetic• Sporadic• Autoimmune diseases:

rheumatoid arthritis (RA), SLE• Hematologic diseases:

Sickle cell disease, hereditary elliptocytosis

• Medications: Amphotericin B, lithium, K+-sparing diuretics

• Toxins:Toluene, glue

• Hypercalciuria, diseases causing nephrocalcinosis

• Vitamin D intoxication• Medullary cystic disease• Glycogenosis type III• Fabry disease• Wilson disease• Hypergammaglobulinemic

syndrome• Obstructive uropathy• Chronic pyelonephritis• Chronic renal transplant rejection• Leprosy• Hepatic cirrhosis• Malnutrition

CLINICAL MANIFESTATIONS

non-anion gap metabolic acidosis

growth failure nephrocalcinosis hypercalciuria

Type 2-Proximal RTA

Defect of the proximal tubule in bicarbonate (HCO3) reabsorption. HCO3 fully reabsorbed only when plasma HCO3 concentration <15–16 mEq/L (compared with normal threshold of 24 mEq/L). Urine pH <5.5 unless plasma HCO3 above reabsorptive threshold.

PATHOPHYSIOLOGY:

It is caused by a failure of the proximal tubular cells to reabsorb filtered bicarbonate from the urine, leading to urinary bicarbonate wasting and subsequent acidemia.

The distal intercalated cells function normally, so the acidemia is less severe than dRTA and the urine can acidify to a pH <5.3. 

it is usually associated with a generalized dysfunction of the proximal tubular cells called Fanconi's syndrome.

Fanconi's syndrome:

Clinical manifestations -phosphaturia, glycosuria, aminoaciduria, uricosuria, and tubular proteinuria. The principal feature of Fanconi's syndrome is bone demineralization due to phosphate wasting.

RISK FACTORS

-Autosomal dominant form is rare.

-Autosomal recessive form is associated with ophthalmologic abnormalities and mental retardation. Occurs in Fanconi syndrome, which is associated with several genetic diseases

ETIOLOGY

Diseases associated with Fanconi syndrome

Sporadic Multiple myeloma & other dysproteinemic

states Amyloidosis Heavy-metal poisoning Medications: Acetazolamide,

sulfanilamide, ifosfamide, outdated tetracycline, topiramate

Autoimmune disease Interstitial renal disease Nephrotic syndrome Congenital heart disease Defects in calcium metabolism

CLINICAL MANIFESTATIONS

growth failure in the 1st year of life polyuria dehydration anorexia vomiting constipation hypotonia Patients with primary Fanconi

syndrome will have additional symptoms

Those with systemic diseases will present with additional signs and symptoms specific to their underlying disease

Type 3 RTA-Combined proximal and distal RTA

Extremely rare autosomal recessive syndrome with features of both type I and type II (juvenile RTA).

Combined dRTA and pRTA is also observed as the result of inherited carbonic anhydrase II deficiency. Mutations in the gene encoding this enzyme give rise to an autosomal recessive syndrome of osteopetrosis, renal tubular acidosis, cerebral calcification, and mental retardation.

•

Type 4 RTA Due to aldosterone resistance or

deficiency that results in hyperkalemia.

It was included in the classification of renal tubular acidoses as it is associated with a mild (normal anion gap) metabolic acidosis due to a physiological reduction in proximal tubular ammonium excretion (impaired ammoniagenesis), which is secondary to hypoaldosteronism, and results in a decrease in urine buffering capacity.

Urine pH <5.5.

RISK FACTORS

Some cases familial, such as pseudohypoaldosteronism type I (autosomal dominant)

ETIOLOGY Medications: Nonsteroidal anti-

inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, heparin/LMW heparin, calcineurin inhibitors (tacrolimus, cyclosporine) (1)

Diabetic nephropathy Obstructive nephropathy Nephrosclerosis due to hypertension Tubulointerstitial nephropathies Primary adrenal insufficiency Pseudohypoaldosteronism(end-organ

resistance to aldosterone) Gordon syndrome Sickle cell nephropathy

CLINICAL MANIFESTATIONS with growth failure in the first few years of

life Polyuria Dehydration Rarely, with life-threatening hyperkalemia Patients with obstructive uropathies may

present acutely with signs and symptoms of pyelonephritis

hyperkalemic non-anion gap metabolic acidosis

Alkaline or acidic urine Elevated urine sodium levels &

inappropriately low urine potassium levels reflect the absence of aldosterone effect.

DIAGNOSIS

History collection Often asymptomatic

(particularly type IV) Failure to thrive in children Anorexia, nausea/vomiting Weakness or polyuria (due

to hypokalemia) Rickets in children Osteomalacia in adults Constipation Polydipsia

Diagnostic Tests Electrolytes - hyperchloremic metabolic

acidosis. Plasma anion gap normal (anion gap =

Na - [Cl + HCO3]) Hypokalemia or normokalemia Hyperkalemia Plasma HCO3 (in untreated RTA) Blood urea nitrogen and creatinine

usually normal (rules out renal failure as cause of acidosis)

Urine pH: Inappropriately alkaline (pH >5.5)

Urine culture: Rule out UTI with urea-splitting organism and chronic infection

Diagnostic Tests continued..

Urine anion gap: Reflects unmeasured urine anions, so inversely related to urine NH4+ (or acid) excretion. Positive urine anion gap in an acidemic patient indicates impaired renal acid excretion.

Urine calcium: High in type I Typically normal in type II

A renal ultrasound - to identify underlying structural abnormalities such as obstructive uropathies as well as to determine the presence of nephrocalcinosis.

TREATMENT

correction of the acidemia with oral sodium bicarbonate, sodium citrate or potassium citrate. This will reverse bone demineralization

Hypokalemia and urinary stone formation and nephrocalcinosis can be treated with potassium citrate tablets

Patients with proximal RTA often require large quantities of bicarbonate, up to 20 mEq/kg/24 hr in the form of sodium bicarbonate or sodium citrate solution

The base requirement for distal RTAs is generally in the range of 2-4 mEq/kg/24 hr.

Patients with Fanconi syndrome generally require phosphate supplementation .

Patients with distal RTA should be monitored for the development of hypercalciuria. Symptomatic hypercalciuria, nephrocalcinosis, or nephrolithiasis may require thiazide diuretics to decrease urine calcium excretion.

Patients with type IV RTA may require chronic treatment for hyperkalemia with sodium-potassium exchange resin

Administration of sufficient bicarbonate to reverse acidosis stops bone dissolution and the hypercalciuria.

Proximal RTA is treated with both bicarbonate and oral phosphate supplements to heal bone disease.

Vitamin D is needed to offset the secondary hyperparathyroidism that complicates oral phosphate therapy

The mainstay of therapy in all forms of RTA is bicarbonate replacement .

PROGNOSIS

• Depends on associated disease, otherwise good with therapy

• Transient forms of all types of RTA may occur.

COMPLICATIONS

• Nephrocalcinosis, nephrolithiasis (type I)

• Hypercalciuria (type I)• Hypokalemia (type I, type II if given

bicarbonate)• Hyperkalemia (type IV, some causes

of type I)• Osteomalacia (type II due to

phosphate wasting)

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