Classification of Metabolic Alkalosis

Dr John Gennari had another typically excellent review of metabolic alkalosis in AJKD in October. He suggests an alternative means of classifying a metabolic alkalosis according to the etiology of the alkalosis along with the physiological basis for the maintenance of the alkalosis once it has occurred. He also goes into some detail explaining the key role that chloride depletion has in the development and maintenance of a metabolic alkalosis.

The 3 subtypes that he suggested are:

1. Secondary stimulation of collecting duct ion transport:

This is the commonest type and results largely from a secondary increase in the activity of ENaC in the distal nephron leading to increased sodium reabsorption and hydrogen ion excretion. The commonest causes are chloride depletion syndromes (GI losses, CF) and the use of thiazide and loop diuretics, with congenital disorders such as Bartter and Gitelman syndrome being rarer. Severe potassium depletion can also precipitate a metabolic alkalosis. The mechanism is complicated but it includes increased proximal tubular hydrogen ion secretion, decreased activity of the Na-2K-Cl transporter in the loop of Henle (with increased NH4 transport in this segment also contributing) and subsequent increased activity of ENaC due to the higher distal delivery of sodium. This form of alkalosis is perpetuated by chloride depletion.

2. Primary stimulation of collecting duct ion transport:

This is almost always due to a pathological increase in sodium reabsorption with consequent hypertension and volume expansion. The commonest cause is primary aldosteronism. Other rarer causes include Cushing’s Syndrome, CAH, Liddle’s Syndrome, 11-hydroxysteroid dehydrogenase inhibition (licorice) or deficiency and exogenous mineralocorticoids.

3. Alkali intake or administration:

This is largely an issue of excess alkali administration in patients who are unable to excrete it rapidly – i.e. patients with abnormal renal function

This paper is highly recommended for anyone wanting to understand more about the pathophysiology of metabolic alkalosis

The Plot Thickens: Role of Plasmin in Edema Formation in Nephrotic Syndrome

I was at the ASN Kidney Week in Philadelphia last week and I had the chance to check out some abstracts and discuss with the authors. Three abstracts called my attention right away. I uploaded a post a few months ago related to the mechanisms of edema in nephrotic syndrome (NS) : in patients with NS, plasminogen is filtered from plasma and activated in distal nephron by enzyme urokinase forming plasmin. Plasmin can then proteolytically activate ENaC by cleavage of the γ-subunit, leading to sodium retention and edema. These are the abstracts:

1. Abstract: [FR-PO1777] Urinary Content of Plasmin(ogen) and Activation of ENaC Current by Urine Resides during Remission of idiopathic Nephrotic Syndrome. Buhl et al.

The same group from University of Southern Denmark who published the original plasmin study came back again and presented more evidence for their hypothesis. They took spot urine samples from 20 children with active idiopathic NS and compared them to urine samples obtained after remission in the same patients. Urine samples were analyzed for plasmin and plasminogen concentrations and urinary protease activity. Urine plasmin and plasminogen concentrations (normalized to urine creatinine concentration) and urine protease activity were found to be significantly higher in the active phase of NS in comparison to the remission phase. Not only that, the urine samples obtained in the active phase were able to evoked stronger ENaC currents than the urine samples obtained in remission phase.

2. Abstract: [FR-PO1776] Preeclampsia Is Associated with Significant Urinary Excretion of Plasmin(ogen) and the Ability of Urine To Activate ENaC In Vitro. Buhl et al.

The same group above also did another study where urine samples from 16 preeclamptic patients and 17 normotensive, non-proteinuric pregnant women (control) matched on age and gestational age were compared. Urine was analyzed for plasminogen and proteolytic activity. ENaC currents after exposure to urine was monitored in M1 cells by whole cell patch clamp. Urine plasminogen concentration (normalized to urine creatinine concentration) and proteolytic activity were increased in the urine of preeclamptic patients but not in controls. What is more, a significant positive correlation was found in the preeclamptic group between urinary plasmin(ogen) and diastolic blood pressure. The ability of the urine samples from preeclamptic patients to evoke ENaC current was abolished by amiloride to a lower level than the controls, suggesting that there might be small amounts of plasmin (ogen) present in the urine under normal conditions. The authors speculated that this might have a natural anticoagulant effect in the urine.

3. Abstract: [FR-PO1779] Nephron Expression and Distribution of the Plasminogen Receptor, PLG-RKT, and Colocalization with ENaC and uPAR, in Murine Kidney. Nangia et al.

Dr. Parmer’s group at UCSD has identified the presence of a novel Plasminogen Receptor (PLG-RKT). This PLG-RKT, apparently colocalizes with urokinase, and ENaC on the apical surface of the distal nephron, and all of these are present in an orientation to promote Plasminogen activation and ENaC processing. They actually found that urokinase was also present in the proximal tubule but in a less prominent way than in the distal nephron. The significance of the latter is unknown. Therefore, the machinery for sodium retention is present even under normal conditions.

I believe these studies give more support to the Plasmin hypothesis.

Tell me who your friends are and I will tell you who you are: NaHCO3 isn't NaCl

When managing patients with metabolic acidosis, some nephrologists are afraid of prescribing NaHCO3 because of the potential adverse consequences of increasing ECF volume and worsening blood pressure. However, there is significant evidence that the kidneys handle NaCl in a different way than they handle NaHCO3.


As far back as 1929, there have been several reports showing that blood pressure increased in hypertensive individuals on a high NaCl diet, but not on high NaHCO3 diet (Berghoff RS et al. IMJ. 1929; 56: 395–397). In 1983, Kurtz et al published a seminal paper in Science. They performed studies in uninephrectomized rats treated with desoxycorticosterone (DOC), a model for sodium-dependent hypertension. They exposed these animals to a high NaCl diet, a high NaHCO3, or Na+-ascorbate diet. The rats exposed to a high NaCl diet developed more hypertension that rats exposed to non-chloride Na+ salts. This study strongly suggests that Na+ has to be administered as a Cl- salt to raise blood pressure.

The explanation for this might be found in the cross talk between Pendrin and the epithelial sodium channel (ENaC) . Pendrin is a Cl-/HCO3- exchanger located in the apical membrane of type B and non-A-non-B intercalated cells. ENaC is a major sodium transporter located in the apical membrane of principal cells. Pendrin and ENaC reside in two different cell types that do not communicate through gap junctions. Therefore, it is not readily apparent that Na+ reabsorption is linked molecularly to Cl- transport. Despite this, significant evidence indicates that Pendrin plays a major role in ECF volume regulation , possibly via its influence on ENaC. How does this occur? The mechanism has not been completely elucidated but because Pendrin mediates HCO3- secretion, an increase in luminal or basolateral HCO3- is at least partially responsible for ENaC activation and subsequent sodium retention.