X linked diseases in kidney !

What about these X linked diseases in kidney !

From board stand point, Alport syndrome and  Fabry disease are important AND both these disorders are X linked.

Alport syndrome : Mutation in COL4A5 gene (Thin membrane disease is a structural anomaly secondary to mutation in COL4A3 and COL4A4)

Fabry disease : Mutation in alpha galactosidase A gene.

There are autosomal variants of these diseases and can rarely affect females but not tested in the boards usually!

Dent’s disease – familial nephrolithiasis is also X linked.

ADPKD  is autosomal dominant (as the name implies) – 40% associated with liver cysts, 5% associated with AVM . It is not cost effective to do screening for AVM in all patients with ADPKD. However, if there is a family history of Hemorrhagic stroke (where the risk of AVM goes up to 20%), Screening is recommended !

Medullary sponge kidney is usually a developmental anomaly but can have a hereditary predisposition!


Answers to Day 1 questions (10 questions)

1) C – ANCA vasculitis treatment  – prednisone and Cyclophosphamide. There is plasmapheresis in the choice . If they specifically ask for initial therapy, then prednisone and plasmapheresis could be considered. This patient did not have pulmonary hemorrhage and was not sick !

2) B – Fabry disease. This is an X linked recessive disease which predominantly affects male ! Deficiency of Alpha galactosidase A causes accumulation of sphingolipids(glycolipids and in this disease specifically galactoacylcerebrosidase) in blood vessels , nerves kidney and heart. The manifestations are neurological(pain and tingling in extremities, progressive CKD-especially in 3 decade, Cardiac hypertrophy, abdominal pain(accumulation of sphingolipids in blood vessels supplying intestines) and skin rash(especially around the umbilicus)

3) D – Sickle cell/Tylenol/NSAID combination should raise suspicion about papillary necrosis

4)A – Arterial line is negative pressure and is causes dialysis catheter to flatten out!

5) B – most common cause of intradialytic hypotension is diastolic dysfunction. I was tempted to choose pericardial effusion given the stem of the case .

6) E – Hyperglycemia- very common cause of PD ultrafiltration failure since it decreases the solute gradient dramatically!

7) C – Isolated scrotal swelling should raise concerns about patent processes vaginalis in a new PD patient

8) E  -Gentamycin toxicity- hypomagnesemia

9) C – Cyclosporine toxicity causes hirsutism

10) B – Increased urine oxalate -pathogenesis for calcium oxalate stone in Chron’s disease


Hope the explanation helps!


Acetazolamide in Salicylate poisoning

We discussed about a case of salicylate poisoning in noon conference today.

We had some interesting discussion about the role of Acetazolamide in salicylate poisoning.

Acetazolamide is a non bacteriostatic sulfonamide which acts as a carbonic anhydrase inhibitor and thereby causes bicarbonate , sodium and potassium loss in urine. It causes urine alkalization and this is favourable for salicylate excretion in its ionic form. However , acetazolamide has a tendency to decrease systemic Ph because of bicarbonate loss in urine and can potentially increase the neurotoxicity of salicylate. In the clinical setting where we are constantly infusing sodium bicarbonate to achieve alkalemia, the systemic acidosis caused by acetazolamide may not have clinical implication, especially since it is a long acting drug which needs several hours to cause systemic acidosis. If we are aggressively infusing sodium bicarbonate(after a bolus of 2-3 mEq/kg) to prevent systemic acidosis, starting acetazolamide appears reasonable.

There are several case reports of using acetazolamide successfully in older literature(1950-1980)

I do not see any evidence for its use or contra-indication in recent literature.

Many of the salicylate poisoning patients have concomitant hypokalemia and volume contraction.

Hypokalemia leads to increased ammoniageneis and subsequent increased net acid excretion. Volume contraction leads to  secondary hyperaldosteronism and subsequent hypokalemia and alkalemia(by increasing net acid excretion). Both hypokalemia and volume contraction do not favor the excretion of salicylate !

The focus should be on aggressively managing hypokalemia(even if not manifested at the time of presentation, we notice hypokalemia while treating with sodium bicarbonate) , alkalinizing the blood and urine. It is not now considered a standard of care to give acetazolamide for salicylate poisoning since it aggravates hypokalemia, volume contraction and systemic acidosis (although theoretically it can help alkalinize urine -which may not occur in the setting of volume contraction and hypokalemia-both factors resist urine alkalinization)and potentially worsens neurotoxicity of salicylate!

Can we consider acetazolamide to sustain high urine pH after aggressively correcting the volume, hypokalemia and achieving systemic alkalosis? The answer is anybody’s guess!




Potassium and acid base

Hypokalemia is associated with alkalosis and Hyperkalemia is associated with acidosis! We have heard about this but did ‘t know if this had mechanistic/pathogenetic significance until we heard Dr.Weiner’s lecture today.

Hypokalemia increases ammonia production in proximal tubule which is absorbed into the interstitium in the ascending loop of Henle through NKCl cotransporter (since the concentration of ammonia is several hundred folds higher than potassium in hypokalemic state). The ammonia  decreases the activity of ENaC in the principal cell , which decreases potassium excretion(this is favourable in hypokaleic state since K is conserved by this) and ammonia combines with proton secreted in the alpha intercalating cell thereby increasing net acid excretion.

In short, hypokalemia signals the cortical collecting duct to decrease potassium excretion by increasing the production of ammonia.

Hyperkalemia decreases ammonia production in proximal tubule and the net acid excretion is decreased.

It was interesting to know the cause of hyperkalemia in acidosis!

This explanation based on ammonia generation hypothesis holds good only in chronic acidosis and not in acute acidosis such as DKA and lactic acidosis.


Water diuresis and osmotic diuresis

Both water diuresis and osmotic diuresis can lead to hypernatremia!  How do we differentiate?


Water diuresis and osmotic diuresis , both present with hypernatremia and polyuria!

In water diuresis, the osmolar excretion per day is less than 1000 mOsm/day (calculated from urine osmolar concentration and urine volume) and in osmotic diuresis, the osmolar excretion per day is>1000   mOsm/day.

Water diuresis occurs in Diabetes insipidus

Osmotic diuresis occurs in Parenteral nutrition with heavy protein intake(10 grams protein yield 50 mOsm of urea) and  Diabetes mellitus(glucose is the osmole in urine that drags water with it)

It is nice to understand this concept. However in clinical situation the numbers don’t matter so much and the free water loss  is usually  from a combination of several factors!

Like,  Critically ill intubated patient recovering from ATN on TPN for nutrition. Here you have no access to free water, water diuresis from recovering ATN(some degree of renal concentrating defect/nephrogenic DI) and osmotic diuresis from TPN!

Nevertheless, it helps us identify the major contributor !



Metabolic alkalosis – understanding the classification and pathogenesis


Metabolic alkalemia is difficult to sustain since Kidneys can excrete excess bicarb and correct alkalosis quickly. When there is chloride depletion or hypokalemia, kidneys have decreased ability to excrete the excess bicarb and metabolic alkalemia ensues.

This takes us to the next question!

1) Why does chloride deficient state decreases the ability to excrete excess bicarb?

2) How does hypokalemia contribute to maintaining metabolic alkalosis?

Chloride deficient state increases bicarb reabsorption in proximal tubule and distal tubule(To maintain electro neutrality either chloride or bicarb( two predominant anions) has to be reabsorbed with sodium, so in chloride deficient state bicarb is reabsorbed). Also, in the cortical collecting duct(beta intercalated cell) chloride from the lumen is exchanged for bicarb from inside the cell. In the chloride deficient state, this is limited. I guess, these are good enough reasons for maintaing the alkalosis in chloride deficient states(what ever be the initial pathology that initiated the alkalosis)

Hypokalemia increases ammonia generation in proximal tubule and thereby facilitates acid excretion(even in alkalemic state). Hypokalemia also causes intracellular acidosis(protons exchanged for K  trying to mitigate hypokalemia)and extracellular alkalosis. This in proximal tubule will lead to increased acid excretion and bicarb reabsorption. Also, most cases of hypokalemia are associated with hyperaldosteronism (either primary or secondary ) which by itself increases acid excretion by activating H/K pump and also by K excretion in principal cell(in response to Na absorption through ENaC) which inturn is exchanged for proton .

Now we understand that to maintain metabolic alkalosis, there should be either chloride depletion or potassium depletion and it makes much more sense to classify metabolic alkalosis as

1) Metabolic alkalosis secondary to chloride depletion

2) Metabolic alkalosis secondary to potassium depletion



Chloride depletion occurs in vomiting, NG suction, diuretics (chloruretic diuretics in contrast to kaliuretic diuretics)

K depletion occurs  in the following conditions

  • Primary hyperaldosteronism
  • Cushing’s syndrome
  • Secondary hyperaldosteronism
  • Kaliuretic diuretics
  • Excessive licorice intake
  • Bartter’s syndrome 
    Severe potassium depletion

The rest of the causes of metabolic alkalosis are usually not sustainable without chloride deficient state or a potassium deficient state(milk alkali syndrome, persistent bone resorption-where kidneys will step up alkali excretion)

Vomiting, NG suction, Diuretic use, Hyperaldosteronism(primary and secondary) and Severe potassium depletion accounts for 90% of the cases of metabolic alkalosis!

Hope this helps to quickly know the differentials of metabolic alkalosis and to quickly think about the pathogenesis .





Follow up/ 03/17/2014 from commentary section

Dr.Weiner’s lecture today gives us the reason why Hypokalemia in RTA is not associated with increase in ammonia production!. The defect in Type 2 RTA is NBE2 in the basolateral membrane(most likely pathogenesis) . This increases bicarb concentration intracellularly in the proximal tubular cells and thereby the systemic acidosis is masked and the proximal tubular cells spill bicarb in the urine much more than what can be reabsorbed by distal mechanism.
In Type 1 RTA although NH3 production is increased proximally, this has to be reabsorbed in the ascending loop of Henle(NKCl cotransporter is used for ammonia reabsorption) and subsequently this reabsorbed ammonia should be secreted in the distal tubule to help H+ excretion. The defect in H+ ATP prevents NH4 + production. So the net Ammonium production is decreased in type 2 RTA and this contributes to acidosis.


Aquired Gitelman syndrome in Sjogren’s

66 y/o f with long history of Sjogren’s syndrome and RA presented with hypokalemia, hyponatremia and metabolic alkalosis. She had a TTKG> 10 when her K was 2.9 indicating K wasting. She had normal calcium level and magnesium level. Aldosterone level was elevated and Plasma renin activity was not suppressed.

24 hour urine K was increased and calcium was pending.


We suspected Gitelman syndrome!

I was very hesitant to agree with this diagnosis given the age of onset of symptomatology and the long history of Sjogren syndrome. A diagnosis which will go with her history of autoimmune disorder would have made more sense.

On reviewing  Sjogren syndrome related hypokalemia, I understood that,

1) SS can lead to Type 1 RTA (hypokalemia and acidosis) – However, the pt had alkalosis and not acidosis

2) SS can lead to Na wasting  and this subsequently leads to K wasting in principle cell(in exchange for sodium). This mechanism is entirely different from RTA

3) Autoantibodies targeted against NCC and subsequently leading to Aquired Gitelman syndrome.


Well, the third possibility sounds reasonable in this clinical setting!

Follow the link to study more about aquired Gitelman in Sjogren syndrome




Update from commentary section

There are other references for the aquired Gittelman Syndrome which I am presenting below.






Understanding free water clearance and water restriction in Hyponatremia – practical approach

On 02/28/2013  Dr.Ather presented a case in noon conference and that stimulates further learning on Free water clearance .

In normal physiologic state , hyponatremia will induce free water excretion by the kidneys(if well functioning normal kidney with adequate suppression of ADH) and thereby hyponatremia is quickly corrected  . In pathophysiologic state with persistent hyponatremia(Appropriate ADH secretion to decreased effective arterial blood volume or Hypovolemia induced appropriate ADH secretion or SIADH from pathologic condition  or medication/nausea/pain related SIADH) there is decreased free water clearance from increased ADH, which eventually results in hypotonic hyponatremia.

Now, looking at the urine electrolytes we should be able to judge if there is positive or a negative free water clearance.

1)Urine osmoles > 300 ( anything more than the serum osmoles) indicate negative free water clearance . ie- more solutes are lost than the water in comparison to plasma.

Urine osmoles <300 (or anything less than the seum osmoles) indicate positive free water clearance. ie-more water is lost than the solute in comparison to plasma.

2) If you want to be more precise in calculating the quantity of free water clearnce, you need the urine volume . Use the formula !

Since urea is not an effective osmole, we generally use electrolyte free water clearance.

3) If urine sodium and urine potassium (added together which gives the total osmotically active urine electrolytes)> serum sodium, there is a negative free waterc clearance ie- If urine sodium is 80 and urine K is 50 in a patient with serum sodium of 120( 130>120). Negative free water clearance in itself generally gives an impression that the hyponatremia cannot be corrected with free water restriction alone.

4) If urine sodium and urine potassium <serum sodium, there is a positive free water clearance ie – If urine sodium is 30 and potassium is 30 in a patient with serum sodium of 120(60<120). In this case one half of urine volume is just free water  ie ( 60/120)urine volume

The ratio of urine sodium and potassium to serum sodium can be used to estimate the amount of water restriction that would work in any given patient.

Ratio > 1 (water restriction alone may not work)—-> negative free water clearance!

Ratio 0.5 – 1.0( water restriction of  upto 500 ml)

Ratio< 0.5(water restriction of upto 1 liter may be sufficient)

This is discussed in the article attached. This article and the teaching point was discussed by Dr.Kazory in the acute consult service. The concept of osmotic free water clearance and electrolyte free water clearance, the claculation of both osmotic and electrolyte free water clearance and the clinical situation when we consider increasing the osmotic load(by increasing protein diet(every 10 gram of protein in a 70 kg man will yield 50 m osm of urea) or by administring crystalline urea or salt tablets) was discussed by several attendings in the consult service this year.


In the case discussion on 02/28/2013,

Dr. Shukla was actually insisting on the free water clearance based on the urine electrolytes(which was positive in the case presented)and Dr. Tantravahi was suspecting an additional free water administration on top of what was cleared based on calculation. In effect, the patient was receiving (either PO or iv ) more free water than what was excreted and this is the only situation where you could expect the sodium to drop !


Water Restriction in Hyponatremia[1]