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]



Understanding SPEP/Immunofixation,UPEP and free light chains

Basic understanding of Monoclonal gamapathy

Normal plasma cells secrete antibodies directed against specific antigens. It is capable of producing 5 different heavy chains (IgA, IgG, IgM,IgD,IgE)and 2 different light chains(Kappa and lambda). So, there is a possible 10 different combination of antibodies(IgG kappa, IgG lambda, IgM kappa, IgM lambda and such)For some reason there is always an excess of light chains than heavy chain which in physiologic state is excreted into the tubules but reabsorbed  completely and broken down into amino acids (recycled by tubules). If there is an excess of light chains than what the tubules can handle(as in the case of monoclonal gamapathy), light chains are excreted in urine (Benze jones protein) .

In Monoclonal gamapathy(MM, Waldenstroms and such) there is clonal proliferation of plasma cell that produces the same antibodies/clonal(not directed against antigen). Some clonal plasma cells produce just light chains and not heavy chains. Rarely some clonal plasma cells produce heavy chains and not light chains.

Now let us see what information we could get from SPEP/Immunofixation, UPEP and free light chains.


Method : Serum proteins are electrophoretically separated in SPEP based on its electrical charge. Serum proteins generally categorize in 5 different zones( albumin, alpha 1 globulin, alpha 2 globulin, beta 1 globulin, beta 2 globulin and gamma) Gamma region has the polyclonal immunoglobulin. If there is a monoclonal protein , we see a spike in the gamma region(occasionally the M spike can be seen in the alpha or beta region). The peak of the M spike in electrophoresis in relation to the total protein will help quantify the M protein. say if the spike is 40% of the total protein , then if we know the total protein quantification , we should be able to calculate the amount of M protein ex / total protein in 10 gm/dl and spike is 40% , then M protein is 4 gram/dl . So, SPEP helps determine two information.

1) The presence of M protein

2) Quantification of M protein


This is used in conjunction with SPEP. By using antibodies against the 5 different known classes of heavy chain and 2 different classes of light chain, we can determine the type of M protein. So, the immunofixation helps

1) Identify the type of M protein such as IgG Kappa or IgM lambda and such..



Some light chains are freely filtered in the glomerulus and quickly cleared from blood. So, SPEP cannot identify these light chains.Under these circumstances, UPEP will increase the sensitivity of identifying the myeloma protein when combined with SPEP. SPEP alone has 80% sensitivity and combining UPEP increases the specificity to 95%. The UPEP is done the same way as SPEP and can quantify the M protein just as in SPEP.

Free light chains

Technically, if we can obtain serum free light chains , we do not need to order UPEP since SPEP and free light chains can together increase sensitivity of identifying M protein to >95%. It is just that it is expensive compared to SPEP and UPEP combined together.


In short,

SPEP — For knowing if there is M protein and if so quantification of M protein

Immunofixation – For identifying the M protein (using antibodies agains heavy and light chains)

UPEP – For light chains in urine

Free light chain — Highly sensitive for identifying even small increase in M protein-expensive though!








Glomerulonephritis – diagnosis based on immune deposit


40 y/o with PMH significant for hep C -untreated and recent history of sore throat presents with photosensitivity rash and generalized weakness. Evaluation shows AKI, anemia, hypercalcemia and SPEP with M spike.UA shows dysmorphic RBC. Serologies are pending !

What could be the etiology of the suspected GN !

a) Hep C related MPGN

b) Post streptococcal GN

c)  Lupus nephritis

d) proliferative GN related to Monoclonal gammapathy

e) Cryoglobulinemic GN related to HepC, Lupus or Monoclonal gammapathy.

This imaginary case brings to focus the diagnosis of GN based on immune deposit.

Of course, the clinical presentation and serologies will indicate the possible diagnosis in real clinical situation! The case presented above and the following explanation is purely for understanding the immune deposits based classification of GN (Which is very useful in teasing out the etiology of GN)


1) Light microscopy in all possible diagnosis may show proliferative GN

2) Immunofluorescence may show

a)  Immune complex mediated disease process( by which I mean immunoglobulin deposition +/_ c3 deposition

If IgA dominant  ———–> IgA nephropathy or IgA dominant post infectious GN( Staph super antigen and such)

If IgG dominant and monoclonal (Either kappa or lambda and not both)——-> Monoclonal gammapathy associated proliferative GN

If IgG dominant and polyclonal (both kappa and lambda)——–> Post infectious GN

If IgM dominant and polyclonal ——————————> Chronic infection such as hepatitis and autoimmune disease

If IgA, IgG, IgM (all Ig classes, C3 and C4- full house or partly full house in appropriate clinical setting)——-> Lupus nephritis and other auto immune diseases

b) No or negligible immune deposit ; pauci-immune GN ——————> ANCA + or ANCA – vasculitis

c) Complement mediated (by which I mean trace or minimal Ig deposit)

C3 dominant with minimal immunoglobulin of any subtype  C3 GN or DDD

This understanding of immunofluorescence finding coupled with location of immune deposit in EM and complement levels will aid the diagnosis

C3 low and C4 normal—-> post infectious GN or shunt nephritis( typically staph epidermidis in patients with chronic shunt)

C4 low and C3 normal or low normal —-> Cryoglobulinemic GN from any cause(Polyclonal gammapathy, Hep C or auto immune)

Both C3 and C4 low —-> lupus nephritis

Normal complements—> ANCA + or ANCA – pauci-immune vasculitis, Good pasture disease(anti-GBM mediated), IgA nephritis or Infective endocarditis related GN which most commonly presents as pauci-immune GN.

Positive cryoglobulin in blood may or may not be pathogenic unless demonstrated as deposits in glomerular capillary loop!


Hope this helps in understanding the immune deposits in GN and its role in identifying the etiology of proliferative GN in a complex case as the one mentioned above.