Delta –Delta or corrected HCO3- where is this other disorder hiding?

Often when we have a severe gap acidosis, we are forced to calculate the “delta/delta” and look for either a non gap acidosis or met alkalosis. How does this work?

Let’s work an example:

Ph 7.1, AG is 22 and serum Hco3 is 10 with a premise of AG metabolic acidosis.

Method one:

            Corrected bicarbonate = measured bicarbonate +( change in AG)

            Corrected bicarbonate = 10 + (22-12) = 20

If corrected bicarbonate is <22, a non gap acidosis is present as well
If corrected bicarbonate is >26, a met alk is also present.
If 22-26, a pure gap acidosis remains.

Method two: 
Think out loud,   “If the AG dropped increased from 12 to 22, there was a change of 10, hence bicarbonate should be roughly down by 10meq.  Normal bicarbonate is 24 and hence bicarbonate should be 14, but it’s 10, hence a non gap acidosis is present as well.”

Most online calculators use this method:

http://www.pharmacologyweekly.com/app/medical-calculators/anion-gap-calculator
http://errolozdalga.com/medicine/pages/AnionGap.DeltaDelta.cr.6.7.10.html

Problem with this method: Assumptions about all buffering occurring in the ECF and being totally by bicarbonate are not correct. Fifty to sixty percent of the buffering for a metabolic acidosis occurs intracellularly.

Method three: using the delta-delta ratio

delta ratio = (Increase in Anion Gap / Decrease in bicarbonate)

delta ratio = ( 10/14)=  <1 giving us the same diagnosis of combined gap and non gap acidosis.

See the below table

Delta Ratio	Assessment Guideline
0.4 - 0.8	Consider combined high AG & normal AG acidosis
1 to 2	Usual for uncomplicated high-AG acidosis Lactic acidosis: average value 1.6 DKA more likely to have a ratio closer to 1
> 2	Suggests a pre-existing elevated HCO3 level so consider: concurrent metabolic alkalosis

 As a general rule, in uncomplicated lactic acidosis, the rise in the AG should always exceed the fall in bicarbonate level.

The situation with a pure DKA  is a special case as the urinary loss of ketones decreases the anion gap and this returns the delta ratio downwards towards one. A further complication is that these patients are often fluid resuscitated with 'normal saline' solution which results in a increase in plasma chloride and a decrease in anion gap and development of a 'hyperchloraemic normal anion gap acidosis' superimposed on the ketoacidosis. The result is a further drop in the delta ratio.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/2240729?dopt=Abstract

Diabetic Kidney Disease: Old and New View

A recent article by Dr Sally Marshall in ACKD reviews the natural history of CKD in diabetic patients and reviews the old and the new view of looking at Diabetic Nephropathy. Highly recommend this article for everyone to review.  Here is a short summary of the review.

Old view:

Microalbuminuria is permanent and progresses to proteinuria in most cases.
The peak incidence of DN is 16 years and few after 35 years>
Classically, the microalbumuria progresses to proteinuria and then GFR declines
Usually, this was an older individual disease.

New view:

Low levels of albuminuria( rather than microalbuminuria) is a reversible phenomenon in majority( likely representing more of a hemodynamic change, inflammatory change or endothelial injury rather than structural damage in the kidney)

Higher levels of albuminuria are more likely to progress to proteinuria.
Peak incidence of diseases now ranging from 16-30 years
Atypical forms of presentations are becoming common where GFR decline can be seen without any prior proteinuric variant.  A vigilant watch is needed to notice this “non classical” DN
Finally, young adults are being effected with this entity and CKD become more of a common disease in Type 2 DM at an earlier age.

Clinical Case 83: Answer and Summary

Which one of these drugs is the most common culprit in acute allergic interstitial nephritis now?

Amoxicillin 13%
Omeprazole 37%
Ciprofloxacin 24%
Ibuprofen 24%

Classically, drug induced AIN has been most commonly linked with antibiotics and NSAIDS. Recently, PPIs have emerged as a more common cause of AIN than the other drugs. This might be due to the massive use of these agents for almost all patients that are admitted to the hospital for ulcer ppx.  A recent study from Mayo Clinic looked at biopsy proven AIN in a single center retrospectively and identified the culprits. Drugs were 70% of the causes followed by autoimmune diseases. The most common class of drugs were antibiotics followed by PPI and then antibiotics. But overall, the top 3 causes were omeprazole, amoxicillin and then ciprofloxacin.  Patients with PPI induced AIN were older, not as symptomatic and had longer duration of drug exposure till getting kidney biopsy. 

TOPIC DISCUSSION: Mechanism of Proteinuria in Diabetic Kidney Disease

What is the mechanism behind this entity that we see so frequently?

If we look at it from different sites of injury, there is data to support each one of these theories.

 Proximal Tubule injury:  leading to decreased protein reabsorption leading to proteinuria.

Hemodynamic injury: leading to glomerular hyperfiltration leading to increase glomerular pressure and proteinuria

Mesangial cell injury: leads to hypertrophy, matrix expansion, and mesangiolysis leading to glomerular hypefiltration and proteinuria

Endothelial cell injury: leading to altered VEGF leading to podocyte damage

GBM injury: leading to decreased negative charge and proteinuria

Podocyte injury: leading to podocytopenia or foot process effacement and leading to apoptosis, degradation or lack of proliferation.

Vascular insult:- leads to ischemia that can lead to tubular injury leading to proteinuria.

Which one is primary and which is secondary mechanism?  Can diabetic disease progress without albuminuria? Yes it can.

Current literature supports that diabetic kidney disease is mainly due to glomerular filtration barrier changes, changes in endothelial damage and GBM and direct injury to podocytes, Mesangial involvement is more of secondary role.   Tubular interstitial damage is also playing a role but it the former factors that if disrupted lead to ongoing proteinuria.  This explains why when we have accelerated HTN on top of diabetic nephropathy, there is increase in proteinuria likely due to increasing glomerular endothelial damage.

A nice review on this topic can be found in an article in KIfrom 2008.

Concept Map: Pathology findings in Hypertension and the Kidney

The different parts of the kidney have classic findings due to HTN. Classically, the glomeruli and vessels are the major targets.  The major "disease" categories that are associated with HTN findings are:

FSGS pattern of injury( due to the chronic changes)
Collapsing FSGS form of injury ( due to ischemic injury)
MPGN pattern of injury that is TMA ( negative IF and no deposits)

Here is a good reference
http://www.ncbi.nlm.nih.gov/pubmed/18408477

Topic Discussion: Diabetic Nephropathy Pathology Classification

As we all know that if there is a clinical history of DMII in someone with proteinuria or renal disease,   DM nephropathy is always on the differential on what one might find on the kidney biopsy.
Take a look at this recentpathology classification of DMII nephropathy. It starts off at classifying it in terms of mesangial expansion and leading to the classic KW lesions. It reminds you of a lupus classification but in this case, its more progressive. This article in JASN published many years ago has been the proposal paper. I am hoping validation studies are underway to confirm this. Does this help us as clinicians? Or is it more for pathologists to have a better handle on how to diagnose DM on kidney biopsy as presentations can be so variable.  Looking at the classification, I think the diagnosis of DM nephropathy will increase. Class I is more of just EM changes of GBM thickening. IIa and IIb are the classic mesangial expansion.  The KW lesion is the cornerstone of Class III and IV is bad advanced diabetic glomerulosclerosis.

Class	Description	Inclusion Criteria
I	Mild or nonspecific LM changes and EM-proven GBM thickening	Biopsy does not meet any of the criteria mentioned below for class II, III, or IV
		GBM > 395 nm in female and >430 nm in male individuals 9 years of age and oldera
IIa	Mild mesangial expansion	Biopsy does not meet criteria for class III or IV
		Mild mesangial expansion in >25% of the observed mesangium
IIb	Severe mesangial expansion	Biopsy does not meet criteria for class III or IV
		Severe mesangial expansion in >25% of the observed mesangium
III	Nodular sclerosis (Kimmelstiel–Wilson lesion)	Biopsy does not meet criteria for class IV
		At least one convincing Kimmelstiel–Wilson lesion
IV	Advanced diabetic glomerulosclerosis	Global glomerular sclerosis in >50% of glomeruli
		Lesions from classes I through III

 Table from JASN paper from above.

What we learned in medical school was one of the secondary causes of membranous GN pattern on injury was diabetes.  Classically, in practice I have rarely seen that. We classically see the mesangial changes and KW lesions. The thickening and EBM changes can appear like Membranous GN on biopsy but there are no classic deposits and there is no mention of those changes on the above classification scheme.  Membranous GN that is primary in nature can likely to co-exist with DM nephropathy. Others have mentioned this as well on websites. There is only one association I found of this in the literature and that was related to potential insulin deposits that were seen in some patients with DM that developed membranous GN and that suggestive of the pathogenetic role in the presentation. 

Diabetes rarely presents as a membranous pattern. The above mentioned patterns are the most common presentations of DMII.

TOPIC DISCUSSION: CONGESTIVE RENAL FAILURE

Concept of congestive renal failure is slowly emerging again in regards to congestive heart failure (CHF) related renal disease. The classic teaching was that renal failure in CHF is related to poor forward flow. That would make sense is the MAP is low and SBP is low and you are in a shock state. That constitutes on 5% of the CHF patients that present with cardiogenic shock. The rest are stable CHF with AKI or CKD. What is then the patho-physiology?

Well, as this article nicely puts it – it’s congestive renal failure.  It’s renal venous congestion. Studies have shown that CVP>24 are more likely to lead to AKI then CVP <8.  It’s not the SBP.  This renal venous congestion and HTN is likely from parenchymal congestion within the confines of the non distensible kidney capsule.  This would then raise the renal interstitial pressure and would lead to affect the entire capillaries and tubules leading to tissue hypoxia.  The effect on tubules and capillaries occurs most at venous pressure >15mm Hg. The best measure of this is intra-abdominal pressures done via bladder pressures.  Intra abdominal HTN might be the best marker for how bad the kidneys might be congested and about to have a renal tamponade( as Jai Radhakrishnan or a cardio-nephroligst would say it). 

Besides the above mechanisms, the active inflammatory mileau, endothelin release, reactive oxidative species release might also be contributing to AKI. 

In other words, CHF leads to venous congestion and decreased cardiac output, but the former plays  a bigger role in AKI then the later.  This below table helps summarize a quick and dirty way of looking at CHF and how to manage it in the setting of AKI based on low perfusion and or congestion at rest.

                                                                                Congestion At Rest

	No	Yes
No	Warm and Dry( good job)	Warm and Wet( most common – optimize diuretics and/or add other agents UF/tolvaptan)
Yes	Cold and Dry( r/o over diuresis)	Cold and Wet( Most dangerous and requiring LVAD/transplant)

Low Perfusion at Rest

image source: http://ahmedshokry.files.wordpress.com/2012/04/hf.jpg