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

AKI- when do we use CRRT?

Many studies have looked at this question but with no real answer that was put forth.  In a recent 2013 AKI ( European best practice position statement) on KDIGO guidelines on RRT, they mention the following:

##Use of CRRT or IHD as complementary therapies in AKI( Grade 1A)

##Using CRRT or SLED than IHD for hemodynamically unstable patients( no grade given)

##Using CRRT rather than IHD for AKI associated with brain injury or increased intracranial pressure ( grade 2D).  – This is based on limited evidence poor quality studies.  Intermittent modes of renal replacement therapy have been shown to cause an increase in intracranial pressure in susceptible patients, including those with acute liver failure and cerebral edema from trauma or post neurosurgery. Such changes are due to the combination of adverse effects on cerebral oxygen delivery and/or cerebral perfusion pressure and the generation of an osmotic gradient between plasma and cerebral tissues. Compared with standard IHD,  CRRT provides an effective therapy in terms of solute clearance, coupled with improved cardiovascular and intracranial stability. The disadvantage of CRRT is that anticoagulation may be required, and anticoagulants with systemic effects may provoke intracerebral hemorrhage.  CRRT also has been shown to help in case reports to decrease intra cranial HTN.

##The dose of CRRT to be delivered an effluent volume of 20-25ml/kg/h for post dilution CRRT in AKI( Grade 1A)

##Medication adjustment based on clearance needs to be taken into account.

Check out the full set of guidelines here.

IgA Nephropathy and Minimal Change Disease?- a potential association

IgA nephropathy can take many variants. Classically, it can present as the nephritic syndrome but can be just benign hematuria with no other complaints. Sometimes it can be aggressive with crescents and or TMA.  Proteinuria usually suggest a bad prognostic marker in IgA nephropathy.  Sudden onset proteinuria might suggest a dual glomerular process or IgA nephropathy with a minimal change disease variant.  A recent series of cases have been described in CJASN.  A retrospective review of pathology cases in the Columbia Univ path database revealed 17 such cases.  Most had normal creatinine, proteinuria was over 8g for average and biopsy showed co dominant IgA with mesangial deposits and MCD.  14/17 patients got complete remission with steroids and additional agents.

Another case presented in this case report.

IN THE NEWS: Transplantation and risk of death from malignancies

 A recent article in KI looked at death from malignancy after renal transplantation.

Some key findings:

Single center study in England looking from 2001-2012
18% deaths were from malignancy(lymphoma>lung>renal and others)
Age and gender stratified malignancy related mortality risk difference was higher than in transplant compared to general population.
Risk factors: pre transplant history of malignancy, DDRT and age.
Lung cancer was the most common cause of malignancy death in men and lymphoma in women.
There was no significant difference in the rate of cancer-related death or location of cancer with ethnicity in our cohort, although a trend was observed toward less overall malignancy-related death in non-whites versus whites.

Not surprising to find these findings given the nature of immunosuppressive medications and prior hx of malignancies. 

IN THE NEWS: CKD and Renal Cancer Risk?

                A recent study in JASN found that those with stage 3 CKD were 39% to 100% more likely to be diagnosed with renal cell cancer over 5 years than people with Stage 2 CKD.  In addition, urothelial cancer was also more common in this group. Risk was greatest for clear cell renal cancer. No association was found with colon, lung and breast cancer or other cancers. This is the largest outcome study in a single health care system in the US looking at cancer risk and CKD.  As GFR declined, the risk of urothelial and bladder cancer increased.
A recent study in AJKD had also shown similar findings.

One thing to keep in mind in the large data base studies is the variables being adjusted for. It appears that the researchers adjusted for many of the classic cancer associated variables.  Cause was CKD was not well discussed in the manuscript. Cause can make a difference. Glomerular diseases with “ net immunosuppressive” exposure such as SLE patients with CKD are more likely to have exposure to cyclophosphamide, CNIs and other medications making them more prone to malignancies than perhaps diabetic CKDs.  They did adjust for proteinuria and hematuria and perhaps that can serve as a best surrogate as a cause.

Where do we go from here?

Should we be screening for renal cell with yearly ultrasounds on everyone with CKD?  Would it make a big difference? Screening for cancer in CKD has been a black box and perhaps studies like these shed some light on the type of cancers we should be more alerted to than the classic screening done in general population.