Topic Discussion: Collapsing GN and high interferon states

Collapsing GN is an interesting entity that is now thought to be related to proliferative epithelial cells in the kidney rather than a form of FSGS. ApolipoproteinL1(APOL1) gene mutation has been linked with this entity as well.

Individuals with genetic variants in the ApolipoproteinL1  gene have greatly increased risk of kidney disease. The high-risk genotypes are associated with elevated risk (7–29 fold) of hypertension-associated end-stage renal disease (H-ESRD), focal segmental glomerulosclerosis (FSGS), and HIV-associated nephropathy.

Nichols et al did an interesting study that sheds light on what might be upregulating these certain genetic foci.  We are aware of interferon associated collapsing GN . This finding raised the possibility that interferons and the molecular pattern recognition receptors that stimulate interferon production may contribute to APOL1-associated kidney disease. In cell culture, interferons and toll-like receptor agonists increased APOL1 expression by up to 200-fold, in some cases with the appearance of transcripts not detected under basal conditions. PolyI:C, a double-stranded RNA TLR3 agonist, increased APOL1 expression by upregulating interferons directly or through an interferon-independent, IRF-3 dependent pathway.

The authors showed that inflammatory factors can induce APOL1 expression, and extended them to include interferon subclasses, multiple cell types, and the appearance of new APOL1 transcript variants. What produces interferons?—viruses such as HIV, HTLV, CMV, H pylori infection and cancers and autoimmune diseases such as SLE( their presence in the kidney is marked by TRI- as I had proposed is a TRI associated nephropathy)

So an APOL1 gene variant patient is doing fine till this second hit happens that increases inflammatory factors and lead to FSGS.  In SLE patients as well, APOL1 G1/G2 alleles strongly impacted the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. How many of these had the FSGS lesions, few of the patients did but there was proliferative GN as well in many of the cases. 

It basically supports the notion that “ high interferon state” + APOL1 Gene mutation == bad renal outcomes!”

In the NEWS: LVADs and ESRD

Should patients on dialysis or kidney transplant be offered LVADS for severe CHF?
A new study just published in JAMA internal Medicine showed that patients with ESRD at the time of LVAD placement had an extremely poor prognosis, with most surviving for less than 3 weeks.

This was a observational analysis of the USRDS data of all patients on ESRD that received an LVAD.  155 Medicare beneficiaries with ESRD (median and interquartile range [IQR] days from ESRD onset to LVAD placement were 1655 days [453-3050 days]) and 261 beneficiaries without ESRD in the Medicare 5% sample received an LVAD. During a median follow-up of 762 days, 127 patients (81.9%) with and 95 (36.4%) without ESRD died. More than half of patients with ESRD (80 [51.6%]) compared with 11 (4%) of those without ESRD died during the index hospitalization. The median time to death was 16 days for patients with ESRD compared with 2125 days for those without ESRD. Most of these patients were hemodialysis with a small minority being PD and transplantation. So, unclear what the data is for PD vs transplantation.

In addition, what would have happened if the patients continued conservative management and not offered LVAD- would their outcomes have been similar or better? This really brings the question on whether LVADS should be offered to ESRD patients on dialysis.

Two recent reviews in AJKD and CJASN discuss the role of the Nephrologist and the Kidney in patients with LVADs.

Clinical Case and Discussion 90

Which has a better prognosis?

C3GN, idiopathic	1 (16%)
C3GN secondary to paraproteinemias	5 (83%)

Which has a better prognosis?

— Kenar Jhaveri (@kdjhaveri) November 29, 2017

One study from the Mayo Clinic found 31% of patients with C3GN had a paraprotenemia. Bone marrow biopsy revealed a diagnosis of monoclonal gammopathy of undetermined significance (MGUS) in 90% of these patients, whereas 10% were diagnosed with low-grade chronic lymphocytic leukemia (CLL). No outcome data was reported. Another study of patients with DDD from the same institution found 71.4% of the patients. All had MGUS at the time of diagnosis, but one patient progressed to MM at 120 months of follow-up. These results are similar to those from the University of Utah, which found 83% of the patients with C3G over the age of 49, had an monoclonal gammopathy. In this cohort, 40% had multiple myeloma (MM) or smoldering MM, 40% had monoclonal gammopathy of renal significance (MGRS), and 10% had polyclonal plasmacytosis. The data was mixed regarding outcomes in that small study.

Chavet et al recently in Blood 2017 reported the outcomes of 50 patients with C3G and monoclonal gammopathy treated after treatment. The patients were divided into groups based on the treatment received: clone-directed therapy (alkylator or bortezomib [or rituximab for CLL]), immunosuppressive therapy (corticosteroids, cyclophosphamide, rituximab, mycophenolate, and azathioprine), or RAS inhibition. In this study clone-directed therapy produced superior renal survival than immunosuppressive and RAS inhibition therapy. No differences in patient survival were noted.  The differences in hematological response helped explain why renal response was superior in patients treated with clone-directed therapy. Only 5% of patients treated with immunosuppressive or RAS inhibition therapy achieved a very good partial response (VGPR) or better vs 31% of patients treated with clone-directed therapy. In fact, 95% of the patients treated with immunosuppressive or RAS inhibition therapy had no hematological response. The authors were also able to show renal function was only preserved in patients who achieved a VGPR or better, similar to other MGRS-associated kidney diseases.

While idiopathic C3GN and C3GN associated with MGUS have not been directly compared, based on the large study by Chavet et al, we can expect the outcomes to be better when there was an MGUS associated with the C3GN and the clone was treated. If you have a secondary cause, fix it and the kidney improves!

Nephro-Cards 2018 symposium

The Heart-Kidney Connection: An Update in Nephro-Cardiology 2018

Northwell health in Long Island New York will host a one-day symposium aimed at providing updates on the Nephro-Cardiology on Saturday March 10th( #nephrocards2018)

Go to this link for more information and to register. Fellow, Students and Residents registration is free

ASN, ISN, NKF and Cardio-renal society of America endorsed

Below is the itinerary


7:30am Registration, Breakfast and Exhibits

8am Contrast Nephropathy? Does it Exist-The Latest Update and Prevention
Paul M. Palevsky, MD

9am Cardio-Renal Syndrome
Jai Radhakrishnan, MD, MS, MRCP

9:30am TAVR and the Kidney
a. Basics of Transcatheter Aortic Valve Replacement: A Primer
Barry Kaplan, MD

b. The Renal Effects of Transcatheter Aortic Valve Replacemen
Kenar D. Jhaveri, MD

10:30am Break

10:45am Left Ventricular Assist Devices
a. Basics of Left Ventricular Assist Devices
David Majure, MD

b. Left Ventricular Assist Devices and the Kidney
Daniel W. Ross, MD

11:30am Novel Agents Used in Hyperkalemia - What Cardiologists and Nephrologists Need to Know
Steven Fishbane, MD

12:15pm Interventional Therapies for Refractive Hypertension
Avneet Singh, MD

12:40pm Lunch 1:30pm Novel Anticoagulants and the Kidney
Nupur N. Uppal, MD

2pm Cardiac Workup of the Kidney Transplant Patient
Alexander Lee, MD

2:30pm Cardiac Surgery and the Kidney
Mitchell H. Rosner, MD

3:30pm Panel Discussion

4pm Program Conclusion

Detective Nephron; Next Venture

Check out the next venture of Detective Nephron
This time the case of AKI

In the News: DNAJB9- a novel autoantigen staining for Fibrillary GN

A new paradigm shift in diagnosis of Fibrillary GN(FGN) has occurred. This rare form of organized deposit related GN might have a pathology staining marker in the making.

Through the use of laser microdissection assisted liquid chromatography tandem mass spectrometry , The Mayo pathologist  recently discovered a novel proteomic biomarker for FGN: DnaJ homolog subfamily B member 9 (DNAJB9), a member of the molecular chaperone gene family. When looking at specific biopsy samples of FGN vs non FGN cases, strong, homogeneous, smudgy DNAJB9 staining of glomerular deposits was seen in all but 2 cases of FGN in one report published in KI-R.

This test had a 98% sensitivity and > 99% specificity. Immunoelectron microscopy showed localization of DNAJB9 to FGN fibrils but not to amyloid fibrils or immunotactoid glomerulopathy microtubules. (http://www.kireports.org/article/S2468-0249(17)30341-8/pdf)

Another similar manuscript in JASN showed the same finding. 

http://jasn.asnjournals.org/content/early/2017/11/02/ASN.2017050566.abstract( below is the visual abstract)

Looks like we may have a diagnostic test and catch more cases of FGN 

TOPIC DISCUSSION: Diuresis in CHF

An amazing article this month in NEJM discusses Diuretic use in CHF- a must read for Cardiologist and Nephrologists.

Some interesting take home points:

1. Diuretic resistance causes: Non adherence, gut edema, impaired diuretic secretion due to CKD or aging, hypoproteinemia, hypotension, nephrotic syndrome, use of NSAIDS, low renal blood flow, nephron remodeling and neurohormonal activation.

2. Bumetanide and torsemide have higher and more consistent oral bioavailability over furosemide and make oral and IV doses kinetics similar( often under utilized by many)

3. Torsemide has the longest half life of all loop diuretics-- 6 hours.

4. Two forms of adaptations: a) A dose of loop diuretic increases urinary Na loss for few hours but then is followed by a period of very low sodium excretion often called " post diuretic Na retention". When dietary Na intake is high, the post diuretic Na retention effect will offset the initial natriuresis. 
The second is braking phenomenon.  When diuresis happens and fluid volume declines, this activates the SNS and RAS leading to nephron remodeling( distal nephron hypertrophy). This is a helpful thing to put brakes on the severe contraction of the ECF. But when this occurs in a patient that is volume overloaded, it's causing harm.

5. Treatment should aim for daily urine volume of 3-5L till euvolemia.  A stepped wise approach is suggested in bolus of furosemide followed by drip if needed. Metolazone or HCTZ( high dose) can be used as additional agents.

6. Tolvaptan: Data is mixed and can be used in some especially if Na issues are also a concern
7. Dopamine and Nesirtide - no data to support use
8. Aldactone didn't improve outcomes in acute CHF patients that require aggressive diuresis
9. Diuretic Resistance: Failure of diuretics to achieve decongestion, so with max doses you still get a a urine Na<10.
10. Use of amiloride and carbonic anhydrase inhibitors may be beneficial in diuretic resistant patients.
11. UF in CHF appears to be indicated primarily when dialytic therapy is also indicated for worsening cardiorenal syndrome.
12. Hypertonic saline with diuresis might be an interesting option -- robust trials still pending.
13. Skillful use of diuretics is the bottom line on how to succeed in treating CHF with renal dysfunction.

I had hoped the authors had commented on use of lung US in this disease. Diuretic use guided by Lung US findings might be more useful in many cases than later exam findings of edema( personal observation).