Friday, September 30, 2016

Topic Discussion: Complement and the Kidney

Image result for complement systemThe complement system can be attacked to help treat kidney disease. Complement activation contributes to the pathogenesis of acute and chronic kidney disease injury.  The aHUS and C3GN story has led us to believe that there might be hope for other potential targets in the complement system for patients with kidney disease.

A recent mini review in KI summarizes the role of the complement system in kidney disease and where future drugs hold promise. The complement activation is initiated via 3 pathways- classical, alternative and lectin.  Full activation leads to the generation of several biologically active fragments, namely C3a, C5a, C3b and C5b-9.  Drugs are currently being developed to block the classical pathway, the alternative pathway and the activation at the level of c3,c5 and c5a.

C1 inhibitors, TNT009( anti C1s) affect the classical pathway
Purified factor H, anti Factor D agents, CR2-factor H, affect the alternative pathway
Compstatin and soluble CR1 inhibits at level of C3
Eculizumab and other anti C5 inhibit at level of C5
and CCX168 inhibits at level of C5a

Check out two excellent reviews, one in KI and other in KIR

Sunday, September 25, 2016

Targeted therapies and the Kidney

Image result for targetNovel targeted anti-cancer therapies have resulted in improvement in patient survival compared to standard chemotherapy. Renal toxicities of targeted agents are increasingly being recognized.
The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. A recent uptodate review by us discusses the adverse renal effects associated with a selection of currently approved targeted cancer therapies, directed to EGFR, HER2, BRAF, MEK, ALK, PD1/PDL1, CTLA-4, and novel agents targeted to VEGF/R and TKIs.

Based on another study and look at the FDA database, electrolyte disorders, renal impairment and hypertension are the most commonly reported events with this agent. Of the novel targeted agents, ipilumumab and cetuximab have the most nephrotoxic events reported. 

Novel agents have also been tried in myeloma treatment. Renal effects of these agents are being reported as case reports and parts of clinical trials. A recent review in CJASN summaries the novel toxicities associated with new anti myeloma agents. 

The early diagnosis and prompt recognition of these renal adverse events are essential for the general nephrologist taking care of these patients.

Tuesday, September 20, 2016

Topic Discussion: Collapsing FSGS and TMA

Endothelial damage as a missing link… perhaps. Recent study published in KI tries to link TMA as a cause of collapsing variant of FSGS or CG.  They looked at 53 patients with renal limited TMA in a native kidney with emphasis on looking for FSGS.  33 of the 53 had FSGS( mostly 19 being CG, 9 with NOS type, 3 with cellular and rest perihalar and tip variant).  

Some interesting findings:

1.      Prognosis of TMA with FSGS was worse than TMA alone
2.      Most of the patients with TMA were from HTN followed by complement disorders, drugs and other causes. The more diffuse the TMA in the kidney in the 53 patients, the more likely they would have systemic TMA, higher crt and higher BP
3.      At the time of the renal biopsy, there was no significant difference between TMA without FSGS, TMA-CG, and TMA with other FSGS variants with respect to age, sex, and ethnicity. The degree of renal impairment also did not differ among the 3 groups. Proteinuria was significantly higher(2.5gm) in cases with FSGS (CG and other FSGS variants) than in cases without FSGS(1.42gm).  Nevertheless, there was no difference of proteinuria between CG and the “other FSGS” category (2.39 vs 2.72gm)
4.      The frequency of nephrotic syndrome was low in each group (5.9%, 11.8%, and 7.7% in “no FSGS,” CG, and “other FSGS” groups, respectively. This is interesting as FSGS classically presents with significant proteinuria.

5.      TMA associated CG and “classical” CG (i.e., CG related to ethnicity, viruses, or drugs, or a combination of these) differ on many points although they are indistinguishable by light microscopy.  Classic CG usually is seen in blacks, there they saw it in whites more.  The nephrotic syndrome is more severe in classic CG compared to TMA associated CG. Third, the authors found that dysregulation of the immunohistochemical phenotype of podocytes was less marked in our TMA-CG cases than in “classical” CG: although we observed podocyte dedifferentiation in one-half of the tested cases, proliferation of podocytes was not detected. This result is in accordance with the fact that the degree of podocyte dysregulation is less prominent in the reactive forms of CG.

6.      TMA-CG is associated with attenuated podocyte changes relative to “classical” CG and may be insufficient to trigger a full-blown clinical, immunohistochemical, and ultrastructural phenotype.

7.      Perhaps the TMA came first and led to HTN and ischemia and that leads to CG( hence the less severe proteinuria). Or is one protecting the other to keep the VEGF balance as too little VEGF leads to TMA and too much to CG.
8.      Clearly, this is an important association and finally something that can be seen in practice. Classically this is seen in HTN as it can lead to both forms of endothelial injury.
9.      Similar concepts have been noticed in post transplant CG in a prior post

Tuesday, September 6, 2016

CONSULT ROUNDS: Glomerular disease with Sickle cell disease

From the largest case series of 18 biopsies
The four most common histology in the glomeruli were

FSGS ( 39%)-- any variant--likely due to hypoxia
MPGN(28%)- not sure if this was immuglobulin only or complement only- but likely null IF making omre likely a chronic TMA
TMA( 17%)
Sickle cell glomerulopathy( 17%)

Here is a nice recent review by Karl Nath( editor in chief of JASN) 

Thursday, September 1, 2016

CME on Onconephrology at MD Anderson

Onconephrology Symposium at MD Anderson, Texax

When: Friday, October 14, 2016, from 8:30 am to 5:00 pm

Where: Onstead Auditorium, 6767 Bertner Ave, Houston, TX 77030
(Discounted conference rates at nearby Marriott Hotel)

Who: Healthcare professionals interested in cancer and the kidney

Topics: Nephrotoxicity of chemotherapy and targeted therapy, AKI in cancer, CKD in stem cell transplant, erythropoiesis agents, hyponatremia, hypercalcemia, ethics, dialysis and CRRT, myeloma and more!!

Speakers: Mark Perazella, Sangeeta Hingorani, Kenar Jhaveri, Ala Abudayyeh, Katy Rezvani, Steven Fishbane, Mitchell Rosner, Biff Palmer, Jennifer Scherer, Kevin Finkel, Amit Lahoti

Tuesday, August 23, 2016

Targeted therapies and tumor lysis syndrome

Novel targeted therapies are being approved in clinical trials for many hematologic malignancies. Tumor lysis syndrome (TLS) is being noticed as a novel side effect of many of these agents. A recent review in AJH summarizes the various drugs that have led to TLS as a potential side effect of targeted therapies.

TLS was most common in drug trials dealing with patients with acute leukemias, high grade non Hodgkin’s lymphomas, mantle cell lymphomas, CLL and myeloma. Some of the risk might be tumor related rather than the drug but below are the drugs that could be potential TLS promoting.
Incidence of TLS based on clinical trials for novel targeted therapies

Alvocidib (cyclin dependent kinase inhibitor) – 42% in poor risk AML patients, 13% in CLL patients
Venetoclax( ABT-199)( small molecule B cell lymphoma/leukemia 2 inhibitor)- 2.7-8.9% in CLL
Dinaciclib( cyclin dependent kinase inhibitor)- 15% in patients with AML or ALL and another 15% in CLL
Ibrutinib( Bruton kinase inhibitor)- 6.7% in CLL patients
Dasatinib( BCR-ABL tyrosine kinase inhibitors)- 4.2% in patients with ALL
Lenalidomide( immunomodulatory agent)- 3-4% in CLL patients
Obinutuzumab( anti CD20 agent)- 3-4.8% in CLL patients
Oprozomib( proteasome inhibitor)- 2.4% in various hematologic malignancies
Brentuximab vedotin( anti cd30 antibody)- 1.7% in anaplastic large cell lymphoma patients
Carfilzomib( proteasome inhibitor)- 1% in myeloma patients

Not much found in the two listed below
Idelasib( phosphatidylinositol 3-kinase inhibitor)- No TLS in CLL patients
Ofatumumab( anti CD20 agent)-No TLS in CLL patients

Wednesday, August 17, 2016

Topic Discussion: Euglycemic Diabetic Ketoacidosis

The first time the term Euglycemic DKA(eDKA) was mentioned was in 1973- in British Medical Journal in patients who were diabetic but didn't have the full blown hyperglyecmic part.  Compared to classic DKA, eDKA presents with mild to moderate hyperglycemia typically <300mg/dl blood glucose levels.  

Why is this more important now?

In 2013, many SGLT2 inhibitors got approved for DM management( the glucoretics).  The FDA performed a FAERS search of adverse effects with these agents and 73 cases were identified of ketoacidosis linked to SGLT-2 inhibitors.  All patients required hospitalization, and 60% had DMII. Blood glucose levels ranged from 90mg/dl - 1300mg/dl( median 211).  Timing of onset was around 43 days or starting or dose change of the agent.  Majority of the cases also had dehydration, infection or change in insulin doses.   No mortality has been reported with this effect.  All patients respond quickly with intravenous hydration and insulin once recognized. The FDA did acknowledge that some of the cases occurred in DMI, where it's an off label use. More detail here

Is it a class effect? 
Yes. The initial FDA reporting was done with canagliflozin(invokana). A more recent study found an incidence rate of 0.07% with this agent.  In a large study with dapagliflozin( Farxiga), 0.1% of patients got eDKA.  Empagliflozin(Jardiance) also has been found to cause eDKA. 

What are the risk factors for development of eDKA with SGLT2 inhibitors?

Alcohol use
decrease in insulin use
Low carbohydrate diet
Reduction in caloric intake
Advance age

Mechanism of action

Ketosis results from restriction of carbohydrate usage with increased reliance on fat oxidation for energy production. The pathogenesis of hyperglyemic DKA is well established. Since SGLT2 are glucoretics as described before, they can lead to volume depletion- like a diuretic and perhaps leading to a "starvation" like ketoacidosis with normal glucose levels. SGLT2 induced glycosuria can happen over 24 hours and this artificial low plasma glucose do not stimulate insulin. In eDKA, insulin deficiency and insulin resistance are milder; therefore, glucose overproduction and under-utilization are quantitatively lesser than in DKA. More importantly, renal glucose clearance (i.e., the ratio of glycosuria to prevailing glycemia) is twice as large with eDKA than with DKA. Ketoacidosis follows with the same sequence of events in eDKA as in DKA. Insufficient insulin levels will then decrease glucose utilization and promote lipolysis and ketogenesis. In addition, these drugs can increase glucagon levels leading to increase ketone production.

In summary, eDKA is pathophysiologically similar to DKA except for the circumstance—SGLT2-induced glycosuria—that “artificially” lowers plasma glucose levels and predisposes to increased ketogenesis.

Prevention and treatment

Blood and urine monitoring of ketones is essential especially when patients get ill or are experiencing one of the risk factors.  Adequate hydration and carbohydrate intake will help and holding the offending agent is indicated.  No data exists on a safe time to restart the agent. 

Here is a nice review on this topic

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