Opinion: Should we focus on targeted therapy and use less of ACEi/ARB, SGLT2i?

In nephrology, we have traditionally focused on treating CKD and fibrosis, often resorting to "band-aid" therapies for many diseases. Most guidelines suggest starting with ACE inhibitors (ACEi) or angiotensin receptor blockers (ARBs), and more recently, adding SGLT2 inhibitors (SGLT2i). This approach has proven effective for diabetic nephropathy, advanced CKD, and perhaps secondary focal segmental glomerulosclerosis (FSGS). However, is this strategy appropriate for other glomerulonephritides (GNs) and disease states?

For instance, if proteinuria is high, KDIGO recommends ACEi/ARB and conservative management as the first-line treatment for IgA nephropathy (IgAN). Should we not reconsider this approach? Why not prioritize treating the underlying disease with targeted therapies first? If these fail or CKD progression continues, we could then add ACEi/ARB, SGLT2i, and other CKD medications. For example, in lupus nephritis (LN), we initially treat the disease itself. Yet, in many GNs, we start with "band-aid" medications, which often leads to the primary disease treatment being sidelined or neglected.

A paradigm shift is needed in renal medicine, especially as new targeted therapies for conditions like IgAN, C3 glomerulopathy (C3GN), membranous nephropathy, and APOL1-mediated FSGS emerge. We should consider starting with these targeted therapies, and following up with ACEi/ARB and SGLT2i as supportive measures.

I propose adopting a methodology similar to rheumatology and oncology, where disease-modifying agents are used as first-line treatments (supported by RCT data), followed by CKD agents. While there is currently no data to support this approach, a shift in mindset is necessary to design and conduct trials based on this concept. This is a lingering thought from a nephrologist who sees other fields advancing faster than ours.

Topic Discussion: Pseudo AKI with anti cancer agents

Legend: AKI, acute kidney injury, MATE, multidrug and toxic compound extrusion; OAT, organic anion transporter; OCT, organic cation transporter

As of April 2024--most updated data on anti-cancer agents and Pseudo-AKI.

Several classes of cancer treatments are associated with pseudo-AKI.  Providers must be aware of this phenomenon, as pseudo-AKI can lead to temporary stopping and even permanent discontinuation of life-saving treatments. When patients present with increases in serum creatinine while on these drugs, checking a serum cystatin C level may help differentiate true AKI from pseudo-AKI.

Shruti Gupta and Kenar Jhaveri 

Anion gap acidosis- CUTE DIMPLES

We know MUDPILES

Then came GOLDMARK

 

Now let's welcome-- CUTE DIMPLES

There are other causes of a true high anion gap metabolic acidosis that are not captured by the MUDPILES and GOLDMARK mnemonics that should be kept in mind and are included in the recently published and modified CUTE DIMPLES mnemonic presented in CJASN by Anika A et al. 

Concept Map: Hypertension in Hemodialysis

 

This is a schematic of the treatment of resistant HTN in the hemodialysis patient. Based on a review published in JASN

Figure made using biorender.com 

In the NEWS: Intravitreal Anti VEGF agents and Kidney disease

 Check out this twitter feed I had done on the topic of Intravitreal Anti VEGF agents and the Kidney. 

In the News: Dense Deposit Disease and ApoE- the new connection

C3 glomerulopathy arises from irregularities in the alternative pathway of complement. It manifests as two types: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), identifiable by bright C3 staining in the glomeruli under immunofluorescence. EM distinguishes DDD by dense deposits along the glomerular basement membranes, contrasting with non-dense deposits in C3GN. A fascinating new study investigating 12 cases each of DDD, C3GN, and pretransplant kidney controls, laser microdissection (LCM) followed by mass spectrometry (MS) revealed a significant accumulation of complement proteins and regulatory factors in both C3GN and DDD compared to controls. Notably, DDD exhibited a much higher concentration of C5-9 and apolipoprotein E (ApoE) compared to C3GN. 

Image courtesy: pathologyoutlines.com 

ApoE staining aligned with dense deposit patterns in DDD but not in C3GN or controls, validated in 31 C3G cases. This is fascinating as perhaps ApoE staining may serve as a diagnostic tool for DDD, particularly when EM is unavailable, as it reflects the enriched presence of ApoE in dense deposits, distinguishing DDD from C3GN.

ApoE is a 34 kDa lipoprotein, that facilitates lipid transportation by binding to lipids. As we are aware, in various diseases like atherosclerosis, Alzheimer’s, and amyloidosis, ApoE plays pivotal roles in plaque formation and fibril assembly. Additionally, I learnt that it is also detected in fibrillary glomerulonephritis, immunotactoid glomerulonephritis, and monoclonal Ig deposition disease, potentially acting as a scaffolding protein. While its accumulation is significant in DDD, it's also found in other diseases but in lesser amounts. Staining for ApoE aids in diagnosing DDD alongside proliferative glomerulonephritis and bright C3 staining. Kidney accumulation of ApoE occurs predominantly in lipoprotein glomerulopathy and ApoE-related glomerulopathies. ApoE interacts with complement factors, inhibiting inflammation and regulating complement pathways. Moreover, it's a component of age-related macular degeneration but hasn't been previously identified in DDD dense deposits. This study suggests ApoE binds to heparan sulfate in the glomerular basement membrane, potentially acting as a chaperone for C5-9 proteins, contributing to dense deposit formation. Further investigation is warranted to confirm ApoE's interaction with C5-9 proteins and potential treatment strategies as a result. Kudos to the authors for making this connection. 

CONSULT ROUNDS: NELL-1 MEMBRANOUS NEPHROPATHY

 After PLA2R, NELL-1 related membranous nephropathy(MN) seems to be the second most common MN.  Initially, the studies had pointed towards a cancer-related cause for NELL-1 MN. In recent years and most recently, 2 papers published in 2024 highlight the role of complementary medications.  

A study from India investigates the clinical outcomes of NELL1-associated MN compared to unidentified antigen-associated MN. Among 46 NELL1 and 36 unidentified antigen-associated MN patients, a significant history of complementary and alternative medicine (CAM) use was noted particularly in the NELL1 group. NELL1-associated MN patients showed a lesser need for immunosuppression, attributed partly to CAM intake, with similar remission rates observed in both groups. The study highlights the distinct clinical features of NELL1-associated MN, including its association with CAM, and suggests a potential for spontaneous remission in these patients. Despite limitations like small sample size and short follow-up, findings indicate CAM's role in NELL1-associated MN and underscore the need for further research in this entity. 

A study spanning three institutions in the USA reviewed NELL1 associated MN cases, revealing that 53% of the 70 patients were male, with a median age of 66 and proteinuria of 5.9 grams/day. Associations included lipoic acid (36%), heavy NSAID use (27%), autoimmune diseases (23%), and malignancy (33%). At a median 11-month follow-up, 72% achieved remission, notably 91% in lipoic acid-associated cases with ≥6 months follow-up. Primary NELL1 MN and greater tubular atrophy and interstitial fibrosis predicted lower remission rates, while lipoic acid use correlated with higher complete remission rates, suggesting its discontinuation as a primary treatment strategy.

I have revised my concept map for NELL-1 MN based on this study to really highlight the CAM and Lipoic acid components. ( created using bio-render).