Detective Nephron: Next Adventure

 Check out the July issue of 2024 Kidney News for the next Detective Nephron.

Consult Rounds: eDKA with GLP-1R Agonists

Euglycemic diabetic ketoacidosis (DKA) is a rare but serious condition characterized by ketoacidosis without significant hyperglycemia. We have seen this complication and heard about it in SGLT2i. Apparently, this can occur in patients using GLP-1 receptor agonists as well. 

GLP-1 (glucagon-like peptide-1) agonists enhance glucose-dependent insulin secretion, suppress inappropriate glucagon release, slow gastric emptying, and promote satiety. Euglycemic DKA is rare but has been reported in patients on GLP-1 agonists, particularly in combination with other diabetes medications like SGLT2 inhibitors. Why and when:- especially in type 1 diabetes (even if undiagnosed), severe illness, surgery, dehydration, and reduced insulin doses. Dehydration and changes in diet or medication regimens can also precipitate euglycemic DKA.

FAERS reporting system study confirmed this association. Using the FAERS database, The authors extracted the number of DKA reports from the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019 and calculated proportional reporting ratios (PRRs). They then examined each FAERS file from Q1 2004 to Q4 2020 to gather detailed information on DKA reports. During the period from Q1 2004 to Q4 2019, there were 1,382 DKA cases (and 1,491 ketosis cases) linked to GLP-1RA in the FAERS database. After excluding the influence of SGLT2 inhibitors, Type 1 diabetes, and insulin, there was a slightly disproportionate reporting of DKA associated with overall GLP-1RA (PRR 1.49, 95% CI 1.24-1.79, p < 0.001). This disproportionality disappeared when GLP-1RA was combined with insulin. When GLP-1RA is not combined with insulin, there was a disproportionality of DKA reports associated with GLP-1RA. The authors's analysis of the FAERS database provides evidence and highlights the potential association between DKA adverse events and GLP-1RA therapy, which clinicians may often overlook.

Here is a case report. This case report is with GLP-1RA and SGLT2i use. Here is a summary from the UK agency. 

Diagnosis requires a high index of suspicion in diabetic patients presenting with typical DKA symptoms but normal or mildly elevated blood glucose.

Let's observe to see if we see more of these cases as more and more prescriptions are being given out in the general medicine, cards and renal community. 

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).

Consult Rounds: Hypophosphatemia and Tumor Genesis Syndrome

What is this entity? Tumor Genesis Syndrome compared to Tumor Lysis Syndrome.

Tumor lysis syndrome (TLS) is a critical medical condition that can arise in leukemias and lymphomas either as an initial presentation or after the initiation of anti-neoplastic treatments. Conversely, tumor genesis syndrome (TGS) is a rare occurrence associated with specific malignancies, particularly those characterized by a high neoplastic burden with rapid proliferation, resulting in the excessive uptake of phosphorus from the serum and leading to hypophosphatemia. Interestingly, a subset of patients may experience a combination of TLS and TGS concurrently, resulting in hypophosphatemia instead of the hyperphosphatemia typically seen in TLS.

From a nephrology perspective, this presents a potential differential diagnosis in leukemic patients. Differentiating hypophosphatemia from TGS is crucial, especially when considering other causes of severe hypophosphatemia related to neoplasms, such as tumor-induced osteomalacia. In this scenario, increased fibroblast growth factor-23 production leads to renal phosphate wasting, mimicking the hypophosphatemia seen in TGS.

In their literature review, Chan et al. highlighted an uncommon presentation involving severe hypophosphatemia, hypokalemia, acute renal failure, and acute respiratory failure in a 16-year-old patient with acute leukemia and significant leukocytosis. Conversely, Zakaria et al. reported a case of a 14-year-old boy with acute T-cell lymphoblastic leukemia who exhibited normal serum biochemistry except for marked hypophosphatemia and elevated LDH levels. Intriguingly, the child showed no symptoms related to low phosphate levels. Additionally, Radi and Nessim described a case of severe hypophosphatemia in an 82-year-old patient with lymphoma, attributing the cause to neoplastic intracellular phosphate uptake. Similarly, Aderka et al. presented a case of a 49-year-old patient with acute myelogenous leukemia experiencing hypokalemia, hypocalcemia, and severe hypophosphatemia (<1 mg/dL) leading to extreme weakness. The hypophosphatemia developed post-chemotherapy initiation and blast lysis, mainly due to the excessive phosphate uptake by leukemic blasts. Recently, another case was described with normal potassium and calcium levels, and despite very low phosphate levels, the patient did not show signs of acute respiratory failure. Additionally, low glucose, elevated LDH, and in some cases elevated lactate may be noted, which may or may not be directly related to TGS but could be a separate effect of leukemia.

Tumor Genesis Syndrome is a rare syndrome that needs to be considered in the differential diagnosis of hypophosphatemia.