Detective Nephron: Next venture

 August 2026 issue for Detective Nephron

Topic Discussion: Futball and the Kidney ( soccer)

What happens to the kidneys during a soccer match?

With the 2026 FIFA World Cup approaching, it's the perfect time to remember that soccer doesn't just challenge the heart and muscles—it also places unique physiological stress on the kidneys. A review in Kidney Medicine explores the fascinating intersection of sports nephrology and soccer. 

⚽ Top 5 Kidney Takeaways

Most kidney changes are physiologic—not pathologic.
Transient rises in serum creatinine, exercise-induced proteinuria, microscopic hematuria, and reductions in eGFR are common after intense matches and usually resolve within 24–72 hours.

Hydration is kidney protection.

Maintaining hydration before, during, and after matches minimizes tubular stress and limits increases in biomarkers such as NGAL and KIM-1, especially during play in heat.

Creatinine isn't the whole story.
Because muscle injury elevates serum creatinine, biomarkers such as cystatin C, NGAL, and KIM-1 may better distinguish physiologic adaptation from true kidney injury in athletes.

Avoid unnecessary NSAIDs.
Dehydration, heat stress, rhabdomyolysis, and NSAID use together substantially increase the risk of acute kidney injury during competition.

Soccer remains kidney-safe for most athletes.
With appropriate hydration, individualized risk assessment, and avoidance of nephrotoxins, even many athletes with CKD, a solitary kidney, or a kidney transplant can safely participate.

Bottom line: Soccer challenges the kidneys—but in healthy athletes these changes are usually adaptive, transient, and reversible. Understanding these physiologic responses helps clinicians avoid overdiagnosis while recognizing the rare athlete who truly needs evaluation.

Figure from paper

Consult Rounds: Mantle Cell Lymphoma and the Kidney

Mantle Cell Lymphoma Isn't Just Renal Infiltration

In a paper published in KI Reports, various GNs were reported with Mantle Cell lymphoma. When we think of kidney disease in mantle cell lymphoma (MCL), we often think about direct lymphomatous infiltration. This multicenter series reminds us that immune-mediated glomerular diseases are actually common and frequently improve with lymphoma-directed therapy.

Study Highlights

• 30 patients with MCL who underwent kidney biopsy from multiple centers.

• 20 had active MCL at biopsy.

• Among those with active disease:

  • 70% had kidney lesions attributable or potentially attributable to MCL.

  • 55% had immune complex (IC) or complement-mediated glomerular disease.

  • 40% had renal lymphomatous infiltration, often coexisting with glomerular lesions.

Interestingly, renal Pathology Was Remarkably Diverse. The spectrum included:

• PGNMID (including IgG3κ cases)

• C3 glomerulonephritis

• Secondary membranous nephropathy

• Lupus-like immune complex GN

• Tubular basement membrane immune deposits

• Concurrent lymphomatous infiltration in many patients.

Perhaps the most important finding: Patients with PGNMID, C3GN, and membranous nephropathy who received lymphoma-directed therapy experienced remission of both their hematologic disease and kidney disease, with marked improvements in creatinine and proteinuria.

Unlike many monoclonal gammopathy-associated kidney diseases, most glomerular lesions were polyclonal rather than monoclonal, suggesting that immune dysregulation and complement activation—rather than direct deposition of a circulating monoclonal protein—may drive kidney injury in MCL.

In summary, Kidney injury in MCL extends far beyond direct lymphoma infiltration.  Consider kidney biopsy in MCL patients with AKI, proteinuria, or hematuria.  Successful treatment of the lymphoma can result in remission of the glomerular disease, emphasizing the importance of multidisciplinary care between nephrology, pathology, and hematology.

Consult Rounds: Histotripsy associated AKI

 

Histotripsy is an emerging non-invasive, non-thermal ablative technology that uses focused ultrasound pulses to mechanically destroy tumors through acoustic cavitation. Approved by the FDA in late 2023 for treatment of liver tumors, histotripsy has generated excitement because it can fragment tissue without surgical incisions, ionizing radiation, or traditional thermal injury. Early studies have also suggested potential downstream immunomodulatory effects beyond localized tumor destruction.

During the procedure, patients typically undergo general anesthesia in an interventional radiology suite or hybrid operating room. Real-time ultrasound guidance is used to localize the lesion and define the treatment field. High-amplitude ultrasound pulses generate dense cavitation bubble clouds that rapidly expand and collapse, mechanically fractionating tissue into acellular debris while largely sparing surrounding structures. Treatment is delivered sequentially in a raster-like pattern across the lesion with continuous imaging feedback.( see above figure created via AI)

While the oncology potential of histotripsy is substantial, nephrologists should be aware of a possible emerging complication: histotripsy-associated acute kidney injury (H-AKI). In a recent brief report published in KI Reports, a patient developed AKI with hematuria shortly after hepatic histotripsy in the absence of alternative clear insults, with improvement following hydration and supportive care.

To further explore whether this represented an isolated event or a broader signal, post-marketing review of the FDA MAUDE database identified additional cases of renal impairment following hepatic histotripsy. Reported patients were often older females with larger treatment volumes (>90 cc). Some required dialysis, while others recovered with conservative management and intravenous fluids. However, MAUDE data remain hypothesis-generating and limited by underreporting, lack of adjudication, and incomplete clinical detail.

Additional support for this phenomenon comes from an abstract presented at the Society of Interventional Radiology describing multiple cases of histotripsy-induced AKI. Interestingly, several reports described dark or discolored urine, raising the possibility of pigment-mediated tubular injury.

At present, no biopsy-proven mechanism has been reported. Proposed pathophysiologic mechanisms include hemolysis with pigment nephropathy, release of cellular debris after extensive tissue fractionation, hemodynamic injury, inflammatory cytokine release, or immune-mediated interstitial injury. Larger treatment fields may increase systemic exposure to hemoglobin, heme pigments, and intracellular contents.

Why does this matter? Histotripsy is rapidly expanding beyond hepatic tumors into renal and other solid organ malignancies. As use increases, nephrologists, oncologists, and interventional radiologists should recognize AKI as a potential procedural complication requiring early identification and supportive management. Future studies are needed to better define incidence, mechanisms, biomarkers, and preventive strategies for H-AKI.

Detective Nephron: Poem Style

 Here is the next detective nephron but a poetic version

https://www.kidneynews.org/view/journals/kidney-news/18/4/article-p12_8.xml

KDIGO updates another IgAN guideline- 2026

 

Since the 2025 IgA nephropathy (IgAN) guideline update, three major therapies have reshaped the treatment landscape. Atrasentan, an endothelin A receptor antagonist, received accelerated approval for patients at high risk of progression (uPCR ≥1.5 g/g) based on the ALIGN trial. Added on top of RAS inhibition, it achieved a 38.1% reduction in proteinuria versus 3.1% with placebo, a significant 36.1% treatment difference.

Later in 2025, sibeprenlimab, an anti-APRIL monoclonal antibody targeting B-cell–mediated IgA production, was approved following the VISIONARY trial. It demonstrated a 50.2% reduction in proteinuria versus a 2.1% increase with placebo (difference 51.2%). Importantly, it also showed robust biologic effects, reducing pathogenic Gd-IgA1 by ~70% along with significant reductions in total IgA, IgM, and IgG.

Most recently, iptacopan, a complement factor B inhibitor, showed strong long-term outcomes. Over two years, it significantly slowed eGFR decline and reduced kidney failure events (HR 0.57), with an overall safety profile similar to placebo, though with higher rates of serious infections.

Together, these therapies target distinct pathways—hemodynamic, immunologic, and complement—marking a new era of mechanism-driven IgAN treatment.

Here is the most recent KDIGO update
Above cartoon was created using AI for illustrating a battle of the new class of agents for IgAN treatment

Perspective : Not All AKI in Cancer Is ATN: A Diagnostic Wake-Up Call

AKI is increasingly common in patients with cancer. Between sepsis, volume depletion, contrast exposure, and nephrotoxic therapies, it is often tempting—and convenient—to attribute kidney injury to acute tubular necrosis. 

But what if we are wrong more often than we think?

The Problem: Diagnostic Anchoring in Onconephrology

Cancer patients represent one of the most complex populations we manage. They are exposed to multiple therapies, experience rapid physiologic changes, and frequently have overlapping clinical syndromes. Despite this, many cases of AKI are still labeled as “ATN” early in the course, often without further evaluation. This diagnostic anchoring creates a critical blind spot—one that risks missing treatable and potentially reversible causes of kidney injury.

What Are We Missing?

Several important entities can mimic ATN in patients with cancer:

Immune checkpoint inhibitor–associated acute interstitial nephritis (AIN):
With the widespread use of PD-1, PD-L1, and CTLA-4 inhibitors, AIN is increasingly recognized. It is often delayed in onset, subtle in presentation, and highly responsive to corticosteroids. Without biopsy, it is frequently missed.

Thrombotic microangiopathy (TMA):
TMA can occur in association with VEGF inhibitors, hematologic malignancies, transplantation, and even cancer itself. Importantly, it may present without classic hematologic features. Complement-mediated mechanisms are increasingly implicated. Renal limited TMA is so common and often gets missed due to lack of heme parameters. 

Light chain–mediated kidney disease:
Cast nephropathy, light chain deposition disease, and other monoclonal protein–related injuries are not always immediately recognized, particularly outside specialized hematologic settings. Often this is missed in the setting of lymphoma and NON plasma cell based heme cancers. 

Drug-induced tubulointerstitial injury:
Proton pump inhibitors, antibiotics, and targeted cancer therapies can all contribute to kidney injury. These often coexist with immunotherapy, further complicating the clinical picture.

Non Dilated Obstruction:

This is definitely missed. We see this in Onconephrology all the time and especially in retroperitoneal mets cancers and or RP masses. Renal sonogram will show NO hydronephrosis but it is still hydronephrosis and b/l PCNs improve the renal function. 

Why This Matters

Multiple studies comparing clinical diagnoses with kidney biopsy findings have demonstrated significant discordance. A substantial proportion of cases initially presumed to be ATN are reclassified after biopsy—many into diagnoses that would change management.

Despite this, kidney biopsy is often deferred due to concerns about procedural risk, patient acuity, or the perception that it will not alter treatment decisions. Increasingly, however, that assumption does not hold true.

A Practical Framework: When to Pause and Reconsider

Before assigning a diagnosis of ATN in a patient with cancer, it is worth pausing and asking whether the full differential has been considered.

Red flags that should prompt further evaluation include:

• Recent or ongoing immunotherapy

• Exposure to VEGF inhibitors or novel targeted agents ( often most folks don't do a good detailed oncology history of meds)

• Underlying or suspected hematologic malignancy

• Lack of kidney recovery despite supportive care

• Presence of proteinuria or active urine sediment

Key questions to consider:

• Would identifying AIN change management (e.g., initiation of steroids)?

• Could this represent TMA requiring targeted or complement-directed therapy?

• Would a kidney biopsy meaningfully guide treatment decisions?

• Would this patient benefit from PCN as clinically seems to have hydronephrosis but no signs on imaging?

In this setting, labeling AKI as “ATN” without careful consideration is no longer sufficient.

AKI in patients with cancer is often more than just ATN. It may reflect immune-mediated injury, complement dysregulation, or monoclonal protein–related disease.

Recognizing these possibilities is essential to delivering the right treatment at the right time.

How often are you performing kidney biopsies in patients with cancer and AKI?
Have biopsy findings changed your management in unexpected ways?
Are we underutilizing kidney biopsy in this population?

Concept Map: APOL1 Mediated Kidney Disease (AMKD)

 

Consult Rounds: the Heart Failure, hyponatremia and no clues on physical exam???-- Detective Nephron style

The Heart Failure That Left No Clues on Physical Exam

Patient: Severe heart failure

Exam: Shockingly normal
Question: Where did the signs go?

CLUE #1: The Missing Congestion

• No crackles

• No JVD

• No edema

What may be happening?
Chronic HF adapts. Lymphatics drain. Veins stretch. Congestion hides.

CLUE #2: The Resting Alibi

• Looks fine in bed

• Symptoms only with exertion

What really is happening?
The exam interrogates patients at rest—CHF commits its crimes on exertion.

CLUE #3: Masked by Modern Therapy

• Diuretics

• ARNI / MRA

• SGLT2 inhibitors

What is possible?
Congestion is controlled. The disease is not.

CLUE #4: The Low-Output Plot Twist

• Poor perfusion

• Fatigue, weakness

• No obvious volume overload

This is Low-output HF leaves few visible footprints.

CLUE #5: Body Habitus Interference

• Obesity

• Thick chest wall

Strange: Classic signs are present—but physically undetectable.

What a nephrologist can do to get FORENSIC EVIDENCE 

What solves the case when the exam fails:

• Echocardiography -- looking also at IVC

• BNP / NT-proBNP

• Lung ultrasound (B-lines > crackles)

• Hemodynamics when needed ( RHC)

Severe heart failure with a silent physical exam

Verdict: The bedside exam detects overt congestion, not chronic compensation or low-output physiology. Use POCUS wisely!