Concept Map: Malaria and the Kidney

 

Created using biorender.com
Credit to topic content to Dr. Mythri Shankar and Mala Sachdeva

KDIGO 2021- GN Management Guidelines: Infection associated GN

The recent KDIGO update 2021

Bacterial infection associated GN- 4 main types

Post infectious GN
Shunt nephritis
Endocarditis associated GN
IgA dominant infection related GN

All 4 of them usually have low complement levels.  No RCT for treatment
Antibiotics or surgical treatment for respective infections

Viral infection associated GN- 

Hep B- Hep B DNA >2000 IU/ml, need treatment with anti Hep B agent and no avoid immunosuppressive agents as can accelerate the viral infection.

HIV disease: HAART therapy is recommended for all HIVAN and HIVICK diseases.

Hep C associated GN:  A kidney biopsy should be performed in HCV-positive patients with clinical evidence of glomerular disease. Patients with mild or moderate forms of HCV-associated GN with stable kidney function and/or non-nephrotic proteinuria should be managed first with a DAA regimen. Patients with severe cryoglobulinemia or severe glomerular disease induced by HCV (i.e., nephrotic proteinuria or rapidly progressive kidney failure) should be treated with immunosuppressive agents (generally with rituximab as the first-line agent) and/or plasma exchange in addition to DAA therapies. Patients with HCV-related glomerular disease who do not respond to or are intolerant of antiviral treatment should also be treated with immunosuppressive agents.

Concept Map: Infections and Renal Transplant

 

Based on a recent article in CJASN by Agrawal et al.

Figure made using biorender.com 

Topic Discussion: Remdesivir in CKD and ESRD patients- what is the data thus far

Acute kidney injury (AKI) occurs at a rate of 30-40% in hospitalized patients with COVID-19.
Chronic kidney disease (CKD) and ESKD are also common comorbidities in patients who develop severe COVID-19. Data on use of these agents in CKD and ESRD is limited. 

The active metabolite of remdesivir is eliminated by the kidneys and can accumulate in patients with reduced estimated glomerular filtration rate (eGFR); moreover, the sulfobutylether-β-cyclodextrin (SBECD)carrier is known to accumulate in these patients. 

The largest clinical trials evaluating the use of this agent in COVID-19 excluded patients with stage 4 CKD or those requiring dialysis.

A multicenter study from Northwell health, BWH, MGH and U of Miami( of 18 patients) and a large study from India (46 patients) recently looked at use of remdesivir in CKD, AKI and ESKD patients. All patients studied had eGFR<30cc/min. 

In the USA study, treatment was well-tolerated, with few other AEs attributed to remdesivir. Five patients discontinued remdesivir early, only 2 of them due to AEs attributed to remdesivir (burning at IV site during the final dose and worsening kidney function); the remainder stopped due to improved clinical status (N=2) or patient preference (N=1). Overall 28-day mortality was 44% (8/18). Among patients requiring intensive care at the time of remdesivir initiation, 8 of 11 died. All 7 patients who were not requiring intensive care at baseline survived to 28 days.

In the India study, most patients tolerated the infusion well. Liver function remained stable in 28 (60.9%) cases. No patient had a severe rise in AST/ALT >5 times the upper limit of normal, therefore therapy was not required to be discontinued for this reason in any of the patients. No kidney function abnormalities attributable to drug were observed. Fourteen (30.4%) patients died, 24 (52.2%) patients were discharged from the hospital after recovery.

 

Publication	USA( Estiverne et al)	India ( Thakare et al)
Total # of AKI on dialysis	3	19
Total # of AKI non on dialysis	5	11( 5 transplant patients)
Total # of CKD patients	8	15
Total # of ESKD patients	2	16
LFT abnormalities attributed to agent	3	3
Remdesivir induced AKI	1	0
Got 5 days course	16	46
Got 10 days course	2	0

Topic Discussion: COVID-19 and the Kidney

Coronavirus disease 2019 (COVID-19) causes a severe acute respiratory syndrome. Similar to SARS outbreak, this virus has caused the 2019-2020 outbreak. It presents with a dry cough, fever, running nose, fatigue and shortness of breath. The elderly, hx of pulmonary disease, immunocompromised are at risk. Mortality rate is around 2-3% from ongoing outbreaks. 

How does this virus affect the Kidney. First and foremost, what is the data on transmission via dialysis units and infection in dialysis patients. Wuhan, China was where the outbreak occurred and started. In a single center study under open access review, 37 cases ( 16%) of HD patients were infected. 7 HD patients died and 6 had COVID-19 during this epidemic. The precaution measures taken by HD units prevented further cases. For some unclear reason, while HD patients were more likely to get this infection, the cases were milder than non HD counterparts. 

Here is the ASN suggestions for HD units for COVID-19 screening and precautions.

What about AKI? Is it common?  Again from Wuhan, in the month of the major outbreak in China, < 20 patients showed mild elevations in BUN and crt and trace albuminuria. 5 patients required CRRT. 
All patients that had CKD after this survived. Moreover, SARS-CoV-2 RNA in urine sediments was positive only in 3 patients from 48 cases without renal illness before, and one patient had a positive for SARS-CoV-2  from 5 cases with CKD. Interpretation Acute renal impairment was uncommon in COVID-19. SARS-CoV-2 infection does not significantly cause obvious acute renal injury, or aggravate CKD in the COVID-19 patients.

Interestingly, another center reported a different finding.  A large tertiary center in China studied 710 consecutive COVID19 patients, 89 (12.3%) of whom died in hospital. On admission, 44% of patients have proteinuria hematuria and 26.9% have hematuria, and the prevalence of elevated serum creatinine and blood urea nitrogen were 15.5% and 14.1% respectively. During the study period, AKI occurred in 3.2% patients. Kaplan-Meier analysis demonstrated that patients with kidney impairment have higher risk for in-hospital death. Cox proportional hazard regression confirmed that elevated serum creatinine, elevated urea nitrogen, AKI, proteinuria and hematuria was an independent risk factor for in-hospital death after adjusting for age, sex, disease severity, leukocyte count and lymphocyte count. Conclusion: The prevalence of kidney impairment (hematuria, proteinuria and kidney dysfunction) in hospitalized COVID-19 patients was high. After adjustment for confounders, kidney impairment indicators were associated with higher risk of in-hospital death. This was in strike contrast to the prior study.

Finally, hypokalemia was a common electrolyte finding in these patients. One would think GI cause as the cause, but GI symptoms were not associated with hypokalemia among 108 hypokalemia patients. Body temperature, CK, CK-MB, LDH, and CRP were significantly associated with the severity of hypokalemia. 93% of severe and critically ill patients had hypokalemia which was most common among elevated CK, CK-MB, LDH, and CRP. Urine K+ loss was the primary cause of hypokalemia.

Topic Discussion: Common Nephrotoxic drugs and their mode of enteries

Common Renal toxic drugs and their mode of entering the tubule and mechanism of toxicity

Drug Name	Mode of entry	Mechanism	Clinical Presentation(s)
Tenofivir(TDF)	Secreted via the basolateral side via OAT and then enters lumen via MRP2 in the urine.	Mitochondrial dysfunction	ATI Proximal tubulopathy Diabetes Insipidus(rare)
Gentamicin(Aminoglycosides)	They are all filtered and they are attracted to negative phospholipids and bind to megalin cubulin receptor and enter the cell.	Lysosomes binding and then cause mitochondrial damage and tubular injury—myelin bodies	ATI Bartter’s syndrome( via activating of the CaSR in the TAHL) Fanconi syndrome(rare)
Polymixin	All filtered, punch holes enter cells via organic cationic transporter(OCT) on apical surface	Apoptosis and necrosis	ATI
Vancomycin	Unclear how it enters	Complement activation Activation of reactive oxygen species Mitochondrial injury Vancomycin cast formations	ATI Worse when combined with Piperacillin / Tazobactam
Amphotericin B	Unclear how it enters	Principal cell defect via holes in the apical membrane	Distal hypokalemic RTA ATI Hypomagnesemia Nephrogenic DI
Heta-Starch, Dextran, Sucrose, Mannitol	Filtered and enter proximal cell – pinocytosis and build up and swell up cells. Cannot be metabolized	Osmotic nephrosis	ATI
Atazanavir	Minimal renal excretion, poorly soluble in urinary ph- leading to crystallization	Crystal formation	Crystal Nephropathy
Cisplatin	Enters via OCT on the basolateral side, enters and activates apoptosis	Oxidative stress	ATI Hypomagnesemia Proximal tubulopathy Salt wasting nephropathy Nephrogenic DI
Ifosfamide	Enters proximal tubular cell via OCT on the basolateral side and then metabolized to its metabolized that causes the damage	Increased oxidative stress and mitochondrial injury	ATI Fanconi syndrome

In the NEWS: Atypical parvovirus causing interstitial fibrosis and AKI

An interesting pathology study just got published in Cell.  It describes an atypical parvovirus infection in the kidney presenting as interstitial disease and fibrosis. Classically, the three lesions that have been described with parvovirus B19 infection are collapsing GN, FSGS and Minimal change disease. Both native kidneys and post transplant cases have been described.

In this study, using metagenomics, the authors identified a spontaneous nephropathy with intranuclear inclusions and the causative agent as an atypical virus, termed “mouse kidney parvovirus” (MKPV), belonging to a divergent genus of Parvoviridae. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in AKI. 

Below is the visual abstract of the study from the journal abstract.

Courtesy: Journal Article from Cell

This study highlights an interstitial inclusion type nephritis associated with parvovirus in mice. While clinically, to my knowledge, interstitial nephritis like this has not been reported with parvovirus.

A recent online discussion on twitter regarding this paper is linked below.

Fellow nephrons have you seen inclusion body nephritis in mice?
An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis https://t.co/afcgYrILuV pic.twitter.com/ffa0wYnXZ8

— Katalin Susztak (@KSusztak) September 14, 2018

Conceptually we have always known that in humans viruses can induce kidney disease and fibrosis such as seen in BK, CMV, Parvovirus and so forth. This is definitely worth studying in humans.

Consult Rounds: Parvovirus b19 and Glomerular disease

Parvovirus b19 has been associated with the following glomerular findings

1.  Collapsing GN
2. Proliferative GN
3. FSGS
4. Thrombotic Microangiopathy

https://www.ncbi.nlm.nih.gov/pubmed/17699510 in an amazing review article that summarizes all renal associated findings with parvovirus b19 especially in the transplanted kidney.

IN the NEWS: Vancomycin induced CAST nephropathy

Recent literature has linked AKI with vancomycin and zosyn and it was thought that the higher vancomycin levels might have been the culprit.

http://aac.asm.org/content/57/2/734.full

https://www.ncbi.nlm.nih.gov/pubmed/23402420?dopt=Abstract’

It was also assumed that the injury was either AIN or ATN. Few biopsies done in these cases were suggestive of ATN in the past( vancomycin mainly). Personal experience, I have seen ATN from vancomycin as well that is biopsy proven.

In JASN,  Luque et al might have discovered what is the mechanism behind vancomycin toxicity. The biopsy of a single case presented showed tubular casts entangled with uromodulin.  EM showed vancomycin particles in the tubular cast when immunogold labeling was used.  Staining with anti-vancomycin antibody revealed the specific accumulation of vancomycin in the tubular lumen mainly. Similar to myeloma casts, this leads to an intratubular obstructive ATN. A CD68+ macrophagic infiltrate was also observed surrounding the casts and within the kidney’s interstitium, suggesting that pathologic casts might induce an inflammatory process. To further confirm the pathogenicity of vancomycin-associated casts, they  retrospectively examined eight additional renal biopsies with ATN that had been performed in the clinical context of high-vancomycin trough levels preceding AKI. Similar findings were noted in the biopsies.  Vancomycin trough levels ranged from 35-106mg/dl in the 8 patients.  50% of the patients required dialysis. To confirm, they did in studies in mice and injected vancomycin and observed effects in the kidney.Kidney injuries have been visible as early as two days after vancomycin injection.

In summary, this article is the first to describe the novel form of injury an antibiotic can give.This can explain the sometimes noticed rapid rises we noted in some cases of acute ATN with vancomycin and perhaps even other antibiotics.

Should we be giving pre and post hydration like we do for acyclovir when giving vancomycin to prevent AKI?

Check out this amazing paper! Kudos on thinking out of the box and finally giving us a potential mechanism!

http://jasn.asnjournals.org/content/early/2017/01/11/ASN.2016080867.full?sid=3ef58699-863c-4696-a720-754c288e21eb

 

TOPIC DISCUSSION: New anti retrovirals and the kidney

As HIV becomes a chronic illness, novel agents to combat this virus have been out in the last decade. We are familiar with the renal toxicities of tenofivir for many years. Tenofivir is the cisplatin of the ID world.  But what about the new novel agents?
Here is a table that summarizes the new agents and their known or unknown renal toxicities

Drug name( trade)	Mechanism of Action	Renal effect	Excretion	Reference
Rilpivirine(Edurant)	Non nucleoside reverse transcriptase inhibitor	Decreases the secretion of creatinine in the proximal tubule via OCT2 , appear after 1-2 weeks after treatment and can then plateau	Renal	https://www.ncbi.nlm.nih.gov/pubmed/23211772 https://www.ncbi.nlm.nih.gov/pubmed/21763936
Dolutegravir(Tivicay)	Integrase inhibitor	Decreases the secretion of creatinine in the proximal tubule via OCT2, appear 1-2 weeks after treatment and then plateau	Liver	https://www.ncbi.nlm.nih.gov/pubmed/22905856
Cobicistat(Tybost)	Inhibitor liver enzymes so other HIV drugs effect gets enhanced	Decreases in secretion of creatinine  in the apical side of proximal tubule as it inhibits MATE 1 transporter, can be as early as day 7 of start.	Liver	https://www.ncbi.nlm.nih.gov/pubmed/22732469

Tenofivir dispoxil fumarate( TDF) is the classic nephrotoxic agent.  It actively taken up by the proximal tubular cell via OAT1 and 3 and released in urinary space by secretion of MDRP-2 and 4. There is a novel tenofivir formulation called tenofivir alafenamide fumrate( TAF) which is used in lower dosage combinations and lower level of parent drug is noted. In addition, TAF does not bind to these organic transporters and hence less renal tubular trafficking. Once out in clinical use, we might see less tenofivir related renal toxicities. 

A lot of combination agents are being used to combat the virus. The list below from FDA approved AIDS website compiles them with their trade names. The most nephrotoxic ones are the ones that contain TDF as expected or one of the above mentioned agents that block creatinine secretion.

abacavir and lamivudine (abacavir sulfate / lamivudine, ABC / 3TC)	Epzicom	No renal concerns
abacavir, dolutegravir, and lamivudine (abacavir sulfate / dolutegravir sodium / lamivudine, ABC / DTG / 3TC)	Triumeq	Slight increase in creatinine
abacavir, lamivudine, and zidovudine (abacavir sulfate / lamivudine / zidovudine, ABC / 3TC / ZDV)	Trizivir	No renal concerns
atazanavir and cobicistat (atazanavir sulfate / cobicistat, ATV / COBI)	Evotaz	Slight increase in creatinine
darunavir and cobicistat (darunavir ethanolate / cobicistat, DRV / COBI)	Prezcobix	Slight increase in creatinine
efavirenz, emtricitabine, and tenofovir disoproxil fumarate (efavirenz / emtricitabine / tenofovir, efavirenz / emtricitabine / tenofovir DF, EFV / FTC / TDF)	Atripla	Contains tenofivir- renal toxicity can be present
elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide, EVG / COBI / FTC / TAF)	Genvoya	Contains tenofivir
elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (QUAD, EVG / COBI / FTC / TDF)	Stribild	Contains tenofivir
emtricitabine, rilpivirine, and tenofovir alafenamide (emtricitabine / rilpivirine / tenofovir AF, emtricitabine / rilpivirine / tenofovir alafenamide fumarate, emtricitabine / rilpivirine hydrochloride / tenofovir AF, emtricitabine / rilpivirine hydrochloride / tenofovir alafenamide, emtricitabine / rilpivirine hydrochloride / tenofovir alafenamide fumarate, FTC / RPV / TAF)	Odefsey	Tenofvir alafenamide does not bind to the proximal tubule transporters and is potentially less nephrotoxic
emtricitabine, rilpivirine, and tenofovir disoproxil fumarate (emtricitabine / rilpivirine hydrochloride / tenofovir disoproxil fumarate, emtricitabine / rilpivirine / tenofovir, FTC / RPV / TDF)	Complera	Contains tenofivir- hence renal failure can occur and rilpivirine can increase crt as well
emtricitabine and tenofovir alafenamide (emtricitabine / tenofovir AF, emtricitabine / tenofovir alafenamide fumarate, FTC / TAF)	Descovy	Novel tenovifir- hence less likely
emtricitabine and tenofovir disoproxil fumarate (emtricitabine / tenofovir, FTC / TDF)	Truvada	Can cause AKI given tenofivir presence
lamivudine and zidovudine (3TC / ZDV)	Combivir	No renal issues
lopinavir and ritonavir (ritonavir-boosted lopinavir, LPV/r, LPV / RTV)	Kaletra	No renal issues