IN the News: Pediatric AKI related with COVID19 and MISC- tale of two NY centers

 

A recent study published in Kidney International looked at a single health system 4 hospital admissions of AKI with COVID19 and MISC in children in NY. It was during the first wave in 2020.  

Over 150 patients met inclusion criteria; 97 (63.8%) with acute-COVID-19 and 55 (36.2%) with MIS-C, AKI occurred in 11.8% of the cohort; 8 with acute-COVID-19 and 10 with MIS-C.  All but one patient with AKI were admitted to a pediatric intensive care unit (PICU). There was no significant difference in age, or ethnicity in those with and without AKI. Those who identified as black had 2.86 times higher odds of AKI (p=0.042; 95%CI 1.04-7.93). 

Majority of AKI occurred early in the course of hospitalization, 72% (N=13) within 24 hours of admission. MIS-C patients with AKI had greater rates of systolic dysfunction, compared to those without AKI (80% vs 49%, p= 0.038).  AKI, in unadjusted models, was associated with a lower serum albumin level (OR 0.17)and higher white blood cell counts (OR 1.11). In addition, patients with AKI had 8.4 day greater length of stay. Major Limitations: 1. Small sample size precluded adjustment for confounders 2. As this was an observational study, we are unable to determine causal associations. 3. Single health system/region of the country
Strengths of this study: One of the largest, detailed cohorts of pediatric patients at the epicenter of the COVID-19 outbreak and represents a diverse racial, ethnic and socioeconomic population.

Similar to reports in other PICU patients, pediatric COVID-19-related AKI was associated with longer lengths of stay published in Kidney360 also from NY area. In that study, 57 children who met inclusion criteria, 46% (26/57) were found to have AKI.  All patients had resolution of AKI at discharge, with 61% achieving recovery by day 2. One patient required dialysis. When compared to those without renal injury, the AKI cohort was older (p < 0.001) and with higher median peak values of CRP (p <0.001), IL-6 (p <0.05), ferritin (p < 0.001), and procalcitonin (p <0.05). More patients with AKI had left ventricular systolic dysfunction (p < 0.001) and lymphopenia (p <0.01), when compared to those without AKI. No differences in Body Mass Index or sex were found. 

These findings may reflect the inflammatory cascade’s complex role in development and perpetuation of COVID-19 related AKI. In addition, decreased intravascular volume and distributive/cardiogenic shock may have contributed to AKI in the MIS-C cohort. 

Check out the tweetorial by Abby Baselely 

Michelis-Castrillo syndrome

Michelis-Castrillo syndrome or Familial Hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)

The other day, I had dinner with the chief of Nephrology at Lenox Hill hospital in Manhattan, Dr. Michael Michelis. In the dinner conversation, he was describing his days in Pittsburg where he had once worked under the direction of Dr. Drash.  Interestingly, he was asked to see a family of siblings with an interesting tubular disorder. At that time he didn’t know what exactly he was dealing with. He called it “Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis : Evaluation of the pathophysiologic role of parathyroid hormone” and published it in the literature. Since then, over 50 cases of similarfindings have been described: hypomagnesemia, hypercalciuria, and nephrocalcinosis. He was told by someone else that the disease has been named after him as Michelis-Castrillo syndrome.  In a recent paper in JASN, it’s quoted as “Gitelman syndrome, and autosomal recessive familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) are two hereditary hypomagnesemic renal disorders. FHHNC was first described by Michelis et al. in 1972 (Michelis-Castrillo syndrome). "  Dr Castrillo also described this entity later in the Spanish literature (Castrillo JM, Rapado A, Traba ML, Esbrit P, Hernando L: Nefrocalcinosis con hipomagnesemia. Nefrología 3:159–165, 1983), almost 11 years after it was initially described by Dr.Michelis. The disease hence gets its name now as Michelis-Castrillo syndrome.

Since then, patients of at least 50 different FHHNC kindreds have been reported. FHHNC is generally complicated by chronic renal failure (CRF) in early childhood or adolescence. Recurrent urinary tract infections (UTI) and polyuria/polydipsia are frequent initial symptoms. In addition to marked hypomagnesemia, all affected individuals exhibit hypercalciuria and nephrocalcinosis. Additional symptoms at manifestation include nephrolithiasis, abdominal pain, convulsions, muscular tetany, failure to thrive, incomplete distal renal tubular acidosis (dRTA), and hypocitraturia. Some authors reported elevated serum parathyroid hormone (PTH) levels early in the course of the disease, independently of GFR.

  

Topic Discussion: Hyperkalemia in Bartter Syndrome

Bartter syndrome is an autosomal recessive disorder characterized by renal salt wasting, hypokalemic metabolic alkalosis, and normotensive hyperreninemic hyperaldosteronism. Five variants of Bartter syndrome have been identified depending on the affected protein in the thick ascending limb of the loop of Henle:

·        Type 1: Inactivating gene mutation that encodes the  Na+-K+-2Cl- contransporter (NKCC2)

·        Type 2: Inactivating gene mutation that encodes the apical  K+ channel (ROMK)

·        Type 3: Inactivating gene mutation that encodes the  basolateral Cl- channel (ClCNKB)

·        Type 4: Inactivating gene mutation that encodes a basolateral accessory Cl- channel subunit Barttin (BSND)

·        Type 5: Inactivating gene mutation that encodes the  basolateral Calcium sensing receptor (CASR)

Apical ROMK ensures functioning of the NKCC2 cotransporter by recycling potassium back into the renal tubular lumen so hypokalemia in patients with defects in ROMK (Bartter's type II) is relatively mild compared with that in the other forms of Bartter's syndrome.

The mechanism of hypokalemia in Bartter syndrome is thought to be increased distal potassium secretion in the CCD caused by increased distal Na+ delivery in the setting of high aldosterone levels and also by activation of the flow-mediated K+ channels (Maxi-K or BK channels).

However, it has been recognized that Type 2 Bartter syndrome can sometimes course with hyperkalemia. The reason for this can be found in the developmental aspects of potassium secretion. Satlin et al have shown that CCDs isolated from newborn rabbits and studied by in vitro microperfusion show no net K+ secretion until after the third week of postnatal life; net K+ secretory rates increase to adult levels by 6 weeks of age. The role of the maxi-K channels appears to assume great importance in regulating K+ homeostasis under conditions where ROMK K+ secretion is limited like in Type 2 Bartter syndrome. Maxi-K channels are not consistently detected in the CCD until the 4th week of life. This is worsened by the fact that children with type 2 Bartter syndrome are usually born prematurely.

Although patients with type 2 Bartter syndrome may exhibit severe hyperkalemia during the first few days of life, the hyperkalemia is usually transitory. In fact, these patients typically exhibit modest hypokalemia beyond the neonatal period probably due to maturation and presence of Maxi-K channels after the 4^th week.

Hyperkalemia during neonatal period has also been described in type I pseudohypoaldosteronism (type I PHA). However, in type I PHA hyperkalemia is sustained beyond the neonatal period and is associated with metabolic acidosis

Post by

Dr. Helbert Rondon

Topic Discussion: IgM Nephropathy

1. Initial was seen in 1978, 12 cases reported.
2. Pathology findings: mesangial proliferation, diffuse granular C3 and IgM, EM with foot process effacement and mesangial deposits ( exclusion criteria includes FSGS and Lupus Nephritis or systemic vasculitis)
3. Appears like minimal change with mesangial deposits - so steroid resistance is clinical picture as well
4. More common in children than adults
5. There is debate in the literature if this entity is real vs a part of spectrum of minimal change disease or immune complex GN with mesangial deposits.
6. Post transplant recurrent cases have been reported.
7. IgM deposition without accompanying deposits or renal dysfunction or proteinuria has been noted in many cases of donors.
8. Some studies have shown circulating IgM heavy molecules( aggregates and immune complexes ) in the serum in IgM nephropathy.

http://www.ncbi.nlm.nih.gov/pubmed/12552495
http://ndt.oxfordjournals.org/content/19/10/2650.full
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1541770/

ASN2011: Complement related disorders

This ASN, there was a series of talks regarding complement glomerulopathy and the use of certain newer agents for treatment. Dr Licht discussed this in detail in one of the talks.

Bottom line

1. MPGN pattern of injury is seen in complement related glomerular diseases.
2. DDD is now part of C3 glomerulopathies
3. Complement factor H antibodies, complement factor B antibodies have been associated with C3 glomerular disease since they will enhance c3 conversion and eventually affect the alternate pathway.
4. Genetic forms such as mutations in Factor H, CFHR5, C3 polymorphisms were also noted in that case.
5. It is possible that what we used to call perhaps C3 only post infectious GN or resolving post infectious GN was really C3 glomerulopathy.
6. Treatment is plasma exchange as there might be antibody that exists ( if you think there is)
7. Complement inhibition is the key- and the only drug we have is eculizumab ( 4 doses 900mg IV per week and 1200mg per week following that for 4 doses):- but expensive
8. Overall, there is a paradigm shift happening in introduction of these disorders.

TOPIC DISCUSSION: Atypical HUS

Hemolytic uremic syndrome (HUS) is the most common cause of pediatric acute renal failure, and need for renal replacement therapy, affecting between 0.2 and 4.28 people per 100,000 worldwide.  Term “Typical HUS” commonly used by paediatricians is referred to be with a preceding prodrome of a diarrhea (D+). Typical HUS representing >90% of HUS cases, and mainly found in childhood. This form of HUS follows gastrointestinal infection with enterohemorrhagic Escherichia coli (EHEC), as a complication of the infection with Shiga toxin–producing bacteria.  These patients require adequate care includes intravascular fluid replacement to improve the perfusion of affected organs, primarily brain, gut, and kidneys. Supportive treatment of HUS includes the transfusion of red blood cells (PRBC) and platelets. Antibiotic therapy of EHEC infection is unnecessary as the intestinal infection is self limiting and non-invasive, and antibiotics might encourage bacterial release of Stx and increase the clinical risk of HUS. Shigella related HUS requires prompt therapy with appropriate antibiotics.

 “Atypical HUS,” indicates a presentation of HUS without preceding diarrhea (D-), is a misnomer. HUS caused by EHEC colonisation, without an antecedent diarrhea is known, and on the other hand, complement mediated HUS is known to be triggered by a diarrheal prodrome.  It may be caused by pneumococcal pneumoniae or HIV, complement dysregulation, drugs (quinine, calcineurin inhibitors, chemotherapy), other pathologies (malignancy, systemic lupus erythematosus, and antiphospholipid antibody syndrome), or, rarely, to defective cobalamin metabolism in infants.

During the last 10 years, it has become evident that atypical HUS is strongly associated with mutations or polymorphism in proteins implicated for activation or regulation of the alternative pathway of complement with the Factor H heterozygous mutations representing the major cause of such HUS. Defects in the plasma and membrane-bound proteins such as complement factor H (FH) and the FH related proteins (CFHRs), factor I (FI), membrane cofactor protein (MCP, CD46), and recently thrombomodulin (THBD) play a major role in the pathogenesis of this atypical HUS. Anti- Factor H autoantibodies represent a significant etiology of atypical HUS (newly discovered), mainly in preadolescent children, but may also be present in adults. This form of HUS is frequently associated with a particular genetic status consisting frequently of unequal recombination occurring in the CFH family locus. Recent guidelines for initial therapy from the European Pediatric Study Group for HUS recommend starting plasmatherapy as early as possible, within 24 hours of presentation. This is justified by the frequent rapid deterioration of renal function in patients with CFH, combined CFI, C3, and CFB mutations (and the possibility of anti-CFH antibodies).

In conclusion, HUS is not a benign disease. Even the so-called “classical” D+ HUS has substantial long-term morbidity. The incidence of Atypical HUS is on the rise, with better understanding of the pathogenesis of the disease. New strategies are emerging including the exciting response shown to Eculizumab by the patients with EHEC 0104:H4 epidemic in Germany and Europe. More newer therapies are urgently needed for this devastating disease.

by Sidharth Kumar Sethi,
Dr Sethi is a well known Pediatric Nephrology blogger from Delhi, India.

https://www.pediatric-nephrology.com/

TOPIC DISCUSSION: Retinal-Renal Diseases

Retinal abnormalities in many inherited renal diseases is common. From CHARGE syndrome, Tuberous Sclerosis, Alports syndrome, LCAT deficiency, to Fabry's disease, VHL Syndrome and Amyloidosis are many diseases that this is noted.

Why is that is the question?
The 4 main reasons are:
1. Kidney and Retina develop at the same embryonic stages
2. The Glomerular filtration barrier is very similar to the design of the retinochoroidal junction.
3. Both glomurelus and chorioretina are large capillary beds
4. Both Podocytes( renal epithelial cells) and Retinal epithelial cells are similar in function and depend on cilia for their functions

A nice review is available on this topic in recent issue of JASN August 2011( has a detailed review of all the diseases and mechanisms)

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21372206
http://www.ncbi.nlm.nih.gov/pubmed/9457747
http://www.ncbi.nlm.nih.gov/pubmed/9227202

Concept Map of CAKUT

Based AJKD Core Curriculum in Nephrology: Kidney Development 2011
by Walker and Bertram

ref:
http://www.ncbi.nlm.nih.gov/pubmed/21514985

Asian Dialysis Modality Survey by Pediatric Nephrology

https://www.pediatric-nephrology.com/index.php?view=entry&year=2011&month=05&day=16&id=495%3Aadms

It is important to understand the preference of the RRT modality

used by various physicians specially in Asia, as it would help to

focus our preventive strategies for the future.

https://qtrial.qualtrics.com/SE/?SID=SV_7OMA39VmMSlzOvi

All Asian physicians involved in the care of children with

renal disorders are welcome to fill up this survey.

Nephrology Crosswords- Pediatric Nephrology

       

Check out the next installment of Crosswords in Kidney International

This time the topic is Pediatric Nephrology, genetic disorders.
http://www.nature.com/ki/journal/v79/n11/abs/ki201155a.html

CONSULT ROUNDS: Renal Involvement in Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS), autosomal recessive, is characterized by rod-cone(retinal) dystrophy (>90%), truncal obesity (72%), postaxial polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism, complex genitourinary malformations, and renal abnormalities and mental retardation. Renal disease is a major cause of morbidity and mortality. This disease entity falls under the category of ciliopathies. The molecular genetic profile of BBS is currently being investigated after the recent identification of 14 BBS genes involved in primary cilia-linked disease. Regular ophthalmologic evaluation, monitoring of renal function and lipid profile, and screening for diabetes mellitus; annual blood pressure measurement

What are the specific renal manifestations of this genetic disease?Renal malformations and abnormal renal function leading to end stage renal disease (ESRD) can be a major cause of morbidity. Renal manifestations include renal dysplasia characterized by malformation of the renal parenchyma and nephronophthisis which often presents with anemia, polyuria, and polydipsia in late childhood. FSGS and glomerular pathology also has been reported. Detrusor instability of the bladder or perhaps even duplication of the collecting system. A recent CJASN article summarized biopsy findings of this disease. This clinical study looked at 33 patients and found that  renal abnormalities, including impairment of renal function and signs of chronic interstitial nephropathy of dysplastic nature, were documented in 82% of the patients. Hypertension was found in >30% of the patients and hyperlipidemia in >60%, and almost 50% had other metabolic abnormalities. Interesting, recently in another paper in Kidney International 2011, this disease model was used to study water absorption in the kidney. A cohort of patients with BBS had a urinary concentration defect even when kidney function was near normal and in the absence of major cyst formation. Subsequent in vitro analysis showed that renal cells in which a BBS gene was knocked down were unciliated, but did not exhibit cell cycle defects. The authors state that  "As the vasopressin receptor 2 is located in the primary cilium, they studied BBS-derived unciliated renal epithelial cells and found that they were unable to respond to luminal arginine vasopressin treatment and activate their luminal aquaporin 2. The ability to reabsorb water was restored by treating these unciliated renal epithelial cells with forskolin, a receptor-independent adenylate cyclase activator, showing that the intracellular machinery for water absorption was present but not activated. These findings suggest that the luminal receptor located on the primary cilium may be important for efficient transepithelial water absorption."

46% of individuals with this entity have structural renal abnormalities, including calyceal clubbing or calyceal cysts, parenchymal cysts, fetal lobulation and diffuse cortical scarring, unilateral agenesis, and renal dysplasia. Clinical, this can manifest as structural abnormalities include decreased urine-concentrating capacity, renal tubular acidosis, and hypertension, stones and urinary tract infections. Progressive renal impairment frequently occurs in BBS and can lead to end-stage renal disease (ESRD) necessitating renal transplantation in up to 10% of affected individuals.

Image source: uscnk.com

Ref:                                                                                                                                                   

1. http://www.ncbi.nlm.nih.gov/pubmed/2253248
2. http://www.ncbi.nlm.nih.gov/pubmed/3249710
3. http://www.ncbi.nlm.nih.gov/pubmed/17604471
4. http://www.ncbi.nlm.nih.gov/pubmed/9509476
5. http://www.ncbi.nlm.nih.gov/pubmed/20876674
6. http://www.ncbi.nlm.nih.gov/pubmed/21270763
7. http://www.ncbi.nlm.nih.gov/books/NBK1363/