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. 2019 Aug 12;5(5):e353.
doi: 10.1212/NXG.0000000000000353. eCollection 2019 Oct.

Impaired kidney structure and function in spinal muscular atrophy

Flávia C Nery  1 , Jennifer J Siranosian  1 , Ivy Rosales  1 , Marc-Olivier Deguise  1 , Amita Sharma  1 , Abdurrahman W Muhtaseb  1 , Pann Nwe  1 , Alec J Johnstone  1 , Ren Zhang  1 , Maryam Fatouraei  1 , Natassja Huemer  1 , Christiano R R Alves  1 , Rashmi Kothary  1 , Kathryn J Swoboda  1
Affiliations

Impaired kidney structure and function in spinal muscular atrophy

Flávia C Nery et al. Neurol Genet. .

Abstract

Objective: To determine changes in serum profiles and kidney tissues from patients with spinal muscular atrophy (SMA) type 1 compared with age- and sex-matched controls.

Methods: In this cohort study, we investigated renal structure and function in infants and children with SMA type 1 in comparison with age- and sex-matched controls.

Results: Patients with SMA had alterations in serum creatinine, cystatin C, sodium, glucose, and calcium concentrations, granular casts and crystals in urine, and nephrocalcinosis and fibrosis. Nephrotoxicity and polycystic kidney disease PCR arrays revealed multiple differentially expressed genes, and immunoblot analysis showed decreased calcium-sensing receptors and calbindin and increased insulin-like growth factor-binding proteins in kidneys from patients with SMA.

Conclusions: These findings demonstrate that patients with SMA type 1, in the absence of disease-modifying therapies, frequently manifest impaired renal function as a primary or secondary consequence of their disease. This study provides new insights into systemic contributions to SMA disease pathogenesis and the need to identify coadjuvant therapies.

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Figures

Figure 1
Figure 1. Kidney histopathology in patients with SMA type 1
Sections from the kidneys of SMA cases show medullary calcifications (yellow arrows, H&E and PAS) along collecting ducts. Medullary interstitial fibrosis is also present (trichrome). Representative images were taken at 100× (indicated as 10× objective) and 400× magnifications. H&E = hematoxylin and eosin; PAS = periodic acid–Schiff; SMA = spinal muscular atrophy.
Figure 2
Figure 2. Medullary calcifications in patients with SMA type 1
The medullary calcifications (black arrows) are positive for von Kossa and Alizarin red stains. Immunohistochemical studies show CD3+ (brown) and CD68+ (blue) cells along calcifications black (arrows). Representative images were taken at 100× (indicated as 10× objective) and 400× magnifications. SMA = spinal muscular atrophy.
Figure 3
Figure 3. Changes in genes involved in calcium reabsorption in the kidney from SMA participants
Volcano plots derived from (A) Nephrotoxicity RT2 Profiler PCR Array and (B) Polycystic Kidney Disease RT2 Profiler PCR Array in kidney samples from SMA and controls. Upregulated and downregulated genes are indicated in red and blue, respectively (n = 3–4). Unpaired 2-tailed Student t tests were used to compare groups. SMA = spinal muscular atrophy.
Figure 4
Figure 4. Increased IGFBPs in kidney from SMA participants
(A) Representative immunohistochemistry (magnification 100×) and (B) quantification of staining intensity for CaSR and CALB1 in kidney samples from SMA and controls (n = 9–10). (C) Representative immunoblot and (D) quantification of protein content in kidney samples from SMA (n = 4) and controls (n = 4). Data are presented as mean SEM with dots as individual values. Unpaired 2-tailed Student t tests were used to compare groups. *p < 0.05; **p < 0.01; ****p < 0.0001. CALB1 = calbindin 1; CaSR = calcium-sensing receptor; IGF = insulin-like growth factor; IGFBP = insulin-like growth factor binding proteins; SMA = spinal muscular atrophy.
See this image and copyright information in PMC

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