Kidney biopsy findings in children with diabetes mellitus

doi:10.21203/rs.3.rs-3345441/v1

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Kidney biopsy findings in children with diabetes mellitus

https://doi.org/10.21203/rs.3.rs-3345441/v1

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published 21 Dec, 2023

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Background

Diabetic glomerulopathy may begin in childhood, but clinical kidney disease ascribable to this is uncommon in children with type 1 (insulin dependent) diabetes mellitus.

Methods

We reviewed our experience of kidney biopsies in children with type 1 diabetes mellitus.

Results

Between 1995 and 2022, there were biopsies in 17 children, with various clinical indications for biopsy, making this the largest series of biopsies in diabetic children with clinical kidney abnormalities. Four biopsies showed diabetic glomerulopathy, three showed diabetic glomerulopathy and IgA nephropathy, and ten showed a variety of conditions other than diabetic glomerulopathy: minimal change nephropathy (2), membranous nephropathy (2), thin glomerular basement membrane disease (2), non-glomerular chronic damage in Wolcott-Rallison syndrome (2), acute vasculitic glomerulonephritis (1), and IgA nephropathy (1). Clinical clues of something other than diabetic glomerulopathy included acute kidney injury, microscopic haematuria or chronic kidney impairment with little or no proteinuria, and the nephrotic syndrome after a short duration of diabetes. In addition, there were biopsies in two children with cystic fibrosis that showed changes identical with diabetic glomerulopathy, although the children were not shown to have diabetes mellitus.

Conclusions

We confirm that changes better known in adults with either type 1 or type 2 diabetes mellitus can occur in children with type 1: overt diabetic glomerulopathy either on its own or combined with other conditions, and kidney disorders other than diabetic glomerulopathy. Also, changes resembling diabetic glomerulopathy can be found in children with cystic fibrosis who are not diagnosed to have diabetes mellitus.

Diabetes mellitus

Kidney biopsy

Diabetic glomerulopathy

Cystic fibrosis

Diabetes mellitus is a major health problem. Both type 1 (insulin dependent) and type 2 (insulin resistant) diabetes mellitus increased in incidence worldwide between 1990 and 2017, although type 1, most commonly beginning in childhood, was much less prevalent than type 2 [1]. In the United Kingdom in 2021, diabetes mellitus was the commonest identifiable kidney disease in adults aged at least 18 years old starting replacement therapy for kidney failure, although no children were reported to have diabetes mellitus as the reason to start replacement therapy [2]. This emphasises the length of time that diabetic glomerulopathy, the most likely explanation of kidney failure in diabetic people, takes to cause failure.

Most adults with type 1 diabetes who had a kidney biopsy were found to have diabetic glomerulopathy, while many with type 2 diabetes had a range of kidney disorders either instead of or as well as diabetic glomerulopathy, rather than just diabetic glomerulopathy [3]. Kidney biopsy is rare in diabetic children, although biopsy has been recommended to be used more often to detect the early stages of diabetic glomerulopathy, which ideally requires sophisticated morphometry on electron microscopic sections [4]. Few series have been published of kidney biopsies in diabetic children, compared with those in adults [5].

We reviewed our experience of kidney biopsies in diabetic children in a period of over twenty-five years. In that time, there were also biopsies from two children that could not be differentiated from diabetic glomerulopathy, although the children were not shown to be diabetic.

Records from 1995 onwards in the Departments of Nephrology and Histopathology in Birmingham Children’s Hospital were searched to find children either who were known to have diabetes mellitus and had a kidney biopsy, or whose kidney biopsy was reported to show diabetic glomerulopathy. Clinical records and all available material on kidney biopsies, including light microscopic and immunohistological sections and electron micrographs, were reviewed.

Pathological diagnoses were made in standard ways [6]. In particular, diabetic glomerulopathy was identified by increased size of mesangium on light microscopy and increased width of glomerular basement membranes on electron microscopy, and often by various other features such as hyalinosis in arterioles, formation of capsular drops, adhesion of the tuft to the tubular origin, and mesangial nodules (Figs. 1, 2) [5]. The Renal Pathology Society classification of diabetic nephropathy was applied: class 1, thickening of glomerular basement membranes only; class 2, mesangial expansion, mild (2a) or severe (2b); class 3, mesangial nodules; class 4, advanced diabetic glomerulosclerosis [7]. The amount of chronic damage in kidney biopsies was measured using a morphometric method on light microscopic sections stained with periodic acid-methenamine silver, and expressed as the index of chronic damage, which is the proportion of cortex with such damage, and can range from 0–100% [8]. The index is 0% in a normal child.

Table 1

Pathological findings in kidney biopsies from 17 diabetic children and two children not known to have diabetes mellitus, arranged by age at initial biopsy, with clinical findings at biopsy and follow-up
number in series; sex	age at biopsy	duration of diabetes at biopsy	indication for biopsy	other features at biopsy	eGFR	salb	UPr/cr	pathological diagnosis	index %	age at follow- up	clinical status at follow-up
1 F	5.9y	19m	ns		88	20	nk	membranous nephropathy	2	17.5y	CKD stage 2 eGFR 68, UPr/cr 41
2 F	7.5y	72m	aki	ANCA positive (aMPO)	4	25	2755	vasculitic glomerulo- nephritis	68	10.5y	Dialysis then kidney transplant at age 10.5y
3(1) M first biopsy	8.5y	60m	ns		87	21	3759	minimal change nephropathy	0	16.1y	See following
3(2) second biopsy	13.7y	122m	cya treatment		nk	nk	nk	slight CNI damage	1	16.1y	CKD stage 2 eGFR 74, still relapsing
4 F	8.7y	104m neonatal onset	crf	Wolcott-Rallison syndrome: small kidneys	62	39	< 20	non- glomerular disorder	3	9.5y	CKD stage 3A eGFR 53, UPr/cr < 20
5 F	10.1y	36m	ns, mic ht	cystic fibrosis	98	24	774	IgA nephro- pathy plus diabetic glomerulopathy class 2b	0	17.5y	CKD stage 1 eGFR 108, UPr/cr 128
6 F	10.8y	not known diabetic	crf, pu	cystic fibrosis	66	36	274	resembles diabetic glomerulopathy class 2b	2	16.3y	CKD stage 3A eGFR 53, UPr/cr 39
7 F	11.0y	109m	mic ht	FH DM	140	nk	nk	thin GBM disease	0	12.3y	CKD stage 1 “normal U&Es”, UPr/cr 11.7
8 M	11.3y	108m	ns, rf, mac ht	HSP	34	35	166	IgA nephro- pathy plus diabetic glomerulopathy class 3	0	16.3y	CKD stage 3A eGFR 51, UPr/cr 20
9 F	12.2y	72m	mic ht	FH mic ht: father, mother, brother	88	42	< 20	thin GBM disease	1	12.4y	CKD stage 1, dipstick 2 + ht, trace pu
10 F	12.5y	73m	pu	diabetic retinopathy	123	40	656	diabetic glomerulopathy class 2a	4	15.8y	CKD stage 1 eGFR > 95, UPr/cr 873
11 F	13.0y	156m neonatal onset	crf	Wolcott-Rallison syndrome: small kidneys	43	38	21	non- glomerular disorder	3	18.4y	CKD stage 3B, UPr/cr 20
12 M	13.3y	79m	crf, pu		73	41	76	IgA nephro- pathy plus diabetic glomerulopathy class 2a	8	16.4y	CKD stage 2 cr 57, UPr/cr 76.6
13 M	13.7y	108m	pu	aPLA2R, aTHSD7A negative	107	40	26	membranous nephropathy	0	18.6y	CKD stage 2 eGFR 80, UPr/cr 21
14 M	13.9y	124m	crf, pu	Down syndrome	62	31	294	diabetic glomerulopathy class 2b	4	15.1y	CKD stage 3A eGFR 50
15 F	14.9y	36m	crf, pu		53	35	91	IgA nephro- pathy	15	15.8y	CKD stage 3B cr 129, UPr/cr < 20
16 M	14.9y	not known diabetic	ns, rf	cystic fibrosis, liver transplant at age 10y	28	30	1426	resembles diabetic glomerulopathy class 3	7	17.7y	CKD stage 5 eGFR 9 Died at age 17.9y
17 F	14.9y	179m neonatal onset	pu		nk	nk	nk	diabetic glomerulopathy class 3	5	15.9y	CKD stage nk, UPr/cr 399
18 F	15.2y	48m	ns		101	15	423	minimal change nephropathy	0	16.2y	No CKD eGFR > 95, UPr/cr < 20
19 F	15.3y	110m	pu	FH DM	89	36	238	diabetic glomerulopathy class 2a	0	16.4y	CKD stage 2 eGFR 88, UPr/cr 83

Abbreviations: aki, acute kidney injury; aMPO, antibodies to myeloperoxidase; ANCA, anti-neutrophil cytoplasmic antibodies; aPLA2R, antibodies to phospholipase A2 receptor; aTHSD7A, antibodies to thrombospondin type 1 domain-containing 7A; CKD, chronic kidney disease; CNI, calcineurin inhibitor; crf, chronic renal failure, meaning reduced eGFR; cya, ciclosporin; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; F, female; FH, family history; GBM, glomerular basement membrane; HSP, Henoch Schoenlein purpura; ht, haematuria; index, index of chronic damage; M, male; m, months; mac ht, macroscopic haematuria; mic ht, microscopic haematuria; nk, not known; ns, nephrotic syndrome; pu, proteinuria; rf, renal impairment; salb, serum albumin concentration in g/L (normal range, 43-54 g/L); U&Es, serum concentrations of urea and electrolytes; UPr/cr, urinary protein/creatinine concentration ratio in mg/mmol (normal, under 20.0 mg/mmol); y, years

Available electron microscopic material, processed in various ways and photographed on different microscopes over many years, was not suitable for detailed retrospective morphometry of the thickness distribution of glomerular basement membranes, which required standardised preparation of electron micrographs with appropriate and accurate calibration of magnification; allowance for the age of a child; unbiased, systematic, and independent sampling; an adequate number of measurements of orthogonal intercepts; and appropriate mathematical calculations [9, 10]. Instead, the pragmatic, subjective approach used by Haas [11] was followed, to identify not only abnormally thin glomerular basement membranes, as Haas did, but also with the necessary changes to identify abnormally thick basement membranes: “Most experienced renal pathologists are able to discriminate between glomerular basement membranes of normal thickness and those that are clearly thin, so in most cases it is not necessary to perform measurements” [11]. Figures 3 to 5 show electron micrographs of glomerular basement membranes that are thin, normal, and thick. In cases of doubt, the basement membranes were considered of normal thickness.

Counts were made of numbers of kidney biopsies at Birmingham Children’s Hospital and of children newly diagnosed with diabetes mellitus from 1995 to 2022 inclusive. Records were incomplete for some years and estimated counts were made by extrapolation from averages of known yearly numbers.

Relevant kidney biopsies were identified from 19 children. Seventeen were known to have type 1 diabetes mellitus, defined as requirement for treatment with insulin. One of these children had two biopsies. Two other children were not known to be diabetic but their biopsies showed changes identical with those of diabetic glomerulopathy. From 1995 to 2022 inclusive there were approximately 860 children newly diagnosed with type 1 diabetes, and approximately 1440 native (nontransplant) kidney biopsies. In this time, under 2% of diabetic children had a kidney biopsy, and under 1.5% of kidney biopsies were included in this series.

Clinical features at the time of biopsy are shown in Table 1, plus pathological diagnoses, the index of chronic damage in biopsies, and clinical outcomes. The diagnoses can be considered in four groups.

Diabetic glomerulopathy in known diabetic children

Four children (cases 10, 14, 17, and 19) had changes of diabetic glomerulopathy without another glomerular disorder (Fig. 1). One biopsy (case 10) also had vacuolation of the straight parts of proximal tubules (Armanni-Ebstein lesion). This was in the only child in the series with diabetic retinopathy. On electron microscopy, all biopsies showed thickening of glomerular basement membranes (Fig. 5), which in two was markedly variable, with irregular epithelial and endothelial surfaces in places and a fibrillary appearance in the membrane (Fig. 6) (cases 10 and 14).

Three children had a longer known duration of diabetes at biopsy than the median of the series, 79 months. Three children were biopsied to investigate heavy proteinuria, which persisted at last follow-up. The other child was biopsied to investigate heavy proteinuria and renal impairment, which also persisted. Three had an index of chronic damage more than the median of the whole series, 2%.

Diabetic glomerulopathy plus IgA nephropathy in known diabetic children

Three children had the combination of diabetic glomerulopathy and IgA nephropathy (cases 5, 8, and 12). Each biopsy showed mesangial expansion on light microscopy with deposition of IgA on immunohistological study. Electron microscopy confirmed mesangial deposits and showed thickened glomerular basement membranes.

One child (case 5) had cystic fibrosis, with a homozygous delta F508 mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The biopsy was to investigate the nephrotic syndrome. Proteinuria persisted. Another child (case 8) had a history of Henoch Schoenlein purpura, and the biopsy was to investigate the nephrotic syndrome, with macroscopic haematuria and renal impairment. Renal impairment persisted. The biopsy in the third child (case 12) was to investigate proteinuria and renal impairment, both of which persisted. This biopsy was the only one of the three with detectable chronic damage.

Kidney disorders other than diabetic glomerulopathy in known diabetic children

Ten children with no definite evidence of diabetic glomerulopathy on either light microscopy or electron microscopy had other disorders. Two children (cases 3 and 18) had minimal change nephropathy (Fig. 4). In a later kidney biopsy, five years after the first biopsy and after treatment with ciclosporin, one (case 3) had evidence of mild chronic damage consistent with effects of a calcineurin inhibitor. Both children were initially biopsied to investigate the nephrotic syndrome, which responded to steroid treatment, with a relapsing course in one.

Two children had membranous nephropathy (cases 1 and 13). One (case 13), with mild proteinuria, had IgG4 in the glomerular subepithelial deposits, without evidence of antibodies to phospholipase A2 receptor (PLA2R) or thrombospondin type 1 domain-containing 7A (THSD7A). Later, this child developed neurological symptoms and was found to have serum IgG4 antibodies to contactin-associated protein-like 2 (CASPR2) and leucine-rich glioma inactivated 1 (LGI1) [12]. The other child (case 1), with the nephrotic syndrome, had no evidence of hepatitis B or C virus infection or systemic lupus erythematosus as the cause of membranous nephropathy, but no other relevant serological tests were available at the time.

Two unrelated children (cases 7 and 9) had thin glomerular basement membrane disease (Fig. 3). Both had persistent microscopic haematuria, with normal kidney function and slight or no proteinuria.

Two unrelated children with Wolcott-Rallison syndrome (cases 4 and 11) had homozygous mutations in the eukaryotic translation initiation factor 2 alpha kinase 3 gene (EIF2AK3) [13]. They had neonatal diabetes mellitus, skeletal dysplasia, developmental delay, and intermittent liver dysfunction. The kidney biopsies were to investigate renal impairment without significant proteinuria. Both biopsies had evidence of a congenital or acquired primarily non-glomerular disorder of the kidneys, with chronic damage, many shrunken or globally sclerosed glomeruli in one, and many fetal glomeruli in the other, but no definite evidence of diabetic glomerulopathy. One child (case 11, reported previously [14]), had normal kidneys on ultrasound examination at ages four months and seven years but had small kidneys at ten years of age, the right on the fifth centile and the left on the 25th centile, with scarring of the upper pole of this kidney on a dimercaptosuccinic acid (DMSA) scan. No material was available for electron microscopy. The other child (case 4) had symmetrically small kidneys on a DMSA scan.

One child (case 2) had vasculitic glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies (ANCA) against myeloperoxidase, and presented with severe acute kidney injury, already with extensive chronic kidney damage. She remained on dialysis until kidney transplantation, three years after presentation.

The other child (case 15) had IgA nephropathy, and was biopsied to investigate renal impairment with proteinuria. There was already a moderate amount of chronic kidney damage. Renal impairment progressed but proteinuria improved.

Changes identical with diabetic glomerulopathy in children not known to be diabetic

Two children had changes identical with diabetic glomerulopathy, although they were not known to have diabetes mellitus (cases 6 and 16). One biopsy contained mesangial nodules (Fig. 2). Both biopsies had marked, irregular thickening of glomerular basement membranes on electron microscopy, as described above (Fig. 6), with chronic kidney damage. Both children had cystic fibrosis, diagnosed at birth, with homozygous delta F508 mutations in the CFTR gene.

One child (case 6), reported previously [15], had one documented episode of glycosuria at six years of age and transient proteinuria at the same age, but no other known glycosuria before a kidney biopsy at nearly 11 years of age, which was to investigate heavy proteinuria and renal impairment. After the biopsy, a glucose tolerance test was normal and there was no further glycosuria before 17 years of age, when the child was transferred to adult care. Proteinuria fluctuated but was still reported to be present at 22 years of age.

The other child (case 16) had a liver transplant at the age of 10 years for hepatic complications of cystic fibrosis. The kidney biopsy, four years later, which was to investigate the nephrotic syndrome and renal impairment, was originally reported to show chronic effects of ciclosporin. After the child’s death, three years after the biopsy, retrospective review by another pathologist showed changes consistent with diabetic glomerulopathy. The clinical notes made no mention of diabetic symptoms or glycosuria, no glucose tolerance test was done, and a random serum concentration of glucose and the proportion of glycated haemoglobin (HbA1C) were both in the normal range six months before death.

The 19 children in our series all had clinical indications for kidney biopsy. In contrast, there was no clinical kidney abnormality apart from microalbuminuria in eight patients among the 243 biopsied by the International Diabetic Nephropathy Study Group in what was almost certainly the largest series of kidney biopsies in children with type 1 diabetes, although the number of children was not specified in the series of patients aged 10 to 40 years at biopsy (mean 16.8 years) [16].

In that study, detailed morphometry on electron micrographs showed, among other things, that the prevalence of thickening of the glomerular basement membrane and of enlarged mesangial volume both increased in proportion to the duration of type 1 diabetes [17]. The morphometric methods used in that study were unrealistic in everyday practice and were to detect the earliest changes of diabetic glomerulopathy before these were clinically evident [9]. Accordingly, the assessment of diabetic glomerulopathy that we used, specifically, judgment of glomerular basement membrane thickness, was practical but crude and subjective [11], and we may have missed early and subtle changes of this in association with recognisable glomerular disorders. Even in the Renal Pathology Society classification of diabetic nephropathy [7], how the thickness of glomerular basement membranes should be measured was not standardised, and so the identification of the earliest stages of thickening of basement membranes may be difficult in routine practice because the definition is to some extent arbitrary.

Only two other series appear to have been published reporting findings in type 1 diabetic children who had a kidney biopsy for a clinical abnormality, both investigating the nephrotic syndrome, and both with few biopsies, two [18] and five [19]. Diabetic glomerulopathy has been reported in children with type 1 diabetes even before clinical abnormalities ascribable to diabetes mellitus were apparent [17], although this does not mean that clinical abnormalities will necessarily develop. In another study that used a sophisticated morphometric method [9], in 71 initially normoalbuminuric type 1 diabetic patients, mostly adults, after a mean of 19.1 years of diabetes at renal biopsy and after a mean of 12.7 years of follow up, two thirds of those with thickened basement membranes remained normoalbuminuric, while only one third progressed to develop proteinuria or end stage renal disease [20].

An electron microscopic feature that we found has been overlooked in most accounts of diabetic glomerulopathy, but was described in 1964 by Dachs et al. [21]. This was a change they called “membranous transformation”, in which the epithelial aspect and, to a lesser degree, the endothelial aspect of thick glomerular basement membranes were irregularly scalloped or studded with spike-like projections, as in our Fig. 6, and as illustrated in human diabetic glomerulopathy [22] and experimental diabetes mellitus in rats [23]. The irregularity of the projections, their scattered distribution on basement membranes, and the lack of immune deposits on immunohistological study differentiated this change from membranous nephropathy.

Four children in our series had diabetic glomerulopathy on its own, and three had diabetic glomerulopathy and IgA nephropathy. This combination has been reported in adults [3, 24, 25], and there has been speculation that IgA nephropathy is commoner in diabetic patients than in non-diabetic people [26]. We also had one child apparently with IgA nephropathy on its own. This was an example of the well-known finding of non-diabetic kidney diseases in diabetic patients, much more commonly reported in adults than in children [3, 18, 19, 24–28]. In diabetic children, minimal change nephropathy seems the commonest condition reported [19]. Clinical clues in our series that a kidney biopsy may show something other than diabetic glomerulopathy included acute kidney injury, either microscopic haematuria or chronic renal impairment with little or no proteinuria, and the nephrotic syndrome with a relatively short duration of diabetes (Table 1).

Two conditions worth special mention are (1) membranous nephropathy occurring with IgG4 antibodies to CASPR2 and LGI1, which are associated with neurological problems although an association with membranous nephropathy does not appear to have been reported previously [12], and (2) Wolcott-Rallison syndrome. In this syndrome, the most usual way in which the kidneys are affected is by episodes of acute, reversible kidney dysfunction when there is liver dysfunction [13]. Permanent structural changes in the kidney have only rarely been reported [14, 29], and in particular, diabetic glomerulopathy seems not to have been reported.

Changes identical with diabetic glomerulopathy in children not known to be diabetic were found in two children with cystic fibrosis, one previously reported [15]. Similar findings were reported by others in adults [30, 31]. The explanation is not known, but the difficulty of diagnosis or exclusion of diabetes mellitus in cystic fibrosis has been stressed [32]. For example, glucose tolerance tests that gave diabetic or impaired findings in some patients could be normal when repeated and vice versa, and hyperglycaemic symptoms, fasting plasma glucose concentrations, and HbA1c concentrations were unreliable indicators of diabetes mellitus in cystic fibrosis [32].

We have shown that (1) overt diabetic glomerulopathy either on its own or combined with IgA nephropathy can be found in children, but is rare; (2) kidney disorders other than diabetic glomerulopathy can be found in children with type 1 diabetes mellitus; and (3) changes apparently identical with diabetic glomerulopathy can be found in children with cystic fibrosis who are not diagnosed to have diabetes mellitus.

Competing interests No author has any competing interest.

Ethics approval and Consent to participate Following consultation with the local research ethics committee, this retrospective review met the criteria for a service evaluation and so did not require any further ethical approval from the committee. All participants and/or parents gave appropriate consent for kidney biopsy, and the children received standard care according to accepted unit protocols. All patient findings are anonymised.

Availability of data and material All relevant information is included in the paper.

Authors’ contributions DVM and AJH planned the study and identified patients; LW collected clinical data; AJH, MPW and SC reviewed pathological material; AJH drafted the paper; all authors contributed to the final paper.

Acknowledgements We are grateful to our colleagues in the Department of Nephrology for allowing access to their patients’ records, especially Dr A A Gupta, Professor S A Hulton, Dr L Kerecuk, Dr A D Lalayiannis, Dr C M O’Brien, and Dr S E Stephens.

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Kidney biopsy findings in children with diabetes mellitus

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Results

Diabetic glomerulopathy in known diabetic children

Diabetic glomerulopathy plus IgA nephropathy in known diabetic children

Kidney disorders other than diabetic glomerulopathy in known diabetic children

Changes identical with diabetic glomerulopathy in children not known to be diabetic

Discussion

Declarations

References

Supplementary Files

Status:

Journal Publication

Version 1