Fabry disease: Kidney manifestations

INTRODUCTION — Fabry disease, also called Anderson-Fabry disease, is the second-most prevalent lysosomal disease after Gaucher disease. It is an X-linked inborn error of the glycosphingolipid metabolic pathway. This results in accumulation of globotriaosylceramide (Gb3) mostly within lysosomes in a wide variety of cells, thereby leading to the protean manifestations of the disease [1].

This topic will review the kidney manifestations of Fabry disease. Other clinical manifestations and the diagnosis and treatment of Fabry disease are discussed elsewhere:

●(See "Fabry disease: Clinical features and diagnosis".)

●(See "Fabry disease: Cardiovascular disease".)

●(See "Fabry disease: Neurologic manifestations".)

●(See "Fabry disease: Treatment and prognosis".)

EPIDEMIOLOGY — Kidney manifestations are common among male and, to a lesser extent, female patients with Fabry disease:

●Proteinuria – Proteinuria, one of the initial kidney findings, occurs in approximately 50 percent of untreated males with classic Fabry disease by the age of 35 years [2]. The prevalence of proteinuria in males increases with age, reaching approximately 90 percent by the age of 50 years [2]. Approximately 30 to 35 percent of females with Fabry disease have overt proteinuria (>300 mg/day), with an onset that is typically later than that in males [3,4]. (See 'Proteinuria' below.)

●Chronic kidney disease – A significant fraction of patients develops chronic kidney disease (CKD) and eventually end-stage kidney disease (ESKD). In a study from the National Institutes of Health (NIH) that included 105 males with classic Fabry disease, all patients who survived to the age of 55 years developed ESKD [2]. However, larger studies that have included patients with classic Fabry disease as well as those with milder disease, such as those with later-onset variants, have reported a lower prevalence of ESKD. As an example, in a North American registry study of over 2000 patients with Fabry disease (mean age 37 to 40 years), the prevalence of ESKD was 14 percent in men and 2 percent in women [5]. By age 55 years, only 32 percent of untreated men and 19 percent of untreated women developed kidney events, which ranged from new-onset CKD (defined as a glomerular filtration rate [GFR] less than 60 mL/min/1.73 m²) to ESKD. However, subsequent studies of the most common late-onset variant, N215S, found similar cumulative risks of CKD as for classic Fabry disease but delayed by approximately 15 years [6]. (See 'Chronic kidney disease' below.)

The prevalence of Fabry disease in dialysis populations has been examined in several screening studies. Random screening has identified less than 1 percent of hemodialysis patients as having Fabry disease, most of whom were already known to have the disease [7-14]. The following findings from different regions are illustrative:

●According to the 2017 annual data report by the United States Renal Data System, there were 243 Fabry disease patients receiving chronic dialysis in the United States [13]. Fabry disease accounted for 119 new cases of ESKD between 2011 and 2015, which represents approximately 0.03 percent of the incident patients each year.

●In a Japanese study, 6 of 514 (1.2 percent) consecutive males on dialysis had low leukocyte alpha-Gal A levels and were found to have a gene mutation [7]. Another Japanese study of 696 consecutive patients (295 females) found only four males and one female (0.7 percent) to have Fabry disease, and three were already known to have it [10].

●In a nationwide screen of the Austrian dialysis population, 85 of 2480 patients (3.4 percent, similar proportions in male and female) had a positive blood spot test with low alpha-Gal A levels [8]. Among these patients, only 5 women and 10 men had confirmed low leukocyte alpha-Gal A levels, representing 0.5 percent of the screened population. Only four males (0.16 percent) had the gene mutation, three of whom were already diagnosed.

However, it is important to consider that each undiagnosed Fabry patient with ESKD may have multiple family members with undiagnosed Fabry disease at earlier and more treatable stages.

As mentioned above, a voluntary international Fabry disease registry has been established to better understand the epidemiology and prognosis of the disease.

PATHOPHYSIOLOGY — Globotriaosylceramide (Gb3) accumulation in the kidney is inversely correlated with residual alpha-Gal A activity in leukocytes [2]. In addition, the magnitude of renal Gb3 content correlates positively with the severity of kidney pathologic changes and inversely with kidney function. Thus, accumulation of Gb3 in the kidney is probably responsible for the kidney manifestations of the disease. (See 'Clinical manifestations' below.)

Gb3 accumulation in the kidney occurs preferentially in the glomeruli (especially podocytes but also in endothelial, mesangial, and parietal epithelial cells), distal tubular cells, and vascular smooth muscle cells. The predilection for podocytes may explain the early kidney manifestations of proteinuria. In children with Fabry disease, for example, podocyte Gb3 accumulation increased with age and was strongly associated with foot process width and the degree of proteinuria, implicating podocyte injury in the early-onset proteinuria observed in this disease [15]. In addition, podocyte loss in the urine (podocyturia) is increased in patients with Fabry disease and correlates with the clinical severity of kidney disease [16], suggesting that podocyte loss may be important in the progression of Fabry nephropathy. This has been confirmed by studies in males with classic Fabry disease, which found that accumulation of Gb3 in podocytes is associated with progressive podocyte loss and proteinuria [17].

The pathophysiology underlying the formation of renal sinus cysts, another manifestation in patients with Fabry disease, is unknown (see 'Renal sinus cysts' below). The presence of cysts is not related to residual alpha-Gal A activity, kidney function, or level of proteinuria. It is unclear whether the cysts contain Gb3 or whether this is due to lymphatic overload or other processes.

PATHOLOGY — Kidney biopsy may be helpful in establishing the diagnosis of Fabry disease. In addition, a kidney biopsy can aid in treatment decisions when evaluating patients with variants of unknown significance and mildly symptomatic or asymptomatic females. Not infrequently, the diagnosis of Fabry disease is made incidentally when a kidney biopsy is obtained to evaluate the cause of proteinuria and/or decreased kidney function in patients with no known family history of Fabry disease at the time of biopsy [2]. (See "Fabry disease: Clinical features and diagnosis", section on 'Tissue biopsy'.)

Kidney biopsy findings by light microscopy and electron microscopy are characteristic in Fabry disease. Immunofluorescence staining does not typically contribute to the diagnosis but may be useful in excluding other superimposed kidney diseases in patients who present with unusual kidney manifestations (eg, nephrotic syndrome, rapid loss of kidney function, or gross hematuria). In addition, immunofluorescence can also help to evaluate for immune complex-mediated nephropathy due to anti-enzyme replacement therapy (ERT) antibodies, which can be missed when electron microscopy is not performed. Glycolipid accumulation is observed throughout the kidney:

●Light microscopy – Light microscopy shows vacuolization of visceral glomerular epithelial cells (podocytes) (picture 1) and distal tubular epithelial cells [2]. This is consistent with the described pattern of glycolipid accumulation, with podocytes and distal tubular cells showing the largest amount. Smaller deposits in cells of the mesangium, glomerular endothelium and parietal cells (picture 1) [18], proximal tubule (picture 2A-B and picture 3) [18-20], and endothelium of peritubular capillaries and arteries may be difficult to appreciate by routine light microscopy. Renal arteries and arterioles show smooth muscle cell globotriaosylceramide (Gb3) accumulation as well as smooth muscle degenerative changes representing death of smooth muscle cells (picture 3). Such degenerative changes are already established in adolescent males with classic Fabry disease and likely contribute to the glomerulosclerosis and interstitial fibrosis characteristic of the later stages of Fabry kidney disease [21,22].

●Electron microscopy – On electron microscopy, deposits of Gb3 appear primarily within enlarged secondary lysosomes as lamellated membrane structures, called myeloid or zebra bodies (picture 4); however, localization in other cellular compartments may also occur [23]. These inclusions, composed of concentric layers with a periodicity of 3.5 to 5 nm and with an onion skin appearance, are considered a hallmark of glycolipid storage disorders [24]. Inclusions may be present in all glomerular cell types (most prominently podocytes) (picture 4), arteriolar smooth muscle cells, and tubules (mostly distal tubules) (picture 5). Electron microscopy may also reveal podocyte foot process changes that may be focal (picture 6) or diffuse. Degenerative changes in smooth muscle cells representing cell death have a distinct electron microscopic appearance (picture 7).

The ultrastructural findings on kidney biopsy are highly characteristic and frequently point to the diagnosis. However, lamellar inclusions have been described in other conditions, such as silicosis, and with the use of cationic amphiphilic drugs such as chloroquine, hydroxychloroquine, amiodarone, chlorphentermine, chlorcyclizine, imipramine, clomipramine, sertraline, and gentamicin [25-33]. Lamellar inclusions associated with gentamicin occur in proximal tubules, whereas those associated with the other drugs are typically in podocytes. In Fabry disease, the inclusions are most striking in podocytes and distal tubules.

Kidney pathologic changes of Fabry disease can be detected early in life [15,34], frequently antedating any clinical or laboratory kidney findings [15,34,35]. As an example, podocyte changes, such as foot process widening and effacement, have been described in young patients with classic Fabry disease and may be the first indicators of podocyte stress [15,34]. The severity of Gb3 accumulation in podocytes, but not endothelial or mesangial cells, appears to increase progressively with age during childhood [15]. Arterial changes may also begin during childhood [21]. Renal Gb3 content is generally significantly higher, and glomerular and tubulointerstitial changes and kidney function are worse, in patients with undetectable alpha-Gal A activity compared with those with greater than 1 percent of normal activity [2].

Nonspecific findings in patients with more advanced disease may include focal segmental and global glomerulosclerosis and tubulointerstitial fibrosis and inflammation, with nonspecific mesangial deposits staining for C3 and immunoglobulin M (IgM) [22]. Foam cells may also be seen but are not diagnostic of Fabry disease, as they may be seen in other lysosomal diseases (where lipid is in podocytes) and proteinuric states (where lipid is primarily in macrophages) [36].

Characteristic electron microscopy Gb3 inclusions in endothelial cells may not be prominent or absent in children, women, and individuals with late-onset variants; in these cases, inclusions will be present in podocytes and vascular smooth muscle cells.

CLINICAL MANIFESTATIONS — Kidney manifestations occur in at least 50 percent of male patients and approximately 20 percent of female patients [1,2,37]. When patients with Fabry disease present with kidney manifestations, the principal findings are proteinuria followed by progressive kidney function impairment and often hypertension [2]. Uncommonly, patients complain of polyuria and polydipsia. Occasionally, patients are discovered by the presence of renal sinus cysts on an imaging study.

Proteinuria — Proteinuria, which is predominantly glomerular but may also be partially tubular in origin, may begin in the early teen years but more typically appears during early adulthood. As an example, a long-term natural history study from the National Institutes of Health (NIH) reported proteinuria (defined as urine protein excretion >200 mg/day) among 66 of 78 (85 percent) male patients with kidney disease, with the average age of onset being 34 years (range 14 to 55 years) [2]. Nephrotic-range proteinuria was uncommon (18 percent of those with kidney disease), and only one-fourth of them developed nephrotic syndrome. However, among those with progressive kidney failure, 80 percent had nephrotic-range proteinuria.

Adult males with Fabry disease with the highest levels of proteinuria (urine protein-to-creatinine ratio >1.5 g/g) also have the fastest decline in kidney function [38,39]. In males with proteinuria of greater than 1 g per 24 hours, glomerular filtration rate (GFR) continues to decline despite long-term enzyme replacement therapy (ERT) [40]. However, proteinuria is much less closely associated with kidney function decline in adult female Fabry patients [38,39]. Thus, the concept that proteinuria is a direct promoter of progression in Fabry disease is partly incorrect in females with mosaicism in the distribution of Fabry phenotype kidney cells [41].

In patients with Fabry disease who have nephrotic-range proteinuria, the urine may contain oval fat bodies (tubular epithelial cells with lipid inclusions) with a lamellar structure and a Maltese cross pattern under polarized urine microscopy. (See "Urinalysis in the diagnosis of kidney disease", section on 'Urinary lipids'.)

Chronic kidney disease — In untreated patients with classic Fabry disease, progressive chronic kidney disease (CKD) develops over time and typically progresses to end-stage kidney disease (ESKD). In the previously described natural history study from the NIH, the following findings were reported [2]:

●Forty-eight percent developed CKD (defined as a serum creatinine concentration ≥1.5 mg/dL [133 micromol/L]), which occurred at a median age of 42 years. In those with the lowest enzyme activity, CKD developed at an earlier mean age (22 versus 47 years).

●Twenty-four patients overall (23 percent), and all who survived to the age of 55 years, eventually developed ESKD (median age 47 years). Progression to ESKD from the diagnosis of CKD occurred over an average of four years (range 1 to 13 years), corresponding to a mean rate of decline in GFR of 12 mL/min/1.73 m² per year. Once CKD developed, the rate of progression to ESKD did not vary with age.

Similar findings with respect to CKD and ESKD were reported in an English cohort study of 98 hemizygous males [42]. Eighty-four percent had proteinuria, and 47 percent had decreased kidney function. However, the 31 percent of patients who developed ESKD did so at a younger age than in the study from the United States, with a mean age of dialysis initiation of 37 years; the youngest presented at 18 years of age.

However, as discussed above, registry data that includes both classic Fabry patients and generally milder later-onset Fabry disease variants have found lower overall incidences of serious kidney disease [37]. (See 'Epidemiology' above.)

Although there are some conflicting observations in females, increased proteinuria in male patients with Fabry disease correlates with an increased risk of progression to ESKD [2,38,39,43-45]. One small observational study found that reducing proteinuria with renin-angiotensin system blockade may help to stabilize GFR [46]; however, larger studies are needed to confirm these findings. (See 'Proteinuria' above.)

ERT may slow the decline of kidney function in patients with a mild reduction in GFR prior to the initiation of therapy but may have no or less benefit in patients with more advanced kidney functional decline and proteinuria. A more detailed discussion of the effect of ERT on the incidence and progression of CKD is presented elsewhere. (See "Fabry disease: Treatment and prognosis".)

Isosthenuria and Fanconi syndrome — Relative to other segments, the distal tubules are preferentially affected, leading to decreased urinary concentrating ability [47] and polyuria. Polyuria and polydipsia may be the earliest functional symptoms of Fabry kidney disease [48]. Globotriaosylceramide (Gb3) deposition in proximal tubules may rarely produce Fanconi syndrome, which includes the manifestations of proximal renal tubular acidosis. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance", section on 'Proximal (type 2) RTA' and "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis".)

Renal sinus cysts — The prevalence of renal sinus and parapelvic cysts is increased in patients with Fabry disease relative to healthy controls [49,50]. As an example, in one study of 24 patients with Fabry disease and 19 age-matched healthy controls, 50 percent of Fabry patients compared with only 7 percent of controls had renal sinus cysts, respectively [49]. By contrast, simple cysts located in kidney parenchyma are commonly found in the adult population [51]. Thus, the incidental discovery of multiple renal sinus cysts with an imaging study should raise the possibility of Fabry disease in the appropriate clinical setting.

Hypertension — In the NIH study, only 30 percent of 105 subjects developed hypertension, with over one-half developing increased blood pressure only after the onset of CKD [2]. Overall, the onset of CKD was followed by the development of hypertension, which was then closely followed by the onset of ESKD.

Recurrent disease after kidney transplantation — Kidney transplantation can be performed in appropriately selected patients with ESKD due to Fabry disease. In general, Fabry kidney disease does not recur in the allograft, although some transplant recipients may be found to have Gb3 deposition within vascular endothelial cells without compromise to graft function. These cells are likely of recipient origin [52]. (See "Fabry disease: Treatment and prognosis", section on 'Transplantation'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fabry disease" and "Society guideline links: Chronic kidney disease in adults".)

SUMMARY

●Epidemiology – Kidney manifestations occur in approximately 50 percent of affected male patients with classic Fabry disease by the age of 35 years, and the prevalence increases significantly with age. A significant fraction of these patients develops chronic kidney disease (CKD) and eventually end-stage kidney disease (ESKD). Approximately 20 percent of females with Fabry disease develop CKD or ESKD, typically in the sixth or seventh decade of life. (See 'Epidemiology' above.)

●Pathophysiology – Accumulation of globotriaosylceramide (Gb3) in the kidney is probably responsible for the kidney manifestations of the disease. Gb3 accumulation occurs preferentially in the glomeruli (especially podocytes but also in endothelial and mesangial cells), the distal tubule, and vascular smooth muscle cells. (See 'Pathophysiology' above.)

●Pathology – Kidney biopsy findings by light microscopy and electron microscopy are characteristic in Fabry disease. Immunofluorescence staining does not typically contribute to the diagnosis but may be useful in excluding other superimposed kidney diseases in patients who present with unusual kidney manifestations (eg, nephrotic syndrome, rapid loss of kidney function, or gross hematuria). Glycolipid accumulation is observed throughout the kidney. Nonspecific findings in patients with more advanced disease may include focal segmental and global glomerulosclerosis and tubulointerstitial fibrosis and inflammation, with nonspecific increased mesangial staining for C3 and immunoglobulin M (IgM). (See 'Pathology' above.)

●Clinical manifestations – When patients with Fabry disease present with kidney manifestations, the principal findings are proteinuria and progressive kidney function impairment. Uncommonly, patients complain of polyuria and polydipsia or are discovered by the presence of renal sinus cysts on an imaging study. (See 'Clinical manifestations' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Raphael Schiffmann, MD, MHSc, FAAN, and Jeffrey Kopp, MD, who contributed to earlier versions of this topic review.