Ocular manifestations of renal ciliopathies.

Renal ciliopathies are a common cause of kidney failure in children and adults, and this study reviewed their ocular associations. Genes affected in renal ciliopathies were identified from the Genomics England Panels. Ocular associations were identified from Medline and OMIM, and the genes additionally examined for expression in the human retina ( https://www.proteinatlas.org/humanproteome/tissue ) and for an ocular phenotype in mouse models ( http://www.informatics.jax.org/ ). Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have an ocular phenotype, including inherited retinal degeneration, oculomotor disorders, and coloboma. Diseases associated with pathogenic variants in ANK6, MAPKBP1, NEK8, and TCTN1 have no reported ocular manifestations, as well as low retinal expression and no ocular features in mouse models. Ocular abnormalities are not associated with the most common adult-onset "cystic" kidney diseases, namely, autosomal dominant (AD) polycystic kidney disease and the AD tubulointerstitial kidney diseases (ADTKD). However, other kidney syndromes with cysts have ocular features including papillorenal syndrome (optic disc dysplasia), Hereditary Angiopathy Nephropathy, Aneurysms and muscle Cramps (HANAC) (tortuous retinal vessels), tuberous sclerosis (retinal hamartomas), von Hippel-Lindau syndrome (retinal hemangiomas), and Alport syndrome (lenticonus, fleck retinopathy). Ocular abnormalities are associated with many pediatric-onset renal ciliopathies but are uncommon in adult-onset cystic kidney disease. However the demonstration of ocular manifestations may be helpful diagnostically and the features may require monitoring or treatment.

Ocular manifestations of the genetic causes of focal and segmental glomerulosclerosis.

Genetic forms of focal and segmental glomerulosclerosis (FSGS) often have extra-renal manifestations. This study examined FSGS-associated genes from the Genomics England Renal proteinuria panel for reported and likely ocular features. Thirty-two of the 55 genes (58%) were associated with ocular abnormalities in human disease, and a further 12 (22%) were expressed in the retina or had an eye phenotype in mouse models. The commonest genes affected in congenital nephrotic syndrome (NPHS1, NPHS2, WT1, LAMB2, PAX2 but not PLCE1) may have ocular manifestations . Many genes affected in childhood-adolescent onset FSGS (NPHS1, NPHS2, WT1, LAMB2, SMARCAL1, NUP107 but not TRPC6 or PLCE1) have ocular features. The commonest genes affected in adult-onset FSGS (COL4A3-COL4A5, GLA ) have ocular abnormalities but not the other frequently affected genes (ACTN4, CD2AP, INF2, TRPC6). Common ocular associations of genetic FSGS include cataract, myopia, strabismus, ptosis and retinal atrophy. Mitochondrial forms of FSGS (MELAS, MIDD, Kearn's Sayre disease) are associated with retinal atrophy and inherited retinal degeneration. Some genetic kidney diseases (CAKUT, ciliopathies, tubulopathies) that result in secondary forms of FSGS also have ocular features. Ocular manifestations suggest a genetic basis for FSGS, often help identify the affected gene, and prompt genetic testing. In general, ocular abnormalities require early evaluation by an ophthalmologist, and sometimes, monitoring or treatment to improve vision or prevent visual loss from complications. In addition, the patient should be examined for other syndromic features and first degree family members assessed.

Ocular manifestations of congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most common birth defects worldwide and a major cause of kidney failure in children. Extra-renal manifestations are also common. This study reviewed diseases associated with the Genomics England CAKUT-associated gene panel for ocular anomalies. In addition, each gene was examined for expression in the human retina and an ocular phenotype in mouse models using the Human Protein Atlas and Mouse Genome Informatics databases, respectively. Thirty-four (54%) of the 63 CAKUT-associated genes (55 'green' and 8 'amber') had a reported ocular phenotype. Five of the 6 most common CAKUT-associated genes (PAX2, EYA1, SALL1, GATA3, PBX1) that represent 30% of all diagnoses had ocular features. The ocular abnormalities found with most CAKUT-associated genes and with five of the six commonest were coloboma, microphthalmia, optic disc anomalies, refraction errors (astigmatism, myopia, and hypermetropia), and cataract. Seven of the CAKUT-associated genes studied (11%) had no reported ocular features but were expressed in the human retina or had an ocular phenotype in a mouse model, which suggested further possibly-unrecognised abnormalities. About one third of CAKUT-associated genes (18, 29%) had no ocular associations and were not expressed in the retina, and the corresponding mouse models had no ocular phenotype. Ocular abnormalities in individuals with CAKUT suggest a genetic basis for the disease and sometimes indicate the affected gene. Individuals with CAKUT often have ocular abnormalities and may require an ophthalmic review, monitoring, and treatment to preserve vision.

Hypertensive/Microvascular Disease and COPD: a Case Control Study.

BACKGROUND/AIMS: This study tested the hypothesis that individuals with chronic obstructive pulmonary disease (COPD) have more small vessel disease and more severe disease than an age- and gender- matched hospital patient comparison group. METHODS: This was a single centre, case-control study of 151 individuals with COPD (FEV1/VC) < 0.7 recruited consecutively immediately after respiratory function tests at a Melbourne teaching hospital over a 4 month period in 2010. Controls were individuals with normal respiratory function tests recruited contemporaneously from the same centre. Retinal images were obtained with a nonmydriatic camera (KOWA or Canon CR5-45NM), deidentiifed and graded by two trained graders for microvascular retinopathy (Wong and Mitchell classification), and vessel calibre using a computer-assisted method and Knudtson's modification of the Parr-Hubbard formula. Differences in microvascular retinopathy and vessel calibre between COPD patients and the comparison group were examined using Fisher's exact test or the t test (StataCorp, Texas). RESULTS: Patients with COPD had more microvascular retinopathy (121, 80% and 76, 50%; OR 3.98, 95%CI 2.39 to 6.64) and more severe disease (42, 28% and 18, 12%; OR 2.85, 95% CI 1.55 to 5.23) than other hospital patients. COPD remained an independent determinant of microvascular retinopathy (OR 4.56, 95%CI 2.49 to 8.36) after adjusting for gender, hypertension, smoking, and diabetes duration. Retinal arterioles and venules were wider in patients with COPD than other hospital patients (mean difference +6.5 µm, 95% confidence interval 1.4 to 11.6; and +17.4 µm, 95%CI 9.4 to 25.5, respectively). Larger venules were more common in younger individuals (+0.6 µm, 0.1 to 1.17) with more cigarette exposure (+0.3 µm, 0.2 to 0.5) or a lower serum albumin (+23.0 µm, 6.0 to 40.0). Venular calibre was not different in current and former smokers (p=0.77). There were trends for venules to be larger with more severe COPD (lower FEV1/VC, p=0.09) and with CT-demonstrated emphysema (p=0.06). CONCLUSIONS: Hypertensive/microvascular disease is more common and more severe in patients with COPD. This is likely to contribute to the associated increase in cardiac risk.

Microvascular Disease After Renal Transplantation.

BACKGROUND/AIMS: Individuals who reach end-stage kidney disease (CKD5) have a high risk of vascular events that persists even after renal transplantation. This study compared the prevalence and severity of microvascular disease in transplant recipients and patients with CKD5. METHODS: Individuals with a renal transplant or CKD5 were recruited consecutively from renal clinics, and underwent bilateral retinal photography (Canon CR5-45, Canon). Their retinal images were deidentified and reviewed for hypertensive/microvascular signs by an ophthalmologist and a trained grader (Wong and Mitchell classification), and for vessel caliber at a grading centre using a computer-assisted method and Knudtson's modification of the Parr-Hubbard formula. RESULTS: Ninety-two transplant recipients (median duration 6.4 years, range 0.8 to 28.8) and 70 subjects with CKD5 were studied. Transplant recipients were younger (p<0.001), with a higher eGFR (p< 0.001), but were just as likely to have a moderate-severe hypertensive/microvascular retinopathy (46/92, 50%) as subjects with CKD5 (38/70, 54%; OR 0.84, CI 0.45 to 1.57, p=0.64), and had similar mean arteriole and venular calibres (135.1 ± 7.5 µm and 137.9 ± 14.9 µm, p=0.12; and 199.1 ± 17.8 µm and 202.4 ± 27.8 µm, p=0.36, respectively). Arteriole and venular caliber were not different in nine patients examined before and after transplantation (p=0.62 and p=0.11, respectively). CONCLUSIONS: Hypertensive/microvascular disease occurred just as often and was generally as severe in transplant recipients and subjects with CKD5. Microvascular disease potentially contributes to increased cardiac events post-transplantation.

A female with X-linked Alport syndrome and compound heterozygous COL4A5 mutations.

BACKGROUND: Female subjects with X-linked Alport syndrome have a single COL4A5 mutation, germ cell mosaicism in affected tissues and typically develop renal failure later or less often than male subjects. Women with two mutations are exceedingly rare, and usually have consanguineous parents or uniparental disomy. We describe here a 20-year-old woman who inherited two different COL4A5 variants, one from her father (c.2677G>C) and one from her mother (c.384 +1 G>A). CASE-DIAGNOSIS/TREATMENT: The index case had normal renal function, proteinuria and no clinically detectable hearing loss, or ocular abnormalities. Her father and paternal uncle developed end-stage renal disease at 37 and 28 years respectively, together with hearing loss, but not lenticonus or central retinopathy. Her mother had mildly impaired renal function, proteinuria, hearing loss, but no ocular abnormalities. Her maternal grandfather and 22-year-old brother, both with this mutation, developed renal failure by 28 years with hearing loss, or had proteinuria and hearing loss respectively. CONCLUSION: The index case has clinical features consistent with germ cell mosaicism of two COL45A mutations associated with adult-onset renal failure, but no ocular abnormalities. Her risk of renal failure is high, but the rate of progression to end-stage disease depends on the underlying mutations, and disease modification with renin-angiotensin blockade.

Clinical and genetic features in autosomal recessive and X-linked Alport syndrome.

BACKGROUND: This study determined the family history and clinical features that suggested autosomal recessive rather than X-linked Alport syndrome. METHODS: All patients had the diagnosis of Alport syndrome and the mode of inheritance confirmed by genetic testing, and underwent examination at a single centre. RESULTS: Patients comprised 9 males and 6 females with autosomal recessive Alport syndrome, and 18 males and 22 females with X-linked disease. Fourteen (93 %) individuals with autosomal recessive Alport syndrome developed early end-stage renal failure, all 15 had hearing loss, and most had lenticonus (12, 80 %), and a central (13, 87 %) or peripheral (13, 87 %) retinopathy. These features occurred as often as in males with X-linked disease. Females with autosomal recessive inheritance were less likely to have an affected family member in another generation (p = 0.01) than females with X-linked disease. They were more likely to have renal failure (p = 0.003), hearing loss (p = 0.02) and lenticonus (p < 0.001). Fifty percent had a central retinopathy compared with 18 % with X-linked disease (p = 0.14), but peripheral retinopathy prevalence was not different (p = 0.64). Nonsense mutations accounted for 67 % (8/12) of these disease-causing mutations. CONCLUSIONS: Autosomal recessive inheritance is increased in females with Alport syndrome and early onset renal failure, hearing loss, lenticonus, and, possibly, central retinopathy.

Ocular manifestations of the genetic renal tubulopathies.

BACKGROUND: The genetic tubulopathies are rare and heterogenous disorders that are often difficult to identify. This study examined the tubulopathy-causing genes for ocular associations that suggested their genetic basis and, in some cases, the affected gene. METHODS: Sixty-seven genes from the Genomics England renal tubulopathy panel were reviewed for ocular features, and for retinal expression in the Human Protein Atlas and an ocular phenotype in mouse models in the Mouse Genome Informatics database. The genes resulted in disease affecting the proximal tubules (n = 24); the thick ascending limb of the loop of Henle (n = 10); the distal convoluted tubule (n = 15); or the collecting duct (n = 18). RESULTS: Twenty-five of the tubulopathy-associated genes (37%) had ocular features reported in human disease, 49 (73%) were expressed in the retina, although often at low levels, and 16 (24%) of the corresponding mouse models had an ocular phenotype. Ocular abnormalities were more common in genes affected in the proximal tubulopathies (17/24, 71%) than elsewhere (7/43, 16%). They included structural features (coloboma, microphthalmia); refractive errors (myopia, astigmatism); crystal deposition (in oxalosis, cystinosis) and sclerochoroidal calcification (in Bartter, Gitelman syndromes). Retinal atrophy was common in the mitochondrial-associated tubulopathies. Structural abnormalities and crystal deposition were present from childhood, but sclerochoroidal calcification typically occurred after middle age. CONCLUSIONS: Ocular abnormalities are uncommon in the genetic tubulopathies but may be helpful in recognizing the underlying genetic disease. The retinal expression and mouse phenotype data suggest that further ocular associations may become apparent with additional reports. Early identification may be necessary to monitor and treat visual complications.

Retinal small vessel narrowing in women with gestational diabetes, pregnancy-associated hypertension, or small-for-gestational age babies.

Background: Gestational diabetes, pregnancy-associated hypertension and small-for-gestational age babies are all associated with impaired placental vascularisation. This study compared the effects of these conditions the systemic small vessel calibre that was examined in the retina. Methods: This was a cross-sectional observational study of consecutive pregnant women recruited from an antenatal clinic. Participants underwent a Glucose Tolerance Test, BP measurements, and were examined for small-for-gestational age babies as per national guidelines. They also underwent retinal photography with a non-mydriatic camera, and vessel calibres were measured with a validated semi-quantitative system at a retinal grading centre. Some participants also underwent testing of retinal vascular responsiveness to a flickering light. Results: Women with gestational diabetes (n = 68) had a higher mean arterial pressure (85 ± 9 mm Hg) than normal pregnant women (n = 27, 80 ± 8 mmHg, p = 0.01). They also had smaller mean retinal arteriole (147.5 ± 13.6 µm and 159.7 ± 6.7 µm respectively, p < 0.01) and venular calibre (221.0 ± 13.4 µm and 232.8 ± 20.1 µm respectively, p < 0.01) than normal. However their babies' mean birth weights were not different from normal (3,311 ± 558 g and 3,401 ± 600 g respectively, p = 0.48). They also demonstrated a trend to reduced retinal arteriolar dilatation (3.5 ± 1.3%, n = 23) in response to vasodilatory stimuli (4.4 ± 1.8%) (n = 11) (p = 0.08) consistent with endothelial dysfunction. Women with pregnancy-associated hypertension (n = 35) had a higher mean arterial pressure (101 ± 12 mm Hg, p < 0.01), a smaller mean retinal arteriolar calibre (139.9 ± 10.6 µm, p < 0.0001), and a lower baby mean birth weight than for normal pregnancies (3,095 ± 443 g, p = 0.02). Likewise, women with small-for-gestational age babies (n = 31) had a higher mean arterial pressure (89 ± 19 mm Hg, p = 0.03), a smaller mean retinal arteriolar calibre (141.6 ± 12.8 µm, p < 0.01) and a lower baby mean birth weight than for normal pregnancies (2,468 ± 324 g, p < 0.0001). Conclusion: Mean retinal arterial calibre was reduced in women with gestational diabetes, pregnancy-associated hypertension or small-for-gestational age babies. The reduction in calibre was greatest in pregnancy-associated hypertension and small-for-gestational age babies. Systemic arteriole narrowing may contribute to the pathogenesis of placental vascular dysfunction in these conditions.

KCTD1 and Scalp-Ear-Nipple ('Finlay-Marks') syndrome may be associated with myopia and Thin basement membrane nephropathy through an effect on the collagen IV α3 and α4 chains.

INTRODUCTION: Scalp-Ear-Nipple syndrome is caused by pathogenic KCTD1 variants and characterised by a scalp defect, prominent ears, and rudimentary breasts. We describe here further clinical associations in the eye and kidney. METHODS: Fifteen affected members from two unrelated families with p.(Ala30Glu) or p.(Pro31Leu) in KCTD1 were examined for ocular and renal abnormalities. The relevant proteins were studied in the eye and kidney, and the mutation consequences determined from mouse knockout models. RESULTS: Five males and 10 females with a median age of 40 years (range 1-70) with pathogenic variants p.(Ala30Glu) (n = 12) or p.(Pro31Leu) (n = 3) in KCTD1 were studied. Of the 6 who underwent detailed ophthalmic examination, 5 (83%) had low myopic astigmatism, the mean spherical equivalent of 10 eyes was 2.38D, and one (17%) had hypermetropic astigmatism. One female had a divergent strabismus.Five individuals had renal cysts (5/15, 33%), with renal biopsy in one demonstrating a thinned glomerular basement membrane identical to that seen in Thin basement membrane nephropathy (AD Alport syndrome).In the eye, KCTD1 and its downstream targets, TFAP2, and the collagen IV α3 and α4 chains localised to the cornea and near the retinal amacrine cells. In the kidney, all these proteins except TFAP2 were expressed in the podocytes and distal tubules. TFAP2B and COL4A4 knockout mice also had kidney cysts, and COL4A3 and COL4A4 knockout mice had myopia. CONCLUSION: Individuals with a pathogenic KCTD1 variant may have low myopic astigmatism and represent a further rare genetic cause for a thinned glomerular basement membrane.

Microvascular dilatation after haemodialysis is determined by the volume of fluid removed and fall in mean arterial pressure.

BACKGROUND/AIMS: The effects of haemodialysis on the microcirculation are poorly understood. This study examined the changes in small vessel calibre. METHODS: 24 patients (including 12 males, median age 62.5 years, range 30-87) underwent digital retinal photography immediately before and after routine haemodialysis. Arteriolar and venular calibres were measured from the images by a trained grader using a highly reproducible, computer-assisted method. RESULTS: Patients had an average 2.0 ± 0.3 litres of fluid removed with dialysis, and their mean arterial blood pressure fell by 6.8 mm Hg (CI 13.8-0.2, p = 0.06). Retinal arteriole calibre did not change (mean difference 2.3 µm, CI -1.1 to 5.7, p = 0.17) but the venules dilated (mean difference 12.7 µm, CI 7.3-18.3, p < 0.001). Calibre returned to baseline by 2 h. Venules dilated less in diabetics than non-diabetics (mean difference -6.2 µm, CI -9.6 to -2.9, p < 0.01). Retinal venular dilatation correlated positively with the volume of fluid removed per kilogramme body weight (5.9, CI 0.2-11.5, p = 0.04), and negatively with the fall in mean arterial pressure (-0.36, CI -0.72 to -0.01, p < 0.05) after adjusting for age, gender, diabetes and dyslipidaemia. CONCLUSION: Haemodialysis is associated with systemic venular dilatation.

Retinal abnormalities characteristic of inherited renal disease.

Many inherited renal diseases have retinal features that are helpful diagnostically. These include coloboma, drusen, atrophy and pigmentation (retinitis pigmentosa), hamartoma, vascular anomalies, and crystals. Retinal abnormalities occur because the kidney and retina share developmental pathways and structural features including basement membrane collagen IV protomer composition and their vascularity, and because both the kidney and retina are functionally dependent on ciliated cells. Diagnosis of inherited renal disease is important because of the risks of further renal and systemic complications, the implications for other family members, the predictability of the clinical course, and the possibility of treatment. Furthermore, retinal abnormalities may help explain the pathogenesis of the renal disease, and can sometimes be used to monitor its course.

Retinal small vessel dilatation in the systemic inflammatory response to surgery.

Retinal microvascular calibre has been proposed as a predictor of cardiac events. Surgery is a major stimulus for inflammation which potentially affects small vessel calibre. This study examined the effects of surgery on retinal, and thus systemic, small vessel size, and the potentially confounding effect of surgery when retinal vessel calibre is used to predict cardiac risk in hospital patients. Consecutive participants were recruited from a preoperative assessment clinic at a teaching hospital. They provided demographic and clinical details, and underwent retinal imaging before and again, within 3 days after surgery, with a non-mydriatic retinal camera. Images were graded for vessel calibre using semi-automated software based on the Parr-Hubbard formula with Knudtson's modification (IVAN, U Wisconsin). Differences were examined using Fisher's exact test or a paired t-test, and calibre determinants identified from univariate and multiple linear regression analysis (STATA version 11.2). Sixty-eight participants (23 men, 34%) with a mean age of 55 ± 14.5 years, were recruited. Fourteen (21%) underwent a laparotomy which was considered major surgery and 54 (79%) had Other surgery. Mean C-reactive protein (CRP) levels increased post-operatively from 7.8 ± 20.2 mg/L to 43.9 ± 55.1 mg/L (p < 0.01), and mean serum albumin decreased from 38.9 ± 4.4 g/L to 33.9 ± 5.5 g/L (p < 0.01). Mean central retinal arteriole and venular equivalent calibre (CRAE, CRVE) increased post-operatively (142.4 ± 13.3 µm to 146.4 ± 13.0 µm, p < 0.01 and 213.1 ± 16.8 µm to 217.9 ± 18.3 µm, p < 0.01, respectively). The systemic microvasculature dilates post-operatively possibly secondary to inflammation and endothelial dysfunction. These changes were present within 3 days of surgery and may confound the use of small vessel calibre to predict cardiac risk in surgical inpatients. Microvascular dilatation in response to other inflammatory stimuli such as pneumonia is a known potential confounder in hospital patients.

Obstructive sleep apnea, chronic obstructive pulmonary disease and hypertensive microvascular disease: a cross-sectional observational cohort study.

Hypertensive microvascular disease is associated with an increased risk of diastolic heart failure, vascular dementia and progressive renal impairment. This study examined whether individuals with obstructive sleep apnoea (OSA) had more retinal hypertensive microvascular disease than those with chronic obstructive pulmonary disease (COPD) and hospital controls. This was a single-centre, cross-sectional, observational study of participants recruited consecutively from a general respiratory clinic and a general medical clinic. OSA was diagnosed on overnight polysomnography study (apnoea:hypopnoea index ≥ 5), and controls with COPD had a forced expiratory volume/forced vital capacity (forced expiratory ratio) < 70%. Individuals with both OSA and COPD were excluded. Hospital controls had no COPD on respiratory function testing and no OSA on specialist physician questioning. Study participants completed a medical questionnaire, and underwent resting BP measurement, and retinal photography with a non-mydriatic camera. Images were deidentified and graded for microvascular retinopathy (Wong and Mitchell classification), and arteriole and venular calibre using a semiautomated method at a grading centre. Individuals with OSA (n = 79) demonstrated a trend to a higher mean arterial pressure than other hospital patients (n = 143) (89.2 ± 8.9 mmHg, p = 0.02), and more microvascular retinopathy (p < 0.001), and narrower retinal arterioles (134.2 ± 15.9 µm and 148.0 ± 16.2 µm respectively, p < 0.01). Microvascular retinopathy and arteriolar narrowing were still more common in OSA than hospital controls, after adjusting for age, BMI, mean arterial pressure, smoking history and dyslipidaemia (p < 0.01, p < 0.01, respectively). Individuals with OSA demonstrated a trend to a higher mean arterial pressure than those with COPD (n = 132, 93.2 ± 12.2 mmHg and 89.7 ± 12.8 mmHg respectively, p = 0.07), and more microvascular retinopathy (p = 0.0001) and narrower arterioles (134.2 ± 15.9 and 152.3 ± 16.8, p < 0.01). Individuals with OSA alone had more systemic microvascular disease than those with COPD alone or other hospital patients without OSA and COPD, despite being younger in age.

Retinal Drusen Are More Common and Larger in Systemic Lupus Erythematosus With Renal Impairment.

Introduction: Complement has been implicated in systemic lupus erythematosus (SLE) pathogenesis on the basis of the associations with inherited complement defects and genome-wide association study risk alleles, glomerular deposits, reduced serum levels, and occasional reports of retinal drusen. This study examined drusen in SLE and their clinical significance. Methods: This cross-sectional observational study compared individuals with SLE recruited from renal and rheumatology clinics with hospital controls. Participants were reviewed for clinical features and underwent imaging with a nonmydriatic retinal camera. Deidentified images were examined by 2 trained graders for drusen number and size using a grid overlay. Results: The cohort with SLE (n = 65) comprised 55 women (85%) and 10 men (15%) with a median age of 47 years (interquartile range 35-59), where 23 (35%) were of southern European or Asian ancestry, and 32 (49%) had biopsy-proven lupus nephritis. Individuals with SLE had higher mean drusen numbers than controls (27 ± 60, 3 ± 9, respectively, P = 0.001), more drusen counts ≥10 (31, 48% and 3, 5%, respectively, P < 0.001), and more medium-large drusen (14, 22% and 3, 5%, respectively, P < 0.001). In SLE, mean drusen counts were higher, and drusen were larger, with an estimated glomerular filtration rate (eGFR) <90 ml/min per 1.73 m2 (P = 0.02, P = 0.02, respectively) or class IV nephritis (P = 0.03, P = 0.02). Conclusion: Drusen composition resembles that of glomerular immune deposits. CFH controls complement activation in the extracellular matrix and CFH risk variants are shared by drusen in macular degeneration and by SLE. CFH represents a possible treatment target for SLE especially with renal impairment.

Increased retinal drusen in IgA glomerulonephritis are further evidence for complement activation in disease pathogenesis.

Drusen are retinal deposits comprising cell debris, immune material and complement that are characteristic of macular degeneration but also found in glomerulonephritis. This was a pilot cross-sectional study to determine how often drusen occurred in IgA glomerulonephritis and their clinical significance. Study participants underwent non-mydriatic retinal photography, and their deidentified retinal images were examined for drusen by two trained graders, who compared central drusen counts, counts ≥ 10 and drusen size with those of matched controls. The cohort comprised 122 individuals with IgA glomerulonephritis including 89 males (73%), 49 individuals (40%) of East Asian or Southern European ancestry, with an overall median age of 54 years (34-64), and median disease duration of 9 years (4-17). Thirty-nine (33%) had an eGFR < 60 ml/min/1.73 m2 and 72 had previously reached kidney failure (61%). Overall mean drusen counts were higher in IgA glomerulonephritis (9 ± 27) than controls (2 ± 7, p < 0.001). Central counts ≥ 10 were also more common (OR = 3.31 (1.42-7.73, p = 0.006), and were associated with longer disease duration (p = 0.03) but not kidney failure (p = 0.31). Larger drusen were associated with more mesangial IgA staining (p = 0.004). Increased drusen counts were also present in IgA glomerulonephritis secondary to Crohn's disease but not with Henoch-Schonlein purpura. The finding of retinal drusen in IgA glomerulonephritis is consistent with complement activation and represents a model for better understanding glomerular immune deposition and a supporting argument for treatment with anti-complement therapies.

Gitelman syndrome and ectopic calcification in the retina and joints.

Gitelman syndrome is a rare inherited renal tubular disorder with features that resemble thiazide use, including a hypokalemic metabolic alkalosis, hypomagnesemia, hypocalciuria and a low or normal blood pressure, hyperreninemia and hyperaldosteronism. Treatment is primarily correction of the potassium and magnesium levels. The diagnosis is confirmed with genetic testing but Gitelman syndrome is often not suspected. However, the association with ectopic calcification in the retina, blood vessels and chondrocalcinosis in the joints is a useful pointer to this diagnosis. Bilateral symmetrical whitish deposits of calcium pyrophosphate are visible superotemporally on ophthalmoscopy and retinal photography but are actually located beneath the retina in the sclerochoroid. Optical coherence tomography is even more sensitive for their detection. These deposits increase in size with time, but the rate of progression slows with long-term correction of the hypomagnesemia. Calcification may be complicated by atrophy of the overlying retina and visual loss. The deposits often correlate with ectopic calcification in the aorta and coronary and cerebral vessels. Chondrocalcinosis occurs in the large joints such as the knees. Ectopic calcification in Gitelman syndrome indicates the need for more aggressive management of Mg levels. Calcification is much less common in Bartter syndrome, which itself is rarer and associated less often with hypomagnesemia.

Increased retinal venular calibre in acute infections.

Population-based studies have demonstrated that increased retinal venular calibre is a risk factor for cardiac disease, cardiac events and stroke. Venular dilatation also occurs with diabetes, obesity, dyslipidemia and autoimmune disease where it is attributed to inflammation. This study examined whether the inflammation associated with infections also affected microvascular calibre. Participants with infections and CRP levels  > 100 mg/L were recruited from the medical wards of a teaching hospital and assisted to complete a demographic and vascular risk factor questionnaire, and to undergo non-mydriatic retinal photography (Canon CR5-45NM, Japan). They were then treated with appropriate antibiotics, and underwent repeat retinal imaging when their CRP levels had fallen to less than 100 mg/L. Retinal images were examined for arteriole and venular calibre using validated semi-automated software based on Knudtson's modification of the Parr-Hubbard formula (IVAN, U Wisconsin). Differences in inflammatory markers and calibre were examined using the paired t-test for continuous variables. Determinants of calibre were calculated from multiple linear regression analysis. Forty-one participants with respiratory (27, 66%), urinary (6, 15%), skin (5, 12%), or miscellaneous (3, 7%) infections were studied. After antibiotic treatment, participants' mean CRP levels fell from 172.9 ± 68.4 mg/L to 42.2 ± 28.2 mg/L (p < 0.0001) and mean neutrophil counts fell from 9 ± 4 × 109/L to 6 ± 3 × 109/L (p < 0.0001). The participants' mean venular calibre (CRVE) decreased from 240.9 ± 26.9 MU to 233.4 ± 23.5 MU (p = 0.0017) but arteriolar calibre (CRAE) was unchanged (156.9 ± 15.2 MU and 156.2 ± 16.0 MU, p = 0.84). Thirteen additional participants with infections had a CRP > 100 mg/L that persisted at review (199.2 ± 59.0 and 159.4 ± 40.7 mg/L, p = 0.055). Their CRAE and CRVE were not different before and after antibiotic treatment (p = 0.96, p = 0.78). Hospital inpatients with severe infections had retinal venular calibre that decreased as their infections resolved and CRP levels fell after antibiotic treatment. The changes in venular calibre with intercurrent infections may confound retinal vascular assessments of, for example, blood pressure control and cardiac risk.

Corneal endothelial cell abnormalities in X-linked Alport syndrome.

Background: X-linked Alport syndrome results from the effect of COL4A5 mutations on basement membranes in the kidney, ear and eye. This study investigated individuals with X-linked Alport syndrome for corneal abnormalities.Patients and Methods: Six men and four women from 8 families with genetically-diagnosed X-linked Alport syndrome underwent ophthalmological examination including slit lamp examination and corneal endothelial specular microscopy. Results for corneal microscopy for men and women with X-linked disease were compared separately with the mean values for age- matched normals using the student's t test.Results: Five of the 6 men had end-stage kidney failure, all 6 had a hearing loss, three had lenticonus, and three had a central fleck retinopathy. Two men had a history of recurrent corneal erosions but no evidence of posterior polymorphous corneal dystrophy. None of the four women had kidney failure, but two had a hearing loss, and two had a central fleck retinopathy. One woman, whose son had recurrent corneal erosions, also had erosions, but no features of a posterior polymorphous corneal dystrophy.Corneal specular microscopy demonstrated abnormalities in affected men and women, with larger endothelial cells (p = .0001 in men, p = .004 in women) fewer 6-sided cells (p = .0001, p = .001 respectively) and reduced cell density (p = .03, p = .02 respectively) than normal.Conclusions: Recurrent corneal erosions are common in men and women with X-linked Alport syndrome, but posterior polymorphous corneal dystrophy is rare. The abnormal corneal endothelial cells in affected men and women are consistent with an abnormal Descemet membrane, and the reduced cell density resembles the reduced podocyte numbers found in the Alport glomerulus.

Increased microvascular disease in X-linked and autosomal recessive Alport syndrome: a case control cross sectional observational study.

BACKGROUND: Retinal microvascular disease reflects, in part, poor blood pressure control and systemic microvascular disease contributes to renal failure progression. This study examined the retinal microvasculature in Alport syndrome. MATERIALS AND METHODS: Retinal images from 28 males and 28 females with X-linked Alport syndrome, and 13 individuals with autosomal recessive disease were reviewed retrospectively for microvascular/ hypertensive retinopathy (Wong and Mitchell classification), and small vessel calibre (using a computerised semiautomated method and revised Knudtson formula). Data were compared with age and gender-matched individuals with normal blood pressure and renal function. RESULTS: Microvascular/hypertensive retinopathy was more common in males and females with X-linked Alport syndrome than age- and gender-matched controls (23, 82% and 10, 36%, p < 0.01; and 21, 75% and 13, 48%, p = 0.05, respectively), and in individuals with autosomal recessive disease compared with controls (12, 92% and 16, 43%, p < 0.01). Moderate microvascular/hypertensive changes were present in males and females with X-linked or autosomal recessive disease but not controls. Arteriolar calibre was reduced in males with X-linked disease (142.5 ± 18.7 µm, and 150.7 ± 10.1 µm, p = 0.046) and in autosomal recessive disease (133.5 ± 11.10 µm and 149.1 ± 10.6 µm, p < 0.0001). Microvascular/hypertensive retinopathy and arteriolar narrowing in males with X-linked disease were not different after renal transplantation and before (p NS). CONCLUSIONS: Microvascular/hypertensive retinopathy was more common and more severe in Alport syndrome than normotensive controls. Improved BP levels may further slow the rate of renal functional decline in Alport syndrome.