Jean-Pierre Grünfeld

Lithium nephrotoxicity revisited

Lithium is widely used to treat bipolar disorder. Nephrogenic diabetes insipidus (NDI) is the most common adverse effect of lithium and occurs in up to 40% of patients. Renal lithium toxicity is characterized by increased water and sodium diuresis, which can result in mild dehydration, hyperchloremic metabolic acidosis and renal tubular acidosis. The concentrating defect and natriuretic effect develop within weeks of lithium initiation. After years of lithium exposure, full-blown nephropathy can develop, which is characterized by decreased glomerular filtration rate and chronic kidney disease. Here, we review the clinical and experimental evidence that the principal cell of the collecting duct is the primary target for the nephrotoxic effects of lithium, and that these effects are characterized by dysregulation of aquaporin 2. This dysregulation is believed to occur as a result of the accumulation of cytotoxic concentrations of lithium, which enters via the epithelial sodium channel (ENaC) on the apical membrane and leads to the inhibition of signaling pathways that involve glycogen synthase kinase type 3β. Experimental and clinical evidence demonstrates the efficacy of the ENaC inhibitor amiloride for the treatment of lithium-induced NDI; however, whether this agent can prevent the long-term adverse effects of lithium is not yet known.

Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome

The HELLP syndrome, defined by the existence of hemolysis, elevated liver enzymes, and low platelet count, is a serious complication of pregnancy-related hypertensive disorders and shares several clinical and biologic features with thrombotic microangiopathy (TMA). Several recent studies have clearly shown that an abnormal control of the complement alternative pathway is a major risk for the occurrence of a peculiar type of TMA involving mainly the kidney. The aim of this study was to screen for complement abnormalities in 11 patients with HELLP syndrome and renal involvement. We identified 4 patients with a mutation in one of the genes coding for proteins involved in the regulation of the alternative pathway of complement. Our results suggest that an abnormal control of the complement alternative pathway is a risk factor for the occurrence of HELLP syndrome.

Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN)

BACKGROUNDnIn Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function.nnnMETHODSnAn international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported.nnnRESULTSnWe assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 micromol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m(2) and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria.nnnCONCLUSIONSnThe development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.

Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations

We studied here the clinical course of heterozygous carriers of X-linked Alport syndrome and a subgroup of patients with thin basement membrane disease due to heterozygous autosomal recessive Alport mutations whose prognosis may be worse than formerly thought. We analyzed 234 Alport carriers, including 29 with autosomal recessive mutations. Using Kaplan-Meier estimates and log-rank tests, autosomal and X-linked carriers were found to have similar incidences of renal replacement therapy, proteinuria, and impaired creatinine clearance. Further, age at onset of renal replacement therapy did not differ between X-chromosomal and autosomal carriers. Both groups showed an impaired life expectancy when reaching renal replacement therapy. RAAS inhibition significantly delayed the onset of end-stage renal failure. Not only carriers of X-linked Alport mutations but also heterozygous carriers of autosomal recessive mutations were found to have an increased risk for worse renal function. The risk of end-stage renal disease in both groups affected life expectancy, and this should cause a greater alertness toward patients presenting with what has been wrongly termed familial benign hematuria. Timely therapy can help to delay onset of end-stage renal failure. Thus, yearly follow-up by a nephrologist is advised for X-linked Alport carriers and patients with thin basement membrane nephropathy, microalbuminuria, proteinuria, or hypertension.

Increased risk of solid renal tumors in lithium-treated patients

Cystic kidney diseases and toxic interstitial nephritis may be complicated by renal tumors. Long-term lithium intake is associated with tubulointerstitial nephritis and renal cysts but to date such an association with tumors has not been determined. We evaluated this in a retrospective study to determine whether lithium-treated patients were at higher risk of renal tumors compared with lithium-free patients with chronic kidney disease (CKD), and to the general population. Over a 16-year period, 14 of 170 lithium-treated patients had renal tumors, including seven malignant and seven benign tumors. The mean duration of lithium exposure at diagnosis was 21.4 years. The renal cancers included three clear-cell and two papillary renal cell carcinomas, one hybrid tumor with chromophobe and oncocytoma characteristics, and one clear-cell carcinoma with leiomyomatous stroma. The benign tumors included four oncocytomas, one mixed epithelial and stromal tumor, and two angiomyolipomas. The percentage of renal tumors, particularly cancers and oncocytomas, was significantly higher in lithium-treated patients compared with 340 gender-, age-, and estimated glomerular filtration rate (eGFR)-matched lithium-free patients. Additionally, the Standardized Incidence Ratio of renal cancer was significantly higher in lithium-treated patients compared with the general population: 7.51 (95% confidence interval (CI) (1.51-21.95)) and 13.69 (95% CI (3.68-35.06)) in men and women, respectively. Thus, there is an increased risk of renal tumors in lithium-treated patients.

Progress in Nephron Sparing Therapy for Renal Cell Carcinoma and von Hippel-Lindau Disease

PURPOSEnPatients with von Hippel-Lindau disease frequently have early, multiple and recurrent renal cell carcinoma. Renal cell carcinoma treatment, which must prevent metastatic disease and spare nephrons, has changed in the last 2 decades. We evaluated renal cell carcinoma treatments in the long term in a large series of patients with von Hippel-Lindau disease.nnnMATERIALS AND METHODSnWe retrospectively evaluated the use and results of surgery and radio frequency ablation in patients with von Hippel-Lindau followed at our institution between 1988 and 2009. Renal anatomical survival was analyzed according to 3 periods, including 1) 1988 to 1994--the learning phase of nephron sparing surgery, 2) 1995 to 2003--routine nephron sparing surgery and 3) 2004 to 2009--the emergence of radio frequency ablation.nnnRESULTSnA first renal cell carcinoma was treated at a mean age of 38 years (range 15 to 67) in 113 patients with von Hippel-Lindau disease. During a median followup of 7.2 years 251 therapeutic procedures were performed in a total of 176 kidneys. We observed a shift of first line renal cell carcinoma treatment with time, that is nephrectomy in 52% of cases in period 1, tumorectomy in 75% in period 2 and radio frequency ablation in 43% in period 3. The shift paralleled improved renal survival. While nephron sparing surgery was primarily done for lesions greater than 30 mm, radio frequency ablation was used to treat less numerous and smaller ipsilateral lesions but they required more frequent intervention. Radio frequency ablation became the most widely used second or third line procedure and allowed renal salvage in 8 patients.nnnCONCLUSIONSnNephron sparing surgery and more recently radio frequency ablation enable earlier treatment of smaller tumors and are associated with a significant improved renal prognosis in patients with von Hippel-Lindau disease.

La biopsie rénale dans la maladie de Fabry : étude multicentrique française

This study has been initiated to test the scoring form developed to evaluate renal lesions in Fabry disease. This has been established by 10 international experts. Thus, we have collected data on 34 Fabry patients from 19 French centersxa0; only 28 renal biopsies were adequate for study. Males (23) and females (five) were of similar age (mean 50 years old). Specific glycolipid storage changes were found in all cases. Fibrous changes, involving glomeruli (in about 25% of the cases), interstitium (35% of the cases) and vascular (50 to 60%), were frequently detected. Renal function was significantly and negatively correlated with this fibrous changes, even though three patients with stages 1 and 2 chronic kidney disease had chronic interstitial fibrosis extending over more than 30% of the renal parenchyma. The extend of fibrous changes was not tightly correlated with age of the patients. The results of this study suggest that renal biopsy is of value before initiating enzyme replacement therapy, in patients older than 30 to 40 years.

La prévention primaire des maladies rénales

Resume Eviter la survenue des maladies renales, c’est la prevention primaire (a distinguer de la prevention secondaire qui consiste a depister tot les maladies renales et a en ralentir la progression). Les facteurs de risque definissent les cibles de la prevention, corrigeables (comme l’hypertension arterielle, le diabete sucre, les medicaments nephrotoxiques etc.) ou non-corrigeables (comme l’âge, le sexe ou l’ethnie). On connait des exemples de prevention primaire reussie, totalement ou partiellement: les nephropathies (N) par abus d’analgesiques, l’insuffisance renale aigue de la grossesse, les glomerulonephrites aigues post-infectieuses, la N due au VIH, la N amyloide de la FMF etc… La prevention primaire peut enfin etre a l’origine de dilemme; par exemple eviter la toxicite renale du lithium ou se priver d’un thymo-regulateur precieux dans la maladie bipolaire ?.

Genetic Diagnosis and Counseling in Inherited Renal Diseases

Inherited kidney diseases are not rare. The main groups are listed in Table 1. All nephrologists are exposed to patients and families with inherited disorders who are seeking diagnosis and counseling. In adults, hereditary renal diseases represent approximately 10%–12% of the causes of end-stage renal disease (ESRD) in most countries, whereas they represent 20%–30% of the causes of ESRD in children. These figures, however, do not reflect the whole clinical scope of inherited kidney disorders, many of which do not progress to ESRD or do not progress in all affected members of an affected family. Thus, many more affected (and unaffected) subjects may require genetic counseling. All nephrologists need some skill in genetics. Much remains to be done in educating physicians and families in genetics (1).